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THE MANAGEMENT OF EATING DISORDERS AND OBESITY

NUTRITION 9

AND 9 HEALTH Adrianne Bendich, Series Editor

The Management of Eating Disorders and Obesity, edited by David J. Goldstein Vitamin D: Physiology, Molecular Biology, and Clinical Applications, edited by Michael F. Holick Preventive Nutrition: The Comprehensive Guide for Health Professionals, edited by Adrianne Bendich and Richard J. Deckelbaum

THE MANAGEMENT OF EATING DISORDERS AND OBESITY Edited by

DAVID J. GOLDSTEIN, MD, PHD Lilly Research Laboratories; Indiana University School of Medicine, Indianapolis, IN

Foreword by

ALBERT J. STUNKARD, MD University of Pennsylvania Medical Center, Philadelphia, PA

HUMANA PRESS TOTOWA, NEW JERSEY

© 1999 Humana Press Inc. 999 Riverview Drive, Suite 208 Totowa, New Jersey 07512 All rights reserved. No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording, or otherwise without written permission from the Publisher. All authored papers, comments, opinions, conclusions, or recommendations are those of the author(s), and do not necessarily reflect the views of the publisher. Cover design by Patricia F. Cleary. For additional copies, pricing for bulk purchases, and/or information about other Humana titles, contact Humana at the above address or at any of the following numbers: Tel.: 973-256-1699; Fax: 973-256-8341; E-mail: [email protected] or visit our website at http://www.humanapress.com This publication is printed on acid-free paper. ' ANSI Z39.48-1984 (American National Standards Institute) Permanence of Paper for Printed Library Materials. Photocopy Authorization Policy: Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by Humana Press Inc., provided that the base fee of US $10.00 per copy, plus US $00.25 per page, is paid directly to the Copyright Clearance Center at 222 Rosewood Drive, Danvers, MA 01923. For those organizations that have been granted a photocopy license from the CCC, a separate system of payment has been arranged and is acceptable to Humana Press Inc. The fee code for users of the Transactional Reporting Service is: [0-89603-407-0/99 $10.00 + $00.25]. Printed in the United States of America. 10 9 8 7 6 5 4 3 2 1 Library of Congress Cataloging-in-Publication Data The management of eating disorders and obesity/edited by David J. Goldstein; foreword by Albert J. Stunkard. p. cm.—(Nutrition and health) Includes index. ISBN 0-89603-407-0 (alk. paper) 1. Eating disorders—Prevention. 2. Obesity—Prevention. 3. Anorexia nervosa. 4. Bulimia. I. Goldstein, David J. (David Joel), 1947— Series: Nutrition and health (Totowa, NJ) [DNLM: 1. Eating Disorders—therapy. 2. Obesity—therapy. WM 175 M266 1999] RC552,E17N364 1999 616.85'2606—dc21 DNLM/DLC for Library of Congress 98-53443 CIP

SERIES INTRODUCTION The mission of the Nutrition and Health Series of books is to provide health professionals with texts that are considered essential, because each book includes (1) a synthesis of the state of the science, (2) timely, in-depth reviews by the leading researchers in their respective fields, (3) extensive, up-to-date-fully annotated reference list, (4) a detailed index, (5) relevant tables and figures, (6) identification of paradigm shifts and their consequences, (7) virtually no overlap of information between chapters, but targeted interchapter referrals, (8) suggestions of areas for future research, and (9) balanced, datadriven answers to patients' questions, which are based on the totality of evidence rather than the findings of any single study. The series volumes are not the outcome of a symposium. Instead, each editor has the potential to examine a chosen area with a broad perspective, both in subject matter as well as choice of chapter authors. The international perspective, especially with regard to public health initiatives, is emphasized where appropriate. The editors, whose training are both research and practice oriented, have the opportunity to develop a primary objective for their books, definite the scope and focus, and invite leading international authorities to be part of their initiative. The authors are encouraged to provide an overview of the field, discuss their own research, and relate their research findings to potential human health consequences. Because each book is developed de novo, the chapters can be coordinated so that the resulting volume imparts greater knowledge than the sum of the information contained in the individual chapters. The Management of Eating Disorders and Obesity, edited by David J. Goldstein, MD, PhD, represents a significant contribution to the Nutrition and Health Series. Dr. Goldstein is to be congratulated for his forward-looking vision and sensitivity toward the treatment of individuals with eating disorders. As Dr. Goldstein indicates, obesity is not technically considered to be an eating disorder; however, the health professionals who care for overweight individuals also often see those with eating disorders. Thus, for many health-care providers, this book targets several related treatment areas. Dr. Goldstein has carefully ensured that this book is up to date and provides chapters by the most respected members of the medical as well as the research community. The Foreword by Dr. Alfred J. Stunkard reminds us of the past difficulties of developing safe drugs for the treatment of obesity, and the authors of chapters related to bulimia and anorexia candidly discuss new options for patients. Yet, the overriding, consistent message from the editor and chapter authors is that prevention is the most effective course. Moreover, preventing further deterioration by the patient's health is given iln-depth analysis in several key chapters. Dr. Goldstein includes chapters related to the opportunities that are presented to many health care providers (1) to raise the warning flag and enhance early diagnosis, (2) to provide varied options including psychological counseling, and (3) to encourage exercise programs and long-term commitments to healthy eating patterns. Equally important, The Management of Eating Disorders and Obesity includes informative chapters on the role of heredity in obesity development as well as insights into the mechanism of action of bioactive molecules identified recently as being critical for weight management. Finally, the book v

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contains authoritative analyses of the latest data concerning new therapeutic options and related case studies to enhance patient care. Thus, The Management of Eating Disorders and Obesity provides the reader with authoritative options for managing some of the fastest growing problems in U.S. health care today. Thus, the book represents a comprehensive, essential resource for health-care providers interested in improving the management of patients with eating disorders and obesity. Adrienne Bendich

FOREWORD As I sit down to write the foreword for The Management of Eating Disorders and Obesity, the world of weight control is still stunned by the accumulated bad news of the recent past. The August 1996 report by Abenhaim (1) alerted us to the devastating complication of primary pulmonary hypertension among persons who had been receiving fenfluramine (1). The blow was somewhat softened by the realization that the disorder was extremely rare. It took 200 cardiology and pulmonary medicine centers two years to find Abenheim’s 95 cases; the risk was 28 cases per million person-years of exposure, about that of penicillin-induced anaphylaxis. Then came the new blow—valvular heart disease—and this time the problem was not rare (2). Still, fragmentary reports suggest that nearly one-third of persons receiving fenfluramine suffered from this complication, usually in combination with another appetite suppressant, phentermine. Dexfenfluramine and its racemic mixture of DL-fenfluramine were promptly withdrawn from the market amid predictions of the end of the drug treatment of obesity, and it is still unclear what to expect. Two entirely different scenarios are possible. One scenario is that drug therapy of obesity will come to a screeching halt. A report in the Wall Street Journal of October 24, 1997 described a meeting of 100 product liability lawyers who discussed what could be the largest class action suit in American legal history. Even smaller legal actions will make physicians think twice about prescribing drugs and pharmaceutical companies about developing drugs for them to prescribe. There is a precedent for such an unfavorable scenario. In the 1970s, congressional hearings on the abuse of amphetamines for weight reduction led, quite appropriately, to their removal from the market. Quite inappropriate was the radical reduction in the prescription of all other appetite-suppressant medication that followed. It was only the landmark report of the effectiveness of the fen/phen in 1992 that emboldened the medical profession to once again prescribe medication for obesity (3). It is entirely possible that the late 1990s has seen a replay of the 1970s and the abandonment of drug therapy for obesity. An entirely different scenario, however, may well unfold. Driven by the remarkable effectiveness of the fen/phen combination, pharmaceutical companies may decide to embark on a reinvigorated program of drug discovery. Two agents, sibutramine and orlistat, have been approved, and a larger number of agents are in various stages of development. Furthermore, the recent discoveries of fundamental mechanisms of metabolism and of the control of food intake mean that new and far better targeted drugs can be designed. The fenfluramine experience will certainly mean that far greater vigilance and safety will be required. However, the fen/phen successes may be only the prelude to a far more extensive use of pharmacotherapy of obesity. A major problem that will affect most pharmacotherapy for obesity is the need to assess safety over long periods of time. It has become clear that any weight lost with the aid of medication is promptly reversed when the medication is withdrawn. The consistency of this finding has evoked the theory that appetite-suppressant medication acts primarily to lower a body-weight set point and only secondarily to suppress appetite. The vii

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implication is clear: medication to treat obesity must be used indefinitely or not at all. Long-term use means long-term monitoring for safety, a requirement that we have not appreciated and to which we will have to become accustomed. The bad news about drug therapy has had one salutary consequence for the treatment of obesity. It means that physicians and patients must carefully weigh the risks and benefits of the treatments that they consider and they must share the decision as to how to proceed. For behavior therapy, the risks are small and they may be acceptable to most people, even those who simply want to lose a few pounds for a wedding. For medications, however, we must assume that there will be risks and that the extent of the risks will be uncertain. However, the benefits to an obese person with severe comorbidity may well be worth taking. Here is an area in which the wisdom of the physician will be tested as never before. This foreword has dealt with the treatment of obesity, as that is the area that presents the greatest current problems. However, the same issues apply to treatment of eating disorders. For both obesity and eating disorders, The Management of Eating Disorders and Obesity should achieve its goal of providing guidance to the general practitioner to improve success and end the cycle of recurrent attempts and failures. I commend it to you. Albert J. Stunkard, MD Department of Psychiatry University of Pennsylvania School of Medicine, Philadelphia, PA References 1. Abenheim L, Monde Y, Brenot F, et al. Appetite suppressant drugs and the risk of primary pulmonary hypertension. N Engl J. Med 1996; 335:609–616. 2. Connolly HM, Crary JL, McGoon MD, et al. Valvular heart disease associated with fenfluramine–fentermine. N Engl J Med 1997; 337:581–588. 3. Weintraub M, Sundaresen PR, Schuster B. Long-term weight control study. Clin Pharm Therapeut 1992; 51:586–607.

PREFACE Eating disorders—bulimia nervosa, anorexia nervosa, and binge eating—are commonly seen in office practice. Symptoms associated with bulimia nervosa are seen in at least 5% of college-age women. Obesity, not generally considered an eating disorder, is prevalent in a third of the US adult population. Binge-eating disorder, which is present in as many as a quarter of obese patients, has been proposed as a separate entity with an obese phenotype. All of these conditions are becoming more prevalent and it can be expected that they will continue to have a substantial impact on the health of those affected and on direct and indirect costs to society. All health practitioners encounter patients with eating disorders and obesity. Popularpress articles on eating disorders are alerting many to the risks of the eating disorders, yet patients often conceal their condition from family, friends, and health professionals as long as they can. Although treatment of bulimia nervosa and anorexia nervosa is often considered the realm of the specialist, there is much that the general practitioner can do. It is important to recognize the signs of these conditions since early intervention may be more successful than intervention when the patient has later developed additional psychiatric comorbidities and physical disabilities. Patients need to be evaluated both medically and psychologically because of the high comorbidity associated with these eating disorders. Uncomplicated cases can be managed by generalists; because the treatment of eating disorders and obesity is often multimodal, occasional input from specialists may still be necessary. Obesity is much more amenable to treatment by the generalist, in part because significant psychiatric comorbidity is less common than for the eating disorders, although input may be required on selected patients with particularly difficult comorbid conditions. Further, the health care practitioner needs a foundation of basic information to guide patients toward effective, long-term solutions. This is particularly important since obese patients are bombarded with lay information on the latest diet, medication, or other magical way to reduce weight and keep it off, and health care professionals need to be able to offer sound, knowledgeable advice. Thus, a major objective of The Management of Eating Disorders and Obesity is to provide information regarding those treatments that are more amenable to general health care. It is hoped that the health care practitioner will be more comfortable intervening earlier, before comorbidities make medical intervention more urgent. Often, health care professionals fail to diagnose these conditions until late in their course. When a diagnosis is made, treatment is frustrating for both the health care practitioner and the patient, because both eating disorders and obesity tend to be chronic and relapsing conditions, requiring lifelong therapy. There is a need for improvement in the treatment of eating disorders and obesity; without more effective treatments, these conditions will continue to impact health care adversely, as well as to incur high individual and societal costs. Thus, the main objective of The Management of Eating Disorders and Obesity is to provide clinical health care practitioners with practical information on the management of eating disorders and obesity. For all eating disorders and obesity, the first step toward effective therapy is a thorough medical and dietary assessment. Based on this information, the initial program is develix

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oped. Such programs should combine cognitive behavioral therapy with other psychotherapy specifically tailored to the patients’ needs. Often this will include dietary counseling and may include exercise counseling. When comorbidities exist, they need specific treatment. Pharmacologic therapy is also considered on a case-by-case basis. In 1992, after reports about the use of combined therapy for obesity were carried by the popular press, sales of phentermine and fenfluramine increased exponentially. The US Food and Drug Administration (FDA) approved dexfenfluramine, the first agent for use in obesity since the 1960s. In 1997 the FDA approved fluoxetine as the first drug for treatment of bulimia nervosa. Sibutramine was approved in 1998 for obesity treatment, and orlistat was approved for the same indication in 1999. Because of the recent impact of pharmacologic agents in treating bulimia nervosa and obesity, each section of The Management of Eating Disorders and Obesity contains a significant proportion of information on treatment with these agents. The Management of Eating Disorders and Obesity consists of three major sections, one each for bulimia nervosa, anorexia nervosa, and obesity. Each section contains brief, practical, and timely reviews of the eating disorders and their management provided by foremost experts in the field. Many share their personal experience in providing treatment. These reviews provide assistance to those practitioners who want to realize a maximal impact on patient health. Recommendations are given for potential early intervention, in an effort to reduce the severity of these conditions and improve outcomes. Insights are given into possible future therapies. Dr. Steven Romano (Chapter 1) reviews the history, diagnosis, prevalence, psychiatric comorbidity, and medical complications of bulimia nervosa. With this background established, Dr. James Mitchell (Chapter 2) reviews the assessment of the patients, monitoring of potential medical complications, and specific counseling strategies, including the use of selfhelp manuals and when to refer the patient. Dr. James Hudson (Chapter 3) reviews the scientific evidence for, and the use of, pharmacologic therapy for bulimia nervosa. The approval of the first pharmacologic agent for treatment of bulimia nervosa is likely to encourage the development of other treatments for bulimia. Dr. Cheryl Rock (Chapter 4) describes the role of dietary patterns and nutrition on the development of eating disorders and provides evidence of predictors of bulimia nervosa and anorexia nervosa. As he did for bulimia nervosa, Dr. Steven Romano (Chapter 5) provides an overview of anorexia nervosa. Dr. George Hsu (Chapter 6) provides an overview of the treatment for anorexia nervosa that contains suggestions based on his own experience. Dr. Walter Kaye (Chapter 7) summarizes the experience with pharmacologic therapy for treatment of anorexia nervosa and offers a suggested guideline for clinical treatment. The section on obesity is much more detailed. Here, I reveal that my personal interest has been focused more intensively on obesity, and my observations that obesity is more commonly observed and more amenable to treatment by generalists than either anorexia or bulimia nervosa. Dr. Richard Atkinson (Chapter 8) discusses the genetic, environmental, and metabolic etiologies of obesity. Dr. Xavier Pi-Sunyer (Chapter 9) describes the epidemiological data on obesity and its many associated complications. The medical consequences of obesity are a primary driver for treatment since weight loss reduces the risks associated with obesity, particularly non-insulin-dependent diabetes mellitus, hypertension, and hyperlipidemia. These benefits of weight reduction are discussed by Dr. George Blackburn (Chapter 10).

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Relatively recently, binge-eating disorder has been proposed as a separate entity. It differs from other eating disorders in several characteristics and some have proposed different treatment approaches for the obese binge eater and the non-obese binge eater. Dr. Marsha Marcus (Chapter 11) describes binge-eating disorder, including its treatment both in general and in detail. The treatments for obesity are summarized by Dr. John Foreyt (Chapter 12). Representatives from the National Institute for Fitness led by Dr. Michael Busk (Chapter 13) review the role of activity and exercise in the treatment of obesity. Clearly exercise is one of the best ways to maintain reduced weight—but is inadequately used by patients. They provide some concrete examples of the issues that prevent patients from initiating and maintaining an exercise program and offer specific suggestions to help motivate the patient. Dr. Thomas Wadden (Chapter 14) discusses the role of behavior treatment. Behavior treatment includes exercise and nutrition behaviors. When large amounts of weight need to be lost rapidly, but nonsurgically, very-low-calorie diets are often used. Dr. Edward Mascioli (Chapter 15) discusses the role of very-low-calorie diets in the treatment of obesity. He describes the diets, as well as the selection and management of patients using those diets. Because behavioral obesity treatments have proven to be unsuccessful in the long term, other strategies have been used. Dr. George Bray (Chapter 16) summarizes the types of and experience with pharmacologic agents for weight reduction. Dr. Richard Atkinson (Chapter 17) discusses combination therapy. Dr. Jose Caro (Chapter 18) summarizes the genetic evidence for obesity and the recent molecular findings that are now contributing to the development of new research strategies and expanding our understanding of the molecular mechanisms involved in eating. His emphasis is on leptin and the leptin receptor. Finally, Dr. Peter Benotti (Chapter 19) describes the surgical management of obesity. Although considered the treatment of last resort for obesity, this technique has been very effective and has improved considerably over the original surgical techniques used. Chapters 20 and 21 describe the practicalities of treating obesity in the private office and in the multidisciplinary team setting. Both of these chapters use case histories to demonstrate specific issues related to treatment. First, in the description about treatment in the office setting, Dr. Ronald S. Rogers summarizes the treatment issues as expressed by patients. He used the Internet to discuss these issues with patients. These have practical implications for a practitioner who wants to establish an effective and patientcomfortable setting. Next, Dr. Richard Lutes describes his experience. He focuses on ascertaining the time when the patient is ready to lose weight, the “teachable moment.” Dr. Roy Blank describes his use of the phentermine–fenfluramine protocol in his office practice. Although fenfluramine is no longer marketed in the United States, this still provides an approach for the use of medications for obesity treatment. Both Dr. Lutes and Dr. Blank agree that it is important to thoroughly evaluate the patient’s history and physical condition before initiating a program. Finally, I discuss a process for maximizing the use of pharmacologic therapy in obesity treatment. To further understand obesity therapy one also needs to understand the barriers to treatment including those of patients, providers, and society. Dr. Arthur Frank (Chapter 22) reviews these.

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The best cure is prevention, and in concluding this volume Dr. Barbara C. Hansen (Chapter 23) reviews research on this issue to provide this perspective. David J. Goldstein, MD, PHD

CONTENTS Series Introduction ......................................................................................................... v Foreword by Albert J. Stunkard .................................................................................. vii Preface ........................................................................................................................... ix Contributors .................................................................................................................. xv PART I BULIMIA NERVOSA A

GENERAL INFORMATION 1

B

C

Bulimia Nervosa ............................................................................... 3 Steven J. Romano

TREATMENT 2

Counseling Patients with Bulimia Nervosa .................................... 11 James E. Mitchell and Sara Engbloom

3

Pharmacologic Therapy of Bulimia Nervosa ................................. 19 James I. Hudson, Harrison G. Pope, Jr., and William P. Carter

PRECEDENTS 4

Prevention of Anorexia Nervosa and Bulimia Nervosa: A Nutritional Perspective ........................................................... 33 Cheryl L. Rock

PART II ANOREXIA NERVOSA A


B

Anorexia Nervosa ........................................................................... 49 Steven J. Romano

TREATMENT 6 Treatment of Anorexia Nervosa ..................................................... 59 L. K. George Hsu 7

Pharmacologic Therapy for Anorexia Nervosa.............................. 71 Walter H. Kaye

PART III OBESITY A


Etiologies of Obesity ...................................................................... 83 Richard L. Atkinson

9

Medical Consequences of Obesity ................................................. 93 F. Xavier Pi-Sunyer

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C

10

Syndrome X and the Benefits of Weight Loss ............................. 113 Margaret C. Flynn, Samuel Chan, and George L. Blackburn

11

Obese Patients with Binge-Eating Disorder ................................. 125 Marsha D. Marcus

TREATMENT 12

Overview and the Future of Obesity Treatment ........................... 139 John P. Foreyt and Walker S. C. Poston II

13

The Role of Physical Activity, Exercise, and Nutrition in the Treatment of Obesity .......................................................... 155 Edward T. Mannix, Jill M. Dempsey, Reed J. Engel, Becky Schneider, and Michael F. Busk

14

Behavioral Treatment of Obesity: New Approaches to an Old Disorder ....................................................................... 173 Thomas A. Wadden and David B. Sarwer

15

Very-Low-Calorie Diets ............................................................... 201 Edward A. Mascioli

16

Pharmacologic Therapy of Obesity .............................................. 213 George A. Bray

17

Practical Aspects of Obesity Treatments: Combination Therapies ............................................................ 249 Richard L. Atkinson

18

Genetics and Potential Treatments for Obesity............................ 261 David J. Goldstein and Jose F. Caro

19

Surgery in the Management of Severe Obesity ........................... 273 Peter N. Benotti

20

Treating Obesity in the Physician’s Office .................................. 285 David J. Goldstein, Ronald S. Rogers, Richard A. Lutes, and Roy C. Blank

21

Obesity Treatment: A Team Approach ......................................... 313 Judy Loper, Richard A. Lutes, and Patrick Mahlen O'Neil

22

Barriers to Treatment .................................................................... 331 Arthur Frank

23

Prevention of Obesity ................................................................... 347 Barbara C. Hansen Index .............................................................................................. 359

CONTRIBUTORS RICHARD L. ATKINSON, MD • Department of Medicine, University of Wisconsin Medical School, Madison, WI PETER N. BENOTTI, MD • Department of Surgery, Englewood Hospital and Medical Center, Englewood, NJ GEORGE L. BLACKBURN • Nutritional Support Services, New England Deaconess Hospital, Boston, MA ROY C. BLANK • Presbyterian Health Care Center, Monroe, NC GEORGE A. BRAY, MD • Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA MICHAEL F. BUSK, MD • Indiana University School of Medicine, Indianapolis, IN; The National Institute for Fitness and Sport, Indianapolis, IN JOSE F. CARO, MD • Vice President of Endocrine Research, Lilly Research Laboratories, Indianapolis, IN WILLIAM P. CARTER • Department of Psychiatry, Harvard Medical School, Boston, MA; Biological Psychiatry Laboratory, McLean Hospital, Belmont, MA SAMUEL CHAN, MD • Department of Anesthesia, University of Pennsylvania, Philadelphia, PA JILL M. DEMPSEY • National Institute for Fitness and Sport, Indianapolis, IN SARA ENGBLOOM • Department of Psychiatry, University of Minnesota, Minneapolis, MN REED J. ENGEL • National Institute for Fitness and Sport, Indianapolis, IN MARGARET C. FLYNN • Nutritional Support Services, New England Deaconess Hospital, Boston, MA JOHN FOREYT, PHD • Department of Behavioral Medicine Research, Baylor College of Medicine, Houston, TX ARTHUR FRANK, MD • Obesity Management Program, George Washington University, Washington, DC DAVID J. GOLDSTEIN, MD, PHD • Neuroscience Division, Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, IN BARBARA C. HANSEN • Obesity and Diabetes Research Center, Department of Physiology, University of Maryland School of Medicine, Baltimore, MD L. K. GEORGE HSU • Department of Psychiatry, New England Medical Center, Boston, MA JAMES I. HUDSON, MD • Clinical Neurophysiology Laboratory, McLean Hospital, Belmont, MA WALTER H. KAYE • Eating Disorders Clinic, Western Psychiatric Institute, University of Pittsburgh, Pittsburgh, PA JUDY LOPER, PHD • Central Ohio Nutritional Center, Columbus, OH SHAN LU, MD • Department of Medicine, University of Massachusetts Medical Center, Worcester, MA RICHARD A. LUTES • Central Ohio Nutritional Center, Columbus, OH EDWARD T. MANNIX, PHD • Indiana University School of Medicine, The National Institute for Fitness and Sport, Indianapolis, IN xv

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MARSHA D. MARCUS, PHD • Western Psychiatric Institute and Clinic, University of Pittsburgh, Pittsburgh, PA EDWARD N. MASCIOLI • Boston Center of Nutrition, Chestnut Hill, MA JAMES E. MITCHELL, MD • Department of Neuroscience, University of North Dakota School of Medicine, Fargo, ND PATRICK MAHLEN O'NEIL • Department of Psychiatry and Behavior Sciences, Medical University of South Carolina, Charleston, SC F. XAVIER PI-SUNYER, MD • Department of Medicine, St. Lukes–Roosevelt Hospital Center, New York, NY HARRISON G. POPE, JR. • Department of Psychiatry, Harvard Medical School, Boston, MA; Biological Psychiatry Laboratory, McLean Hospital, Belmont, MA WALKER S. C. POSTON II, PHD • Department of Behavioral Medical Research, Baylor College of Medicine, Houston, TX CHERYL L. ROCK, PHD, RD • Department of Family and Preventive Medicine, Cancer Prevention and Control, University of California, San Diego, CA RONALD S. ROGERS • Eli Lilly & Co., Indianapolis, IN STEVEN J. ROMANO, MD • Department of Clinical Research, Lilly Research Laboratories, Indianapolis, IN DAVID B. SARWER • Department of Psychiatry, University of Pennsylvania, Philadelphia, PA BECKY SCHNEIDER • National Institute for Fitness and Sport, Indianapolis, IN THOMAS A. WADDEN, PHD • Department of Psychiatry, University of Pennsylvania Medical Center, Philadelphia, PA

Chapter 1 / Bulimia Nervosa

I

1

BULIMIA NERVOSA

2

Part I / Bulimia Nervosa


1

3

Bulimia Nervosa Steven J. Romano

1. INTRODUCTION This chapter focuses on the psychiatric presentation, prevalence, and medical complications associated with bulimia nervosa, as well as highlights comorbid psychopathology (Table 1). A more extensive discussion of etiological factors and treatment approaches can be found elsewhere in this text. Bulimia nervosa, like anorexia nervosa, represents a clinical syndrome with multiple factors contributing to its etiology and affecting clinical presentation. The term bulimia is from the Greek meaning “ox-hunger” and is an apt description of a primary feature of the disorder, binge-eating. Interestingly, although Stunkard (1) described binge-eating in obese patients decades ago, bulimia as part of a clinically distinct syndrome affecting normal-weight individuals, and coupled with compensatory mechanisms to guard against weight gain, was not described in the medical literature until much later. At that time, Russell (2) put forth criteria for bulimia nervosa that included urges to engage in periods of overeating, attempts to avoid the “fattening” effect of food through vomiting or use of purgatives and, similar to the central psychological feature of anorexia nervosa, the presence of a morbid fear of becoming fat. The latter feature underscored the anxiety and avoidance behavior which are an integral part of the syndrome. Bulimia nervosa was once postulated to be an affective subtype, in part due to the preponderance of depressive features frequently accompanying the disorder’s clinical presentation. The results of antidepressant treatment studies illustrating a specific response of bulimic symptoms strengthened that opinion. Nevertheless, newer information has led to an evolution in concept, and bulimia nervosa is now considered a primary eating disorder distinct from anorexia nervosa. Since the initial description of bulimia nervosa, there has been an explosion of information, in both scientific and lay literature, regarding the apparent surge in bulimicrelated behaviors. With the recognition of the extent of eating-disorder behaviors in certain populations, such as college-aged women, as well as the description of a significant level of comorbid psychiatric symptomatology, have come advances in both the understanding of the biological underpinnings and efficacious approaches to treatment.

2. PREVALENCE As the syndrome of bulimia nervosa was only described in the medical literature in the late seventies, and was not incorporated into the Diagnostic and Statistical Manual of From: The Management of Eating Disorders and Obesity Edited by: D. J. Goldstein © Humana Press Inc., Totowa, NJ

3

4

Part I / Bulimia Nervosa Table 1 Chapter Overview 1. 2. 3. 4. 5. 6. 7.

Introduction Prevalence Psychiatric comorbidity Clinical description Differential diagnosis Medical complications Conclusion

Mental Disorders (DSM) until 1980, prevalence studies are few. Furthermore, the diagnostic criteria for bulimia nervosa have evolved to more specifically describe the symptoms of binge-eating as part of a syndrome associated with purging and other nonpurging compensatory behaviors, and including criteria for frequency and chronicity (as illustrated in DSM-IV, Table 2) (3). Thus, the early prevalence studies reflect the prevalence of specific behaviors, such as binge-eating or, in a smaller number, vomiting, and generally in subpopulations such as college-aged females. Thus, they do not accurately assess the prevalence of the syndrome of bulimia nervosa, as outlined in current diagnostic research criteria, in the general population. Focusing on specific populations, a number of studies utilizing DSM-III criteria found the prevalence of bulimia to be approximately 4–9% in high-school- and college-aged students (4–7). Prevalence studies of binge-eating in special populations described levels of disordered eating as high as, for example, 90% in ballet dancers (8). A study that focused on the assessment of vomiting in college students described a prevalence of 9.9% (9) and another study that examined attendees at a family-planning clinic found a prevalence of 2.9%. Family studies in bulimia nervosa are less extensive than for anorexia nervosa. Increased rates of the eating disorders, including bulimia nervosa, were assessed by Strober (10) in a study comparing first- and second-degree relatives of anorectic patients with the relatives of a control group of nonanorectic psychiatrically ill patients. Furthermore, a number of studies indicated increased rates of affective disorders in the families of patients with anorexia nervosa and bulimia nervosa (11–14). More studies need to be conducted to better elucidate familial patterns and to clarify a potential link between bulimia and affective disorder. Regarding the latter, possible heritable biological vulnerability to a spectrum of psychopathology may exist to explain the observed increase in the incidence of affective disorder in the families of bulimic patients. Functional dysregulation of serotonin, a potent neurohormone involved in both mood and appetitive behavior, may represent an etiological link and, along with potential disturbances in other neruotransmitter systems, is a focus of research interest. Similarly to anorexia nervosa, bulimia nervosa predominantly affects young women, although the age of onset tends to be later in adolescence. In contrast to anorexia nervosa, many patients with bulimia nervosa present in their 20s and 30s, often after having suffered with the disorder for a number of years. Although college educated white females are most often described, clinical experience has appreciated a greater degree of heterogeneity than that generally regarded in anorexia nervosa, a situation which may


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Table 2 Diagnostic criteria for 307.51 Bulimia Nervosa A. Recurrent episodes of binge eating. An episode of binge eating is characterized by both of the following: (1) eating, in a discrete period of time (e.g., within any-2-hour period), an amount of food that is definitely larger than most people would eat during a similar period of time and under similar circumstances (2) a sense of lack of control over eating during the episode (e.g., a feeling that one cannot stop eating or control what or how much one is eating). B. Recurrent inappropriate compensatory behavior in order to prevent weight gain, such as selfinduced vomiting; misuse of laxatives, diuretics, enemas, or other medications; fasting; or excessive exercise. C. The binge eating and inappropriate compensatory behaviors both occur, on average, at least twice a week for 3 months. D. Self-evaluation is unduly influenced by body shape and weight. E. The disturbance does not occur exclusively during episodes of anorexia nervosa. Specify type: Purging Type: during the current episode of bulimia nervosa, the person has regularly engaged in self-induced vomiting or the misuse of laxatives, diuretics, or enemas Nonpurging Type: during the current episode of bulimia nervosa, the person has used other inappropriate compensatory behaviors, such as fasting or excessive exercise, but has not regularly engaged in self-induced vomiting or the misuse of laxatives, diuretics, or enemas. Source: ref. 3.

reflect the relatively high incidence of dieting in populations at risk. Males appear to be affected more frequently by bulimia nervosa than by anorexia nervosa, representing perhaps as many as 10–15% of cases. The prevalence and incidence data available on bulimia nervosa, although yet limited, provide a clue as to those populations most at risk for the development of clinically significant disturbances. In general, the single most important factor leading to an eating disorder is dieting, and significant sociocultural influences affect weight- and bodychange behavior. Particular antecedents to dieting, such as equating beauty with thinness and viewing attractiveness as a prominent measure of success, both incorporated as values in Western society, represent such influences and are more likely to affect young women. Dieting in this group is also peer supported, leading to the persistence of periods of nutritional deprivation and the subsequent development of disordered means of managing food intake in those unable to sustain restrictive dieting. Given the prevalence of dieting in this culture and the fact that this behavior is considered the most potent stressor contributing to the development of an eating disorder in an otherwise vulnerable individual, the group at risk is expanding and represents a spectrum of personality types from a range of socioeconomic backgrounds. Of course, in those professions which are most likely to stress the aforementioned values, such as professional modeling, acting, and dance, a higher incidence of bulimia nervosa can be expected. Professions which espouse body-change behavior in the service of improved performance, such as certain sports, would likely support the development of this disorder. Regarding the latter, wrestling is one of the few areas in which males are significantly influenced.

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3. PSYCHIATRIC COMORBIDITY Comorbid psychiatric symptomatology is frequently encountered in patients with bulimia nervosa. Affective symptoms are particularly common, as are features of anxiety and impulsivity. Some comorbid symptoms can be associated more directly with the primary eating disorder, whereas others may represent coexistent syndromes. The latter generally require thorough evaluation and subsequent management in order to enhance treatment response of the primary eating disorder. The significance of depressive features presenting in a majority of patients with bulimia nervosa was evident in the earlier conceptualization of this syndrome as an affective subtype. This diagnostic construct was buttressed by the effectiveness of antidepressant treatment strategies. Currently, depressive features are most often viewed as secondary to the eating disturbance and often moderate or abate with the treatment and resolution of the bulimic behaviors. The etiology of depressive symptoms in this setting may be, in part, physiological and linked to the negative effects and consequences of malnourishment and purging behaviors. In the case of some, for whom bulimia evolves into a strategy for reducing stress or moderating negative affective states such as anxiety or depression, depressive symptoms can emerge following control of bulimia. In other words, bulimia may be initially employed as a weight-reducing strategy but develop into a defense in the psychological sense, whereby removal of the behavior results in the emergence of negative affects previously held in check. This is more often the case in individuals manifesting significant comorbid character pathology. In others, affective symptoms may predate bulimia nervosa and represent a separate and primary psychiatric disorder. Anxiety features are commonly associated with bulimia. Phobic avoidance of certain food items or meals is clearly an aspect of the primary eating disturbance, as is the anxiety associated with the ingestion of unwanted food or following a binge when the ability to purge is obstructed or delayed, as in the case of social interruption. Generalized anxiety, panic attacks, or obsessive–compulsive features may also be evident, with obsessive– compulsive features most often associated with eating or weight- and shape-related concerns. Certainly, the aforementioned anxiety symptoms can be evidence of other primary psychiatric disorders and should be thoroughly evaluated and pursued during an initial psychiatric evaluation. Impulsivity is often noted in bulimic individuals and is a dimensional feature which seems to distinguish the personalities of patients with bulimia from those with restricting anorexia. Impulsivity in this regard may speak to the presence of a personality disorder as described in DSM-IV. Especially apparent are traits associated with the dramatic cluster, which include borderline and histrionic personality disorders. Impulsivity may also be evidenced by certain concomitant behaviors, including substance abuse, sexual promiscuity, or shoplifting. The rates of comorbid psychopathology have been assessed by a number of researchers, and confirm many of the aforementioned clinical impressions. Lifetime rates of major depression in bulimia nervosa have been reported to be from 36% to 70% (15–17). The significance of concurrent depressive symptomatology at the time of presentation is well recognized and affects between one-third and one-half of the patients. The intensity of the depressive episode at presentation may influence the initial management of the individual with bulimia and will be addressed in more detail elsewhere in this text.


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Supporting the clinical description of features associated with impulsivity and anxiety in many patients presenting with bulimia nervosa, the rates of personality disorders in both the dramatic cluster and the anxious cluster have been reported to be relatively high. In one recent study, Braun et al. (18), employing the Structure Clinical Interview for DSM-Personality (SCID-P) diagnostic interview, established that one-third of the individuals in the bulimic subgroups met the criteria for a dramatic cluster personality disorder. One-third of those met the diagnosis for borderline personality disorder. In addition, onethird of the individuals in the bulimic subgroups met the criteria for a personality disorder in the anxious cluster, most often avoidant or obsessive–compulsive personality disorders. Interestingly, the rate of personality disorders from the anxious cluster was similar to the rate seen in the anorectic restrictor group. Previous studies assessing the rate of personality disorders in patients with bulimia nervosa revealed a wide range of findings. Specifically, the percentage of patients with at least one DSM-III-R personality disorder has been reported as 77% (19), 69% (20), 62% (21), 61% (22), 33% (23), and 28% (24). The rate of substance abuse, including alcoholism, in patients with bulimia nervosa has been reported in a number of studies, and it varies from 18% to 33% (25–27). In all these studies, the rates in the bulimic groups were significantly greater than those for the control groups. Braun et al. (18) more recently found that all bulimic subgroups evidenced significantly higher rates of substance abuse in comparison with a subgroup of anorexic restrictors. Given the breadth of psychopathology encountered in patients with bulimia nervosa discussed above, it may be helpful to consider an underlying biological disturbance or vulnerability that may contribute to the development of various behavioral outcomes. For example, the neurotransmitter serotonin has been implicated in several functional areas, including appetitive behavior, mood and affect modulation, and impulsivity, and serotonergic dysfunction has been proposed in the etiology of a spectrum of obsessive compulsive syndromes. A disturbance in the functioning of serotonin neurotransmission or pathways could thus influence the modulation of normal behavior or the development of pathological symptomatology, leading to various clinical presentations. Further research will help elucidate the possible links that may underlie the comorbid presentation of bulimia and various other psychiatric conditions.

4. CLINICAL DESCRIPTION The disorder of bulimia nervosa affects approximately 2–3% of young women, although bulimic behaviors, as described earlier, may be encountered in many more. Such behaviors are generally precipitated by periods of restrictive dieting. Individuals with bulimia engage in regular episodes of binge eating, followed by compensatory behaviors that are an attempt to counteract the weight-gaining effect of ingested calories. Binge eating is characterized by the rapid consumption of large amounts of food over a distinct period of time, usually one to two hours. Binge eating is associated with the sense of losing control and is often followed by feelings of guilt or shame. Frequently, other dysphoric affective states, such as depression or anxiety, follow the binge eating and purging. Some patients report alleviation of dysphoria or even emotional numbing immediately following the episode, although this is short-lived. During a binge, an individual may consume a few thousand calories or more. Some individuals describe trigger foods, often a fattening sweet such as chocolate, precipitating a binge, although the

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overall content of food consumed, by macroanalysis of nutritional content, varies. The bulimic individual almost exclusively binge-eats in private, as the behavior of grossly overeating is humiliating. In this setting, embarrassment can lead to varying degrees of social avoidance and isolation. Contributing further to avoidant behavior is the need to compensate for consumption, frequently in the form of purging. Most bulimic individuals induce vomiting during or after a binge, and some use laxatives or diuretics alone. Recognizing the various compensatory behaviors encountered in this disorder, two subtypes are delineated: purging and nonpurging. Nonpurging compensatory behaviors include compulsive exercising and restrictive dieting or fasting between binges. In many individuals with bulimia nervosa, a variety of purging behaviors are utilized following binge-eating in a desperate effort to avoid weight gain. Another characteristic of bulimia nervosa is dissatisfaction with one’s body shape or weight. For many, this may evolve into a significant degree of obsessional preoccupation. This is coupled with a self-evaluation which is overly influenced by these physical characteristics. The latter can have a profound effect on self-esteem as evidenced, in part, by the majority of patients presenting with comorbid depressive symptomatology. A notable degree of impulsivity is encountered in many individuals with bulimia nervosa, and associated behaviors reflecting this characterological dimension include, in some, substance abuse, sexual promiscuity, and stealing or shoplifting.

5. DIFFERENTIAL DIAGNOSIS Few medical or psychiatric disorders present in such a manner as to confound the diagnosis of bulimia nervosa. Frequently, it is the finding of certain physical signs or symptoms in a young woman, who does not admit to binge-eating or purging behaviors, which leads the clinician on a search for some other primary medical diagnosis. Usually, the complaints are a direct result or consequence of self-induced vomiting and diuretic or laxative use. Signs and symptoms associated with gastritis, esophagitis, dehydration, or electrolyte disturbances lead to consultation with primary care physicians or to emergency room visits, postponing psychiatric consultation and evading more primary interventions. As significant affective symptoms frequently accompany the presentation of bulimia nervosa and bulimic individuals may initially be hesitant to admit to the extent of their eating-disorder behaviors, one needs to distinguish an eating disorder from a primary depressive disorder. Although antidepressants are effective treatment for both disorders, the treatment of bulimia generally requires a multimodal approach with more specific attention paid to particular eating-related behaviors and cognitions in order to achieve and sustain a marked improvement. Treatment of the associated depressive symptoms alone, without recognition of the underlying eating disorder, will lead to suboptimal management of both disturbances, with probable persistence of bulimia. One needs also to recognize or rule out personality disorders, as certain features associated with bulimia nervosa, such as impulsivity, may be seen as evidence of primary character pathology and limit further evaluation of disordered eating. Such patients may be initially referred for more dynamic psychotherapy, which may not address specific bulimic symptoms as effectively as is generally required to effect a marked change. Importantly, one must distinguish bulimia from anorexia. If the patient is underweight, amenorrheic, and is


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binge eating and purging, she has anorexia nervosa, binge–purge subtype, rather than bulimia nervosa.

6. MEDICAL COMPLICATIONS The majority of medical complications due to bulimia nervosa are consequences of purging behaviors. Self-induced vomiting can lead to gastritis, esophagitis, periodontal disease, and dental caries, the latter due to the corrosive effect of acidic stomach contents on the dental enamel. Gastric dilitation and gastric or esophageal rupture are rare medical emergencies that may lead to shock. Metabolic alkalosis with the development of clinically significant hypokalemia in patients who vomit is not unusual, and serum electrolytes will reveal typical indices. Electrocardiogram changes in this setting carry significant import, as arrhythmias can lead to cardiac arrest if hypokalemia and related disturbances are not effectively corrected. Use of diuretics can cause similar electrolyte disturbances. Metabolic acidosis can be encountered in those who use large numbers of stimulant-type laxatives. Dehydration, sometimes requiring intravenous hydration, can accompany each of the aforementioned purging behaviors. More often associated with bulimic behaviors are general physical complaints such as fatigue and muscle aches. Although becoming less frequently encountered in clinical practice, long-term use of the emetic syrup of ipecac can lead to myopathies, including, most seriously, cardiomyopathy. The latter is not an infrequent cause of death in patients abusing this toxic substance.

7. CONCLUSION Patients with bulimia nervosa or exhibiting the spectrum of eating-disorder behaviors associated with this syndrome have become increasingly common in clinical practice. This apparent increase in bulimic symptomatology has stimulated research interest that, in turn, has informed treatment strategies. Given the significant psychiatric and medical morbidity encountered in patients with bulimia nervosa, efforts should be made to improve recognition and ensure proper referral. The development of effective psychotherapies and adjunctive pharmacological treatments, in conjunction with the public’s growing awareness, should encourage more individuals to present for management of their disorders. Further exploration into the biological underpinnings of bulimia, continued assessment of treatment outcome, and attempts to identify predictive patient characteristics should lead to more specific tailoring of therapy and enhancement of treatment response.

REFERENCES 1. Stunkard AJ. The current status of treatment of obesity in adults. Stunkard AJ, Stellar E, eds. In: Eating and Its Disorders. Raven, New York, 1984, pp. 157–174. 2. Russell, GFM. Metabolic, endocrine and psychiatric aspects of anorexia nervosa. Sci Basis Med Annu Rev 1969;14:236–255. 3. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, DSM-IV, American Psychiatric Association, Washington, DC, 1994, pp. 549–550. 4. Stangler RS, Printz AM. DSM-III: Psychiatric diagnosis in a university population. Am J Psychiatry 1980; 137:937–940. 5. Johnson CL. Bulimia: A descriptive survey of 316 cases. Int J Eat Disord 1982; 2:3–16. 6. Pyle RL, Mitchell JE, Eckert ED, Halvorson PA, Neuman PA, Goff GM. The incidence of bulimia in freshman college students. Int J Eat Disord 1983; 2:75–86. 7. Carter JA, Duncan PA. Binge eating and vomiting: A survey of a high school population. Psychol Schools 1984; 21:198–203.

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8. Abraham SF, Mira M, Llewellyn-Jones D. Eating behaviors amongst young women. Med J Austr 1983; 2:225–228. 9. Halmi KA, Falk JR, Schwartz E. Binge-eating and vomiting: A survey of a college population. Psychol Med 1981; 11:697–706. 10. Strober M. A family study of anorexia nervosa. Paper presented at the International Conference on Anorexia Nervosa & Related Disorders, University College, Swansea, Wales, 1984. 11. Winokur A, March V, Mendels J. Primary affective disorder in relatives of patients with anorexia nervosa. Am J Psychiatry 1980; 137:695–698. 12. Hudson PL, Pope HG, Jonas JM, Todd D. Family history study of anorexia nervosa and bulimia. Br J Psychiatry 1983; 142:133–138. 13. Gershon ES, Schreiber Jl, Hamovit JR, Dibble ED, Kaye W, Nurnberger JI, et al. Clinical findings in patients with anorexia nervosa and affective illness in their relatives. Am J Psychiatry 1984; 141:1419–1422. 14. Rivinius TM, Biderman J, Hertzog DB, Kemper K, Harper GP, Harmatz JS, et al. Anorexia nervosa and affective disorders: A controlled family history study. Am J Psychiatry 1984; 141:1414–1418. 15. Piran, N, Kennedy S, Garfinkel PE, Owens M. Affective disturbance in eating disorders. J Nerv Ment Dis 1985; 173:395-400. 16. Walsh BT, Roose SP, Glassman AH, Gladis M, Sadik C. Bulimia and depression. Psychosom Med 1985; 47:123–131. 17. Laessle R, Kittl S, Fichter M, Wittchen HU, Pirke KM. Major affective disorder in anorexia nervosa and bulimia. A descriptive diagnostic study. Br J Psychiatry 1987; 151:785–789. 18. Braun DL, Sunday SR, Halmi KA. Personality disorder distribution among eating disorder subgroups. J Clin Psychiatry 19. Powers PS, Coovert DL, Brightwell BR, Stevens BA. Other psychiatric disorders among bulimic patients. Compr Psychiatry 1988; 29:503–508. 20. Wonderlich S, et al. DSM-III-R personality disorders in patients with eating disorders. Int J Eat Disord 1990; 9:607–616. 21. Gartner AF, Marcus RN, Halmi KA, Loranger AW. DSM-III-R personality disorders in patients with eating disorders. Am J Psychiatry 1989; 146:1585–1591. 22. Schmidt MB, Telch MJ. Prevalence of personality disorders among bulimics, non-bulimic binge eaters and normal controls. J Psychopath Behav Ess. 1990; 12:170–185. 23. Ames-Frankel J, Devlin NJ, Walsh BT, Strasser TJ, Sadik C, Oldham JM, Roose SP. Personality disorder diagnoses in patients with bulimia nervosa: clinical correlates and changes with treatment. J Clin Psychiatry 1992; 53:90–96. 24. Herzog DB. Are anorexic and bulimic patients depressed. Am J Psych 1984; 141:1594–1597. 25. Hatsukami D, Eckert E, Mitchell JE, Pyle R. Affective disorder and substance abuse in women with bulimia. Psychol Med 1984; 14:701–704. 26. Mitchell J, Hatsukami D, Eckert E, Pyle R. Characteristics of 275 patients with bulimia. Am J Psychiatry 1985; 142:482–485. 27. Bulik C. Drug and alcohol abuse by bulimic women and their families. Am J Psychiatry 1987; 144:1604–1606.

Chapter 2 / Counseling Patients with Bulimia Nervosa

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Counseling Patients with Bulimia Nervosa James E. Mitchell and Sara Engbloom

1. INTRODUCTION This chapter is designed to provide an introduction to the basic principles of counseling outpatients with bulimia nervosa who are being seen in a general medical setting and the material to be covered is summarized in Table 1. The purpose is not to make psychiatrists or counselors out of family physicians or other generalists, but to briefly review some basic principles which can be of use in an office setting in working with these patients. The goal is improved patient care. Emphasis is placed on a few issues that may significantly increase the likelihood that a woman with bulimia nervosa will become engaged in treatment and will take the first steps in the in the process of recovering from this disorder.

2. ASSESSMENT OF THE PATIENT The first step for the physician is a thorough assessment of the patient. In the case of an individual with bulimia nervosa, this requires a detailed assessment of the various normal and abnormal eating and eating-related behaviors that may be present (1). This assessment (see also Chapter 1) will then lead logically into treatment planning. The following issues should be addressed in the assessment:

2.1. Weight A careful weight history is essential. This includes an assessment of the patient’s current height and weight (and calculation of the percent of ideal body weight) as well as high and low weight during adulthood and, in particular, any history of being markedly overweight or underweight. Also, family history of weight is useful in that there is a high heritability for adult body weight. As a corollary, it is very useful to evaluate how the patient “feels” at her current weight in general, and how she feels about certain specific body parts in particular. Many patients with eating disorders are very concerned about body weight in general, but others worry specifically about certain body parts, particularly their waist, hips, buttocks, and thighs. It is of note that these are the areas with which many young women in the general population are dissatisfied even if they are of normal weight. From: The Management of Eating Disorders and Obesity Edited by: D. J. Goldstein © Humana Press Inc., Totowa, NJ

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Part I / Bulimia Nervosa Table 1 Chapter Overview 1. Introduction 2. Assessment of the Patient 2.1. Weight 2.2. Meal Pattern 2.3. Eating-Related Behaviors 2.4. Associated Psychiatric Problems 2.5. Current Symptoms 3. Medical Monitoring 3.1. Laboratory Evaluation 3.2. Dehydration 4. Specific Counseling Strategies 4.1. Self-Monitoring 4.2. Prescription of Regular, Balanced Meals 4.2.1. Flexibility 4.2.2. Sympathetic, But Firm Approach 4.3. Behavioral/Cognitive Behavioral Counseling 4.3.1. Concentrate on Successes 4.3.2. Teach Normal Weight Expectations 4.3.3. Maintain Active Life Style 4.3.4. Identify Cues 4.3.5. Highly Structured Counseling 4.3.6. Use of a Self-Help Manual

2.2. Meal Pattern It is useful to sketch out the meal pattern, including what the patient is eating and the frequency and timing of meals and snacks. Does the intake appear adequate? Most individuals with eating disorders markedly restrict food intake when not binge eating and important goals of treatment are not only to suppress or eliminate binge eating but also to increase the number of regular meals and snacks as a way of minimizing the dietary restriction that proceeds binge eating.

2.3. Eating-Related Behaviors There should be a very careful assessment of the presence of abnormal eating related behaviors such as binge-eating (2). This includes the age of onset, duration and frequency of the symptoms, and any periods of remission. Behaviors that should be included in addition to binge eating are self-induced vomiting, use of laxatives for weight control, use of diuretics or diet pills (number per day, type), and any use of serum of Ipecac ® to stimulate vomiting (3). In obtaining this information, it is important that a straightforward, nonjudgmental approach be employed in questioning. It is also important to examine for other behaviors that at times are associated with eating disorders, including excessive exercise, protracted fasting, chewing and spitting out food without swallowing it, ruminating food, and, in rare situations the use of saunas or enemas for weight control.


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2.4. Associated Psychiatric Problems Many patients with eating disorders have other associated psychiatric problems (1,4). These most commonly include mood disturbances (usually depression), problems with anxiety, substance use disorders including alcohol abuse, and personality disorders. The assessment should also touch on the presence or absence of each these associated problems, with appropriate diagnoses being made where indicated. This again may impact significantly on treatment planning.

2.5. Current Symptoms In obtaining information about current symptoms and in obtaining the review of systems, it is important to focus on areas that are often problems for patients with eating disorders. In bulimia nervosa, these would include salivary gland hypertrophy, abdominal bloating and postprandial distress, symptoms of dehydration, constipation, and diarrhea, edema and any evidence of blood loss with vomitus or through laxative-induced diarrhea.

3. MEDICAL MONITORING Fortunately, most patients with bulimia nervosa are medically stable, and the medical mortality from this disorder appears to be very rare. However, there are certain issues that may be of concern and laboratory parameters that often require monitoring (5).

3.1. Laboratory Evaluation Relative to screening laboratory work, probably the single best test that can be obtained is serum electrolyte determination. The classical pattern seen in bulimia nervosa patients is hypochloremic, and possibly hypokalemic, metabolic alkalosis. The examiner is particularly interested here in evidence of severe alkalosis or hypokalemia that may predispose to organ failure, although such abnormalities are rare. It is important to remember that in attempting to correct contraction alkalosis and hypokalemia, potassium supplementation should be accompanied by the strong advice to increase fluid intake, as much of the potassium loss is attributable to the volume concentration. The addition of other laboratory tests can be guided by the presentation and physical examination (e.g., serum amylase and lipase if there is any suggestion of pancreatis or salivary gland changes, and careful assessment of cardiovascular status if someone has been abusing Ipecac® [Roxane Laboratories, Columbus, OH] [3]).

3.2. Dehydration Laxative and diuretic abuse frequently result in profound dehydration acutely and reflex edema when they are discontinued. Also and in the case of laxative abuse, one sees reflex constipation upon discontinuation. In managing these behaviors, the best approach seems to be to have patients discontinue the use of these drugs abruptly. In the case of laxative abuse, the patient should be counseled to eat a high-fiber diet, to avoid adding salt to the diet, and if necessary to use a stool softener. Lactulose can be added if needed, but stimulant-type laxatives should be avoided if at all possible. Generally, the fluid retention will remit within 7–10 d and most patients will start having bowl movements on a regular basis by then. Although some clinicians have advocated gradual reduction in the use of these drugs, this probably only prolongs the process and abrupt discontinuation should be encouraged.

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4. SPECIFIC COUNSELING STRATEGIES These strategoes are interventions that should be considered, all of which can be initiated by the physician (but one-third of which probably will eventually require the involvement of a psychotherapist). These include teaching the patient to begin selfmonitoring (6,7), the prescription of a pattern of regular balanced meals (8), and behavioral/cognitive behavioral techniques for behavior control (9–12).

4.1. Self-Monitoring Self-monitoring is very important for several reasons. Many patients with bulimia nervosa are not completely aware of the severity of the pattern of their behavior. Selfmonitoring can be very useful in terms of the patient beginning to realistically appraise their current pattern. Also, self-monitoring has been shown in itself to significantly improve eating behavior in bulimia nervosa. Patients can self-monitor on a sheet of paper, and they are asked to record all food intake and any episodes of binge eating and vomiting with the times indicated. Specific sheets can be provided to facilitate this process. It is important to have patients monitor not only the problem eating behaviors such as binge eating and vomiting but also the healthier eating behaviors in hopes that these records can be used to point out both deficiencies and strengths in dietary intake (9). It is important to remember and to communicate to the patient that dietary restriction during most of the day is a very important determinant of binge eating and that many patients will markedly decrease the frequency of their binge eating and purging behavior if they develop a more regular pattern of intake; and self-monitoring forms can be very useful in shaping this improved pattern.

4.2. Prescription of Regular, Balanced Meals The prescription of regular food intake, often with at least minimal intake every four hours, can be helpful for patients in terms of gaining control of their eating behavior (8). It is also important to remember that many seem to have lost a normal sense of hunger and satiety, and most try to restrict their intake early in the day knowing that they may binge eat later when returning home from work or school. Therefore, the physician or the dietitian working in cooperation with the physician should prescribe the regular intake of three meals and often three small snacks, with enough calories to ensure that the patient will not be severely hungry at the end of the day when they are most likely to binge eat. 4.2.1. FLEXIBILITY It is also important to encourage flexibility in the diet (8). Many patients with bulimia nervosa have “feared” or avoided certain foods, often foods that they perceived to be high in fat content. Although it is important to encourage flexibility and variety from the beginning, often it is helpful for patients to avoid certain feared foods early in treatment, as these food may precipitate binge eating. A better approach is to encourage the reintroduction of these foods gradually. 4.2.2. SYMPATHETIC, BUT FIRM APPROACH It is important for the clinician to remember that both of these interventions—selfmonitoring and nutritional counseling—are difficult issues for these patients, and the doctor will usually experience a great deal of resistance. Many bulimic patients will not


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self-monitor when initially asked to do so, and most will have a great deal of difficulty instituting a pattern of regular balanced meals. A tolerant and sympathetic but firm approach will often yield improved results. In particular, the physician must make sure that the records/homework assignments from the previous week are carefully reviewed with the patient. If the practitioner does not clearly place importance on the records, neither will the patient. Problems with self-monitoring and with the meal pattern should be pointed out and specific suggestions offered.

4.3. Behavioral and Cognitive/Behavioral Counseling Relative to the third intervention—the behavioral and cognitive behavioral component—the typical practitioner will not have time or expertise to embark on a full course of psychotherapy using those techniques which have been shown to be effective in controlled trials (1,4,6,9–11,13–18). However, using these techniques, there are certain elements that can be suggested if the opportunity arises in the sessions when the practitioner sees the patient. 4.3.1. CONCENTRATE ON SUCCESS Have the patient concentrate on “what works.” For example, if the patient comes in for an appointment and reports that they have been able to go for several days without binge eating, it is important to focus on how they accomplished this. Were they busy doing other things? Were they able to eat regular meals and therefore were not as hungry? Were they feeling better about themselves for some other reason? If something “works,” it is a good idea to try to figure out what it was and to use it again. 4.3.2. TEACH NORMAL WEIGHT EXPECTATIONS Most patients with bulimia nervosa are convinced that if they start eating regular, balanced meals, they will gain weight. With the exception of those patients who retain fluid during withdrawal from laxatives or diuretics, most patients with bulimia nervosa do not gain weight when they start eating regularly, although, again, there are exceptions. It is best to educate the patient to be willing to tolerate minor weight gains or fluctuations, but to stress that overall she should not gain weight and, indeed, she will be better able to control her weight, and her weight will be more stable over time if she is able to control the binge eating and vomiting behavior. 4.3.3. MAINTAIN ACTIVE LIFESTYLE Put simply, it is important for patients to “stay busy” at the times when she is most prone to be binge eating and vomiting. Technically, this is known as “behavioral alternatives.” Typically patients engage in binge-eating in the evening, when they are home alone. Therefore, if they schedule activities with others or plan to be in public places, the behaviors will be much less likely to occur. Identifying high-risk periods and developing a repertoire of behavioral alternatives at those times can prove quite useful. 4.3.4. IDENTIFY CUES Many patients are able to identify specific cues or stimuli in their environment which seems to be associated with binge-eating episodes. Many times, this stimulus may be hunger induced by a long period of dietary restriction. Not uncommonly, and perhaps somewhat surprisingly, one of the most common stimuli is boredom. People tend to binge eat and then vomit during periods of time when nothing much else is occurring. The

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behaviors often becomes “institutionalized;” individuals tend to engage in binge eating and vomiting at set times, such as right when they return home after work or school. Therefore, developing a repertoire of alternative behaviors in which to engage at this time can be a very powerful deterrent to binge eating and vomiting. 4.3.5. HIGHLY STRUCTURED COUNSELING Although all of these techniques can be quite useful, the literature suggests that the best counseling approach for patients with bulimia nervosa is a highly structured one that begins with either group or individual therapy sessions conducted at least twice each week, and that involves a therapist specifically trained in cognitive behavioral techniques (19). Such therapy can result in dramatic reductions in the frequency of target behaviors, and in the majority of cases it will result in a complete remission of symptoms as well as improvement in associated problems such as depression, self-esteem and impaired interpersonal relationships. 4.3.6. USE OF A SELF-HELP MANUAL Recently there has been interest in combining drug therapy with the use of a self-help manual given to the patient, or using such a manual alone as the first choice in treatment. The results thus far obtained have been mixed, and further study is necessary before this strategy can be recommended.

5. MEDICATIONS AND REFERRAL FOR COUNSELING Relative to initial treatment, however, the preferred sequence remains a matter of debate. Some advocate conservative management, including the use of antidepressants; others favor an initial approach, including psychotherapy with or without antidepressants (17,19–25). The use of medications in treating bulimia nervosa is discussed in Chapter 3. The practitioner should certainly consider referring patients to a professional counselor if cost is not an obstacle to obtaining these services and if therapists well trained in the techniques shown to work with these patients are available. Unfortunately, welltrained therapists are often unavailable, as many therapists are not formally trained in the specific forms of therapy shown to help for these patients in controlled trials. Fortunately, medications that are helpful for many of these patients are widely available and decrease the need for referral. The primary physician can encourage the patient to engage in self-monitoring, stress the importance of regular meal intake, and prescribe an antidepressant such as fluoxetine hydrochloride (Prozac®, Eli Lilly, Indianapolis, IN). Prozac has been shown to help reduce binge-eating episodes in bulimia nervosa patients when prescribed at higher dosages (60 mg/d) (17,21,22). Even at the higher dosage most patients experience minimal or no side effects, and if any occur, such as nausea or insomnia, they are usually transitory. Therefore, the physician should be aggressive in escalating the dosage, or might initiate treatment at 60 mg/d. Alternative selective serotonin reuptake inhibitors have not been studied systematically but are used clinically. The exception is fluvoxamine, which was found to be ineffective in two randomized trial.However, if this regimen of physician encouragement, education, monitoring, and medication management is not found to be helpful, the patient may be referred to a professional counselor to facilitate recovery.


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In the event that referral is necessary, communication between the general practitioner and counselor can be beneficial in several ways. This interplay can assure that both professionals are receiving the same “message” from the patient regarding progress in recovery. Additionally, this communication can keep counselors aware of any physical symptoms the patient may be experiencing as well as any changes in medication which may affect the patient’s mental state. However, it is important to remember that the advice and encouragement of the primary physician, who places a strong emphasis on improving the pattern of regular food intake and on self-monitoring of problematic and normal eating behavior, can go a long way in starting the patient in the process of recovery.

ACKNOWLEDGMENTS This work was supported in part by the Neuropsychiatric Research Institute, a Center Grant on Eating Disorders Research from the McKnight Foundation, and an National Institute of Health Obesity Center grant.

REFERENCES 1. Lacey JH. Bulimia nervosa, binge-eating and psychogenic vomiting: A controlled treatment study and long-term outcome. Br Med J 1983; 286:1609–1613. 2. Mitchell JE, Hatsukami D, Eckert ED. Characteristics of 275 patients with bulimia. Am J Psychiatry 1985; 142:482–485. 3. Mitchell JE, Pomeroy C, Huber M. A clinician’s guide to the eating disorders medicine cabinet. Int J Eat Disord 1988; 7:211–223. 4. Mitchell JE, Pyle RL, Pomeroy C, Zollman M, Crosby R, Seim M, et al. Cognitive-behavioral group psychotherapy of bulimia nervosa: importance of logistical variables. Int J Eat Disord 1993; 14:277–287. 5. Halmi KA. Medical aberrations in bulimia nervosa. In: Kaye WH, Gwirtsman HE, eds. A Comprehensive Approach to the Treatment of Normal Weight Bulimia. American Psychiatric Press, Washington, DC, 1985, pp. 37–46. 6. Agras WS, Rossiter EM, Arnow B, Schneider JA, Telch CF, Raeburn SD, et al. Pharmacologic and cognitive-behavioral treatment for bulimia nervosa: a controlled comparison. Am J Psychiatry 1992; 149:82–87. 7. Connors ME, Johnson CL, Stuckey MK. Treatment of bulimia with brief psychoeducational group therapy. Am J Psychiatry 1984; 141:1512–1516. 8. Boutacoff LI, Zollman MR, Mitchell JE. Healthy Eating: A Meal Planning System, unpublished manual, University of Minnesota, 1984. 9. Fairburn CG, Kirk J, O’Connor M, Cooper PJ. A comparison of two psychological treatments for bulimia nervosa. Behav Res Ther 1986; 24:629–643. 10. Fairburn CG, Jones R, Peveler RC. Three psychological treatments for bulimia nervosa: a comparative trial. Arch Gen Psychiatry 1991; 48:463–469. 11. Fairburn CG, Jones R, Peveler RC, Hope RA, O’Connor M. Psychotherapy and bulimia nervosa. Longer term effects of interpersonal psychotherapy, behavior therapy, and cognitive behavior therapy for bulimia nervosa. Arch Gen Psychiatry 1993; 50:419–428. 12. Mitchell JE, Pyle RL, Hatsckami D. Bulimia Nervosa: Individual Treatment Manual, unpublished manual, University of Minnesota, Minneapolis, MN, 1987. 13. Freeman CPL, Munro JKM. Drug and group treatments for bulimia/bulimia nervosa. J Psychosom Res 1988; 32:647–660. 14. Garner DM. Cognitive therapy for bulimia nervosa. Adolesc Psychiatry 1986; 13:358–390. 15. Kirkley GB, Schneider JA, Agras WS, bachman SA. Comparison of two group treatments for bulimia. J Consult Clin Psychol 1985; 5:43–48. 16. Mitchell JE, Pyle RL, Eckert ED, Matsukami D, Pomeroy C, Zimmerman R. A comparison study of antidepressants and structured intensive group psychotherapy in the treatment of bulimia nervosa. Arch Gen Psychiatry 1990; 47:149–157.

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17. Mitchell JE, Raymond N, Specker S. A review of the controlled trials of pharmacotherapy and psychotherapy in the treatment of bulimia nervosa. Int J Eat Disord 1993; 14:229–247. 18. Ordman AM, Kirschenbaum DS. Cognitive-behavioral therapy for bulimia: an initial outcome study. J Consult Clin Psychol 1985; 53:305–313. 19. Crosby RD, Mitchell JE, Raymond N, Specker S, Nugent SM, Pyle RL, et al. Survival analysis of response to group psychotherapy in bulimia nervosa. Int J Eat Disord 1993; 13:359–368. 20. Abbott DW, Mitchell JE. Antidepressants vs. psychotherapy in the treatment of bulimia nervosa. Psychopharmacol Bull 1993; 29:115–119. 21. Fluoxetine Bulimia Nervosa Collaborative Study Group. Fluoxetine in the treatment of bulimia nervosa. Arch Gen Psychiatry 1992; 49:139–147. 22. Goldstein DJ, Wilson MG, Thompson VL, Potvin JH, Rampey Jr AH, The Fluoxetine Bulimia Nervosa Research Group. Long-term fluoxetine treatment of bulimia nervosa. Br J Psychiatry 1995; 166:660–666. 23. Herzog DB, Keller MB, Lavori PW. Outcome in anorexia nervosa and bulimia nervosa: a review of the literature. J Nerv Ment Dis 1988; 176:131–143. 24. Walsh T. Pharmacological treatment of bulimia. In: Halmi KA, ed. Psychobiology and Treatment of Anorexia Nervosa and Bulimia Nervosa. American Psychiatric Press, Washington, DC, 1992, pp. 329–431. 25. Walsh BT, Devlin MJ. The pharmacologic treatment of eating disorders. Psychiatr Clin North Am 1992; 15:149–160.

Chapter 3 / Pharmacologic Therapy of Bulimia Nervosa

3

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Pharmacologic Therapy of Bulimia Nervosa James I. Hudson, Harrison G. Pope, Jr., and William P. Carter

1. INTRODUCTION Pharmacologic therapy is used increasingly in the management of patients with bulimia nervosa. Over the last 17 yr, many studies have reported beneficial effects of antidepressants and other agents for bulimia nervosa, and a large amount of clinical experience has also accumulated over this time period. In this chapter, we review the evidence for the efficacy of antidepressants and other medications and provide guidelines for clinical practice based on this evidence and our experience (Table 1).

2. EFFICACY OF ANTIDEPRESSANTS IN BULIMIA NERVOSA 2.1. Placebo-Controlled Studies of Marketed Antidepressants We searched the literature for placebo-controlled trials of medications, marketed in the United States as “antidepressants,” that have been studied in the treatment of bulimia nervosa and where adequate documentation was available to permit analysis. We found 15 studies: 10 of tricyclic antidepressants (1–10), 2 of selective serotonin reuptake inhibitors (SSRIs) (11,12) 1 of monoamine oxidase inhibitors (MAOIs) (13) and 2 of other antidepressant agents (trazodone [14], bupropion [15]). These studies are summarized in Table 2. We excluded three studies of medications not marketed in the United States: one each of brofaromine (16), isocarboxazid (17), and mianserin (18). The study of isocarboxazid found a significant benefit of drug vs placebo. The other two failed to find a significant difference between drug and placebo, but they are difficult to interpret, in part because of very high placebo response rates. We also excluded one study (19) presented briefly in a letter to the editor (reporting an advantage of phenelzine and nomifensine vs placebo), and one study (20) that reported significant improvement of bulimic symptoms in patients with atypical depression. The studies indicate that drugs from several different classes of antidepressant reduce the frequency of binges and the frequency of vomiting. Also, the great majority of studies From: The Management of Eating Disorders and Obesity Edited by: D. J. Goldstein © Humana Press Inc., Totowa, NJ

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Part I / Bulimia Nervosa Table 1 Chapter Outline 1. Introduction 2. Efficacy of Antidepressants in Bulimia Nervosa 2.1. Placebo-Controlled Studies of Marketed Antidepressants 2.2. Long-Term Antidepressant Studies 2.3. Open-Label Trials of Antidepressants 2.4. Theoretical Implications 2.5. Summary of Antidepressant Efficacy 3. Other Medications 3.1. Mood Stabilizers 3.2. Opiate antagonists 4. Studies of Antidepressants and Behavioral Therapy 5. Practical Considerations—Treatment Guidelines

have shown antidepressants produce significant benefit on various measures of global improvement and of attitudes toward food and weight. In addition, several studies have shown a significant improvement in the patients’ depressive symptoms on medication vs placebo, although others have shown equivocal or no improvement on these indices. Interpretation of these results is limited by at least two considerations. First, only a minority of patients in these studies had current major depressive disorder, and many bulimic patients started treatment with little or no associated depressive symptomatology. Thus, when studies report that “depression” or “depressive symptoms” failed to improve, it cannot be determined whether this finding was owing to a failure of medication treatment to change these symptoms or whether it merely reflected a low baseline level of symptoms that could not be improved appreciably. Second, measures of “depressive symptoms” include many items in addition to depressed mood (such as sleep disturbance, appetite disturbance, and anxiety) that are not specific to depression but occur in a wide range of conditions. Thus, when studies report that “depressive symptoms” improved, it is unclear what symptoms may have changed. In short, we can draw few definitive conclusions about the effects of antidepressants on depressive symptoms in patients with bulimia nervosa. As most of these studies were relatively small, it is difficult to assess whether there are any predictors of a favorable response to antidepressants among bulimic patients. One finding is quite clear, however: Bulimic patients respond to antidepressant medications equally well regardless of whether they exhibit symptoms of depression. For example, two studies (2,14) specifically excluded bulimic patients with current major depressive disorder, but nevertheless found response rates comparable to those of studies that included depressed bulimic patients. Also, no study has found significantly different rates of improvement in nondepressed vs depressed patients. Only 2 of the 15 studies, both using tricyclics (1,10), failed to find significant differences between drug and placebo on frequency of binge eating or frequency of vomiting episodes. However, these negative results may have been owing to methodologic limitations of the studies. In the first study (1), the amitriptyline-treated group had a greater than 70% mean reduction in frequency of binge eating and vomiting, whereas the placebo-treated group had a greater than 50% mean reduction, perhaps because “minimal behavioral therapy” was also employed. In the other study (10), only seven patients were


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Table 2 Placebo-Controlled Studies of Antidepressants in Bulimia Nervosaa

Study (ref.) Tricyclics Mitchell and Groat (1) Hughes et al. (2) Barlow et al. (3) Blouin et al. (4) McCann and Agras (5)

Druga (maximum dose)

Duration No. of of trialc b subjects (wk) 32 22 47 10

8 6 6 6 23

Desipramine 300 mg Imipramine 200 mg Imipramine 300 mg Imipramine 200 mg Imipramine 200 mg

68 19 20 74 15

d

+ ++ ++ ++ ++

6 6 16 12 8

Parallel group Parallel group Crossover Crossover 12-wk parallel group Parallel group Parallel group Parallel group Parallel group Parallel group

387

8

Parallel group

+ ++

398

16

Parallel group

++

Monoamine oxidase inhibitors Walsh et al. (13) Phenelzine 90 mg

50

8

Parallel group

++

Other antidepressants Horne et al. (14) Pope et al. (15)

81 42

8 6

Parallel group Parallel group

++ ++

Walsh et al. (6) Pope et al. (7) Agras et al. (8) Mitchell et al. (9) Alger et al. (10)

Amitriptyline 150 mg Desipramine 200 mg Desipramine 150 mg Desipramine 150 mg Desipramine 300 mg

Design

Improvement in bulimic e symptoms

Selective serotonin reuptake inhibitors Fluoxetine Bulimia Fluoxetine 20 mg/ Collaborative Study fluoxetine 60 mg Group (11) Goldstein et al. (12) Fluoxetine 60 mg

Bupropion 450 mg Trazodone

++ ++ ++ ++ 0

a Restricted b

to medications marketed currently in the United States. Number of subjects receiving drug or placebo who completed the trial or enough of the trial to be included in data analysis. c Period of time that subjects received active drug rather than total duration of the study. d All studies were randomized, placebo-controlled, double-blind trials. e ++: drug significantly superior to placebo in reducing frequency of binge eating and/or frequency of vomiting; +: some evidence that drug superior to placebo but not clearly significant; 0: little or no difference between drug and placebo.

treated with imipramine; thus, the failure to find a significant drug-placebo difference in efficacy may have represented a type II error (failure to detect a significant difference when in fact one exists), because of the very small sample. On balance, then, the weight of the evidence strongly suggests that antidepressants are superior to placebo in the shortterm treatment of bulimia nervosa. For the most part, these studies have found antidepressants well tolerated and safe in the treatment of bulimia nervosa. The one important exception is that bupropion was associated with a high incidence of grand mal seizures (4 of 55 bupropion-treated patients) in the only controlled study using this drug in bulimia nervosa (14). Although it is impossible to assess the relative tolerance of bulimic patients to these medications, because studies have not compared medications directly to one another it appears that the

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SSRI fluoxetine is the best-tolerated medication and that the MAOI phenelzine—despite excellent efficacy—is associated with more adverse effects than other agents. Upon examining these studies, several methodologic limitations should be noted. First, most of the studies were of short duration, with a median of 8 wk, and all but four employed less than 3 mo of drug treatment. Thus, few address the potential long-term efficacy of these agents (a topic to which we return later). Second, many of the studies involved small sample sizes, with the majority reporting fewer than 15 patients per treatment group; only the two studies with fluoxetine enrolled more than 50 patients per group. It is noteworthy, however, that in spite of these small sample sizes, most of the studies nevertheless produced highly significant differences between drug and placebo— suggesting that antidepressants are associated with a large beneficial effect in bulimia nervosa. Third, two studies (3,4) used a crossover design, which has potential difficulties with maintenance of blindedness and with carryover effects. Fourth, although all studies used the frequency of episodes of eating binges or vomiting as primary outcome measures, the studies varied considerably in their choice of secondary outcome measures, such as measures of global improvement, attitudes toward food and weight, and associated psychiatric symptoms.

2.2. Long-Term Antidepressant Studies Only a few studies have examined the effect of antidepressant medications for more than 12 wk. Two of these were simple placebo-controlled trials (8,12); one (6) was a complex design with placebo-controlled periods; two (21–23) were open label tricyclic medication studies; and one (17) was an open-label followup of a placebo-controlled study of an MAOI. In the two placebo-controlled trials, Agras and associates (8) found imipramine more effective than placebo, and Goldstein and colleagues (12) found fluoxetine more effective than placebo, both in 16-wk studies. Using a rather elaborate study design, Walsh and colleagues (6) randomized patients initially to either desipramine or placebo for 6 wk on a double-blind basis. At the end of 6 wk, they offered desipramine-responsive patients open maintenance treatment with desipramine for an additional 16 wk, and they offered placebo-treated nonresponders desipramine treatment for 6 wk. The placebo nonresponders who responded to desipramine were offered an additional 16 wk of open maintenance treatment with desipramine. Next, following this 24-wk total period of desipramine treatment, they randomized treatment responders to 26 wk of either desipramine or placebo. The investigators enrolled 80 subjects. Although they found a good short-term response to desipramine, they gradually lost most subjects for a variety of reasons, such that of the 21 patients in the open maintenance period, only 11 completed this period, and of 9 patients entered, only 8 completed the final 24-wk period. Thus, this study documented high attrition using long-term desipramine therapy for bulimia nervosa. Tricyclic medications were used nonblinded in two studies as one arm of treatment studies involving comparisons with psychotherapy alone or psychotherapy plus medications. One study (21,22) found that patients who received desipramine for 16 wk and then discontinued treatment were more likely to relapse by 32 wk and more likely to be doing poorly on 1-yr follow-up than patients who had received 24 wk of desipramine and then stopped. Another study (23) was designed to compare 20 wk of desipramine vs cognitive-behavior therapy (CBT) vs combination treatment. However, this study was stopped prematurely because of a high dropout rate, largely owing to side effects in the desipramine-treatment-alone group.


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Kennedy and associates (17) reported that 1 yr after treatment in a placebo-controlled trial of isocarboxazid, 7 of 18 patients were doing well on isocarboxazid, and 11 patients had stopped the medication, mainly because of intolerable side effects. Long-term studies of single agents are difficult to interpret because they do not reflect how medications are used in clinical practice, particularly in that there was no option of adding or switching drugs over the entire study interval. Extensive experience from clinical practice and data from several studies (6,24–27) have shown that most bulimic patients who fail to respond adequately to one antidepressant, or who tolerate it poorly, will achieve a beneficial response or better tolerance on another agent. Furthermore, in one of the single-agent studies (21,22), medication was stopped after 16 or 24 wk, and was not reintroduced if symptoms reemerged. In clinical practice, one would usually stop medications only after at least 24 wk with an excellent response and would restart medication promptly if the patient had a relapse of symptoms. Thus, the single-agent studies certainly underestimate the efficacy of antidepressant treatment as it is actually practiced. Our group reported two long-term open-label studies that followed patients using “doctor’s choice” treatment. In these studies, patients who failed to respond to one agent were permitted to change to another. In the first (25), we collected follow-up data for up to 2 yr on 20 bulimic patients who initially participated in a placebo-controlled study with imipramine (7). At the time last seen in follow-up, 10 (50%) of these subjects had experienced a complete remission of bulimic symptoms and 19 (95%) had experienced at least partial improvement. The only subject who did not exhibit improvement at last follow-up was a woman who had chosen to discontinue her antidepressant medication and who relapsed to her original level of bulimic symptoms. We also found that most subjects displayed a marked reduction in depressive symptoms as well as bulimic symptoms at follow-up. However, these encouraging findings were tempered by the observation that most subjects required one or more changes in antidepressant treatment over the course of the follow-up period, and only three subjects had successfully discontinued antidepressants at follow-up. In the second long-term study (26), we examined 36 bulimic patients who had participated in a placebo-controlled double-blind trial of trazodone. In this group, 26 patients had “pursued pharmacotherapy,” meaning that they had been willing to try up to three different antidepressant medications if they had failed to respond. The remaining 10 subjects had not pursued pharmacotherapy to this degree. At follow-up, after 9–19 mo, 17 (65%) of those who had pursued pharmacotherapy exhibited a remission of their bulimic symptoms and 22 (88%) of this group had experienced at least some improvement. By contrast, only 1 (10%) of the 10 patients who had failed to pursue pharmacotherapy exhibited a remission of bulimic symptoms and 7 (70%) of these patients were unimproved or worse. These findings again suggest that considerable experimentation with antidepressants may be necessary to achieve an optimal result. Abandoning pharmacological treatment after only one or two trials may lead to inferior outcomes.

2.3. Open-Label Trials of Antidepressants In addition to medications evaluated in placebo-controlled trials, several other antidepressants have been evaluated on an open-label basis. They deserve mention either because they have proven to be useful treatment options in clinical practice or because they indicate possible future avenues for treatment. Looking at tricyclics, we have consistently found a nortriptyline effective in openlabel trials (24–26). Like desipramine, nortriptyline has two advantages relative to

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most other tricyclics: fewer anticholinergic effects and a well-established therapeutic range of plasma concentrations known to be effective in a major depressive disorder. This range of plasma concentrations can be used as a confirmation of adequate treatment in bulimia nervosa. Although fluoxetine is the only member of the SSRI class whose efficacy has been established in placebo-controlled studies, case reports or small case series have reported beneficial effects for three other SSRIs currently marketed in the United States: fluvoxamine (28,29), paroxetine (30), and sertraline (31). Turning to MAOIs, we have reported tranylcypromine effective in open-label trials (24–26). In clinical practice, we have found that tranylcypromine is often better tolerated than phenelzine. As in the treatment of a major depressive disorder, clinicians will often employ augmentation strategies; in other words, use a second medication to enhance the response of the first antidepressant. We have found that the addition of lithium or triiodothyronine sometimes improves a partial response to other antidepressants (24–26). Finally, considering newer types of antidepressants, we have found in our anecdotal experience that venlafaxine, a nonselective norepinephrine and serotonin reuptake inhibitor (NSNSRI), is often effective and well tolerated in bulimic patients. Also of note is one report (32) that the investigational 5HT-1A agonist ipsapirone (which appears to have antidepressant properties [33]) is effective in bulimia nervosa. Thus, NSNSRIs and 5HT-1A agonists represent promising possible new treatments for bulimia nervosa.

2.4. Theoretical Implications Although it is beyond the scope of this chapter to discuss the theoretical implications of the above findings in detail, we should point out that there are logically two possible explanations for the efficacy of antidepressants in bulimia nervosa. One is that these drugs treat bulimia nervosa via the same chemical mechanism by which they treat depression; the alternative possibility is that these drugs possess two independent chemical mechanisms, one of which treats bulimia nervosa and the other of which treats depression. Upon inspecting the data, however, the second of these two possibilities would appear unlikely, as we would have to postulate that each of the several different, chemically distinct families of antidepressants each possessed both an antidepressant mechanism and, by chance, an independent anti-bulimic mechanism. Although a single class of drugs might share two entirely independent chemical mechanisms, it would be most improbable that several unrelated classes would all share exactly the same two mechanisms. Therefore, the much more likely (and parsimonious) possibility is that antidepressants treat both bulimia nervosa and depression via a single chemical mechanism which operates at the same physiologic “step” in the chain of “steps” required to produce each of the disorders. For a more detailed discussion of this argument, we refer the reader to ref. 34.

2.5. Summary of Antidepressant Efficacy The available data regarding antidepressant treatment of bulimia nervosa indicate that antidepressant agents from several chemical families are highly effective, at least in the short term, in the treatment of bulimia nervosa. These agents appear not only to reduce bulimic symptoms per se, but also to reduce associated symptoms of preoccupation with


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Table 3 a Placebo-Controlled Studies of Other Medications in Bulimia Nervosa

Study (ref.)

Drug; (maximum dose)

Kaplan et al. (35) Hsu et al. (36) Mitchell et al. (37) Alger et al. (10) Wermuth et al. (38)

Carbamazepine g Lithium carbonate Naltrexone 50 mg Naltrexone 150 mg Phenytoinf

f

No. of b subjects

Duration of trialc (wk)

Design

Improvement in bulimic e symptoms

6 91 16 15 19

6 8 3 8 6

Crossover Parallel group Crossover Parallel group Crossover

0 0 0 0 +

d

a Restricted b

to medications marketed in the United States. Number of subjects receiving drug or placebo who completed the trial or enough of the trial to be included in data analysis. c Period of time that subjects received active drug rather than total duration of the study. d All studies were randomized, placebo-controlled, double-blind trials. e +: some evidence that drug superior to placebo, but not clearly significant; 0: little or no difference between drug and placebo. fDose not specified, but plasma levels adjusted to therapeutic range for use in epilepsy. g Dose varied between 600–1200 mg, with median level of 0.62 mEq/L.

food and weight. The only antidepressant that appears contraindicated in bulimia nervosa is bupropion, because of the high risk of seizures in bulimic patients. Data regarding the long-term benefits of antidepressant treatment in bulimia nervosa are limited. Studies in which only a single antidepressant agent was administered have found high dropout rates and frequent relapse. However, studies in which the physician was permitted to try a second or third antidepressant agent if the first one failed have produced much more promising results. Given that actual clinical practice allows the clinician to substitute a different agent if the first fails, these open-label studies reflect more accurately the prognosis of bulimia nervosa when treated with antidepressants under normal circumstances.

3. OTHER MEDICATIONS Several types of medications other than antidepressants have been tried in bulimic patients. We summarize controlled trials of such medications marketed in the United States in Table 3. The table does not include one- or two-day studies because these trials are of largely theoretical interest in that they were not designed to provide information on the clinical utility of the compounds. None of these agents has been shown to be unequivocally efficacious on the basis of the studies done, nor has any achieved widespread use in clinical practice. Nevertheless, several of these medications may have a role in the treatment of particular types of bulimic patient, especially those with concomitant bipolar disorder or cyclothymia.

3.1. Mood Stabilizers First, we consider three medications with mood-stabilizing properties useful in bipolar disorder: lithium carbonate, carbamazepine, and valproate. On the basis of an encouraging open trial (39), Hsu and associates (36) conducted a placebo-controlled study of

26


lithium carbonate in 91 bulimic patients. Although this study found little overall advantage of lithium vs placebo, interpretation of the results is hampered by a large placebo response rate (perhaps augmented by the use of concomitant minimal behavior therapy) and by plasma levels of lithium that are lower (mean level of 0.62 mEq/L in this trial) than those used in the treatment of bipolar disorder (0.8–1.2 mEq/L). Thus, it is unclear whether lithium might be effective in bulimia nervosa. As mentioned earlier, we have sometimes added small doses of lithium to augment the effects of antidepressant medications. However, because of the propensity for weight gain on lithium and many more attractive alternative medication treatments for bulimia nervosa, use of lithium alone would appear to have little place currently in the treatment of most bulimic patients. Similar considerations apply to carbamazepine. In a small placebo-controlled crossover study, Kaplan and colleagues (35) failed to find a beneficial effect of carbamazepine vs placebo in the overall analysis. Although mood stabilizers may not be useful routinely in the treatment of patients with bulimia nervosa, they do have a role in the treatment of bulimic patients with cyclothymia or bipolar disorder. For example, Kaplan and associates (35) reported that a patient with bulimia nervosa and cyclothymia responded well to carbamazepine, and we (40) have reported a similar case of a woman with bulimia nervosa and bipolar disorder who responded to valproate. Given the high comorbidity between bulimia nervosa and bipolar disorder (41), this combination of disorders is encountered frequently. In our anecdotal experience, bulimic symptoms in patients with concomitant bipolar disorder or cyclothymia appear to respond well when these patients are treated in the standard manner for bipolar disorder. Specifically, bulimic patients with hypomanic or manic symptoms often respond to mood stabilizers alone; bulimic patients without current hypomania or mania often respond to mood stabilizers, either alone or in combination with cautiously administered antidepressants.

3.2. Opiate Antagonists On the basis of encouraging open studies (42,43), Mitchell and colleagues (37) and Alger and associates (10) conducted placebo-controlled trials of naltrexone in bulimia nervosa. Mitchell and colleagues (44) also conducted a two-d trial of intravenous naloxone, a related opiate antagonist. These trials failed to show a beneficial effect of opiate antagonists. However, the studies are difficult to interpret because the 50 mg dose of naltrexone used in the study of Mitchell and colleagues was less than others have used for successful treatment openly, and the study by Alger and associates had only seven patients on medication.

4. STUDIES OF ANTIDEPRESSANTS AND BEHAVIORAL THERAPY Five studies (9,21,23,45,46) have compared the outcome of bulimic patients receiving antidepressants with that of patients receiving behavioral therapy or the combination of antidepressant and CBT. Mitchell and colleagues (9) randomly assigned 171 bulimic patients to 1 of 4 treatments for 12 wk: 200 mg imipramine; placebo; intensive group CBT plus imipramine; and CBT plus placebo. The investigators found significant benefits for all three active treatments versus placebo. In comparisons among the active treatments, CBT and CBT plus imipramine were both significantly superior to imipramine alone in improvement of bulimic symptoms. Agras and associates (21) randomly assigned 73


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bulimic patients to one of three treatments: desipramine up to 350 mg daily; individual CBT; and desipramine up to 350 mg plus CBT. The total treatment period was 24 wk; after 16 wk, half of the desipramine-treated subjects were randomly discontinued from medication for the final 8 wk. Subjects were evaluated at 16, 24, and 32 wk after initiation of treatment. The authors found that CBT and CBT plus desipramine were superior to desipramine alone at 16 wk, and that the 32-wk outcome of CBT plus desipramine given for 24 wk was superior to that of the group that had received desipramine alone for 16 wk. Subsequently, subjects were re-evaluated at 1 yr. Subjects who had received desipramine treatment for 16 wk had a significantly inferior outcome compared to those in the other three groups. In the intervening 28 wk after the completion of the active study period, only four of the subjects (one in each treatment group) had received antidepressant treatment. Fichter and associates (45) treated 40 bulimic patients for 5 wk with either intensive inpatient behavioral therapy or fluoxetine 60 mg plus intensive inpatient individual therapy. They found no significant difference in outcome between the two groups, but they did find that both groups had improved significantly compared with baseline. Next, Leitenberg and colleagues (23) enrolled 21 bulimic patients in a 20-wk study to compare the effects of 3 treatments: desipramine; individual CBT; and desipramine plus individual CBT. They stopped this study prematurely because of a high number of dropouts in the desipramine-alone group, largely owing to side effects from medication. Finally, in the most ambitious and methodologically rigorous study thus far, Walsh and colleagues (46) treated 120 bulimic women for 16 wk in a randomized trial with 5 treatment arms: (1) CBT alone plus placebo; (2) supportive psychotherapy plus placebo; (3) CBT plus medication; (4) supportive psychotherapy plus medication; (5) medication alone. The medication treatment was a two-stage intervention, in which a second antidepressant (fluoxetine 60 mg/d) was employed if the first (desipramine up to 300 mg/d) was either ineffective or poorly tolerated. The results showed significant improvement of symptoms for CBT vs supportive psychotherapy, and for medication in combination with psychological treatment vs psychological treatment alone. Furthermore, CBT plus medication was significantly superior to medication alone, but supportive psychotherapy plus medication was not superior to medication alone. Finally, there was no difference in efficacy between CBT plus placebo and medication alone. The results of these studies of antidepressants vs behavioral therapy must be interpreted with regard to a number of methodological limitations. First, except in the study by Walsh and associates (46), there is no control psychological treatment. Thus, in most of the studies, it is not possible to judge what portion of the improvement in behavioral therapy represented an actual therapy-specific effect and what portion represented a nonspecific “placebo” effect from extensive human contact alone. Second, drug therapy in these studies does not mirror actual clinical practice. By allowing treatment with only a single agent (or in the case of the study by Walsh and colleagues [46], two agents), it seems likely that the studies may have underestimated the efficacy of antidepressants as they are used in the field, as we have discussed earlier in our consideration of long-term studies using single antidepressant agents. Indeed, the best results of medication in comparison with psychotherapy were obtained in the only study to allow use of two medications (46). Furthermore, one of the studies of medication vs CBT specifically showed that the response rate to antidepressants was much improved when a second antidepressant trial was allowed after the conclusion of the 12-wk comparison study (27).

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Table 4 Treatment Guidelines for Bulimia Nervosa 1. Select cognitive behavioral therapy or pharmacologic therapy. 2. If cognitive behavioral therapy is chosen, strongly consider pharmacologic therapy if response to cognitive behavioral therapy is inadequate. 3. If pharmacologic therapy is chosen, begin with SSRI. 4. If partial response and maximum dose limited by side effects, consider a second SSRI 5. If no response, try a tricyclic (generally desipramine or nortriptyline) or venlafaxine; monitor tricyclic concentrations if response inadequate. 6. If still no response, try MAOI. 7. With response, continue therapy for at least 6 mo. 8. If relapse occurs, restart medication promptly and continue for at least 6 mo prior to attempting discontinuation.

Third, in one (21) of the studies, antidepressant treatment was simply stopped after a fixed period of time, regardless of whether it appeared clinically appropriate to do so. Although it might be argued that such a strategy is “fair,” in that behavioral therapy, by comparison, is typically given for a time-limited period, such a technique is incompatible with ordinary clinical practice in antidepressant treatment. In summary, these five studies suggest that CBT and antidepressants both represent effective treatments for bulimia nervosa. However, as a result of the methodologic limitations described earlier, little can be concluded regarding the relative efficacy of the two techniques. Future comparison studies should be designed to reflect how medication treatment is given optimally in clinical practice.

5. PRACTICAL CONSIDERATIONS—TREATMENT GUIDELINES In this section, we offer guidelines for the pharmacologic management of bulimic patients based on the scientific literature, our clinical experience, and discussions with other experienced clinicians. These guidelines, summarized in Table 4, are admittedly somewhat subjective. The clinician should feel free to modify his or her approach based on the circumstances of individual patients and his or her own clinical experience. The first practical question to be addressed by the clinician is whether to begin with drug treatment or some other therapy in a bulimic patient who presents for treatment for the first time. Given the ambiguity of the evidence for the relative efficacy of CBT vs antidepressants, as discussed earlier, there is no clear “best treatment” for bulimia nervosa at this time. Therefore, some clinicians may prefer to begin with a trial of CBT in bulimic patients, reserving pharmacologic therapy for those who fail to respond or who improve in some aspects of their eating disorder, but nevertheless continue to display significant residual bulimic or depressive symptoms. Alternatively, many clinicians may prefer to begin with pharmacologic treatment, especially if expert CBT is not readily available. In any event, both of these two modalities should be actively considered in any new bulimic patient, as they are the only modalities shown to be effective in controlled trials. There may be special cases in which antidepressants are particularly indicated, such as bulimic patients with severe depressive symptoms or suicidal ideation. However, it is important to note that antidepressants should not be reserved only for bulimic patients who are depressed because antidepressants are equally effective in bulimic patients without depression.


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If drug treatment is selected, one passing question to be addressed is whether to choose an antidepressant or some other agent from the list of non-antidepressant drugs that have been tried in bulimia. Here, the decision seems clear: Aside from special cases (such as patients with concomitant bulimia nervosa and bipolar disorder), antidepressants are the treatment of choice. Once the decision is made to choose an antidepressant, which drug should be chosen? Although, as we have shown in this chapter, there is no clear evidence that one family of antidepressants is more efficacious than another, the data suggest that drugs of the SSRI class may have fewer side effects than other families of antidepressants. Therefore, we generally start with a trial of an SSRI, usually fluoxetine. We do not have an established algorithm for the choice of drugs for subsequent trials, and the three of us differ somewhat in our preferred approach. Generally speaking, our approach to pharmacologic therapy of bulimic patients is virtually identical to our approach for depressed patients. Hence, if a patient fails to respond to an SSRI, we switch to a different class of medication. However, if the patient has had a partial response but cannot increase the dose because of adverse effects, we will often try a second SSRI (indeed, we have found that some patients respond to a second SSRI even when they completely fail to respond to the first). Our choice for a second non-SSRI agent is usually a tricyclic or venlafaxine. For tricyclics, we prefer desipramine or nortriptyline because they have less anticholinergic effect than the other tricyclics and because the adequacy of the dose can be optimized by achieving plasma concentrations comparable to those established as efficacious in a major depressive disorder. Thus, desipramine concentrations of at least 160 ng/mL or nortriptyline concentrations of 50–140 ng/mL appear optimal. Even though there are no published reports of its efficacy in bulimia nervosa, we often use venlafaxine as a second choice for three reasons: It is chemically distinct from SSRIs in that it has noradrenergic effects in addition to serotonergic effects; we have found anecdotally that SSRI nonresponders often respond to venlafaxine; and it has fewer adverse effects than tricyclics. We usually reserve MAOIs for a third or subsequent trial, and we have had better experience with tranylcypromine than phenelzine, particularly because tranylcypromine seems less likely to induce weight gain. We note that MAOIs should not be used in conjunction with SSRIs and that the clinician should allow a generous washout period between trials of SSRIs and MAOIs (at least 2 wk in either direction, except when going from fluoxetine to an MAOI, in which case we recommend 5 wk, in view of the long halflife of fluoxetine). We have had good results at times with trazodone, but usually we do not use this agent for a first or second trial. Finally, we recommend considering augmentation strategies for tricyclics and SSRIs, using 600 mg lithium or 25–50 µg triiodothyronine daily. Having chosen a medication, we need to consider the dose and the duration of treatment. We recommend using doses of medication that are equal or slightly greater than doses used in the treatment of major depressive disorder. For example, 20 mg fluoxetine is often an effective dose for a major depressive disorder. However, this dose was not markedly superior to placebo treatment in a large trial (11), whereas 60 mg was unequivocally superior to placebo. For tricyclics, as mentioned earlier, we suggest using doses that achieve plasma concentrations established as the therapeutic range for a major depressive disorder. We have had success clinically with this approach, and one study of desipramine

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(2) found that nonresponding bulimic patients whose level was less than the therapeutic level for depression improved when their dose was raised in the therapeutic range. Turning to duration of treatment and guidelines for discontinuation, we recommend an approach identical to that used in the treatment of a major depressive disorder. We first conduct serial trials of antidepressants as outlined earlier in an attempt to achieve either a remission or marked improvement of bulimic symptoms. Once this level of response has been achieved, we treat for 6–12 mo before considering discontinuation of medication. We discontinue medication at a time when the patient is comfortable with the possibility of relapse, and then monitor the patient carefully. If relapse occurs, we restart medication promptly and treat for another 6–12 mo before attempting discontinuation again. Overall, although our approach to antidepressant therapy in bulimic patients is very similar the one we use in depressed patients, there are three differences of note. First, we tend to use somewhat higher doses, as discussed earlier. Second, we are more sensitive to the issue of possible weight gain as a side effect. This consideration makes SSRIs even more appealing, especially because fluoxetine and fluvoxamine have been associated with significant weight loss compared with placebo in patients with bulimia nervosa (11,12) and the related binge-eating disorder (47,48). As mentioned earlier, this consideration is also one of our reasons for preferring tranylcypromine over phenelzine for MAOI therapy. Finally, because of their association with weight gain in patients with mood disorders, we are somewhat less likely to use tricyclics and lithium, even though they have not been associated with weight gain in reported studies of bulimic patients. Third, because of the risk of seizures, we do not use bupropion except in the unusual case in which an antiepileptic is also given.

REFERENCES 1. Mitchell JE, Groat R. A placebo-controlled, double-blind trial of amitriptyline in bulimia. J Clin Psychopharmacol 1984; 4:186–193. 2. Hughes PL, Wells LA, Cunningham CJ, Ilstrup DM. Treating bulimia with desipramine: a double-blind, placebo-controlled study. Arch Gen Psychiatry 1986; 43:182–186. 3. Barlow J, Blouin J, Blouin A, Perez E. Treatment of bulimia with desipramine: a double-blind crossover study. Can J Psychiatry 1988; 33:129–133. 4. Blouin AG, Blouin JH, Perez EL, Bushnik T, Zuro C, Mulder E. Treatment of bulimia with fenfluramine and desipramine. J Clin Psychopharmacol 1988; 8:261–269. 5. McCann UD, Agras WS. Successful treatment of nonpurging bulimia nervosa with desipramine: a double-blind, placebo-controlled study. Am J Psychiatry 1990; 147:1509–1513. 6. Walsh BT, Hadigan CM, Devlin MJ, Gladis M, Roose SP. Long-term outcome of antidepressant treatment for bulimia nervosa. Am J Psychiatry 1991; 148:1206–1212. 7. Pope HG Jr, Hudson JI, Jonas JM, Yurgelun-Todd D. Bulimia treated with imipramine: a placebocontrolled, double-blind study. Am J Psychiatry 1983; 140:554–558. 8. Agras WS, Dorian B, Kirkley BG, Arnow B, Bachman J. Imipramine in the treatment of bulimia: a double-blind controlled study. Int J Eat Disord 1987; 6:29–38. 9. Mitchell JE, Pyle RL, Eckert ED, Hatsukami D, Pomeroy C, Zimmerman R. A comparison study of antidepressants and structured intensive group psychotherapy in the treatment of bulimia nervosa. Arch Gen Psychiatry 1990; 47:149–157. 10. Alger SA, Schwalberg MD, Bigaouette JM, Michalek AV, Howard LJ. Effect of a tricyclic antidepressant and opiate antagonist on binge-eating behavior in normoweight bulimic and obese, binge-eating subjects. Am J Clin Nutr 1991; 53:865–871. 11. Fluoxetine Bulimia Collaborative Study Group. Fluoxetine in the treatment of bulimia nervosa: a multicenter placebo-controlled, double-blind trial. Arch Gen Psychiatry 1992; 49:139–147. 12. Goldstein DJ, Wilson MG, Thompson VL, Potvin JH, Rampey AH Jr.,The Fluoxetine Bulimia Nervosa Research Group. Long-term fluoxetine treatment of bulimia nervosa. Br J Pschiatry 1995; 166: 660–666.


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13. Walsh BT, Gladis M, Roose SP, Stewart JW, Stetner F, Glassman AH. Phenelzine vs placebo in 50 patients with bulimia. Arch Gen Psychiatry 1988; 45:471–475. 14. Horne RL, Ferguson JM, Pope HG Jr, Hudson JI, Lineberry CG, Ascher J, et al. Treatment of bulimia with bupropion: a controlled multi-center trial. J Clin Psychiatry 1988; 49:262–266. 15. Pope HG Jr, Keck PE Jr, McElroy SL, Hudson, JI. A placebo-controlled study of trazodone in bulimia nervosa. J Clin Psychopharmacol 1989; 9:254–259. 16. Kennedy SH, Goldbloom DS, Ralevski E, Davis C, D’Souza JD, Lofchy J. Is there a role for selective monoamine oxidase inhibitor therapy in bulimia nervosa? A placebo-controlled trial of brofaromine. J Clin Psychopharmacol 1993; 13:415–422. 17. Kennedy SH, Piran N, Warsh JJ, Prendergast P, Mainprize E, Whynot C, Garfinkel PE. A trial of isocarboxazid in the treatment of bulimia nervosa. J Clin Psychopharmacol 1988; 8:391–396. 18. Sabine EJ, Yonace A, Farrington AJ, Barratt KH, Wakeling A. Bulimia nervosa: a placebo controlled double-blind therapeutic trial of mianserin. Br J Clin Pharmacol 1983; 15:195S–202S. 19. Price WA, Babai MR. Antidepressant drug therapy for bulimia: current status revisited. J Clin Psychiatry 1987; 48:385. 20. Rothschild R, Quitkin MH, Quitkin FM, Stewart JW, Ocepek-Welikson K, McGrath PJ, et al. A doubleblind placebo-controlled comparison of phenelzine and imipramine in the treatment of bulimia in atypical depressives. Int J Eat Disord 1994; 15:1–9. 21. Agras WS, Rossiter EM, Arnow B, Schneider JA, Telch CF, Raeburn SD, Bruce B, Perl M, et al. Pharmacologic and cognitive-behavioral treatment for bulimia nervosa: a controlled comparison. Am J Psychiatry 1992; 149:82–87. 22. Agras WS, Rossiter EM, Arnow B, Telch CF, Raeburn SD, Bruce B, et al. One-year follow-up of psychosocial and pharmacologic treatments for bulimia nervosa. J Clin Psychiatry 1994; 55:179–183. 23. Leitenberg H, Rosen JC, Wolf J, Vara LS, Detzer MJ, Srebnik D. Comparison of cognitive-behavior therapy and desipramine in the treatment of bulimia nervosa. Behav Res Ther 1994; 32:37–45. 24. Pope HG Jr, Hudson JI, Jonas JM. Antidepressant treatment of bulimia: preliminary experience and practical recommendations. J Clin Psychopharmacol 1983; 3:274–281. 25. Pope HG Jr., Hudson JI, Jonas JM, Yurgelun-Todd, D. Antidepressant treatment of bulimia: a two-year follow-up study. J Clin Psychopharmacol 1985; 5:320–327. 26. Pope HG Jr, McElroy SL, Keck PE Jr, Hudson JI. Long-term pharmacotherapy of bulimia nervosa. J Clin Psychopharmacol 1989; 9:385–386. 27. Mitchell JE, Pyle Rl, Eckert ED, Hatsukami D, Pomeroy C, Zimmerman R. Response to alternative antidepressants in imipramine nonresponders with bulimia nervosa. J Clin Psychopharmacol 1989; 9:291–293. 28. Spigset O, Pleym H. Case report of successful treatment of bulimia nervosa with fluvoxamine. Pharmacopsychiatry 199; 24:180. 29. Ayuso-Gutierrez JL, Palazón M, Ayuso-Mateos JL. Open trial of fluvoxamine in the treatment of bulimia nervosa. Int J Eat Disord 1994; 15:245–249. 30. Prats M, Diez-Quevedo C, Avila C, Planell LS. Paroxetine treatment for bulimia nervosa and binge eating disorder. In: Abstracts of the Sixth International Conference on Eating Disorders, New York, NY, April 1994; Abstract 308. 31. Roberts JM, Lydiard RB. Sertraline in the treatment of bulimia nervosa. Am J Psychiatry 13; 540:1753. 32. Geretsegger C, Greimel KV, Roed IS, Hesselink JMK. Ipsapirone in the treatment of bulimia nervosa: an open pilot study. Int J Eat Disord 1995; 17:359–363. 33. Heller AH, Beneke M, KuemmelB, Spencer D, Kurtz NM. Ipsapirone: evidence for efficacy in depression. Psychopharmacol Bull 1990; 26:219–222. 34. Hudson JI, Pope HG Jr. Affective spectrum disorder: does antidepressant response identify a family of disorders with a common pathophysiology? Am J Psychiatry 1990; 147:552–564. 35. Kaplan AS, Garfinkel PE, Darby PL, Garner DM. Carbamazepine in the treatment of bulimia. Am J Psychiatry 1983; 140:1225–1226. 36. Hsu LKG, Clement L, Santhouse R, Ju ESY. Treatment of bulimia nervosa with lithium carbonate: a controlled study. J Nerv Ment Dis 1991; 179:351–355. 37. Mitchell JE, Christenson G, Jennings J, Huber M, Thomas B, Pomeroy C, et al. A placebo-controlled, double-blind crossover study of naltrexone hydrochloride in outpatients with normal weight bulimia. J Clin Psychopharmacol 1989; 9:94–97. 38. Wermuth BM, Davis KL, Hollister LE, Stunkard AJ. Phenytoin treatment of the binge-eating syndrome. Am J Psychiatry 1977; 134:1249–1253.

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39. Hsu LKG. Treatment of bulimia with lithium. Am J Psychiatry 1984; 141:1266–1262. 40. Herridge PL, Pope HG Jr. Treatment of bulimia and rapid-cycling bipolar disorder with sodium valproate. J Clin Psychopharmacol 1985; 5:229–230. 41. Hudson JI, Pope HG Jr, Yurgelun-Todd D, Jonas JM, Frankenburg FR. A controlled study of lifetime prevalence of affective and other psychiatric disorders in bulimic outpatients. Am J Psychiatry 1987; 144:1283–1287. 42. Jonas JM, Gold MS. Naltrexone reverses bulimic symptoms. Lancet 1986; 1:807. 43. Jonas JM, Gold MS. Treatment of bulimia with the opiate antagonist naltrexone: preliminary data and theoretical implications. In: Hudson JI, Pope HG Jr, eds. Psychobiology of Bulimia. American Psychiatric Press, Washington, DC, 1987. 44. Mitchell JE, Laine DE, Morley JE, Levine AS. Naloxone but CCK–8 may attentuate binge-eating behavior in patients with the bulimia syndrome. Biol Psychiatry 1986; 21:1399–1406. 45. Fichter MM, Leibl K, Rief W, Brunner E, Schmidt-Auberger S, Engel RR. Fluoxetine versus placebo: a double-blind study with bulimia inpatients undergoing intensive psychotherapy. Pharmacopsychiatry 1991; 24:1–7. 46. Walsh BT, Wilson GT, Loeb KL, Devlin MJ, Pike KM, Rouse SP, et al. Medication and psychotherapy in the treatment of bulimia nervosa. Am J Psychiatry 1997; 154:523–531. 47. Hudson JI, Carter WP, Pope HG Jr. Antidepressant treatment of binge-eating disorder: research findings and clinical guidelines. J Clin Psychiatry 1996; 57(Suppl 8):73–79. 48. Hudson JI, McElroy SL, Raymond NC, Crows S, Keck PE Jr, Carter WP, et al. Fluvoxamine in the treatment of binge-eating disorder: a multicenter placebo-controlled double-blind trial. Am J Psychiatry 1998; 155:1756–1762.

Chapter 4 / Prevention of Anorexia Nervosa and Bulimia Nervosa

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Prevention of Anorexia Nervosa and Bulimia Nervosa A Nutritional Perspective

Cheryl L. Rock 1. INTRODUCTION: NUTRITION AND THE EATING DISORDERS This chapter reviews the issues related to the influences of dietary patterns and nutrition on eating disorders, the risk factors associated with the development of eating disorders, and suggestions for prevention and early intervention for the eating disorders (Table 1). Abnormal nutritional status and dietary patterns are the central features of the eating disorders. The objectives of this chapter are to provide the scientific background supporting this, the likely characteristics of at-risk individuals, and potential interventions. In the pathogenesis of anorexia nervosa (see Chapter 5), nutritional factors are among both precipitating and perpetuating factors (1). Dieting or other purposeful changes in food choices triggers the onset of the disorder, and the physiological and psychological consequences of starvation serve as perpetuating factors that can impede progress toward recovery. Nutritional rehabilitation is the first goal of treatment (2), although other components of therapy are necessary to prevent relapse. In the patient with bulimia nervosa (see Chapter 1), dieting appears to play a key etiologic role. The onset of bulimia nervosa typically follows a period of dieting to lose weight (3), and a causative link between dietary restraint and bulimia is strengthened by similar observations of obese patients who binge eat and of normal subjects following a period of food deprivation (4,5). The abnormal eating patterns that develop with repeated episodes of dieting and binge eating serve to perpetuate the disorder. The physiological consequences of these abnormal eating patterns contribute to its often intractable nature. The clinical eating disorders are only the most extreme form of pathological eating attitudes and behaviors. Many engage in pathological dieting behaviors without meeting the current diagnostic criteria for anorexia or bulimia nervosa and may be regarded as having subclinical eating disorders. As described by Fairburn and Beglin (6), a broad spectrum of eating disorders appears to exist in the general population, as a continuum of dieting behavior and weight concerns, especially among women. The prevalence of anorexia nervosa and bulimia nervosa has been estimated at 32. Thus, the toll of overweight on mortality applies to women as well as men. This had previously been clearly observed in the Framingham data. Although it is clear that risk increases with a longer follow-up, this does not mean that older populations are not at risk. For instance, risk of death was twofold greater for people with BMIs * to the 70th percentile at both 55 and 65 yr of age in the Framingham study (19). This was true even when levels of serum cholesterol, blood glucose, and systolic blood pressure were taken into account. In a more recent study, an analysis of the Longitudinal Study of Aging (20), lowest mortality was at a BMI of 27–30 for men and 30–35 for women older than 70 yr. Stevens et al. (21) have quite comparable data. Despite all the positive data on the relationship of obesity to mortality, it must be stated that there have been a number of studies that have not found a relationship (22– 32). There are two potential reasons for this lack of effect. The first is that many of these studies have had a shorter follow-up period, a problem that has already been discussed. The second is that in most of these studies, diseases that are often associated with and made worse by obesity, so-called comorbid conditions, have been eliminated or controlled for. For example, people with diabetes mellitus have not been allowed into the studies, and/or people’s blood pressure has been taken into account. This has been done with the defense that an independent effect of obesity is being looked for in the study. The difficulty with such an approach is that because obesity exerts much of its effect through these conditions, the elimination of the conditions greatly attenuates the adverse effect of obesity. This has been thoroughly discussed by Manson et al. (33). They have pointed out that in 25 major prospective studies on the association of body weight and longevity, each study had at least one of three biases that led to the systematic underestimation of the impact of obesity on premature death. The three biases were (1) failure

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Part II / Anorexia Nervosa Table 4 Average Univariate Standardized Logistics-Regression Coefficients for Death and Cardiovascular-Disease Incidence: Framingham study. 18-yr follow-up Cardiovascular disease Independent variable Relative weight Serum cholesterol Systolic blood pressure Diastolic blood pressure Vital capacity Diabetes LVH-EKG Cigarettes per day

Death

Men

Women

Men

Women

0.125 0.230 0.419 0.342 –0.173 0.169 0.223 0.223

0.216 0.270 0.470 0.378 –0.332 0.202 0.252 0.038

–0.189 –0.099 0.294 0.195 –0.384 0.116 0.361 0.226

–0.060 –0.017 0.254 0.172 –0.411 0.218 0.294 0.130

Note: Logistics regressions were calculated for each 10-yr age group in the range 45–74 yr and weighted by the inverse of their variances to compute average coefficients. Estimated by Walker– Duncan method. a Left ventricular hypertrophy on electrocardiogram. Source: ref. 35.

to control for cigarette smoking, (2) inappropriate control for the biological effects of obesity, such as hypertension and hyperglycemia, and (3) failure to control for weight loss due to subclinical disease. A recent meta-analysis of 10 longitudinal studies describes a J-shaped curve of mortality, with enhanced risk at both the low and the high ends of the BMI scale (34). In summary, the data, although not all in total agreement, suggest that a relationship exists between overweight and mortality. This relationship is particularly strong in longterm studies, even when the effect of obesity on other risk factors is taken into account (19).

3. MORBIDITY 3.1 Cardiovascular Disease The prevalence of cardiovascular disease (CVD) is related significantly to the effect of hypertension and dyslipidemia, as well as to direct adverse effects on the heart. Therefore, the discussion of health risks relating obesity to CVD will be addressed focusing separately on these variables. 3.1.1. HYPERTENSION The association between hypertension and obesity is well documented. Table 4 shows the average univariate standardized logistic-regression coefficients for death and cardiovascular disease incidence in the Framingham study at the 18th year of follow-up (35). Blood pressure is the leading variable documented. Numerous other studies have also documented the increased risk of developing high blood pressure with increasing body weight (36–39). The Second National Health and Examination Survey (NHANES II), a cross-sectional study conducted from 1976 to 1980 on a representative sample of US residents, showed that the prevalence of hypertension among overweight adults was 2.9 times greater than that among nonoverweight adults (39). The risk in persons 20–44 yr

Chapter 9 / Medical Consequences of Obesity

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old was 5.6 times greater than that in persons 45–74 yr old, a figure that, in turn, was two times higher than that for nonoverweight adults (40). The data from NHANES II were calculated using as the reference population those persons who were at or below the 85th percentile of weight for height in the first 1960 survey. This cutoff comes at a BMI of 27.8 for men and 27.4 for women (39). The NHANES II data also showed that the relationship between BMI and high blood pressure rises in the 25–54 yr age group and drops in the 65–75 year group (35). Also, a series of cross-sectional studies have shown that those persons who are 20% or more overweight have a prevalence of hypertension that is twice that among persons of normal weight (41). In the Framingham longitudinal study, the relationship of hypertension to an increase in weight was certainly found. In men, for every 10% increase in relative weight, systolic blood pressure increased by 6.5 mm Hg. A 15% gain in weight was associated with an 18% increase in systolic pressure (42). Persons who were only 20% overweight had an eightfold greater incidence of hypertension (43). Also, in Bjerkedal’s Scandinavian study of 67,000 adults (44), there was an increase of 3 mm Hg of systolic and 2 mm Hg of diastolic pressure for every 10-kg increase in body weight. The Evans County study in Georgia documented that a gain in weight during a 6-yr period of observation doubled the risk for developing hypertension (45). In addition, a prospective study of college men followed for a subsequent 32 yr showed that the BMI was associated with high blood pressure and that weight gain over the years significantly increased both systolic and diastolic blood pressures (46). In the Nurses Health Study, the relative risk for developing hypertension went from 1.0 for a BMI < 23, to 1.67 for a BMI of 23–25, to 2–8 for a BMI of 26–28, to 3.86 for a BMI of 29–31, to 5.70 for a BMI > 32 (47). This is nearly identical to the risk found in the Framingham study (47). It is interesting to note that in populations where there is not an age-related bodyweight increase, an elevation of blood pressure with age is not apparent. There is also good documentation for the fact that blood pressure drops as weight is lost (36,48–53) and this is as effective in the old as in the young (54). Despite the solid epidemiologic documentation of the association between obesity and hypertension, the pathophysiology and etiology have not been well defined. One possible cause proposed is a decreased renal filtration surface, leading to renal sodium retention (55). Also, obesity is known to enhance insulin resistance and raise prevailing insulin levels and insulin increases tubular reabsorption of sodium (56). It is also possible that an activation of the sympathetic nervous system occurs with obesity (57), although this has been difficult to establish definitively. In addition, plasma renin has been reported to be elevated in obese persons with hypertension (58). It is important to point out that an increase in hypertension leads to an increased risk of stroke. This is clearly documented in the Framingham study where the incidence of stroke went from 22 to 30 to 49 per thousand for men younger than 50 yr and from 8 to 14 to 35 per thousand for women in the same age group with relative weights of 110, 110– 129, and 130 lb or more, respectively. Among persons older that 50 yr, these figures went from 70 to 92 to 80 per thousand for men and from 45 to 64 to 121 per thousand for women with relative weights of 110, 110–129, and 130 lb or more, respectively (59). 3.1.2. DYSLIPIDEMIA Dyslipidemia is often associated with obesity. The most commonly abnormal lipid fraction is the serum triglycerides (60,61). With weight gain, levels of triglycerides rise

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(60). In association with the rise in triglycerides, there is almost always a decrease in high-density lipoprotein (HDL) cholesterol (62–64). When total or low-density lipoprotein (LDL) cholesterol have been measured in obese persons, they have been found to be normal (65) or elevated (66). However, obesity predisposes to small dense LDL particles, which are more atherogenic (67–68). In the Framingham study, every 10% increase in relative weight was associated with an increase in plasma cholesterol of 12 mg/dL (33). In NHANES II, the relative risk of hypercholesterolemia (set at 6.47 mmol/ L, a clear risk) is 1.5 times greater for obese than lean individuals. If these data are divided into younger and older age groups, the younger group (aged 20–45 yr) has a relative risk of 2.1 and the older group (aged 45–75 yr) has no enhanced risk. The population study carried out in Tecumseh, Michigan found that in men < 39 yr of age, total cholesterol correlated with the relative weight, but not for men > 40 yr (69). In blood donors of both sexes, cholesterol increased as relative weight increased, and this was more pronounced in men than women and in those subjects < 49 yr than those > 49 yr (70). Because both triglycerides and HDL cholesterol are independent risk factors for coronary heart disease, the nature of the dyslipidemia of obesity clearly predisposes to this disease. 3.1.3. CORONARY HEART DISEASE In epidemiologic studies, coronary heart disease (CHD) is generally defined as nonfatal myocardial infarction and angina pectoris (71). The role of obesity on CHD morbidity has been widely debated. There are two reasons for this. First, obesity can enhance other risk factors such as high blood pressure, dyslipidemia, and insulin resistance with hyperinsulinemia, all of which have been documented to increase CHD. Second, obesity has an independent negative morbidity effect on CHD. As mentioned earlier, this has been difficult to establish because it requires a long period of follow-up (1–3). For instance, in studies where periodic reports of longitudinal studies were published, such as the Framingham study (59) and the Los Angeles Heart study (72), a stronger association was noted between body weight and CHD in the later (59,72,80) as compared to the earlier reports (73,74). Of seven representative, prospective, high-quality studies of CHD, four reported a positive association and three did not (75). The US pooling study compared data from several previously reported longitudinal studies. Again, some showed a positive association and some did not. However, when the data from these studies were pooled for greater statistical power, a positive relation between obesity and CHD was noted (76). When other factors associated with CHD are included in the analyses and controlled for, obesity decreases in importance as an independent risk factor (1). This decrease occurs because obesity exerts much of its effects through the enhancement of other risk factors, such as high blood pressure, diabetes, and dyslipidemia (1,59,70). The importance of obesity as an independent risk factor for CHD has been recently emphasized by the relationship between BMI and coronary risk death in Seventh Day Adventists (77). This group of nonsmokers was followed for 26 yr and three items in the outcome are important. First, no increased mortality was noted in the leanest group. The authors state, “ The relatively large number of subjects who were lean by choice, rather than as a result of preclinical disease or smoking, may explain these findings” (77). Similar data had been reported in the Albany (78) and the Kaiser Permanente (79) studies that showed that lean nonsmoking men do not have an increased risk for death. Second,


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an increasing trend was found toward increasing mortality rate with increasing BMI for all end-point studies (including cardiovascular cancer and cerebrovascular death), so that a continuously increasing relationship between BMI and death was found. Third, survival analysis was done, and the protective effect associated with low body weight decreased with advancing age and disappeared by 90 yr of age. Although the protective effect associated with the lowest quintile of BMI on CHD death decreased significantly with increasing age, the effect remained greater than one at all ages in men (77). Thus, this study in nonsmoking, nondrinking men eliminates the higher mortality at the low end of weight, showing a direct relationship between increasing weight and increasing mortality. A change in body weight after full linear growth has been achieved may be more important than obesity itself in producing CHD. Life-long obesity has different consequences for morbidity than obesity that begins after adulthood. The studies of Heyden et al. (81) and Abraham et al. (82) suggest that CHD and hypertensive disease incidence is greater in those who have become overweight as adults than in those who have been overweight since childhood. More studies are required to elucidate this interesting possibility. Stamler et al. (83) in a 10-yr prospective study of middle-aged men in Chicago, expressed weight as relative weight, (i.e., weight for height); those at median weight for their height were assigned a relative weight of 100. They found that the CHD incidence rates were lowest in those with relative weights < 90, 33% higher in those with relative weights between 90 and 109, 68% higher in those with relative weights between 110 and 129, and 180% higher in those with relative weights * 130. The data were similar in women. A series of longitudinal studies of 4–15 years’ duration could find no relationship of weight to CHD (84–87). The Manitoba study, a 26-yr follow-up of a cohort of men with a mean entry age of 31 yr, compared baseline weights with incidence of CHD and found that after adjusting for age and blood pressure, the BMI was a significant predictor of CHD (3). The association with weight was most apparent in men aged < 40 yr and was not evident until 16 yr of follow-up. The Nurses’ Study, previously mentioned, has reported on CHD in relation to weight (88). The increased risk with increasing weight begins at very low weights, so that even weights that are considered “normal” cause an increased risk. This excellent study on a very large number of women over a period of 16 yr seems to be quite definitive proof of the risk of overweight in relation to CHD. In summary, the principal data on the relationship between obesity and CHD suggests that obesity is an important independent long-term risk factor in producing morbidity and mortality from CHD. Obese individuals are at even greater risk if other risk factors are also present, including, most importantly, high blood pressure, decreased HDL cholesterol, and elevated serum triglycerides (80). The longer observation period necessary for the effect of obesity on CHD may reflect the time required for young men to reach the age of high risk. It is, therefore, probable that body weight can be considered a long-term risk factor for ischemic heart disease, which perhaps requires the development of a certain amount of coronary atherosclerosis to exert an independent effect. The risk is more acute in younger age groups, and longitudinal studies of under 10 yr of follow-up are unlikely to assess adequately the risk of obesity on health.

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Table 5 Prevalance of Adult Onset Diabetes: United States. 1976 (n = 64 142) Men, by BMI Age 20–44 yr 45–54 yr 55–64 yr 65+ yr

Women, by BMI

< 24

24–25

26–27

> 28

< 22

22–25

26–27

> 28

0.5 3.0 4.3 6.7

0.5 2.5 4.7 8.0

0.6 3.4 5.9 8.2

1.3 6.9 9.9 9.4

0.5 1.6 2.5 5.6

0.6 2.1 3.7 6.4

1.1 3.6 5.1 8.9

3.4 9.1 9.6 13.2

Note: Prevalence is given in percent. Source: ref. 96.

3.2. Diabetes Mellitus Years ago, epidemiologic studies described the association between the average weight of population groups and the prevalence of diabetes (89,90). In a prospective Scandinavian study, moderate obesity was associated with a 10-fold rise in the risk of diabetes that rose much higher with more severe obesity (26). The risk for diabetes in the United States has been reported to be about twofold in mildly obese, fivefold in moderately obese, and 10-fold in severely obese persons (91). The NHANES II data also showed that the overall relative risk of developing diabetes was 2.9 times greater for obese people 20–75 yr of age (39). The relative risk for those 20–45 and 45–75 years of age was 3.8 and 2.1, respectively. The risk for developing diabetes increases with age (92,93) if there is a family history of diabetes (94) and if obesity is centrally located (95). Table 5 gives prevalence rates for diabetes in relation to age and BMI (96). The prevalence rates increase with age and with greater BMI in both men and women (97,98). Similar relationships have been reported in Israel (99). The reason for the increased incidence of diabetes with obesity is partly related to the insulin resistance created by the obese state (100). It is well known that with obesity, there is a downregulation of insulin receptors in insulin-sensitive tissues and an increase in prevailing insulin levels. More importantly, there are also a series of postreceptor defects that decrease the ability of glucose to enter the cells and to be oxidized or stored as glycogen (101,102). The net result is that the beta cells of the pancreas are required to produce more insulin to do the same job of glucose disposal. In persons with the genetic predisposition to diabetes, this increased stress on the beta cells tends to lead to their eventual exhaustion and to overt diabetes (103).

3.3. Gall Bladder Disease Both cross-sectional (104) and longitudinal (105) studies have shown that increasing body weight is associated with a greater incidence of gallbladder disease. Gallstones occur three or four times more often in obese than nonobese persons (104–106). The incidence increases with age and with increasing obesity (107). Women are particularly at risk, as documented in the Nurses’ Health Study (108). Women with a BMI greater than 30 had a yearly symptomatic gallstone incidence rate of more that 1%, and those with a BMI greater than 45 had a rate of approximately 2% (109). In morbidly obese individuals, the prevalence rate of gallbladder disease is 28–45% (110).


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At least two factors are known to contribute to the predisposition of obese persons to form gallstones. The usual gallstones that form in obese people are cholesterol stones (111) and occur because there is a supersaturation of bile with cholesterol (112,113). This is true even when both sex and age are taken into account (114). In addition, gallbladders of obese persons do not contract appropriately (115). This atony of the gallbladder leads to poor emptying and resulting bile stasis. If obese persons attempt to lose weight while they are taking a hypocaloric diet, their bile will manifest an increase of cholesterol supersaturation, predisposing them to gall stone formation during the weight-loss phase (115,116). Thus, repeated cycles of trying to losing weight tend to increase the risk in obese persons.

3.4. Respiratory Disease As weight increases, more work is required just to move a heavier chest (117). Increased fat in the chest wall and abdomen reduces effective lung volume, alters respiratory pattern, and causes a decreased compliance of the respiratory system (117,118). Vital capacity and total lung capacity are frequently diminished. As more severe obesity supervenes, a ventilation–perfusion abnormality begins to occur, characterized by hypoxia but normal arterial pCO2 (119,120). Also, sleep apnea may occur, which may be obstructive (due to a combination of excess fatty tissue and increased relaxation of the pharyngeal and glossus muscles) (121), central (due to abnormal control of breathing), or a combination of the two (122). When the full-blown obesity–hypoventilation syndrome occurs, it is associated with depression of hypercapnic and hypoxic respiratory drives, irregular breathing, frequent apneic periods with resultant severe hypoxia (123), and daytime somnolence. Cor pulmonale may finally occur (124).

3.5. Cancer The prospective American Cancer Society (ACS) study previously mentioned, which followed over 750,000 men and women for 12 yr found that the mortality ratio for cancer for men who were * 40% overweight was 1.33 and for women 1.55 (125). Overweight men had significantly higher mortality ratios for colorectal and prostate cancers, and overweight women had significantly higher rates of endometrial, gallbladder, cervical, ovarian, and breast cancers (125,126). These data are shown in Table 6. In longitudinal prospective studies, the relation of the degree of obesity to increased mortality rate from breast cancer has been well documented in postmenopausal women (127–129). In premenopausal women, there seems to be a protective effect, with the incidence being lower than in lean women. Certainly, endometrial cancer has been consistently found to be elevated in obese women (130–133). In men, the Japan–Harvard study showed a strong positive relationship between colon cancer and BMI for men over age 55 yr (134). Prostate cancer had a significant but weak association with BMI.

3.6. Arthritis Because of the excessive weight-bearing, degenerative arthritis is a greater problem in obese than lean individuals (135–138). As weight increases in men and women, the prevalence of osteoarthritis increases from 0.75% to 1.45% in men and from 0.4% to 1.45% in women (139).

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Part II / Anorexia Nervosa Table 6 Mortality Ratios for Cancer Sites at Which Incidence of Overweight Is Greater Than for Average Weight Weight index Site of cancer Male Colon, rectum Prostate Female Endometrium Uterus, unspecified Cervix Ovary Gall Bladder Breast

110%– 119%

120%– 129%

130%– 139%

140% +

— —

— 1.37

1.53 1.33

1.73 1.29

1.36 — — — 1.59 —

1.85 1.81 1.51 — 1.74 —

2.30 1.40 1.42 — 1.80 —

5.42 4.65 2.39 1.63 3.58 1.53

Source: ref. 131.

3.7. Gout There is a sexual dimorphism with regard to the relationship of overweight to gout. In the cross-sectional Canadian Health Survey, the percentage of men with uric acid levels greater than 416 µmol/L increased from 7% to 31% as the BMI increased from 21 to 31 (140). Women were not affected until they reached a BMI greater than 31, when the percentage prevalence was 7% (141). Correlations between level of uric acid and weight have been repeatedly reported (80,142).

4. REGIONAL FAT DISTRIBUTION Regional fat distribution has become recognized as an important factor in determining health risk in obese individuals. Prospective, population-based studies (143–145) have confirmed that an excess of abdominal fat is a potent risk factor for the eventual development of obesity-related illnesses such as diabetes mellitus and cardiovascular disease in men (143,144) and women (145,146). However, the data are not as extensive as for obesity per se. One of the problems has been the measurement of fat distribution. Central- or upper- body obesity has been measured by anthropometric means using the waistto-hip ratio (WHR) or the waist circumference or ratios of skinfolds. More sophisticated studies have used computer-aided tomographic scanning or magnetic resonance imaging. The impact of regional fat distribution on health is related to the amount of truncal or abdominal fat (upper-body fat) and to the amount of visceral fat located in the intraabdominal cavity, which is difficult to measure accurately and for which there is only a small amount of epidemiologic evidence regarding its impact. Six prospective studies (145–151) have investigated the impact of body fat distribution on mortality. In all these studies, there was a significant association of increased abdominal or upper-body fat with increased mortality. Four of these studies were on men, one on women, and one on both. Three of the studies used skinfold measures to assess central vs peripheral fat distribution and three used waist-to-hip ratios.


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In addition to mortality, morbidity was also studied, and in the six studies quoted above and others, increased abdominal or truncal fat was significantly related to CVD (145–151), hypertension (152–154), and diabetes (144). The Gothenburg study of men (143) and the Gothenburg study of women (146) showed that the waist-to-hip ratio, independent of BMI, was associated with a number of risk factors for CVD, including cholesterol, triglycerides, smoking, hypertension, decreased glucose tolerance, and fibrinogen. A number of studies have reported that adipose tissue distribution is a risk factor for hypertension (153–158). the Canadian Fitness Survey (159) also showed such an association. Other studies, however, have not observed this (160). In the Framingham study (80), the Honolulu Heart Study (147), the Paris Prospective Study (148,149), the Gothenburg study of men (143), and Gothenburg study of women (145), truncal or upper-body fat was associated positively with an increased risk of CVD. For four of these five studies, this significant association was independent of other CHD risk factors. In the Honolulu study, central subcutaneous distribution of fat was an independent risk factor for CHD in men. In the Paris Prospective Study, fat in the upper part of the body predicted CHD better than did the degree of obesity. Thus, central or abdominal fat mass distribution is an important risk factor for CHD. In some cases, there is the strong suggestion that fat distribution may be more important than the degree of obesity. If one looks at the relative independent contribution of certain indexes of obesity to the 22-yr incidence of CHD in the Framingham study, truncal obesity is a better predictor of CHD than is the degree of obesity measured as BMI or waist circumference (80). Després et al. (161,162) have shown that an increase in abdominal fat is associated with high concentrations of serum triglycerides and low concentrations of serum HDL cholesterol, although these associations are weaker for women than for men. A number of studies have reported that the WHR is an important predictor of glucose intolerance and hyperinsulinemia (163–165). In obese persons, increasing WHRs are correlated with decreasing hepatic insulin extraction and a decline in metabolic clearance rate of insulin (166) with resulting hyperinsulinemia. The positive impact of central obesity on gallbladder disease has been documented (167). However, the data for cancer are unclear, with more investigation required.

5. SUMMARY The evidence that obesity increases both morbidity and mortality risk is clear. In addition, central fat distribution is an important independent contributor to that risk. Although there is controversy with regard to the independent effect of obesity as opposed to the effect exerted through comorbid conditions which may be present, a severe impact of obesity on health does not seem debatable. The point in the human body-weight curve where risks begin is not easy to define. The rate of mortality is steeper as higher weights are attained. Also, the rate of increase is steeper in men and women younger than 50 yr than in older individuals, and the increase associated with duration of obesity is also steeper. Thus, a particular effort to prevent weight gain in younger persons should be made. As there is little evidence of health risk at lower weights when adjustments are made for smoking and concurrent disease, from a public health viewpoint it seems reasonable to persuade individuals to maintain average or somewhat below average weight. Much can be gained in quality of life and in reduced health costs.

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ACKNOWLEDGMENTS Much of this material has been previously published in refs. 168 and 169.

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Chapter 10 / Syndrome X and the Benefits of Weight Loss

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Syndrome X and the Benefits of Weight Loss Margaret C. Flynn, Samuel Chan, and George L. Blackburn

1. INTRODUCTION Obesity is the most common metabolic disorder in the Western world. Defined by a body mass index (BMI) equal to or greater than 30, it affects an estimated 33% of Americans, including more than 58 million adults in the United States (1). According to the National Institute of Health (NIH) guideline published in 1998, approximately 97 million or 55% of adults in the United States are overweight or obese (2). Though a major contributor to the cost of illness in the United States, the prevalence of obesity is increasing despite evidence indicating that weight loss, even if moderate, can improve health status and lessen the incidence of obesity-related disease (3–6). Studies show that a 10% decline in body weight cuts death and morbidity rates per million by 280 and 400, respectively (6,7). Because obesity is so common, it has profound adverse economic repercussions. Obesity-related medical complications including type 2 diabetes mellitus, hypertension, dyslipidemia, cardiovascular disease, osteoarthritis, and some malignancies add substantially to the cost. McGinnis and Foege (8) found that each year, obesity and its complications results in 300,000 deaths and estimated costs in excess of $100 billion (9,10). In 1995, obesity accounted for 11% of total national health expenditures and estimated indirect costs of $52 billion (9,10). Wolf and Colditz, using the 1988 National Health Institute Survey (NHIS) (11), estimated that obesity and/or its associated maladies led to 43 million excess physician visits. Obesity, or factors directly related to it, also contributed to 87 million bed days, more than 50 million lost work days, and 230 restricted activity days (9,10,12). This chapter summarizes the medical benefits of weight loss (see Table 1). Such information is important to use to encourage patients who achieve health benefits from a weight reduction program despite not fully achieving their weight loss goals.

From: The Management of Eating Disorders and Obesity Edited by: D. J. Goldstein © Humana Press Inc., Totowa, NJ

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Part II / Anorexia Nervosa Table 1 Chapter Overview: Syndrome X and the Benefits of Weight Loss 1. Introduction 2. Syndrome X 2.1. Link to Non-Insulin-Dependent Diabetes Mellitus 2.2. Link to Hypertension 2.3. Link to Hyperlipidemia 2.4. Link to Cardiovascular Disease 3. Type 2 Diabetes Mellitus 4. Hypertension 5. Dyslipidemia 6. Cardiovascular Disease 7. Other Benefits of Weight Loss 7.1. Osteoarthritis 7.2. Malignancy 7.3. Sleep Apnea 8. Conclusion

2. SYNDROME X 2.1. Link with Type 2 Diabetes Mellitus Insulin resistance is frequently linked to obesity, type 2 diabetes mellitus, hypertension, dyslipidemia, and cardiovascular disease. This cluster of cardiovascular risk factors has been called Syndrome X, or the insulin resistance syndrome (13). Syndrome X is most closely associated with a central fat distribution (“apple shaped”) as opposed to a peripheral one (“pear shaped”) (14). Clinically, the most convenient way to measure a central fat distribution is by an increased waist-to-hip ratio. Even though centrally obese individuals are at the greatest risk, noncentral obesity is anything but metabolically benign. Compared to leaner people, those with peripheral obesity run a substantially higher risk for hypertension, glucose intolerance, and unfavorable lipid profiles (15).

2.2. Link with Hypertension The link between obesity and hypertension may be insulin resistance and hyperinsulinemia (16,17). Studies show that most obese patients, and many lean hypertensive ones, are resistant to the effects of insulin (18). Estimates indicate that up to 50% of hypertensive patients are insulin resistant (19). Indeed, insulin itself may promulgate high blood pressure. It has, for example, been shown to increase renal tubular resorption of sodium (20,21), a process that promotes hypertension by raising circulating plasma volumes. Insulin also boosts intracellular stores of free calcium in the smooth muscle cells that line blood vessels (22). This increase, in turn, may bolster vascular smooth muscle tone, upping intravascular resistance. The sympathetic nervous system (SNS) is another putative bond between insulin and hypertension. There is a positive correlation between increased body mass index and heightened SNS activity (23). Moreover, plasma insulin and 24-h urine norepinephrine levels have a significant correlation with blood pressure (24).


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It may be that insulin is the mediator between obesity and increased SNS activity. Exogenous insulin is known to elevate plasma norepinephrine levels even when plasma glucose levels remain constant (25). Greater caloric intake is accompanied by increases in both sympathetic nervous activity and insulin levels. In contrast, caloric restriction is accompanied by decreases in sympathetic nervous activity and insulin levels (26). One teleological explanation for the link between SNS activity and dietary intake is the regulation of energy (24,27). During fasting, both insulin secretion and SNS activity decline. These events lead to reduced thermogenesis, and thus, energy conservation. In times of high-energy intake, intensified SNS activity boosts thermogenesis, a process that helps limit excess energy storage. However, obesity-related hypertension is an unfortunate byproduct of this compensatory rise in SNS activity and pressor hormones.

2.3. Link to Hyperlipidemia The etiology of obesity-related hyperlipidemia is probably multifactorial. There’s a positive correlation between daily cholesterol production and both body fat (28) and energy intake. Caloric restriction, on the other hand, reduces the activity of HMG-Co-A reductase (29), the rate-limiting enzyme in cholesterol synthesis. Decreased affinity for the low-density lipoprotein (LDL) receptor, which is secondary to obesity-related insulin resistance, may impair clearance of LDL particles. Likewise, insulin resistance may be responsible for production of a more atherogenic, dense LDL (30). The hypertriglyceridemia of obesity is related to changes in lipoprotein lipase activity and free fatty acids. The activity of lipoproteinlipase—the enzyme that transforms triglyceride-rich chylomicrons to high-density lipoproteins (HDL), and very-low-density lipoproteins (VLDL) to LDL—declines with insulin resistance and increases with weight loss (31). Owing to expanded fat mass, obese patients also suffer from an excess of free fatty acids. Finally, hyperinsulinemia may raise hepatic triglyceride production. Owing to the effects of the cholesterol ester transfer protein (31), this increased triglyceride release could further reduce HDL production.

2.4. Link to Cardiovascular Disease Obesity, even mild to moderate, has long been known as a major risk factor for coronary artery disease. The Nurse’s Health Study (32) demonstrated that, compared to their lean counterparts, moderately overweight women (BMI25–28.9) had an 80% greater risk of developing coronary artery disease. Even after accounting for other risk factors (e.g., smoking, hypertension, diabetes), results showed that obesity was responsible for 40% of coronary events. This heightened risk of cardiovascular disease has, for many years, been connected to the cluster of metabolic abnormalities associated with obesity; specifically dyslipidemia, hypertension, and impaired fibrinolysis. Insulin resistance also plays a major role in the development of cardiovascular disease. The Quebec Cardiovascular Cohort, a 5-yr prospective study of over 2000 men, clearly demonstrated that hyperinsulinemia is an independent risk factor for ischemic heart disease that cannot be explained by any concomitant dyslipidemia or hypertension (33). The San Antonio Heart Study (34) produced similar results.

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Hyperinsulinemia, through stimulation of arterial smooth muscle proliferation (35), has been implicated in the development of atherosclerotic plaque. Insulin infusions have been shown to promote marked expansion of the intima and media of arterial walls of dogs (36). Shinozaki et al. (37) demonstrated a significant correlation between the degree of insulin resistance and coronary artery disease as well as the presence of insulin resistance in lean, nondiabetic normotensive patients with documented coronary disease. The association between insulin resistance and cardiovascular disease may also be secondary to a hypercoaguable state. Tissue plasminogen activator inhibitor (tPA) converts plasminogen to plasmin, which in turn, degrades the fibrin polymers of clots. Type I plasminogen activator inhibitor (PAI-1) suppresses tPA. Higher levels of PAI-1, which reduce degradation of clot polymers, are found in insulin-resistant obese patients as well as those with hypertension, diabetes, and coronary artery disease. Fibrinogen may play a role as well. Ample evidence indicates that elevated fibrinogen levels are a risk factor for coronary artery disease (38–40). The Framingham Study followed 1315 healthy participants for a 12-yr period after measuring of their fibrinogen levels. Analysis showed a positive correlation between fibrinogen levels and the risk of developing cardiovascular disease, an association that persisted after multivariate analysis for other known cardiac risk factors, including systolic blood pressure, cholesterol level, smoking, and left ventricular hypertrophy.

3. TYPE 2 DIABETES MELLITUS Insulin resistance, a state in which target organs are less able to respond to the metabolic effects of insulin, is characterized by elevated serum insulin levels and a decreased ability to oxidize and store glucose (41). Euglycemic insulin clamp studies demonstrate a 30–40% decrease in insulin sensitivity in patients who are 35–40% above their ideal body weight (42). Insulin-resistant, nondiabetic obese subjects maintain euglycemia via a compensatory increase in insulin. Although able to secrete enough insulin to do so, they eventually suffer the consequences of chronically high insulin levels (12). One result, a prolonged prediabetic phase, is characterized by normoglycemia compensatory hyperinsulinemia. With time or further weight gain, however, the beta cell is unable to sustain the degree of hyperinsulinemia, and hyperglycemia ensues (43). Numerous epidemiological studies demonstrate increased incidence of type 2 diabetes mellitus in the obese population. These studies also show that as weight goes up, so does the risk of diabetes. The Nurse’s Health Study (44), which followed over 100,000 nondiabetic women for 14 yr, documented the close relationship between weight and the probability of developing diabetes. Compared to lean women with a BMI of less than 22, women with a BMI of 27.0–28.9 had a 15-fold higher risk. Thus a 5 ft 4 in. woman weighing 156 lb (BMI = 27) has 15 times the odds of developing type 2 diabetes mellitus than a woman of the same height who weighs 125 lb (BMI = 22). Moreover, the higher the weight gain, the greater the risk; for example, a BMI greater than 35 (a 5 ft 4 in. woman weighing >200 lb) boosts it more than 90-fold. The study also revealed a link between the age at which weight is added and the risk of type 2 diabetes mellitus. For instance, the relative risk of developing type 2 diabetes doubled with a weight gain of 8–10 kg after age 18.


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3.1. Effects of Weight Loss Effects of insulin resistance can, to some extent, be reversed with weight loss. A reduction improves insulin sensitivity, increases glucose disposal and decreases hepatic glucose production (45,46). In obese subjects with type 2 diabetes mellitus, a 16% drop in body weight (16.8 kg) boosted peripheral glucose disposal by 165% and lowered basal hepatic glucose production by 40% (46). A weight loss as small as 7 kg significantly improved blood sugar while reducing 24-h insulin secretion. For patients with established disease, weight loss lowered the risk of developing type 2 diabetes mellitus. Similarly, it improved glycemic control and insulin resistance. Moderate weight reduction benefits type 2 diabetes mellitus patients in several ways. Manson et al. (6,7) showed that modest weight loss significantly cut the risk of developing adult onset diabetes. Compared to women who maintained a steady weight, those with a 5-kg weight loss had a relative risk of 0.6. In a Wing et al. (47) study of 114 individuals with AODM, those who lost 6.9–13.6 kg (mean 9.9 kg), or 5% of their body weight, showed marked improvements in glycohemoglobin, fasting blood glucose, and insulin levels. At one year, the average hemoglobin A1c fell from 9.8–8.7%; fasting blood sugars decreased an average of 29 mg/dL (191–162); and fasting insulin dropped from 131 to 75. Of participants on oral hyperglycemics or insulin, more than 60% were able to reduce their dosages of medication after a loss of 9.9 kg, or 5% of their body weight. Even subjects who remained 42% above their ideal body weights attained these benefits. The more substantial the weight loss, the greater the positive impact. Obese patients who lost more than 13.6 kg through caloric restriction and increased physical activity enjoyed a decline in fasting blood sugars of over 70 mg/dL (from 186–109), a drop of almost 25% (from 9.7–7.1) in average hemoglobin A1c, and an 86% reduction in fasting insulin levels (41). Results from morbidly obese subjects who lost weight after gastric bypass surgery were even more impressive. A 14-yr study followed 330 preoperative type 2 diabetes mellitus patients with a mean postsurgical weight reduction of 100 lb. After surgery, over 90% of these individuals maintained normal fasting blood sugars and glycohemoglobins (47). Most of the improvements in glycemic control occur relatively early in the weight loss process (45). Henry et al. (48), in a study of subjects treated with a very-low-calorie diet (VLCD), reported that nearly 90% of the decrease in blood sugars took place within the first 10 days of a 40-d program. This occurred despite progressive weight loss during the remaining 30-d period. In the first 10 d, subjects lost an average of 5 kg, or less than 50% of their total weight loss at the study’s end. This disproportionate improvement in blood sugars relative to weight loss indicates that the primary reason for improved glycemic control, at least early on, was reduced caloric intake. Other research supports this view. For example, a Wall et al. (49) study of 200 obese subjects with type 2 diabetes mellitus showed that 80% of participants achieved good glycemic control with dietary restriction, and that the majority of them did so without appreciable weight loss. This strongly suggests that even modest weight loss when sustained by reduced caloric intake can have significant clinical benefits for obese patients with type 2 diabetes mellitus.

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4. HYPERTENSION Epidemiological studies have long linked obesity with hypertension (50,51). Likewise, they’ve demonstrated that weight loss ameliorates this complication. Of patients who took off more than 20% of their body weight with a VLCD, 71% showed significant improvements in blood pressure (52,53). This finding applied to both moderate and substantial weight loss. In a study of 170 obese men between the ages of 46 and 80, a 10% decrease in total body weight (average 9.5 kg) led to reductions in systolic and diastolic blood pressures of 8% and 7%, respectively. Those declines, in turn, were accompanied by significant drops in fasting glucose and insulin levels (54). The Trial of Antihypertensive Interventions and Management (TIAM) study showed that patients who lost as little as 4.5 kg experienced an 11.6 mm Hg drop in diastolic blood pressure (53). Obese women who took off 1 kg of weight reduced their blood pressure by 1.0 mm Hg. And over 60% of patients who had hypertension preoperatively resolved their high blood pressure with weight loss (54) after gastric bypass. Even though there is a link between the absolute amount of weight lost and the resolution of hypertension, subjects did not need to achieve ideal body weight to attain beneficial effects. According to follow-up results, subjects who were within 133–170% of their ideal body weights also realized resolution (53). Although it could be hypothesized that the weight reduction was associated with dietary modification, possibly including reduction in salt intake, positive results from weight loss are not linked to concomitant decreases in sodium intake (27). Maxwell et al. (24) compared two groups of obese hypertensive patients: those on a hypocaloric diet with typical sodium restriction (40 meq sodium), and those on a hypocaloric diet supplemented with sufficient sodium to maintain baseline intake. Sodium-restricted subjects had a slightly greater decrease in blood pressure during the first week of the study only; thereafter, the two groups showed identical blood pressure and weight reductions. Resolution of the hyperinsulinemic and hyperadrenergic states of Syndrome X may be one means by which weight loss lessens hypertension. Reduced weight, as we have seen, has been linked to decreases in insulin levels and SNS tone. A study of obese adolescents demonstrated parallel reductions in blood pressure and serum insulin concentrations along with weight loss (55). Maxwell et al. (56) also showed a correlation between decreases in insulin and norepinephrine as well as lower blood pressure and weight loss.

5. DYSLIPIDEMIA Multiple epidemiological studies link obesity to increases in serum lipid levels. Indeed, excess weight is typically associated with elevations in total cholesterol, LDL cholesterol, and triglycerides with decreased plasma HDL. A recent meta-analysis (57) of 70 studies revealed significant improvements in lipid profiles with weight loss. Every 1 kg decline in body weight reduced total cholesterol by 0.05 mmol/L (1.93 mg/dL), LDL-C by 0.02 mmol/L (0.77 mg/dL), and triglycerides by 0.015 mmol/L (1.33 mg/dL). During active weight loss, HDL cholesterol dropped by 0.009 mmol/L. But during weight loss maintenance, HDL cholesterol increased by 0.009 mmol/L (0.35 mg/dL) (57). A person losing 10 kg could thus expect decreases of 19.3 mg/dL in total cholesterol, 7 mg/dL in LDL cholesterol, and 13 mg/dL in triglycer-


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ides. During weight maintenance, he or she could also expect a 3.5 mg/dL increase in HDL cholesterol. As with hypertension and AODM, significant improvements in lipids can be gained with moderate weight loss. A recent study of 170 obese men between the ages of 46 and 80, showed that a 10% weight loss (average 9.5 kg) reduced triglycerides by 18% and LDL-C by 7%. It also increased HDL-C (57) by 1%.

6. CARDIOVASCULAR DISEASE Numerous reports demonstrate the beneficial effects of weight loss on coronary risk factors (35–40). As discussed in this chapter, weight loss clearly lessens hypertension and improves atherogenic lipid profiles. As noted earlier, weight loss reduces insulin resistance, hyperinsulinemia, and blood pressure. It also reduces fibrinogen levels. A study of 584 healthy obese individuals (BMI 25.1–71.0) showed a correlation between fibrinogen levels and increasing BMI and WHR (58). After an average 20.3 kg weight loss, those in the most obese subset (with a BMI > 42 kg/m2), had significantly reduced fibrinogen levels. Fanari et al. (59) achieved similar results in a study of 20 healthy obese adolescents. At the outset, the participants had elevated plasma fibrinogen levels when compared to lean controls. One month after initiating a hypocaloric diet, plasma fibrinogen was significantly down from the subjects’ basal values.

7. OTHER BENEFITS OF WEIGHT LOSS 7.1. Osteoarthritis The mechanisms involved in this heightened jeopardy for developing osteoarthritis in the obese patient are believed to be both mechanical and hormonal (59). Obesity quadruples the risk of osteoarthritis (OA) of the knees (60), and doubles it for OA of the hips (61). Effects of OA, which range from pain and decreased mobility to orthopedic surgery with total hip and knee arthroplasty, can significantly erode life quality. Every step a person takes puts approximately six times their body weight on the knees, and three times their body weight on the hips. Excess weight, which adds to the amount of stress borne by joints, leads to cartilage breakdown and erosion (62). Because obesity is also associated with an increased risk of OA in non-weight-bearing joints, such as the hand, it is possible that excess adipose tissue may produce a circulating factor that promotes cartilage breakdown or bone growth. The Framingham Study (63) detailed the OA-related benefits of weight loss. Results showed that weight change in women during their middle or later years affected the risk for subsequent symptomatic knee OA. For obese women (BMI > 25), the odds of developing symptomatic OA fell by more than 50% for every 2-U reduction (approximately 11 lb for women of normal height) in body mass. The greater the weight loss, the greater the benefit. Patients with established OA also profited from weight reduction. In a group of 105 morbidly obese subjects who underwent gastric stapling, weight loss led to a significant drop in joint pain. At one year, after an average 44 kg (96.8 lb) of weight loss, 89% of patients reported relief of lower back, hip, knee, ankle, and foot pain (64).

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7.2. Malignancy A strong link exists between obesity and cancer. The American Cancer Society’s 12-yr study of 750,000 individuals showed increased mortality from cancers of the endometrium, gallbladder, cervix, breast, and ovary in overweight women, and increased mortality from colorectal and prostate cancer in overweight men (65). Changes in the hormonal milieu are believed to be partly responsible for those findings. Specifically, the obese population is exposed to chronically high estrogen levels. This heightened exposure is due to the enzyme aromatase. Present in adipose cells, aromatase converts andrestendione (produced by the adrenal gland) to estrone. Evidence indicates that this persistent stimulation of breast and endometrial tissue by estrogenic compounds creates the predisposition to malignant transformation (66). Weight loss, however, may break this cycle by lowering aromatase levels, and thus, estrone production.

7.3. Sleep Apnea Obstructive sleep apnea is a major cause of disability and mortality in the obese population. Among the morbidly obese, it occurs at a 12- to 20-fold rate of frequency (67). This complication is characterized by loud snoring, nocturnal hypoxia, frequent awakening, and daytime somnolence. The disturbed and fragmented sleep of those who suffer from sleep apnea may impair daytime functioning. A sevenfold increase in automobile accidents among patients with obstructive sleep apnea (68) underscores this effect. Other sequelae of sleep apnea include cognitive impairment, personality changes, pulmonary hypertension, right-sided heart failure, polycythemia, and sudden death (69). Weight loss, however, can effectively reduce sleep apnea. The volume of fat adjacent to the pharyngeal airways is related to the number of apneas and hypopneas per hour of sleep. Weight loss, in turn, reduces the volume of pharyngeal fat and the degree of obstructive sleep apneic symptoms (70). A study of 12 patients treated with a VLCD, demonstrated that an average weight loss of 21 kg reduced hypopnic and apneic episodes. The amount of weight loss, however, did not correlate with the degree of improvement (71). Other studies have shown a lessening of obstructive sleep apnea with an average weight loss of 9.2 kg (72). In a group of patients who underwent gastric bypass surgery for morbid obesity (65–211% over ideal body weight), 40% completely resolved their sleep apneas, whereas 72% enjoyed a marked decrease in apneic episodes (72,73). Large weight losses are required to produce clinically relevant reductions in sleep apnea. Nevertheless, the seriousness of this condition warrants this.

8. CONCLUSION Although the medical repercussions of obesity are immense, the benefits of weight loss are equally profound. Evidence indicates that even mild to moderate weight reduction can mitigate and/or prevent insulin resistance, type 2 diabetes mellitus, hypertension, dyslipidemia, cardiovascular disease, osteoarthritis, malignancy, and sleep apnea (3,4). Along with L. Arthur Campfield (74), we propose a paradigm shift in the definition of obesity (75). Clearly, the state is one of metabolic dysfunction that includes insulin resistance or Syndrome X pathophysiology, increased sympathetic tone and hyper-


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estrogenemia. Indeed, much of the benefit from weight loss may derive from the restoration of a normal hormonal milieu or “metabolic fitness” (74,75). We have reviewed a substantial number of studies that support the benefit of weight management. These show that among the obese, metabolic disorders of insulin resistance and elevated SNS activity, together with multiple endocrine abnormalities along the hypothalamo-adrenal, gonadal, and growth hormone axes, are responsible for increased cardiovascular disease, hypertension, type 2 diabetes, and other comorbidities of obesity. Indeed, weight loss, with the consequent normalization of insulin sensitivity and sympathetic tone, may well reduce much of the morbidity associated with obesity. Similarly, weight loss and the subsequent resolution of a hyperestrogenemic state could lower the risk of breast and endometrial cancers. Bear in mind that individuals do not need to attain ideal body weight to derive the benefits of weight loss. Moderate reductions of 5–10% bring substantial medical advantages. That being so, it is imperative to encourage patients at risk of morbidity, disability, and mortality from obesity to strive for moderate weight loss rather than ideal body weight and to aim for what may be a more achievable goal and a more sustainable weight. The documented role of weight loss in the reduction of obesity-related morbidity (3–7,11), provides an urgent impetus for increased medical awareness and intervention. Obesity treatment suffers from a high recidivism rate, especially among individuals with a long history of weight cycling. Because 95% of patients return to their prediet weight within 5 yr, we need to consider new and innovative approaches to weight loss (76). Examples include the adjunctive use of long-term pharmacologic management of obesity. Weintraub in 1992 showed that a low-dose combination of d,l-fenfluramine and phentermine maintain moderate weight loss for up to 3–1/2 years (77). However, this combination appetite suppressant was withdrawn from the United States’ market in September 1997 after reported concern of its association with valvular heart disease (78,79). To date, sibutramine is the only appetite suppressant approved by the Food and Drug Administration (FDA) for treatment of obesity (3). Sibutramine is a serotonergic and noradrenergic reuptake inhibitor, which has been shown to achieve a 5% or greater reduction in body weight, decreases in plasma triglycerides, total cholesterol, LDL cholesterol, and improved glycemic control (80–82). XENICAL® (orlistat) (Hofmann-LaRoche, Basel, Switzerland) is the first nonappetite suppressant approved in Europe and pending approval by the FDA in the United States for treatment of obesity (83). It is a pancreatic lipase inhibitor that decreases triglyceride digestion and induces weight loss (84,85). For intractable (severe and morbid) obesity that fails to respond to medication, restrictive gastric surgeries represent another adjunctive approach (86). Still, the best treatment for obesity is prevention—a trend that can be fostered through public education, heightened awareness of what constitutes a healthy lifestyle, and the promotion of paradigms that feature sound nutritional choices, dietary restraint, physical activity, and regular exercise (3–7,87,88).

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Chapter 11 / Obese Patients with BED

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Obese Patients with Binge-Eating Disorder Marsha D. Marcus

1. INTRODUCTION The subgroup of obese individuals who have persistent and frequent problems with binge eating has been the focus of substantial attention in the obesity and eating-disorders literature (1,2). Although early research suggested that binge eating was associated with attrition and poorer outcome in obesity treatment programs (2,3) this has not been confirmed by more recent studies (4–8). These conflicting data raise the question of how best to treat this group of patients. This chapter describes binge eating among obese individuals and examines findings that relate to its treatment in overweight patients in order to provide recommendations for treatment (Table 1). Although the phenomenon of binge eating as a problem seen in obesity was described in the late 1950s (9), binge eating began to receive systematic attention only in the 1980s (10,11). Proposed diagnostic criteria for binge-eating disorder (BED) were subsequently developed and evaluated by Spitzer and colleagues in two field trials (12,13). The Spitzer et al. investigations led to the inclusion of BED in the Diagnostic and Statistical Manual of the American Psychiatric Association—Fourth Edition (DSM-IV) as a proposed diagnostic category requiring further study and as an example of an eating disorder not otherwise specified (ED NOS) (14). Binge-eating disorder is characterized by regular episodes of binge eating (the ingestion of large amounts of food with an associated sense of loss of control over when, what, or how much one is eating) without the regular compensatory behaviors (purging, fasting, or excessive exercise) that are seen in bulimia nervosa (14) (see Chapters 1–4 for additional information on bulimia nervosa). Binge episodes are associated with rapid eating, eating until uncomfortably full, eating large amounts when one is not hungry, eating alone because of embarrassment over the amount eaten, or feeling disgusted, depressed, or guilty after overeating (14). Binge-eating disorder is common among individuals seeking treatment for obesity and affects as many as 30% of these individuals (12), but it is much less common in the general population. Available evidence has indicated that the disorder occurs in about 2% of the population, but in as many as 8% of obese individuals (15). Binge-eating disorder occurs in women and men in a ratio of about 3:2, and similar rates of BED have been observed in nonwhite and white individuals (16,17). There is a strong association between severity of binge eating and degree of obesity (12,13). For example, Telch et al. (18) found a linear From: The Management of Eating Disorders and Obesity Edited by: D. J. Goldstein © Humana Press Inc., Totowa, NJ

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Part II / Anorexia Nervosa Chapter 1 Chapter Overview 1. Introduction 2. Differences Between Obese Individuals With and Without BED 3. Eating-Disorder Treatments for BED 3.1. Cognitive Behavior Therapy 3.1.1. First Phase of Treatment 3.1.2. Second Phase of Treatment 3.1.3. Third Phase of Treatment 3.2. Interpersonal Therapy 4. Pharmacotherapy of BED 4.1. Antidepressant Treatment 4.2. Opioid Antagonists 4.3. Anorectic Agents 5. Weight-Loss Programs 6. Selection of Treatment for Specific Patients 6.1. Eating Disorder and Obesity History 6.2. Psychiatric Status 6.3. Available Resources 7. Summary

relationship between body mass index (BMI) and prevalence of binge eating in a group of individuals seeking obesity treatment, with 40% of individuals with a BMI between 31 and 42 reporting clinically significant binge problems. Little is known about the course of BED, but the disorder appears to be fluctuating and chronic. Fichter and colleagues (19) recently reported on the course and outcome of 68 BED patients who had received intensive inpatient treatment. They found that the course of BED patients closely resembled that of bulimia nervosa patients treated in their center. Specifically, 57.4% had good outcome, 35.3% intermediate outcome, 5.9% poor outcome, and 1.4% died. Although, the course was benign for a significant number of patients, more than half of the patients with no DSM-IV eating disorder at 6-yr follow-up were obese (BMI * 30), and more than half of the total sample reported a mood disorder.

2. DIFFERENCES BETWEEN OBESE INDIVIDUALS WITH AND WITHOUT BINGE-EATING DISORDERS It is important to consider whether obese individuals with BED should be treated differently than those without binge-eating problems. To do so, the differences between obese patients with and without binge-eating disorder will be reviewed. A substantial body of research has shown consistently that BED is associated with eatingdisorder psychopathology, factors related to obesity such as weight fluctuations, and psychiatric symptoms. When compared with equally overweight individuals without binge-eating problems, BED patients report markedly less control over eating, more fear of weight gain, preoccupation with food, and body dissatisfaction (20). BED patients also have a strong desire to lose weight and continually struggle to gain control over eating-related problems (3). Indeed, obese patients with BED report levels of eating disorder symptomatology that are


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comparable to those of normal-weight patients with bulimia nervosa (21). Compared to patients with bulimia nervosa, however, BED patients do not report elevated levels of dietary restraint, i.e., they often do not succeed in limiting calorie intake between binge episodes, and they do not report overvalued ideas about the importance of extreme thinness (21). Available laboratory data have confirmed that compared to their equally overweight peers, BED patients ingest more calories both at regular meals and when directed to eat as much as possible (22,23). Findings from studies that have utilized food diaries also have indicated that BED patients report higher calorie intakes than nonbinge eaters on both binge days and nonbinge days (24). Thus, it appears that BED patients tend to overeat both during and between episodes of binge eating. Perhaps, because individuals with BED report periods of marked dyscontrol over eating, they also report earlier onset of obesity, more frequent episodes of dieting, marked weight fluctuations, and more severe obesity than those without binge-eating problems. The clinical picture in BED is often one of numerous periods of relative control over eating, or weight loss during periods of successful calorie restriction, and periods characterized by binge eating, overeating, and weight gain (1). It is hard to overestimate the distress associated with BED, and a large body of evidence has confirmed that the disorder is associated with considerable psychological morbidity. Binge-eating disorder patients consistently have endorsed high levels of psychiatric symptomatology, particularly depression and anxiety (25,26). BED patients also have high rates of diagnosable psychiatric disorder. When compared with weight-matched individuals without binge-eating problems, individuals with BED report significantly higher lifetime prevalence rates of major depressive disorder and anxiety disorders (27,28). Higher rates of personality disorders also have been reported (27,29). Comorbid psychiatric symptomatology has been found to covary with severity of binge eating when patient weight is controlled; therefore, high rates of psychiatric symptoms appear to be related to disordered eating rather than obesity itself (30).

3. EATING-DISORDER TREATMENTS FOR BINGE-EATING DISORDERS Because investigations comparing obese binge eaters and nonbinge eaters consistently have confirmed marked between-group differences and because BED patients resemble other eating-disorder patients, treatments found to be efficacious in the treatment of other eating disorders have been utilized in the treatment of BED. Data from randomized clinical trials have shown that cognitive behavior therapy and interpersonal therapy significantly affect eating-disorder behavior in BED patients.

3.1. Cognitive Behavior Therapy The best studied treatment for BED is cognitive behavior therapy (CBT), and thus eating-disorder specialists consider CBT to be the frontline treatment for these patients. Cognitive behavior therapy was developed as a treatment for bulimia nervosa (31), and has been adapted for the treatment of both anorexia nervosa and BED (32). The treatment is based on strategies developed by Beck and colleagues (33) for the treatment of depression, in combination with behavioral weight and eating-management skills. CBT is based on a clearly specified model of the maintenance of binge-eating behavior. Specifically, a cognitive-behavioral model of binge eating posits that maladaptive beliefs and attitudes

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about eating, shape, and weight perpetuate a cycle of efforts to diet, repeated disruptions of dietary restraint, and aberrant overeating (31). The model is supported by a substantial body of work that has shown habitual dietary restraint (i.e., stringent rules related to the control of calorie intake despite physiological pressures to eat) is associated with a vulnerability to periodic overingestion of food (34,35). Data from numerous controlled trials of the treatment of bulimia nervosa have shown that CBT is more effective than waiting-list or no-treatment control groups, whose binge frequency tends to remain stable or increase over time (20). Bulimia nervosa patients treated with CBT have shown mean reductions of binge eating from 73% to 93%, and remission rates of 51–71% (36–41). Because of its efficacy in the treatment of bulimia nervosa, CBT has been adapted for the treatment of BED (32). Modifications of CBT for BED patients include inclusion of a program of regular exercise, targeting overeating as well as the tendency to restrict dietary intake, and promotion of acceptance of a larger-than-average body size (1). Initial work has shown that CBT is effective in ameliorating binge-eating and eating-disorder psychopathology in BED patients with episode reductions of 70–80% (42–44). A detailed manual has been published that includes the adaptations for BED patients (32). Treatment consists of approximately 22 sessions over a 6-mo period, and patients are seen in 60-min sessions. Both group and individual formats have been utilized in research investigations, but there have been no controlled trials comparing the outcome of individual vs group therapy. Thus, the decision to use one or the other format should be dictated by clinician preference and practical considerations. The primary goal of CBT is the amelioration of binge eating and the maladaptive thoughts and beliefs that accompany disordered eating. Treatment is semistructured, problem-oriented, and present-focused. The patient assumes primary responsibility for change, and the therapist provides information, guidance, and support. As in the treatment of bulimia nervosa, BED patients are told that the primary goal of treatment is the normalization of eating. It is important to note that CBT treatment may not lead to weight loss. Although some patients may lose weight with abstinence from binge eating (4,42), other investigations have shown that elimination of binge episodes does not, on average, lead to weight loss (6,43). Agras and colleagues (45) reported 1-yr follow-up data on 93 obese patients who were treated with cognitive behavior therapy followed by behavioral weight loss. These data indicated that those patients who achieved abstinence from binge eating during initial treatment lost 4 kg over the year follow-up. In contrast, patients who did not stop binge eating during the initial period of CBT gained 3.6 kg over the year posttreatment. They concluded that abstinence from binge eating is a critical prelude to weight loss in BED patients. Patients with BED have difficulties in moderating food intake in combination with maladaptive beliefs about dieting, shape, and weight; that is, they may have forbidden foods and stringent beliefs about restricting (11), coupled with an inability to actually restrict intake. Accordingly, BED patients are instructed that normalization of eating involves learning to say no to food (i.e., to binge eating, over eating, and chaotic eating), as well as learning to say yes to food (i.e., to healthy and moderate consumption of all foods). Three stages of treatment (Table 2) can be distinguished as follows. 3.1.1. FIRST PHASE OF TREATMENT The first phase of treatment consists of eight weekly sessions. The goals of the first stage are to (1) provide information about binge eating and obesity, (2) disrupt the


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Table 2 Cognitive Behavior Therapy Program for Binge-Eating Disorder Phase 1. Treatment Initiation—Eight Weekly Sessions Goals 1. Provide information about binge eating and obesity 2. Disrupt disordered eating patterns and regain control over eating 3. Initiate exercise program Tools 1. Self-monitoring Record all foods and beverages ingested Note all episodes of binge eating Record thoughts and feelings before, during, and after eating 2. Identification and practice of alternative behaviors 3. Goal setting 4. Stimulus control techniques (e.g., not buying high-risk foods) Phase 2. Congnitive Restructuring—Eight Weekly Sessions Goals 1. Identification and modification of maladaptive thoughts and beliefs 2. Learn and practice problem-solving skills Phase 3. Termination and Maintenance of Change-Six Sessions over 2 Months Goals 1. Promote body acceptance Identify positive role models Encourage body enjoyment (e.g., exercise) Decrease social avoidance due to body size 2. Development of maintenance plan Anticipate future difficulties and identify high-risk situations Develop restart plan to minimize consequences of setbacks

disordered eating pattern and regain control over eating, and (3) begin a regular program of exercise. Patients are provided with information about the nature of disordered eating, weight regulation, and the importance of a pattern of regular and healthful eating. The role of unrealistically strict dieting in perpetuating binge eating is emphasized and principles of sound nutrition are introduced. As in the treatment of bulimia nervosa, patients are told that maladaptive thoughts about dieting, shape, and weight play a critical role in maintaining eating problems. In BED, however, it is often the contrast between maladaptive thoughts and stringent beliefs (e.g., “I should never eat more than 1200 calories a day”), and actual eating behavior (e.g., daily intake in excess of 2500 cal) that contributes to feelings of shame and hopelessness and perpetuates disordered eating. A variety of behavioral strategies are utilized to help patients establish normal eating, but the introduction of self-monitoring is of particular importance. Patients are taught to record all food and beverages ingested and to indicate which eating episodes were felt to be binges. They also record time of eating, place where the food was consumed, and the thoughts and feelings before, during, and after eating. Diaries are used to identify the specific context of binge behavior and to examine the functions of binges, as well as the factors serving to maintain binge eating. The therapist and patient then work together to identify

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alternative behaviors or solutions suited to the individual. Self-monitoring, stimulus control techniques, reasonable goal setting, and feedback are utilized to help each patient manage his or her eating behavior. Finally, exercise is introduced as both a tool to self-manage tension and stress and as a critical tool for long-term weight management (46). Patients are directed to begin a regular program of walking (bicycling or swimming may be substituted for patients who cannot walk) and are provided with stepwise goals for increasing exercise up to 45 min three to five times per week. The recommendations for physical activity are consistent with those made by the Centers for Disease Control and Prevention and the American College of Sports Medicine for all Americans (47). 3.1.2. SECOND PHASE OF TREATMENT The second phase of treatment also consists of eight weekly sessions. It is more cognitively oriented, and a major goal is to identify and modify maladaptive thoughts and beliefs that perpetuate the eating problem. Examples of dysfunctional beliefs among BED patients are often associated with obesity and include acceptance of negative societal attitudes about obese individuals (e.g., large people have no self-discipline), belief in the necessity of stringent dieting to control weight, and extreme body-image disparagement (e.g., obese individuals are disgusting). During the second phase of treatment, patients are also taught problem-solving techniques in order to cope more effectively with life circumstances and moods that lead to binge eating. 3.1.3. THIRD PHASE OF TREATMENT During the final six sessions of treatment, termination is anticipated and maintenance of change is emphasized. Patients are encouraged to take the initiative for structuring the content of the sessions and to continue problem solving and cognitive restructuring as the therapist decreases his or her involvement. In this phase, there is also an emphasis on working to help the patient to accept a larger-than-average body size. The goal is to promote recognition that a larger body can be both attractive and healthy (an ongoing emphasis on physical activity is also helpful in promoting body acceptance). Patients are encouraged to dress well at their current size in order to promote feelings of self-confidence, to identify attractive large individuals as positive role models, and to identify and enjoy positive aspects of their bodies. Therapists also work to help patients identify social situations that they have avoided because of body size, and focus on decreasing weightrelated social anxiety. Finally, patients are taught to anticipate future difficulties, particularly at stressful times, and are helped to develop a maintenance plan to be consulted if eating problems recur. Following Marlatt and Gordon (48), patients are taught relapse-prevention techniques designed to aid in identifying and avoiding high-risk situations and for minimizing consequences of setbacks (i.e., an immediate return to normal eating coupled with an avoidance of negative thoughts). Patients are taught to view setbacks as an opportunity to learn more about their eating behavior with a view toward preventing future problems.

3.2. Interpersonal Therapy Not all BED patients benefit from CBT, and some patients resist a symptom-focused approach to treatment. Recent work has demonstrated convincingly that it is not necessary to target specific behaviors to effect improvement in disordered eating. Another


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short-term psychotherapy, interpersonal therapy (IPT), appears to be effective in the treatment of normal weight eating-disorder patients (39,49). Interpersonal therapy was initially developed for the treatment of depression and its effectiveness has been extensively reported (50). Interpersonal therapy subsequently was adapted for use in the treatment of bulimia nervosa (51). Fairburn et al. found that bulimia nervosa patients treated with CBT or IPT showed equivalent and substantial improvements on all outcome measures at 1-yr follow-up (39). The rationale for the use of IPT in the treatment of disordered eating is that interpersonal factors appear to play a major role in its maintenance and improvement in interpersonal functioning will lead to the amelioration of aberrant eating behavior. Thus, an initial goal of treatment is to identify interpersonal issues that impact on self-esteem, mood, and the onset and maintenance of the eating problem. Once this framework is established, IPT proceeds exactly as it is utilized in the treatment of depression, that is, the treatment focuses on the interpersonal context, not the eating disorder. As has been the case with CBT, favorable findings regarding the use of CBT in the treatment of bulimia nervosa have led to its use in the treatment of BED. Wilfley et al. (52) reported that IPT delivered in a group format was as effective as CBT in reducing binge eating in BED patients both at posttreatment and 1-yr follow-up. Neither approach was associated with weight loss in this investigation. Although further research is needed, it appears that IPT may be a useful alternative for BED patients who do not want a symptom-focused treatment or who fail to benefit from CBT. Further, it may be that a combination of CBT and IPT may be useful in treating some BED patients. For example, Agras and colleagues (53) examined whether IPT would enhance the treatment outcome of BED patients who did not respond to CBT. The addition of IPT did not lead to further symptom reduction among patients in this investigation, but it may be that longer or individual treatment would demonstrate an advantage for combined treatment. In summary, two semistructured, short-term psychotherapeutic approaches have demonstrated efficacy in the treatment of BED; neither eating-disorder approach, however, is associated with significant weight loss. Moreover, BED appears to be a chronic and fluctuating disorder, and there are, as yet, no long-term outcome data relating to either CBT or IPT. Nevertheless, given the marked distress associated with BED, the availability of interventions that yield significant improvements for as long as 1-yr posttreatment is an important first step.

4. PHARMACOTHERAPY OF BINGE-EATING DISORDERS 4.1. Antidepressant Treatment There is a large and consistent literature that has shown that antidepressant treatment is superior to placebo in ameliorating binge-eating and purge behaviors in bulimia nervosa (see Chapter 3 for a summary of treatment of bulimia nervosa with medications) (54). Unsurprisingly, because of the similarities between BN and BED, researchers have begun to study the efficacy of antidepressant treatment in BED. McCann and Agras (55) reported that desipramine treatment (100–300 mg/d) was effective in moderating binge eating in a group of binge eaters in a 12-wk, double-blind placebo-controlled trial. In another double-blind trial (56), fluvoxamine (50–300 mg/d for 9 wk) was significantly superior to placebo in reducing binge eating in patients with BED. In a third study (57), 8 wk of imipramine treatment (150–200 mg/d) was not superior to placebo in reducing

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binge episodes among obese binge eaters (both imipramine- and placebo-treated groups showed significant reductions in binge frequency), but the treatment was associated with significant decreases in the duration of episodes. Thus, short-term investigations have shown that antidepressant treatment is associated with moderate reductions in binge eating over a 2–3 mo period. There has been only one study to date of antidepressant treatment in combination with other modalities in the treatment of BED (4). This study indicated that desipramine plus CBT and weight-loss therapy did not yield greater reductions in binge eating among BED patients than CBT and weight-loss therapy alone after 9 mo of treatment. Three months after treatment, however, desipramine treated patients had lost significantly more weight than those who did not receive medication. Data from weight-loss studies that have included both binge eaters and nonbinge eaters also have suggested that fluoxetine treatment may be useful in treating obesity in BED patients. For example, in a year-long double-blind trial of fluoxetine (60 mg/d) vs placebo in the treatment of obese individuals with and without binge eating problems, fluoxetinetreated patients lost significantly more weight than did placebo treated patients (58). The effects of drug treatment on binge eating were not directly assessed in this investigation, but self-reported bulimic symptoms improved equally among binge eaters treated with either fluoxetine or placebo. Findings that suggest that antidepressant treatment may enhance weight loss in obese binge eaters require systematic investigation. It may be that antidepressant treatment serves to enhance dietary restraint in BED patients (59), or may improve compliance to a weight loss program (4,58). Antidepressant treatment also may be useful in treating depression associated with BED, although most studies have not shown significant effects of antidepressant treatment on depressive symptoms in BED patients (4,55,58). In contrast, de Zwaan and colleagues (60) evaluated obese binge and nonbinge eaters treated with dietary management or CBT, and either fluvoxamine (100 mg/d) or placebo. Fluvoxamine treatment was not associated with greater weight loss in either binge eaters or nonbinge eaters, but was more effective than placebo in reducing depressive symptoms among binge eaters. Despite the fact that current support for the effects of antidepressant treatment on depressive symptoms in BED is weak, the utility of antidepressant treatment for depression in BED deserves further investigation. It is possible that long-term antidepressant treatment may help break into the negative mood, binge eating, and weight gain cycle that characterizes BED. Approximately half of BED patients report a lifetime history of major depressive disorder (27,28), and individuals seeking treatment report significant depressive symptomatology (6,25,26). Obese individuals may be especially likely to report weight gain and decreases in activity when depressed (61). Furthermore, weight gained during episodes of depression can be considerable; for example, in one study, the average weight gain during a depressive episode was more than 17 lb (62). The tendency to gain or lose weight during depression is consistent across episodes (61), and because depression is often recurrent, it is not hard to see that weight gain associated with mood disorder can contribute to obesity in BED patients. Thus, it seems possible that long-term antidepressant treatment may be useful for at least some BED patients. Until there is more research available to guide clinical decision making, the risks and benefits of antidepressant treatment can be considered on a case-by-case basis.


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4.2. Opioid Antagonists In a laboratory study, Drewnowski et al. (63) have shown that the opiate blocker naloxone suppressed the intake of high-fat, sweet foods in obese binge eaters but not in obese nonbinge eaters. These investigators reasoned that opiate blockade reduces food reward, and may thus ameliorate the heightened preference for sweet, high-density foods among binge eaters. In a single case study, Marrazzi and colleagues (64) reported that naltrexone treatment at 200 mg and 400 mg was superior to placebo. However, in an 8-wk double-blind trial of naltrexone (100–150 mg/d) vs placebo (57), drug treatment did not lead to differential reductions in binge eating or weight among obese binge eaters. Future studies using opiate blockers may enhance our understanding of the neurobiology of binge eating, but available data do not support the clinical use of these agents.

4.3. Anorectic Agents Stunkard and colleagues (65) assessed the utility of the appetite suppressant d-fenfluramine in the treatment of BED in an 8-wk double-blind placebo-controlled trial. They found that binge eating decreased significantly in the d-fenfluramine treated group. Among the 10 patients who had adequate blood levels of d-fenfluramine, 8 were bingefree at the end of the study. However, after reports that anorexic drugs were associated with the development of primary pulmonary hypertension (66,67) and heart-valve problems, fenfluramine and dexfenfluramine were withdrawn by the Food and Drug Administration. Further research is needed to determine if newer anorectic agents such as sibutramine or orlistat have utility in the treatment of BED. In summary, available research findings suggest a role for antidepressants in the treatment of BED, but further evidence is necessary before firm conclusions can be drawn. Additional trials over longer periods of time and utilizing other agents are needed. The role of antidepressant treatment in conjunction with other modalities (e.g., CBT and IPT) requires further study, as do the effects of antidepressant treatment on BED-associated depression. There are few data on the use of anorectic agents in treating BED, and careful consideration of the risk–benefit ratio on a patient-by-patient basis is indicated until more information is available. The use of drugs, in any event, should be considered as only one aspect of either weight-control or eating-disorder-treatment.

5. WEIGHT LOSS PROGRAMS The issue of obesity treatment is a critical one for BED patients. Almost all BED patients want to lose weight and have persistent concerns about obesity. We know, however, that there is considerable evidence that weight lost through dieting is frequently regained (most BED patients have had numerous experiences with this) and that sustained weight change involves a permanent modification of eating and exercise patterns (68). It is precisely these sustained changes that BED patients typically have been unable to accomplish. Finally, there is ongoing concern that dieting or repeated bouts of weight loss and regain may be particularly deleterious for individuals with BED. Although there is ample evidence that chronic calorie restriction and dieting is undesirable for normal weight individuals (1), recent studies have documented that, in contrast to earlier reports, calorie restriction and weight loss does not exacerbate binge eating in BED patients (4–8). Participation in weight control programs appears to improve binge eating and mood in BED patients (6). Moreover, weight regain in BED patients does not

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appear to be associated with worsening of mood or binge eating (6). In addition, recent reviews of the empirical evidence have concluded that concerns about the potentially deleterious effects of dieting (69) or weight cycling (70) should not deter obese individuals from weight-control efforts. Finally, although obesity is associated with increased risks for heart disease, diabetes, and other diseases, it is not necessary to achieve large weight losses to improve risk factors. There is substantial evidence that sustained weight losses of about 10% of initial body weight can lead to significant improvements in modifiable risk factors such as lipids and blood sugar levels (71). The strongest evidence that weight control does not harm individuals with BED is results from a study conducted at our center (6). We directly compared cognitive behavior therapy for binge eating and behavioral weight control in the treatment of BED. In this study, 115 obese women with BED were randomized to 6-mo of individual CBT for binge eating, 6-mo of individual standard behavioral weight control with moderate calorie restriction (1200–1500 cal/d), or a 6-mo delayed-treatment control group. Attrition from the treatment program was approximately 30%, but dropouts were evenly distributed between treatments. Posttreatment and 1-yr follow-up assessments indicated that for individuals who completed treatment, CBT and behavioral weight control were equally effective in ameliorating binge eating and associated eating-disorder psychopathology in BED patients. However, in contrast to patients treated with CBT who remained weight stable, those who received behavioral weight control lost significant amounts of weight (an average of 21.6 lb at the completion of treatment). At 1-yr follow-up, weight-control patients had regained a significant amount, but overall weight loss remained significant (an average of 13.2 lb).

6. SELECTION OF TREATMENT FOR SPECIFIC PATIENTS In summary, available evidence has shown that treatments focusing either on disordered eating or on obesity can help individuals with BED regain control over eating and reduce eating-disorder psychopathology. Clearly, however, no available treatment approach is effective for all patients, and at this time, it is not possible to predict which therapy will be most effective for a particular individual. Although it may be that longterm evaluation of treated patients will demonstrate the superiority of one form of treatment over another, future research is needed to provide data that will guide treatment selection. For example, there is preliminary evidence that earlier-onset binge eaters may have a more severe variant of an eating disorder (72). Individuals who participated in the treatment study at our center (described above) were stratified into two groups, those who reported onset of binge- eating by age 18 and those who first had binge-eating problems after age 18. Results indicated that those in the earlier-onset group had an early onset of obesity and dieting, higher levels of eating-disorder psychopathology, and were likelier to report a lifetime history of bulimia nervosa and mood disorder. Although it is not known whether such factors reflect differing etiologies or response to treatment, such findings may have implications for management (e.g., it may be that early-onset patients will benefit from antidepressant treatment). Thus, it is to be hoped that future research will provide both treatment alternatives and data that will be useful in decision-making for individual patients. Until there is such information, individual clinicians and patients must decide on a course of treatment that


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may include eating-disorder treatment or a weight-loss program with or without adjunctive drug treatment. Decisions must be based on careful assessment of individual cases by the clinician or treatment team, and a thorough discussion of the pros and cons of available treatment options with each patient.

6.1. Eating Disorder and Obesity History A history of early onset of binge eating or obesity in combination with numerous bouts of weight loss and regain over time suggest a course of CBT to treat the eating disorder. Weight-loss programs for these patients may be indicated after CBT, but careful consideration of the risks and benefits of such an endeavor is recommended. It is important for each individual to evaluate the likelihood that they will be able to sustain lifelong changes in eating and exercise, as well as the consequences of weight regain on their sense of wellbeing. Some patients report that they no longer wish to diet because of repeated failures to sustain improvements. In these instances, eating-disorder treatment is clearly the treatment of choice, and patients can be reassured that significant improvements in the aberrant eating and eating-disorder psychopathology associated with BED can be obtained without weight loss. Anecdotal clinical evidence has indicated that patients who report adult-onset binge eating and obesity and do not have a history of marked weight fluctuations may be likelier to benefit from a weight-control approach. Again, in the absence of research support, a decision to focus on treatment of obesity in a patient with BED should be made only after a discussion of all treatment options.

6.2. PSYCHIATRIC STATUS Given the high psychiatric comorbidity in BED, a careful psychiatric assessment is important for all patients who seek treatment. Although mild or even moderate depression or anxiety is likely to improve during BED treatment, the presence of marked or severe current illness suggests primary treatment of the mood or anxiety disorder prior to treatment for BED. Similarly, the presence of personality disorders characterized by emotional, dramatic, or impulsive behavior may be a negative prognostic factor for BED treatment. Finally, patients with comorbid psychiatric disorder may be particularly likely to benefit from adjunctive pharmacotherapy that targets the psychiatric symptomatology.

6.3. Available Resources Clinicians trained in the use of CBT or IPT for eating disorders are likely to be found in most metropolitan areas but may not available in smaller cities or rural areas. Some insurance plans may pay for obesity treatment where there is a clear medical indication (e.g., hypertension or other cardiovascular risk) and may not pay for eating-disorder treatment. Thus, treatment decisions may need to be made on the basis of pragmatic factors such as clinician availability or patient insurance plan.

7. SUMMARY In summary, BED is a chronic disorder with a fluctuating course that is common among obese individuals who seek treatment. BED patients differ in robust ways from individuals without binge-eating problems in weight and eating history, eating behavior,

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and psychiatric profile. Nevertheless, available research indicates that most BED patients can be helped with either weight-control or eating-disorder treatment and that the benefits of either approach are apparent for at least a year posttreatment. More research is necessary to improve outcome and to provide strategies for long-term management of these patients.

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50. Klerman GL, Weissman MM, Rounsaville BJ, Chevron, ES. Interpersonal Psychotherapy of Depression. Basic Books, New York, NY, 1984. 51. Fairburn CG. Interpersonal psychotherapy for bulimia nervosa. In: Klerman GL, Weissman MM, eds. New applications of interpersonal psychotherapy. American Psychiatric Press, Washington, DC, 1994. 52. Wifley DE, Agras WS, Telch CF, Rossiter EM, Schneider JA, Cole AG, et al. Group cognitive-behavioral therapy and group interpersonal psychotherapy for the nonpurging bulimic individual: a controlled comparison. J Consult Clin Psychol 1993; 61:296–305. 53. Agras WS, Telch CF, Arnow B, Eldredge K, Detzer MJ, Henderson J, et al. Does interpersonal therapy help patients with binge eating disorder who fail to respond to cognitive-behavior therapy? J Consult Clin Psychol 1995; 63:356–360. 54. Walsh BT, Devlin MJ. Pharmacotherapy of bulimia nervosa and binge eating disorder. Addict Behav 1995; 20:757–764. 55. McCann UD, Agras WS. Successful treatment of nonpurging bulimia nervosa with desipramine: a double blind, placebo-controlled study. Am J Psychiatry 1990; 147:1509–1513. 56. Hudson JI, McElroy SL, Raymond NC, Crow S, Keck PE, Jonas JM. Fluvoxamine treatment of binge eating disorder: a multicenter, placebo-controlled trial. In: Proceedings of the American Psychiatric Association, 1995, p. 218. 57. Alger SA, Schwalberg MD, Bigaouette JM, Michalek AV, Howard LJ. Effect of a tricyclic antidepressant and opiate antagonist on binge-eating behavior in normoweight bulimic and obese, binge-eating subjects. Am J Clin Nutr 1991; 53:865–871. 58. Marcus, MD, Wing RR, Ewing L, Kern E, McDermott M, Gooding W. A double blind, placebocontrolled trial of fluoxetine plus behavior modification in the treatment of obese binge-eaters and nonbinge-eaters. Am J Psychiatry 1990; 147:876–881. 59. Craighead LW, Agras WS. Mechanisms of action in cognitive-behavioral and pharmacological interventions for obesity and bulimia nervosa. J Consult Clin Psychol 1991; 59:115–125. 60. DeZwaan M, Nutzinger DO, Schoenbeck G. Binge eating in overweight women. Compr Psychiatry 1992; 33:256–261. 61. Stunkard A, Fernstrom M, Price A, Frank E, Kupfer D. Direction of weight change in recurrent depression. Arch Gen Psychiatry 1990; 47:857–860. 62. Weissenburger J, Rush A, Gilles DE, Stunkard AJ. Weight change in depression. Psychiatry Res 1986; 17:275–283. 63. Drewnowski A, Krahn DD, Demitrack MA, Nairn K, Gosnell BA. Naloxone, an opiate blocker, reduces the consumption of sweet high-fat foods in obese and lean female binge eaters. Am J Clin Nutr 1995; 61:1206–1212. 64. Marrazzi MA, Markham KM, Kinzie J, Luby ED. Binge eating disorder: response to naltrexone. Int J Obes 1995; 19:143–145. 65. Stunkard A, Berkowitz R, Tanrikut C, Reiss E, Young L. D-Fenfluramine treatment of binge eating disorder. Am J Psychiatry 1996; 153:1455–1459. 66. Abenhain L, Moride Y, Brenot F, Rich S, Benchou J, Kurz X, et al. Appetite suppresant drugs and the risk of primary pulmonary hypertensions. N Engl J Med 1996; 335:609–616. 67. McCann UD, Seiden LS, Rubin LJ, Ricaurte GA. Brain serotonin neurotoxicity and primary pulmonary hypertension from fenfluramine and dexfenfluramine. JAMA 1997; 278:666–672. 68. NIH Technology Assessment Conference Panel. Methods for voluntary weight loss and control. Ann Intern Med 1992; 116:942–994. 69. French SA, Jeffery RW. Consequences of dieting to lose weight: effects on physical and mental health. Health Psychol 1994; 13:195–212. 70. National Task Force on the Prevention and Treatment of Obesity. Weight cycling. JAMA 1994; 272:1196–1202. 71. Atkinson, RL. Proposed standards for judging the success of the treatment of obesity. Ann Intern Med 1993; 119:677–680. 72. Marcus MD, Moulton MM, Greeno CG. Binge eating onset in obese patients with binge eating disorder. Addict Behav 1995; 20:747–756.

Chapter 12 / Overview and Future of Obesity Treatment

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Overview and the Future of Obesity Treatment John P. Foreyt and Walker S. C. Poston II

1. INTRODUCTION The focus of this chapter will be to address the future of obesity treatment. After a brief background related to the importance of obesity treatment owing to the socioeconomic and personal costs, we briefly review the effectiveness of current interventions so that we can assess the past and present of obesity treatment. We then examine current issues and controversies that we believe will affect the future of obesity treatment, including the changing definition of obesity, whether short-term changes in weight and normalization of comorbid conditions translate into long-term improvements in health, the cost-effectiveness and feasibility of long-term treatment to improve maintenance of weight loss, the shift toward more comprehensive health models in obesity treatment, and promising directions in the prevention of obesity. Table 1 provides an overview of the organization of the chapter.

1.1. Social, Economic, and Personal Costs of Obesity Obesity is epidemic in the United States. The current age-adjusted prevalence is 19.5% for men and 25% for women, which represents greater than a 40% increase over the last decade (1). African-American and Mexican-American women face an even more alarming picture, as over 60% meet the current definition for overweight (body mass index [BMI] * 25, even after adjustment for age (1). Obesity is associated with increased risk for numerous medical problems and health hazards, including hypertension, dyslipidemia, coronary heart disease, noninsulindependent diabetes mellitus (NIDDM), gallbladder disease, sleep apnea, osteoarthritis, and various forms of cancer (2–7). For example, the prevalence of hypertension among overweight individuals is 2.9 times greater than nonoverweight adults. Overweight women experience substantially greater risk for all-cause and some cause-specific mortality than leaner women (8). Among women who never smoked and recently had stable weight, the relative risks of death for women were 1.6 (95% confidence interval [CI] = 1.1–2.5) for BMI = 27.0–28.9; 2.1 (95% CI = 1.4–3.2) for BMI = 29.0–31.9; and 2.2 (95% CI = 1.4–3.4) for BMI > 32. These data indicate that obese women have 60–120% greater risk for death than their leaner counterparts. Solomon and colleagues (6) concluded that “the preponderance of evidence suggests that even mild overweight is probably associated with some increase in mortality risk.” From: The Management of Eating Disorders and Obesity Edited by: D. J. Goldstein © Humana Press Inc., Totowa, NJ

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Part III / Treatment Table 1 Chapter Overview: Overview and the Future of Obesity Treatment 1. Introduction 1.1. Social, Economic, and Personal Costs of Obesity 2. Obesity Treatment 2.1. Psychosocial/Life-Style Interventions 2.1.1. Life-Style Intervention 2.2. Pharmacotherapy 2.2.1. Fenfluramine 2.2.2. Dexfenfluramine 2.2.3. Drug Combinations (Fenfluramine–Phentermine) 2.2.4. Fluoxetine 2.2.5. Orlistat 2.2.6. Sibutramine 2.2.7. Sertraline 2.3. Very-Low-Calorie Diets 2.4. Surgery 3. Issues for the Future of Obesity Treatment 3.1. Issue 1: What is a Healthy Weight 3.2. Issue 2: Short-Term Weight Loss and Improved Health and Longevity 3.2.1. Weight Cycling 3.3. Issue 3: Weight Maintenance and Cost Effectiveness 3.4. Issue 4: Environmental Intervention and Prevention 4. Conclusions

Obesity is also associated with increased health and socioeconomic costs. Wolf and Colditz (9–10) estimated the direct and indirect health care costs associated with obesity. Direct costs of obesity were defined as “the value of resources (personal health care, hospital care, physician’s services, nursing home services, other professional services, and drugs) that could be allocated to other uses in the absence of disease” (11). Amounts are determined by estimating the directs costs associated with different medical conditions and multiplying those costs by the proportion of obese patients with those conditions. Using this method, the direct costs of obesity were estimated to be 45.8 billion dollars in 1990 (9). Indirect costs were defined as “the value of lost output because of cessation or reduction of productivity caused by morbidity and mortality” (11). The indirect estimated costs of obesity were $23.0 billion in 1990, leading to a total economic cost of $68.8 billion (9). In fact, it has been estimated that between 6% and 7% of total sick care costs can be attributed to obesity and obesity-related conditions in western countries (12). The costs of obesity are not only economic. There are socioeconomic and personal tolls involved in the increasing prevalence of obesity. Obese women suffer the brunt of socioeconomic costs (13). In a longitudinal study, women who had been overweight as adolescents completed fewer years of school, were less likely to be married, had lower household incomes, and had higher incidence of household poverty (13). Results were all adjusted for baseline socioeconomic status and aptitude test scores. The obese are significantly underrepresented in the top third of their high school class when compared to their lean counterparts, even though there is no difference in their mean intelligence


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quotient or Scholastic Aptitude Test scores (14). In addition, obese individuals tend to receive lower salaries and lower attainment of social class, regardless of their level of education or intelligence test scores. Finally, obese individuals are subject to prejudice, discrimination, and intense stigmatization, and the severely obese experience greater risk for impaired psychosocial and physical functioning and psychiatric disability, which negatively impacts their quality of life (15). In summary, obesity extracts tremendous societal and personal costs in the forms of increased risk for disease and death, health care costs associated with the increased prevalence of comorbid conditions, and reduced social status, educational attainment, and employment opportunities. Given these significant costs and the fact that therapeutic weight loss produces short-term improvements in several important risk factors (5,16,17) (e.g., NIDDM, dyslipidemia, and hypertension), it is no surprise that substantial efforts have been made to develop effective treatments for obesity.

2. OBESITY TREATMENT 2.1. Psychosocial/Life-Style Interventions Life-style and psychosocial treatments have their roots in behavior modification and include a multitude of techniques and approaches that focus on changing behaviors that are thought to contribute to or maintain obesity. Most of the various life-style approaches have several factors in common, including the use of self-monitoring and goal setting, stimulus control and modification of eating style and habits, the use of reinforcement for healthy behaviors, nutritional education and counseling, physical activity, and cognitive behavior therapy interventions that focus on improving coping skills (e.g., cognitive restructuring, stress management and inoculation training, relaxation skills, and relapseprevention training) (18,19). Stunkard (20) categorizes these approaches as “conservative” treatments for obesity because they produce moderate weight losses, have minimal side effects, and are reversible (in contrast to surgery). Using this categorization, conservative treatments are most useful (as a primary or adjunctive form of treatment) for patients with mild obesity (BMI = 27–30). 2.1.1. LIFE-STYLE INTERVENTION Life-style interventions are effective in producing gradual and moderate weight losses. In a recent review, Perri and Fuller (19) summarized the results of the last two decades of research on life-style interventions. Average weight loss across studies was 8.4 kg and attrition rates were generally low (16–18%). Life-style interventions lasted approximately 20 wk and usually included multiple treatment interventions. Patients were able to maintain, on average, about two-thirds of their initial weight loss 9–10 mo after treatment termination. Life-style interventions have not fared as well when long-term maintenance was assessed. In most studies with long-term follow-up, patients gradually return to baseline within a few years after treatment termination (18,21–23). Thus far, only the continuouscare model of life-style intervention (24), which views obesity as a chronic disease requiring continuous support or contact after the conclusion of formal treatment, has been found to produce significant maintenance. Patients treated with this approach (with extended therapist support as a constant) lost between 9.6 and 13.7 kg and maintained between 60% and 107% of their initial weight loss 6–11 mo after the termination of the

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posttreatment care programs (25–27). In a replication of the continuous therapist support program, patients reported almost 100% maintenance of initial weight losses 12 mo after formal treatment termination and 9 mo after termination of the therapist-facilitated maintenance program (28).

2.2. Pharmacotherapy Early pharmacological interventions for obesity produced temporary reductions in weight but were associated in some cases with aversive side effects, health risks, and abuse potential, especially with noradrenergic drugs (29). Progress in the development of new obesity drugs has been hindered by the unfortunate history of amphetamine abuse, by the perception that obesity is a disorder of willpower, and by the belief that drugs are not an appropriate treatment approach because they must be taken indefinitely (29). However, there is a renewed interest in pharmacological approaches owing to the recognition that obesity is a chronic disease that cannot be cured but can be managed (30). Stunkard (20) also characterized pharmacotherapies as conservative treatments that should be used for patients with mild to moderate obesity. Pharmacotherapies for obesity are reviewed in Chapter 16. 2.2.1. FENFLURAMINE Several early studies evaluated the effectiveness of fenfluramine treatment alone, fenfluramine combined with behavior therapy, and behavior therapy alone. Fenfluramine alone or combined with behavior therapy produced significant weight loss at the end of treatment (31,32). Patients in these studies lost 15.3 ± 1.2 kg in the combined treatment group, 14.5 ± 1.1 kg in the drug alone group, and 10.9 ± 1.0 kg in the behavior therapy group, whereas patients in the control group gained 1.3 ±1.3 kg. Unfortunately, when the treatments were discontinued, patients in both drug conditions experienced greater than 50% weight regain within 1 yr after drug withdrawal (31–33). Although the behavior therapy group only regained 1.9 ± 1.0 kg, a later sequencing study by Craighead (33) found that patients in all groups (behavior therapy alone, behavior therapy followed by medication, medication followed by behavior therapy, and medication alone) regained a substantial portion of their weight after the withdrawal of all treatment. Valvular heart disease was reported recently as a potentially serious side effect associated the use of fenfluramine and the fenfluramine–phentermine combination (34). Based on these data, as well as previous concerns about primary pulmonary hypertension, the Food and Drug Administration requested voluntary withdrawal of fenfluramine from the market (35,36). 2.2.2. DEXFENFLURAMINE Dexfenfluramine, a serotonin releaser, produces substantial weight losses and improvement in metabolic risk factors at the end of 1-yr of treatment (37–39). For example, in the INDEX trial, patients were randomized to drug treatment plus usual care or placebo plus usual care (usual care consisted of a calorie-restricted diet and educational programs, dependent on the practice of a particular center). Patients treated with dexfenfluramine lost 9.82 ± 0.50 kg, but experienced a moderate weight regain of 2.0 ± 0.20 kg within 2-mo after drug withdrawal (37,38,40). This pattern of initial weight loss, plateau at 6 mo, and regain after treatment termination has been documented in several other studies. Two trials found that patients treated with dexfenfluramine and life-style


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modification (e.g., dietary education, prescribed exercise, and behavior modification) regained approximately 60% of their initial weight loss within 5 mo after drug withdrawal and approximately 110% 3 yr after drug withdrawal (41,42). Because of potentially serious side effects associated with the use of fenfluramine, dexfenfluramine also was withdrawn from the market in September, 1997 (36). 2.2.3. DRUG COMBINATIONS (FENFLURAMINE–PHENTERMINE) Several studies have examined the effectiveness of long-term treatment with drug combinations. The best known example of long-term combination pharmacological treatment was published by Weintraub and associates (43–46). These investigators used a combination of phentermine and fenfluramine, along with a behavior-modification component. Phentermine is a stimulant anorexiant which appears to decrease appetite through noradrenergic and dopaminergic mechanisms and fenfluramine is a serotonin reuptake inhibitor. Thus, while one drug reduces appetite, the other enhances early satiety. When used in combination, a smaller dose of each can be effective, thus reducing adverse side effects (47). The Weintraub et al. studies (43–45) resulted in an overall 9.4 ± 0.8 kg weight loss at 3 yr, with a plateau in weight loss at 18–20 wk. However, the design of the study involved breaking the double blind after 34 wk and allowing dosage to be determined by patient weight changes. Because weight changes are the result of behaviors not necessarily under the influence of medications, some experimental control was lost. Weintraub (46) concluded that the pharmacological intervention enhanced weight loss more than behavior modification, exercise, and calorie restriction. In recent open-label trials, Atkinson and colleagues (47) reported that patients lost a maximum of 16.5 kg at 6 mo, maintained their weight loss for 18 mo, and experienced improvements in comorbid conditions as long as they remained on the medication. Again, because of potentially serious cardiac side effects, fenfluramine was withdrawn from the market in September, 1997, so the off-label use of this combination is no longer available (36). 2.2.4. FLUOXETINE The effectiveness of fluoxetine, which is used for depression, obsessive–compulsive disorder, and bulimia nervosa, has been evaluated in several clinical trials. In general, fluoxetine treatment produces significant initial weight losses and improvement in obesity complications (48). For example, patients in a double-blind placebo-controlled study treated with fluoxetine plus behavior modification lost an average of 13.9 ± 12.7 kg compared to a 0.6 ± 5.0-kg gain for the placebo plus behavior modification group at 52 wk (49). Unfortunately, more recent studies reported that patients tended to regain weight while on fluoxetine after 20 wk of treatment and experienced almost complete regain by 52 wk of treatment (50,51). In fact, only 8.6% of patients successfully maintained their weight losses at 52 wk (52). One problem with these studies was that behavioral and nutritional interventions were not consistent across the various study sites, possibly contributing to the weight regain. 2.2.5. ORLISTAT Orlistat, a lipase inhibitor expected to be approved for marketing in 1999, produces weight losses of up to 4.74 ± 0.38 kg at a dose of 360 mg/d (compared to 2 to 3-kg losses in placebo groups) after 12 wk of treatment (53–55). The results of a yearlong controlled trial demonstrated sustained and significant weight losses (56). Weight losses appear to

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be dose dependent (i.e., lower doses produce smaller weight losses) and some patients report mild and transient gastrointestinal side effects. None of these studies reported the effects of drug withdrawal on weight loss. 2.2.6. SIBUTRAMINE Sibutramine, a novel norepinephrine and serotonin reuptake inhibitor, was approved for obesity treatment in 1997. In clinical trials, it produced weight losses of 4.7–7.6 kg in several clinical trials lasting from 12 to 52 wk (57,58). With doses of 10 and 15 mg/d, sibutramine produced weight losses that were 3–5 kg better than placebo. Weight losses were dose dependent and tended to plateau by 24 wk. Sibutramine-induced weight losses were accompanied by favorable reductions in plasma triglycerides, total cholesterol, low-density lipoproteins (LDL), and waist-to-hip ratio (WHR) (59). 2.2.7. SERTRALINE Drug treatment with sertraline, a serotonin reuptake inhibitor used in the treatment of depression, following a very low-calorie diet produced initial short-term weight loss during the first 6-wk of a recent study, followed by weight regain over the last 54 wk, demonstrating no long-term advantage over placebo (60).

2.3. Very Low Calorie Diets Very-low-calorie diets (VLCDs) have less than 800 kcal/d with sufficient protein to promote rapid weight loss and preservation of lean body mass (19). VLCDs promote rapid weight losses of up to 20 kg after 12–16 wk (61,62). VLCDs produce substantial short-term weight loss and improvement in obesity complications; however, long-term results are disappointing. Wadden and associates (23,62) reported that the majority of patients in randomized trials who receive VLCD treatment experience significant regain within the first 2 yr after treatment. VLCD’s are not generally viewed as very costeffective or practical for many obese patients because they require intensive medical monitoring, patients experience fairly rapid weight regain after treatment, and they have numerous problematic side-effects (19,62).

2.4 Surgery Surgical procedures are considered adjunctive treatment and are generally used with severely obese individuals whose lives are potentially threatened by their excess weight (63). The most common surgical techniques are the vertical banded gastroplasty and the gastric bypass. Morbidity and mortality associated with these procedures have dropped in experienced surgical centers, but some patients suffer complications and side effects, such as nutritional deficiencies and “dumping” syndrome (64). Studies have documented substantial weight losses in surgical patients and reductions in comorbidities. Intermediate follow-up data demonstrate fairly good weight-loss maintenance (64). Results of a recent study suggest that surgical treatment for the severely obese patient may be more cost-effective than VLCDs supplemented with behavior therapy and 1-yr maintenance program (65).

3. ISSUES FOR THE FUTURE OF OBESITY TREATMENT Obesity treatments are effective in producing short-term weight loss and reducing risks for complications associated with obesity (19), but there several important issues and limitations that need to be addressed in future obesity-treatment research.


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3.1. Issue 1: What Is a Healthy Weight? The prevalence of obesity and overweight is increasing in the United States at a rapid rate (1), but understanding secular trends and the impact of obesity on the development of comorbid conditions depends on how obesity is defined. The old definition of overweight (BMI * 27.3 for women and BMI * 27.8 for men) is a statistical one, using the 85th percentile from NHANES II (66). Many researchers and health care professionals view this definition of overweight as problematic, since it is derived statistically and not empirically. In addition, based on the NHANES III, the 85th percentile of BMI is now greater than 27.8 and 27.3, indicating that the population has become more obese. Definitions should be empirically derived, based on studies of the relationship between BMI and morbidity and mortality. Using this approach, Simonpoulos (66) estimates that the healthy range of BMI should be 19–25 for women and 20–25 for men. These ranges are consistent with past and recent cohort studies that have consistently found that BMIs above 25 are associated with increased risk for morbidity and mortality, even after adjustment for age, smoking status, and other risk factors (7,8). Of course, the new lower BMI guidelines have a direct impact on our definitions of healthy weights for women and men at a time when the US population is getting heavier, there is increasing debate about the psychological risks of obesity treatment, and current obesity treatments (except for surgery) are not effective for long-term weight loss (1,67). This is an important issue because if the majority of obese individuals have failed to meet current guidelines utilizing prevailing obesity treatments, it is likely that more will fail under the new guidelines. It is interesting that while some researchers and clinicians are suggesting that obesity treatment should focus on healthy and “reasonable” weights (68), there is a push by others to make healthy-weight guidelines more stringent. It should also be noted that the new definitions of overweight using lower BMIs automatically increased prevalence rates beyond the older estimates. Although it is important to empirically derive definitions for research purposes, we feel that obese individuals and health care providers should focus primarily on maintaining a “reasonable” weight (68) and a healthy life-style. This includes focusing broadly on engaging in regular exercise, eating a low-fat diet, and normalizing eating patterns (18,69), rather than on which BMI category individuals fit into and what their resultant risk may be, as morbidity and mortality ratios do not reflect direct risk to an individual. Finally, future research should focus on assessing the impact of redefining obesity on treatment outcome, the potential psychological risks of obesity treatment, and the benefit of broader outcome measures, including dietary changes, psychosocial functioning, physical activity levels, and control or prevention of obesity-related complications.

3.2. Issue 2: Short-Term Weight Loss and Improved Health and Longevity Obesity research has not shown that the short-term weight losses and improved metabolic functioning produced by current treatments leads to long-term improvements in health, quality of life, and longevity. Although there is little dispute about the short-term effects of moderate weight loss on improvements in hypertension, lipid levels, and insulin resistance (5,16,17), there are few data to suggest that these benefits are long-standing, particularly because weight loss maintenance is so difficult for most people (70). In terms of improved longevity, it is clear that there is a strong, positive relationship between BMI and risk for all-cause and some forms of cause-specific mortality (6–8), but

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it is unclear how much excess weight is dangerous and whether weight loss changes this risk in the long term (71,72). For example, a recent, large cohort study found only minimal and nonsignificant increases in mortality risk associated with moderate degrees of obesity (BMI 32 to < 36) (71). Relatedly, Andres and colleagues (73) concluded that mortality rates were lowest for adults who had gained moderate amounts of weight and highest for individuals who had lost weight or gained excessive weight. In contrast, when intentional weight loss was examined in a prospective cohort study with adult, middleaged women, data suggested that intentional weight loss in women with obesity-related illnesses was associated with decreased risk for all-cause mortality in a dose-dependent manner (74). Results were equivocal for healthy, middle-aged women. 3.2.1. WEIGHT CYCLING Although it is somewhat unclear as to whether weight loss confers long-term benefits, the impact of weight cycling is even more unclear (75). Weight cycling is a problem because so many individuals who try to lose weight, regardless of the method they use, typically regain the lost weight over a period of several years (18). Some data suggest that weight variability is associated with greater risk for cardiovascular disease and all-cause mortality in men (76). Other studies have not found a relationship between weight fluctuation and mortality in healthy men who had never smoked, whereas men who smoked or had preexisting illness and whose weight fluctuated experienced greater risk for death (77). The National Task Force on the Prevention and Treatment of Obesity (78) summarized the issue by stating that “the currently available evidence is not sufficiently compelling to override the potential benefits of moderate weight loss in the severely obese.” It is still not clear if weight cycling has any significant psychological side effects, such as depression owing to repeated failed attempts at losing weight (75–80). Clearly, the jury is still out on this controversial issue and it will remain a puzzle until we can more adequately study the effects of intentional long-term weight loss.

3.3. Issue 3: Weight Maintenance and Cost Effectiveness Long-term weight maintenance is a goal that current obesity treatments have not adequately met. This has led to the view that obesity is a chronic disease that cannot be cured (30) and speculation that obesity may need to be viewed like diabetes mellitus, which requires treatment indefinitely (81). It is not unreasonable that the treatment of obesity should require long-term management and that obese patients should receive long-term interventions. This philosophy is the backdrop to the recent emphasis on evaluating the benefits of long-term pharmacotherapy and life-style interventions (19,82–84). Given the effectiveness of the continuous care model of life-style intervention, with a focus on long-term support and therapist contact (25,28,83) and the effectiveness of continuous drug therapy (19,84), it likely that greater emphasis will be put on these approaches. There are important barriers to this new long-term approach, including the lack of insurance reimbursement for obesity (85) and the lack of data to support the cost-effectiveness and feasibility of continuous care. Future research needs to address the costeffectiveness and feasibility of treating obesity (and potentially preventing comorbid conditions) versus the direct and indirect costs of treating obesity complications as they arise. In addition, more research should focus on methods of implementing life-style interventions at the lowest cost possible and evaluating which elements of multicompo-


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nent treatments are most effective for which patients. For example, this could be done by studying the cost-effectiveness of life-style interventions delivered by paraprofessionals or the benefits of aerobic exercise vs social support for different patient groups.

3.4. Issue 4: Environmental Intervention and Prevention Current policies need to be changed to an emphasis on prevention and health promotion (69,86). Without effective changes, Goodrick and Foreyt’s (87) prediction that 100% of adults in the United States will be overweight by the year 2230 may become a reality (even sooner given the changes in the definition of overweight). At the policy and environmental intervention level, greater emphasis should be placed on the role of diet and sedentary life-style in the development and maintenance of obesity. Cross-sectional, migrant, and ecological studies have demonstrated the impact of increasing dietary fat on relative weight (88–90). Because Americans eat substantial amounts of dietary fat and large portion sizes, more research on developing and implementing effective population and community nutritional interventions is needed (90–92). In addition, greater emphasis should be put on increasing physical activity. Current data suggest that less than 10% of American women and men engage in regular and vigorous physical activity (93). Decreasing sedentary life-style and increasing physical activity of all Americans, particularly individuals who are obese, should be an important public health priority. This is very important because regular physical activity has been found to be an important predictor of weight maintenance (18,93–95). More research is necessary to develop community intervention strategies to increase adherence (93,94) and examine the potential for “healthy” overweight (e.g., individuals who are physically fit, but remain overweight). For example, Barlow and colleagues (96) found that moderate- and high-fit men, regardless of BMI, experienced significantly lower age-adjusted risk for all-cause mortality compared to sedentary or low-fit men. Greater research and treatment emphasis should focus on targeted prevention programs for high-risk individuals and populations. For example, there are ample data linking perinatal risk factors (e.g., hyperinsulinism and maternal adiposity) and low infant birth weight to the development of NIDDM, hypertension, hyperlipidemia, and coronary heart disease in adulthood (89,97–99). These problems are particularly problematic for low-income and minority women because they experience a higher prevalence of overweight (100). Future generations are potentially at risk for repetitive cycles of obesity and related health problems because of these perinatal risks. Research should focus on developing targeted, safe, and effective treatment and prevention programs for at-risk pregnant women, as this method of transmitting risk for obesity is potentially preventable and could reduce the prevalence of obesity and obesity-related disorders in future generations. Finally, more resources should be directed at treating obese and overweight children with the focus on potentially preventing adult obesity. Epstein and associates (101) reported long-term outcome data on treatment targeted at obese children. Ten years after treatment, more than 30% of the children had decreased their percentage overweight by 20% or more and 30% were no longer obese. Although this study needs to be replicated, it gives hope for the potential of preventing adult obesity by providing treatment in childhood.

4. CONCLUSIONS What is the future for obesity treatment? We believe that treatment will be most fruitful when the health care community and the general public recognize obesity as a chronic

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condition, without a cure, requiring long-term management, similar to diabetes and hypertension. Many chronic diseases do not have cures, yet we do not view their longterm management as a failure, even though treatment withdrawal precipitates a recurrence of the problem. In addition, we do not consider treatment a failure just because patients experience difficulty adhering to the interventions. Rather, we acknowledge that many health care problems require long-term management and focus on improving adherence to treatment (102). Kirschenbaum and Fitzgibbon (103) suggest that obesity treatment is judged more stringently than other chronic conditions and this illustrates cognitive biases against obesity treatments. Would the withdrawal of insulin or antihypertensive medication and dietary modification be appropriate for a patient with diabetes or severe hypertension without appropriate weight loss? Obesity is likely to defy simple solutions because its cause is multifactorial and it is partially the result of a mismatch between modern life-style and the life-style in which humans evolved, as well as complicated behavioral, genetic, and metabolic factors. For example, the total fat intake in late Paleolithic diets was estimated to be about 20% of calories from fat, compared to the current American diet of about 34% of calories from fat (104,105). Data from humans who continue to exist as hunter-gatherers as well as anthropological data suggest that humans were significantly more active and their diets were less energy dense, higher in fiber, and lower in fat than current Western societies (105). Given this mismatch, we believe that long-term management of obesity, as well as genetic and metabolic studies, should be given the highest research priority. Research should focus on evaluating the cost-effectiveness of long-term management compared to usual care. In addition, more research is needed on the complicated genetic, metabolic, and environmental interactions that play a role in the development and maintenance of obesity. The prevention of obesity and an emphasis on environmental change is another area that requires greater attention. For example, in spite of our knowledge about the role of dietary fat in childhood obesity, school lunch programs often provide significantly more fat than current dietary guidelines suggest (106). Chapman et al. (107), found that less than 5% of schools sampled offered lunches that came close to current dietary recommendations for fat. At a time when obesity is increasing among adults and children in the United States, it is ironic that fast-food companies provide lunches in schools and outlets in hospitals. There is even a fast-food restaurant in one of Houston’s premier children’s hospitals. It is imperative that population and community-based dietary programs focus on teaching children prudent exercise and dietary habits (87). More research and legislative support for potential environmental controls on obesity should be examined: taxing high-fat foods, providing monetary incentives to food manufacturers to develop low-fat alternatives, and increasing access to exercise facilities as methods of external or environmental control (91). We must also begin to recognize the value of targeted interventions (e.g., obese children and obese pregnant women) and support their development and implementation. Finally, the concept of “healthy” obesity (i.e., an individual who is obese yet exercises regularly and eats a healthy diet) deserves further research. Health care providers and researchers should not presume that obesity automatically is synonymous with poor health or increased mortality (15,96,109). Many Americans, regardless of their weight status, engage in unhealthy behaviors (93,109). Some obese individuals exercise regularly and eat a healthy diet and still do not lose


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weight, possibly due to strong genetic factors. Recent data suggest that obese individuals can improve their risk profiles with exercise and dietary change (110,111) and that improvements in lipid profiles often attributed to weight loss might also be due to changes in dietary composition (110,112). Researchers and health care providers should investigate healthy obesity and encourage their patients to engage in healthy life-styles, regardless of the impact on weight (113). We believe that these approaches are the future of obesity treatment.

ACKNOWLEDGMENTS The authors wish to acknowledge that this work was partially supported by a Minority Scientist Development Award to Dr. Poston from the American Heart Association and with funds contributed by the AHA, Puerto Rico Affiliate and a grant from the National Heart, Lung, and Blood Institute (HL47052).

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restriction, and exercise by fenfluramine plus phentermine versus placebo. Clin Pharmacol Ther 1992; 51:586–594. Weintraub M, Sundaresan PR, Schuster B, Madan M, Ginsberg G, Balder A, et al. Long-term weight control study II (weeks 34 to 104): an open-label study of continuous fenfluramine plus phentermine versus targeted intermittent medication as adjuncts to behavior modification, caloric restriction, and exercise. Clin Pharmacol Ther 1992; 51:595–601. Weintraub M, Sundaresan PR, Schuster B, Moscucci M, Stein EC. Long-term weight control study III (weeks 104 to 156): an open-label study of dose adjustment of fenfluramine and phentermine. Clin Pharmacol Ther 1992; 51:602–607. Weintraub M. Long-term weight control study: Conclusions. Clin Pharmacol Ther 1992; 51:642–646. Atkinson RL, Blank RC, Loper JF, Schumacher D, Lutes RA. Combined drug treatment of obesity. Obes Res 1995; 3(Suppl 4):497S–500S. Sayler ME, Goldstein DJ, Roback PJ, Atkinson RL. Evaluating success of weight loss programs, with an application to fluoxetine weight reduction clinical trial data. Int J Obes Relat Metab Disord 1994; 18:742–751. Marcus MD, Wing RR, Ewing L, Kern E, McDermott M, Gooding W. A double-blind, placebocontrolled trial of fluoxetine plus behavior modification in the treatment of obese binge-eaters and nonbinge-eaters. Am J Psychiatry 1990;147:876–881. Goldstein DJ, Rampey AH, Enas GG, Potvin JH, Fludzinski LA, Levine LR. Fluoxetine: a randomized clinical trial in the treatment of obesity. Int J Obes Relat Metab Disord 1994; 18:129–135. Goldstein DJ, Rampey AH, Roback PJ, Wilson MG, Hamilton SH, Sayler ME, et al. Efficacy and safety of long-term fluoxetine treatment of obesity—Maximizing success. Obes Res 1995; 3(Suppl 4):481S–490S. Goldstein DJ, Roback PJ, Holman SL, Wilson MG, Tollefson ED, Brunelle RL, et al. Individualizing pharmacological therapy for weight reduction: the Lovan example. In: VanItallie TB, Simonpoulos AP, eds. Obesity: New Directions in Assessment and Management. Charles, Philadelphia, PA, 1995, pp. 234–240. Drent ML, van der Veen EA. Lipase inhibition: a novel concept in the treatment of obesity. Int J Obes Relat Metab Disord 1993; 17:241–244. Drent ML, Larsson I, William-Olsson T, Quaade F, Czubaybo F, von Bergmann K, et al. Orlistat (RO 18-0647), a lipase inhibitor, in the treatment of human obesity: a multiple dose study. Int J Obes Relat Metab Disord 1995; 19:221–226 Drent ML, van der Veen EA. First clinical studies with orlistat: A short review. Obes Res 1995; 3(Suppl 4):623S–625S. James WPT, Avenell A, Broom J, Whitehead J. A one-year trial to assess the value of orlistat in the management of obesity. Int J Obes Relat Metab Disord 1997; 21(Suppl 3):S24-S30. Ryan DH, Kaiser P, Bray GA. Sibutramine: a novel new agent for obesity treatment. Obes Res 1995; 3(Suppl 4):553S–559S. Stock MJ. Sibutramine—A review of the pharmacology of a novel anti-obesity agent. Int J Obes Relat Metab Disord 1997; 21(Suppl 1):S25-S29. Lean MEJ. Sibutramine—A review of clinical efficacy. Int J Obes Relat Metab Disord 1997; 21(Suppl 1):S30-S36. Wadden TA, Bartlett SJ, Foster GD, Greenstein RA, Wingate BJ, Stunkard AJ, et al. Sertraline and relapse prevention training following treatment by Very-Low-Calorie-Diet: a controlled clinical trial. Obes Res 1995; 3:549–558. National Task Force on the Prevention and Treatment of Obesity. Very low-calorie diets. JAMA 1993; 270:967–974. Wadden TA, Bartlett SJ. Very low calorie diets: An overview and appraisal. In: Wadden TA, VanItallie TB, eds. Treatment of the Seriously Obese Patient. Guilford, New York, NY, 1992, pp. 44–79. Kral JG. Surgical treatment of obesity. In Wadden TA, VanItallie TB, eds. Treatment of the Seriously Obese Patient. Guilford, New York, NY, 1992, 496–506. Benotti PN, Forse RA. The role of gastric surgery in the multidisciplinary management of severe obesity. Am J Surg 1995; 169:361–367. Martin LF, Tan TL, Horn JR,Bixler EO, Kauffman GL, Becker DA, et al. Comparison of the costs associated with medical and surgical treatment of obesity. Surgery 1995; 118:599–607.

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66. Simonpoulos AP. Body weight reference standards. In: VanItallie TB, Simonpoulos AP, eds. Obesity: new directions in assessment and management. Charles, Philadelphia PA, 1995, pp. 12–21. 67. Garner DM, Wooley SC. Confronting the failure of behavioral and dietary treatments for obesity. Clin Psychol Rev 1991; 11:729–780. 68. Brownell KD, Wadden TA. Etiology and treatment of obesity: understanding a serious, prevalent, and refractory disorder. J Consult Clin Psychol 1992; 60:505–517. 69. Foreyt JP, Poston WSC, Goodrick GK. Future directions in obesity and eating disorders. Addict Behav 1996; 21:767–778. 70. Institute of Medicine. Weighing the Options: Criteria for Evaluating Weight-Management Programs. National Academy Press, Washington DC, 1995, pp. 37–63. 71. Bender R, Trautner C, Spraul M, Berger M. Assessment of excess mortality in obesity. Am J Epidemiol 1998; 147:42–48. 72. Williamson DF, Pamuk ER. The association between weight loss and increased longevity: a review of the evidence. Ann Intern Med 1993; 119(7 Pt 2):731–736. 73. Andres R, Muller DC, Sorkin JD. Long-term effects of change in body weight on all-cause mortality: a review. Ann Intern Med 1993; 119(7 Pt 2):737–743. 74. Williamson DF, Pamuk ER, Thun M, Flanders D, Byers T, Heath C. Prospective study of intentional weight loss and mortality in never-smoking overweight U.S. white women aged 40–64 years. Am J Epidemiol 1995; 141:1128–1141. 75. Foster GD, Sarwer DB, Wadden TA. Psychological effects of weight cycling in obese persons—A review and research agenda. Obes Res 1997; 5:474–488. 76. Blair SN, Shaten J, Brownell K, Collins G, Lissner L. Body weight change, all-cause mortality, and cause-specific mortality in the Multiple Risk Factor Intervention Trial. Ann Intern Med 1993; 119(7 Pt 2):749–757. 77. Iribarren C, Sharp DS, Burchfiel CM, Petrovich H. Association of weight loss and weight fluctuation with mortality in Japanese American men. N Engl J Med 1995; 333:686–692. 78. National Task Force on the Prevention and Treatment of Obesity. Weight cycling. JAMA 1994; 272:1196–1202. 79. Venditti EM, Wing RR, Jakicic JM, Butler BA, Marcus MD. Weight cycling, psychological health, and binge eating in obese women. J Consult Clin Psychol 1996; 64:400–405. 80. Foreyt JP, Brunner RL, Goodrick GK, Cutter G, Brownell KD, St. Jeor ST. Psychological correlates of weight fluctuation. Int J Eat Disord 1995; 17:263–275. 81. Yanovski SZ. Are anorectic agents the “magic bullet” for obesity? Arch Fam Med 1993; 2:1025–1027. 82. Gullo SP. Food control training as a successor to dieting: A new model for weight management. In: VanItallie TB, Simonpoulos AP, eds. Obesity: New Directions in Assessment and Management. Charles, Philadelphia, PA, 1995, pp. 153–171. 83. Perri MG. Improving maintenance of weight loss following treatment by diet and lifestyle modification. In: Wadden TA, VanItallie TB, eds. Treatment of the Seriously Obese Patient. Guilford, New York, NY, 1992, pp. 456–477. 84. Guy-Grand B. Long-term pharmacological treatment of obesity. In: Wadden TA, VanItallie TB, eds. Treatment of the Seriously Obese Patient. Guilford, New York, NY, 1992, pp. 478–495. 85. Institute of Medicine. Weighing the Options: Criteria for evaluating weight-management programs. National Academy Press, Washington DC, 1995, pp. 152–170. 86. Fries JF, Koop, CE, Beadle CE, Cooper PP, England MJ, Greaves RF, et al. Reducing health care costs by reducing the need and demand for medical services. N Engl J Med 1993; 329:321–325. 87. Foreyt JP, Goodrick GK. The ultimate triumph of obesity. Lancet 1995; 346:134–135. 88. Curb JD, Marcus EB. Body fat and obesity in Japanese Americans. Am J Clin Nutr 1991; 53:1552S–1555S. 89. James WPT. A public health approach to the problem of obesity. Int J Obes Relat Metab Disord 1995; 19(Suppl 3):S37–S45. 90. Lissner L, Heitman BL. Dietary fat and obesity: Evidence from epidemiology. Eur J Clin Nutr 1995; 49:79–90. 91. Battle EK, Brownell KD: Confronting a rising tide of eating disorders and obesity: treatment vs. prevention and policy. Addict Behav 1996; 21:755–765. 92. Institute of Medicine. Weighing the Options: Criteria for Evaluating Weight-Management Programs. National Academy Press, Washington DC, 1995, pp. 102–117.


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93. USDHHS. Physical activity and health: A Report of the Surgeon General. US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Atlanta, GA, 1996. 94. Grilo CM. The role of physical activity in weight loss and weight loss management. Med Exercise Nutr Health 1995; 4:60–76. 95. Klem ML, Wing RR, McGuire MT, Seagle HM, Hill JO. A descriptive study of individuals successful at long-term maintenance of substantial weight loss. Am J Clin Nutr 1997; 66:239–246. 96. Barlow CE, Kohl HW, Gibbons LW, Blair SN. Physical fitness, mortality, and obesity. Int J Obes Relat Metab Disord 1995; 19(Suppl 4):S41–S44. 98. Dorner G, Plagemann A. Perinatal hyperinsulinism as a possible predisposing factor for diabetes mellitus, obesity, and enhanced cardiovascular risk in later life. Horm Metab Res 1994; 26:213–221. 97. Barker DJP, Hales CN, Fall CHD, Osmond C, Phipps K, Clark PM. Type 2 (non-insulin-dependent) diabetes mellitus, hypertension, and hyperlipidaemia (syndrome X): relation to reduced fetal growth. Diabetologia 1993; 36:62–67. 99. Fall CH, Vijayakumar M, Barker DJ, Osmond C, Duggleby S. Weight in infancy and prevalence of coronary heart disease in adult life. Br Med J 1995; 310(6971):17–19. 100. Bowen DJ, Tomoyasu N, Cauce AM. The triple threat: A discussion of gender, class, and race differences in weight. Women Health 1991; 17:123–143. 101. Epstein LH, Valoski A, Wing RR, McCurley J. Ten-year outcomes of behavioral family-based treatment for childhood obesity. Health Psychol 1994; 13:373–383. 102. Burke LE, Dunbar-Jacobs J. Adherence to medication, diet, and activity recommendations: From assessment to maintenance. J Cardiovasc Nurs 1995; 9:62–79. 103. Kirschenbaum DS, Fitzgibbon ML. Controversy about the treatment of obesity: Criticisms or challenges? Behav Ther 1995; 26:43–68. 104. Anonymous. Daily dietary fat and total food-energy intakes—Third National Health and Nutrition Examination Survey, Phase 1, 1988–91. MMWR 1994; 43:116–124. 105. Burkitt DP, Eaton SB. Putting the wrong fuel in the tank. Nutrition 1989; 5:189–191 106. Whitaker RC, Wright JA, Finch AJ, Deyo RA, Psaty BM. School lunch: A comparison of the fat and cholesterol content with dietary guidelines. J Pediatr 1993; 123:857–62. 107. Chapman N, Gordon AR, Burghardt JA. Factors affecting the fat content of National School Lunch Program lunches. Am J Clin Nutr 1995; 61(Suppl 1):199S–204S. 108. Goodman WC. The Invisible Woman: Confronting Weight Predjudice in America. Gürze Books, Carlsbad, CA, 1995, pp. 18–45. 109. Eaton SB. Humans, lipids and evolution. Lipids 1992; 27:814–820. 110. Andersen RE, Wadden TA, Bartlett SJ, Vogt RA, Weinstock RS. Relation of weight loss to changes in serum lipids and lipoproteins in obese women. Am J Clin Nutr 1995; 62:350–357. 111. Björntorp P. Evolution of the understanding of the role of exercise in obesity and its complications. Int J Obes Relat Metab Disord 1995; 19(Suppl 4):S1–S4. 112. Wooley SC. Maelstrom revisited. Am Psychol 1995; 50:943–944. 113. Foreyt JP, Goodrick GK. Living Without Dieting. Warner Books, New York, NY 1994, pp. 15–126.

Chapter 13 / Physical Activity and Nutrition in Treatment of Obesity

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The Role of Physical Activity, Exercise, and Nutrition in the Treatment of Obesity Edward T. Mannix, Jill M. Dempsey, Reed J. Engel, Becky Schneider, and Michael F. Busk

1. INTRODUCTION This chapter discusses (1) the benefits of physical activity and exercise, (2) individualizing an exercise program, (3) identifying and overcoming barriers to exercise, and (4) the role of proper nutrition (Table 1) for both the general population and the obese. Imagine a new drug that could decrease stress, increase energy levels, improve sleep, decrease body fat and blood pressure, and improve levels of cholesterol. Most individuals would rush to their physicians to get a prescription and would not hesitate to seek out a lifetime supply. Unfortunately, no such wonder drug exists; however, all of the physical and mental health benefits mentioned above are possible with a consistent program of regular physical activity, exercise, and proper nutrition. Likewise, these factors are all components of a treatment plan for obesity.

2. THE BENEFITS OF PHYSICAL ACTIVITY AND EXERCISE The benefits of physical activity and exercise have been professed for centuries. Maimonides declared in the 12th century that “anyone who sits around idle and takes no exercise will be subject to physical discomforts and failing strength.” The importance of an active body and mind was articulated by former President John F. Kennedy when he said, “ . . . We know what the Greeks knew: that intelligence and skill can only function at the peak of their capacity when the body is healthy and strong, and that hardy spirits and tough minds usually inhabit sound bodies” (1). One of the first steps to incorporating physical activity and exercise into any lifestyle is to acquire knowledge of the benefits of exercising. In understanding the benefits of physical activity and exercise, we must also be able to distinguish the difference between the two terms. Physical activity has been characterized as “any bodily movement, produced by skeletal muscles that results in energy expenditure.” It is a more global term, and includes activities performed at a moderate intensity such as walking, cycling for pleasure, mowing the lawn, gardening, dancing, raking leaves, shoveling snow, and so From: The Management of Eating Disorders and Obesity Edited by: D. J. Goldstein © Humana Press Inc., Totowa, NJ

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Part III / Treatment Table 1 Chapter Overview 1. Introduction 2. The Benefits of Physical Activity and Exercise 2.1. Increased Physical Activity and Health 2.2. Reduction in Coronary Heart Disease Risk Factors 2.2.1. Hypertension 2.2.2. Lipoprotein Profiles 2.2.3. Obesity 2.2.4. Glucose Intolerance and Diabetes Mellitus 2.3. Improvement in Cardiovascular and Respiratory Function 2.4. Maintenance of Basal Metabolic Rate 2.5. Effect on Food Intake and Appetite 2.6. Reduction of Colon and Breast Cancers 2.7. Enhanced Psychological Effects 3. Individualizing an Exercise Program 3.1. Health Assessment Prior to Beginning an Exercise Program 3.2. Exercise Goal Setting and Program Components 3.3. Breaking Down Barriers to Exercise 4. Fueling Your Body for Activity and Weight Management 5. Conclusion

forth. Exercise is one aspect of physical activity and is defined as any “planned, structured, and repetitive bodily movement done to improve or maintain one or more components of physical fitness.” It includes vigorous and continuous activities such as jogging, swimming, and cycling (2). There are conflicting reports in the literature regarding the amount and type of activity necessary to achieve the health benefits; however, most researchers have concluded that many of the benefits can be realized by individuals who expend approximately 200 kcal per day in either physical activity or exercise (3). A recommendation from the American College of Sports Medicine (ACSM), the Centers for Disease Control (CDC), the President’s Council on Physical Fitness and Sports (PCPFS), and a consensus panel from the National Institutes of Health (NIH) have advised that all Americans should accumulate at least 30 min of moderate intensity physical activity or planned exercise on most days of the week to reap the benefits (4,5). Physical activity has many possible health benefits including (1) increased physical activity and health, (2) reduction in coronary heart disease risk factors, (3) improvement in cardiovascular and respiratory functions, (4) maintenance of basal metabolic rate, (5) effect on food intake and appetite, (6) reduction of certain cancers and osteoporosis, and (7) enhanced psychological effects. The health risks of a sedentary life-style and benefits of physical activity in the obese are similar to those listed for the general population; however, obesity magnifies many of the medical consequences of inactivity (i.e., hypertension, atherosclerosis, coronary heart disease, congestive heart failure, diabetes mellitus, osteoarthritis, and reduced pulmonary function) and the benefits of physical activity and exercise can be immense.

2.1. Increased Physical Activity and Health Throughout the decades, researchers have conducted numerous studies to determine the importance of regular physical activity as a means of preventing disease. Such


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research has become necessary as individuals become increasingly sedentary and reliant on labor-saving devices. Evidence suggests that obesity is related more to reduced activity than to increased ingestion (6). From elevators and escalators, to home shopping and remote controls, such advances in our culture have created an environment where individuals have to consciously think about opportunities to integrate physical activity into their lives. In 1949, Morris et al. (7) investigated the relationship between vocational and leisuretime physical activity and risk of coronary heart disease (CHD). They found that highly active conductors who climbed the stairs on London’s double-deckered buses were at lower risk for CHD than the more sedentary bus drivers (7). They also discovered that sedentary secretaries and supervisors had higher rates of CHD than postal workers who delivered the mail on foot (7). Such research served as the cornerstone for more sophisticated studies that have affirmed the relationship between the amount of activity (measured by caloric expenditure or minutes of physical activity) and death rate from CHD. A significantly lower mortality rate from CHD has been observed in studies of individuals who performed an average of 47 min of activity per day vs 15 min (8). Another study found that men who expended more than 2000 kcal per week experienced a lower death rate from CHD than those who expended less than 500 kcal per week (9). A prospective study by Blair and co-workers underscores the importance of regular exercise in decreasing mortality (10). In 9777 individuals observed in a 5-yr period, the highest age-adjusted, all-cause death rate was noted in people who maintained sedentary lifestyles, whereas the lowest death rate was observed in people who where classified as physically fit over the span of the study. These findings were recently corroborated by another investigative team who found that older men (61–81 yr) who walked more than 2 miles per day had mortality rates nearly half that of older men who walked less that 1 mile per day (11). The large body of evidence linking increased physical activity with decreased morbidity and mortality spawned a set of recommendations published by the American Heart Association (12) emphasizing the fact that regular exercise plays a vital role in primary and secondary prevention of cardiovascular disease. Without question, physical activity and exercise can be a powerful ally in protecting against heart disease and other life-style diseases for both the general and the obese populations.

2.2. Reduction in Coronary Heart Disease Risk Factors Physical activity and exercise influence a number of CHD risk factors including: hypertension, lipoprotein profiles, obesity, glucose intolerance, and diabetes mellitus. 2.2.1. HYPERTENSION Epidemiologists have found that physically active individuals have a lower prevalence of hypertension (13). For individuals with hypertension, regular, moderate physical activity has been shown to decrease systolic blood pressure up to 10 mm Hg (14). This blood-pressure-lowering effect appears to be independent of weight loss (15). For individuals who are sedentary and obese, weight gain has been shown to correlate with the development of hypertension (16). When encouraging obese patients, physicians should refer to the Fifth Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure, which indicated that a weight loss of as little as 10 lb has a blood-pressure-lowering effect for many individuals (17). The

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report incorporated aerobic activity as one of the life-style modifications for hypertension control and reduced overall cardiovascular risk. 2.2.2. LIPOPROTEIN PROFILES Vigorous activity in endurance athletes has been associated with an increased level of high-density lipoprotein cholesterol (HDL-C) (18). In prospective training studies of apparently healthy subjects (19) and obese individuals (20), endurance exercise has increased HDL-C levels. In addition, individuals who reduce their body fat through activity or weight loss have experienced increases in levels of HDL-C (21,22). Moreover, regular, moderate intensity exercise has a favorable impact on the high-density lipoprotein/low-density lipoprotein cholesterol ratio (a significant factor in preventing CHD) in both obese and lean individuals (23). Dietary strategies have also been implemented to lower high levels of LDL cholesterol, another CHD risk factor. One recent report noted that a widely accepted diet designed to reduce LDL was only successful if participants were engaged in regular, aerobic exercise during its adminstration (24). Also, physically active individuals appear to have lower triglyceride levels; sedentary individuals with high triglycerides have experienced up to a 20– 40% reduction in plasma triglycerides during a controlled exercise program (20). A recent study comparing obese with nonobese patients has confirmed these benefits (25). 2.2.3. OBESITY Without a doubt, one of the most common benefits exercise participants seek is weight loss and a reduction in body fat. Incorporating more activity into one’s life-style and engaging in regular exercise increases overall energy expenditure and favorably impacts caloric balance. Increases in proportion of lean body mass have been noted in research studies in which the participants engaged in vigorous physical training performed consistently for 3 or more months (26,27). Although there are conflicting reports in the literature, many reports do indicate that regular physical activity reduces fat while preserving lean body mass (28–31). Although weight loss and reduction of body fat are primary objectives of diet and exercise programs for obese individuals, maintenance of lower body weight following weight loss should be an important secondary objective. A meta-analysis of 493 studies published between 1969 and 1994, which reported weight loss in obese men and women, indicated that a typical 15-wk diet or diet plus exercise program produces an average weight loss of 11 kg, with a 6.6 and 8.6 kg maintained weight loss after 1 yr, respectively (32). It is clear that even successful weight loss programs cannot guarentee that the new, lower weight will be maintained. A recent study of 77 obese women whose weight loss averaged between 13.5 and 17. 3 kg over 48 wk of diet plus aerobic exercise, diet plus strength training, diet plus aerobic exercise and strength training, or diet alone may offer a solution to the problem of weight maintenance following weight loss (33). A 1-yr follow-up study of these women found that those who exercised regularly during the 4 mo preceding follow-up testing regained significantly less weight than those who did not exercise during the same time period. This report confirms the belief that regular exercise can help maintain weight loss in this population. It is important to remind obese individuals who are frustrated about exercise and weight loss that, independent of weight loss, exercise can counteract many of the ill-effects of obesity, such as high blood pressure and low cardiorespiratory function (34). In addition, even if no weight is lost, favorable body composition changes may be taking place.


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2.2.4. GLUCOSE INTOLERANCE AND DIABETES MELLITUS Regular vigorous exercise has been associated with a decrease in plasma insulin levels, with little effect on glucose tolerance. Hence, an increase in insulin sensitivity is noted regardless of a decrease in body fat (35). All of these factors can work together in preventing and controlling diabetes, particularly noninsulin-dependent diabetes mellitus (NIDDM). For the obese diabetic patient with insulin insensitivity, regular exercise may be an effective treatment. A study of obese subjects found an increase in insulin sensitivity the day following strenuous exercise; this effect lasted 4–6 d following exercise (36). Another study involved six previously inactive moderately obese men with NIDDM who rode a cycle ergometer five times per week for 3–6 mo. Intravenous glucose tolerance increased, but the serum insulin level was not increased, suggesting that insulin sensitivity increased. However, after 2 wk of inactivity, participants reverted to their preexercise status (33). Thus, maintenance of an exercise program is a critical component of managing NIDDM. Two recent publication emphasize the importance of exercise in the treatment of obese individuals suffering from diabetes mellitus. One study documented the efficacy of shortterm (7 d) aerobic training in improving insulin sensitivity and glucose metabolism in 12 obese, hypertensive African-American women, a segment of our population known to have a higher prevalence of insulin resistance, obesity, and hypertension (38). Results indicate that although there was no significant improvement in maximal O2 consumption, body composition, or body weight, this short-term program aided in the treatment of the underlying disease process, as significant improvements in insulin sensitivity and glucose metabolism were observed. A second report examined the effects of long-term (32 wk), moderate intensity (50–55% of maximum heart rate), intermittent exercise (10 min, three times/d, 5 d/wk) on its ability to improve aerobic capacity, body composition, blood lipids, insulin sensitivity, and glucose metabolism in 13 sedentary, obese females (39). Those subjects who were least fit and had the highest percentage of body fat at the beginning of the study had significant improvements in body weight, fat weight, maximal O2 consumption, insulin levels, and insulin sensitivity by the end of the study. Again, these investigative reports uphold the axiom that exercise, even of short-term or of moderate intensity, can help in the treatment of obesity and diabetes mellitus.

2.3. Improvement in Cardiovascular and Respiratory Functions Individuals who participate regularly in continuous aerobic exercise often experience an improvement in cardiovascular and respiratory functions, including increased ability to use oxygen efficiently, decreased resting heart rate, increased stroke volume, and a lower heart rate and total peripheral vascular resistance at submaximal intensities (40). This results in the ability to perceive or experience increased stamina and endurance. For the obese population, the combination of weight reduction and improved cardiovascular function may produce similar results (41). In the extremely obese individual, there is increased deposition of adipose tissue overlying the thoracic and abdominal cavity, resulting in reduced pulmonary function, particularly decreases in resting end-expiratory volumes. The functional residual capacity (FRC) and expiratory reserve volume (ERV) are both decreased with preservation of the residual volume (RV) (42). As the ERV decreases, abnormalities in the ventilation–

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perfusion distribution increase from the restricted lung mechanics causing abnormalities in gas exchange. During exercise, these abnormalities are exacerbated. Therefore, the slightest exertion may cause dyspnea in an extremely obese individual. Although there is reduced FRC and ERV in the slightly or moderately obese individuals, there are no significant abnormalities in ventilation–perfusion distribution or gas exchange. Thus, the majority of these individuals may start an exercise program without any consequences to their cardiorespiratory function. For those obese individuals who become so severely dyspneic that exercise tolerance is impaired, weight loss may be required before they are able to participate in exercise (43). The ERV and FRC of the extremely obese individual return to near-normal levels after significant weight loss (44). Interestingly, gas exchange does not improve until these individuals decrease weight to within 30% in excess of ideal (45).

2.4. Maintenance of Basal Metabolic Rate A significant portion of daily caloric expenditure is due to the basal metabolic rate (BMR). An individual’s BMR is related to both lean body mass and body fat, with a higher BMR for a higher proportion of lean body mass (46). Thus, one would expect endurance-trained athletes with high fitness levels to have an increased BMR. However, studies examining this notion have not been consistent. Some studies have reported higher BMRs among male endurance athletes (47,48), whereas another study did not report that fitness level impacts BMR significantly (49). Significant reduction of body weight in obese individuals is a primary goal of treatment modalities for this population. This seemingly intuitive objective may have two potentially negative outcomes. First, when individuals strive to lose weight through caloric restriction alone, there is often a reduction in lean body mass and, consequently, a lower BMR (50). Second, reports indicate that maintenance of reduced body weight in obese subjects is often associated with the compensatory changes in energy expenditure that counteract the maintenance of the newly achieved lower weight (51). Exercise, particularly when it includes strength training, may have a positive effect on preservation of lean body mass (23); however, it does not seem to prevent the decrease in BMR during weight loss, which appears to be related to the degree of caloric deprivation and rate of weight loss (52,53). Thus, even with the addition of exercise, those who severely restrict caloric intake and lose weight rapidly are likely to experience a decrease in BMR.

2.5 Effect on Food Intake and Appetite There is considerable controversy regarding the effect of exercise on food intake and appetite. The results of studies examining increased physical activity and the effect on intake in the obese have been inconsistent. Two studies support the notion that exercise has no effect on food intake in the obese (54,55); other research of documented weight loss provided evidence of decreased intake (56–58). Another study examining vigorous physical activity and intake in the obese reported an increase in intake (59). In the obese population, food-derived signals or sensory characteristics of the food may impact the determination of intake more than cues elicited from exercise. In short, the effect of exercise on food intake and appetite is a complex matter influenced by many variables, such as intensity and duration of exercise, as well as food appeal (60).

2.6. Reduction of Colon and Breast Cancers Much is yet to be understood regarding the relationship between physical activity and exercise, and the prevention of certain cancers. There is evidence that consistent exercis-


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ers have increased protection from colon cancer. A recent review indicates that inactive individuals have 1.2–3.6 times the risk of colon cancer (60). The reduced risk among regular exercisers is most often associated with a decrease in intestinal transit time. In addition, obesity has been suggested as a greater risk for certain cancers (such as colon) (61,62). For the obese individual, physical activity and exercise may reduce the risk through a decrease in body fat and weight. The research encompassing breast cancer and physical activity is more controversial. However, a recent finding suggested that the amount of time spent in physical activity was a critical variable. The results indicated that sedentary women had 2.4 times the breast cancer risk than women who engaged in greater than 3.8 h of exercise per week (63). An increase in body fat may make finding lumps through breast self-examination more difficult for the obese population, potentially delaying diagnosis. An increase in physical activity may facilitate decreasing body fat, improving detection.

2.7. Enhanced Psychological Effects Individuals contemplating the benefits of an active life-style often focus solely on reaping physical benefits, with little or no attention given to psychological benefits. Many of these psychological benefits produce an immediate sense of well-being, in contrast to physical benefits that often require more time and patience. The primary mental benefit of exercise is an improved ability to manage stress (64– 66). A meta-analysis of 34 studies concluded that aerobically fit subjects exhibited a reduced psychosocial response to stress, regardless of the type of physiological or psychological measure used (67). The preliminary explanation for this result was that exercise may serve as a catalyst to facilitate a more constructive response to stress and a coping strategy that decreases the physiological response to stress. Improved self-esteem and self-concept are reported as psychological benefits of regular exercise among obese individuals (68–70). Other possible effects of regular exercise among obese individuals include increased self-satisfaction and acceptance, improved self-perception, improved social interactions, and more balanced perspectives (67–69). All of the aforementioned psychological benefits of physical activity and exercise can be extremely beneficial for obese individuals desiring to lose weight. Research on dieting alone validates what many individuals have known for years. Restricting food intake results in depression, anxiety, fatigue, and irritability in half of all dieters (71). For obese individuals with weight-loss goals, exercise can help reduce stress and enhance selfesteem and self-concept (which is oftentimes profoundly reduced after years of obesity). The increased sense of personal control and mastery gained through exercise may indirectly influence eating habits and other positive life-style changes by cultivating a series of small successes. Physicians and other health professionals should convey the importance of improved psychological function through activity and exercise to their patients. The ability of physical activity and exercise to elicit an immediate sense of well-being should not be underestimated and must not be overlooked.

3. INDIVIDUALIZING AN EXERCISE PROGRAM Obese individuals desiring to perform weight-bearing activity may have difficulty owing to their excess body fat or perceived excessive exertion (72). They may have

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adopted a sedentary life-style with subsequent loss of bone density and a greater likelihood of future injury. A reasonable recommendation is to begin with non-weight- bearing activities (such as cycling), progress to lower-impact weight-bearing activities (such as walking), and gradually incorporate a moderate resistance/strength training component into an exercise program to maintain and eventually increase bone density (73). When regular physical activity is tailored to an individual’s needs, interests, and abilities rather than applying the more generic “get some exercise” solution, it becomes a powerful tool that the individual is capable of wielding in an effort to gain some degree of control over his/her own health. Furthermore, when potential obstacles to maintaining an effective exercise program are recognized and accounted for, success (adherence leading to improved health) is much more likely. A recent study suggests that most patients will achieve greater weight loss if they are instructed to complete home-based exercise (74).

3.1. Health Assessment Prior to Beginning an Exercise Program Individuals desiring to begin an exercise program and health professionals should discuss this prior to determining which of the many possible paths to take. Conversations should begin by focusing on the current health status of the individual in order to determine suitability for exercise. In some cases, a graded exercise test (GXT) may be indicated if the patient is deemed to be at risk for CHD (75). The health professional can then advise him/her regarding activities which are appropriate, safe, and effective vs those which may be contraindicated due to his/her current health status, CHD risk factors, musculoskeletal limitations, and so forth. The performance of an initial individual fitness assessment by a qualified exercise specialist is a desirable complement to the discussion of current health status. Such an assessment provides valuable benchmark information from which future progress can be measured in the following areas: (1) cardiovascular endurance, (2) muscular strength, (3) muscular endurance, (4) body composition (girth measurements may be most appropriate for an obese population), and (5) flexibility. A current health status review and initial individual fitness assessment will point out the most obvious patient needs, such as weight control, blood pressure management, stress reduction, and so forth. A discussion about which activities are best suited to accomplish these objectives should begin during the initial fitness assessment. Suggesting several cardiovascular-based options gives the individual the freedom to choose an enjoyable activity and enhances his/her ability to vary the routine, yet remain focused on goals. Equally important to a consideration of patient needs is an accounting of patient interests. If an exercise prescription is given without first eliciting individual desires, the probability of compliance and, therefore, success will diminish owing to lack of patient input, choice, and program ownership. The health professional should delve into what the individual enjoys, so that the suggested activities are not perceived as boring or, worse, punishment. Taking an exercise history of past experiences may eliminate unpopular, frustrating, and/or painful activities. Having determined and discussed the patient’s current health status, fitness level, activity needs, and interests, the health professional is ready to recommend an exercise program.

3.2. Goal-Setting and Program Development The first step in any serious endeavor involves the setting of appropriate goals. Incorporating physical activity and exercise into one’s life-style is no different. Some indi-


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viduals may aspire to embark upon an exercise program that will result in being mistaken for Arnold Schwarzenegger. Others may just say that they want to “get (back) into shape.” The problem with these goals is that they set individuals up for failure. Rare is the individual who can realistically (and safely) reach and maintain the professional bodybuilder physique. Likewise, the “get (back) into shape” objective is vague and can go unfulfilled because no parameters exist to show if, and when, the goal is realized. The health professional can increase the probability of success by assisting the individual with the setting of goals that are specific, measurable, attainable, realistic, and time-based (S.M.A.R.T.) An example of a S.M.A.R.T. goal is the plan to lose 20 lb in 20 wk by emphasizing both prudent eating habits (i.e., 55–65% carbohydrate, 15% protein, and 20–30% fat) and regular exercise (i.e., three to five sessions per week, 20–60 min per session, at an appropriate target heart rate). These prudent eating habits are discussed in the Subheading 4. The health professional should encourage the individual to take an active role in setting his/her own long-term outcome goal(s), with short-term participation goals serving as milestones of progress toward the ultimate objective. The role of the health professional here is twofold: to ensure that proper goals are being set and that the patient understands how to reach those goals by developing a program of activity that is safe, effective, and enjoyable. A widely recognized set of general exercise guidelines developed by the American College of Sports Medicine (ACSM) (75) includes recommendations for frequency, intensity, duration, mode, and rate of progression (Table 2). Physical activity recommendations should never be made in a vacuum. These guidelines may serve collectively to comprise a comprehensive exercise prescription. However, even the lower end of the aforementioned general guidelines may be perceived as physically and/or psychologically daunting to the deconditioned, overweight individual. Equipped with information regarding current health status, fitness level, needs, interests, and exercise history, the exercise prescription can and should be modified to meet special considerations. In part, because of a misperception on the part of many potential exercisers about the need for vigorous physical activity in order to bring about significant health gains and the subsequent failure of many Americans to start and/or maintain an exercise program, the National Institutes of Health (NIH) issued a Consensus Development Conference Statement which recommends “that children and adults should set a long-term goal to accumulate at least 30 minutes or more of moderate-intensity physical activity on most, or preferably all, days of the week. Intermittent or shorter bouts of activity (at least 10 minutes), including occupational, nonoccupational, or tasks of daily living, also have similar cardiovascular and health benefits if performed at a level of moderate intensity (such as brisk walking) and accumulate to 30 minutes per day” (5). This statement effectively makes guidelines for an exercise program appear less rigid and may serve as a more realistic starting point for previously sedentary individuals. Still, the sedentary individual may not be ready for 30 min a day, most days of the week. Thus, the intermittent, but accumulated minutes of physical activity allows a gradual adaptation to increasing amounts of exercise, decreases the chances of injury from too much, too soon, and results in better compliance. Another concern for beginning exercisers revolves around exercise intensity. As an alternative to pulse-taking and measured heart rates, patients can also ensure moderate intensity by utilizing either the Talk Test or the Rating of Perceived Exertion (RPE). The

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Table 2 American College of Sports Medicine General Exercise Guidelines 1. Frequency of Exercise Recommendation: 2. Intensity of Exercise Recommendation:

3. Duration of Exercise Recommendation: 4. Mode of Exercise Recommendation: 5. Rate of Progression Recommendation:

3–5 exercise sessions/week 50–85% of maximal oxygen uptake (VO2 Max) or heart rate reserve (HRR). Note: Because not all patients undergo Graded Exercise Tests, and most will not know or comprehend VO2 Max, the HRR may be a more useful tool. See Fig. 1. 20–60 min of continuous activity Aerobic, rhythmic activities involving large muscle groups (i.e., walking, swimming, cycling, rowing, and stair-climbing) Initial stage = Weeks 1–5, 3 exercise sessions/wk, 40–70% of HRR, 12–20 min/session Improvement stage = Weeks 6–27, 3–5 exercise sessions/wk, 70– 85% of HRR, 20–30 min/session Maintenance stage = Weeks 28+, 3 exercise sessions/wk, 70–85% of HRR, 30–45 min/session

220– _______ = Predicted maximal heart rate (PMHR) Age

_______– __________________________ = ___________________ PMHR

Resting heart rate (RHR)

Heart Rate Reserve (HRR)

_______ ×0 .5 = ____________ + _______ = ___________________ HRR

RHR

Lower End of Target Heart Rate

_______ ×0 .85 = ___________ + _______ = ___________________ HRR

RHR

Upper End of Target Heart Rate

Fig. 1. Formula for estimating target heart rate (using heart rate reserve).

Talk Test emphasizes exercising at a level in which it is possible to converse without being short of breath. Table 3 illustrates the RPE scales (original and revised) in which exercisers rate the difficulty of exertion (75). Moderate-intensity exercisers should attempt to stay in the 12–14 (somewhat hard-original scale) or 3–5 (somewhat strongrevised scale) range on these continuums during activity. Individuals may find the revised RPE Scale easier to comprehend. The types of physical activities suggested are as important as the other components of an exercise program. Important activity selection considerations include: safety, enjoyment, effectiveness, and accessibility. Table 4, adapted by Buskirk (43), lists activities of various aerobic quality and their respective caloric values in a 10-min time period. Cardiovascular-based activities (as opposed to strengthening/toning exercises) should be emphasized first because of their more direct effect on caloric expenditure. Non-weight-


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Table 3 Borg Rating of Perceived Exertion Scales Original 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

Revised

Very, very light Very light Fairly light Somewhat hard Hard Very hard

0 0.5 1 2 3 4 5 6 7 8 9 10 •

Nothing at all Very, very weak Very weak Weak Moderate Somewhat strong Strong Very strong

Very, very strong Maximal

Very, very hard

Table 4 a Calories Expended for 10 Minutes of Physical Activity

Activity Sitting quietly Domestic housework Walking downstairs Walking upstairs b Walking (2 mph) Walking (4 mph) Jogging (5.5 mph) Running (7 mph) Cycling (5.5 mph) Cycling (13 mph) Mowing grass (power) Mowing grass (manual) Chopping wood Bowling (nonstop) Dancing (moderate) Dancing (vigorous) Golfing (walk) Skiing (cross-country) Swimming (moderate crawl)

(kg) (lbs)

56.8 125

Body Weight 68 80 150 175

91 200

113.6 250

10 34 56 146 29 52 90 118 42 89 34 38 60 56 35 48 33 98 40

12 41 67 175 35 62 108 141 50 107 41 45 73 67 42 57 40 117 48

16 53 88 229 46 81 142 187 67 142 53 58 96 90 55 75 55 158 63

20 68 111 288 58 102 178 232 83 178 67 74 121 111 69 94 68 194 80

14 47 78 202 40 72 125 164 58 124 47 52 84 78 48 66 48 138 56

a

Approximate values for activities that can be undertaken by many obese individuals. Values will vary with rate of exercise and efficiency with which the activity is performed. Interposition and extrapolation can be used for subject’s actual weight (adapted from ref. 68). b Conversion factor mph to km/h: multiply by 1.6093.

bearing and non-impacting modes of cardiovascular activity are important to consider because of the reduced risk of musculoskeletal injuries. For many, walking should be

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encouraged because no special equipment is required (except for proper shoes) and it can be easily incorporated into the daily routine. Regardless of which activities the individual chooses, the health professional should be sure to encourage a variety of exercise (crosstraining) to decrease the chance of overuse injury and/or mental burnout. Finally, no exercise program recommendation would be complete without an explanation of the reasons for proper warm-up and cool-down. If the patient understands that warming-up decreases early muscle stiffness and the likelihood of injury, the individual is more apt to comply. An effective warm up consists of very low-intensity exercise that slowly mimics the chosen form of activity, for a period of 5–10 min, followed by 10–15 min of stretching of the affected muscle groups. The cool-down, on the other hand, helps to prevent postexercise dizziness owing to pooling of blood in the extremities, and lessens the likelihood of delayed-onset muscle soreness (DOMS) that so frequently plagues those just getting started in an exercise program. Upon completion of exercise, the individual should continue to be active at a low intensity until the heart rate approaches, or goes under, 100 beats/min. Postexercise stretching of the muscles used in the activity (10–30 s/stretch) not only helps decrease muscle soreness but also promotes flexibility. Having assessed the patient’s health, approved a program for the patient’s physical activity, and assisted with the setting of exercise program goals and guidelines, the health professional can then increase the odds of success by preparing the individual for potential pitfalls in their exercise program.

3.3. Breaking Down Barriers to Exercise Just as individuals vary in their health needs and interests, so to do their actual and perceived abilities to accomplish their goals. Exercise excuses may signal uncertainty over whether or not physical activity is worth the time and effort, and/or frustration over previously unsuccessful attempts. The health professional can assist the patient in gaining insight into the value of physical activity by asking the individual to consider and focus on the potential benefits to be derived from such an endeavor. For the obese patient, these benefits may include both physical and psychological improvements (see Subheading 2). An individual’s concern regarding lack of desired results from earlier exercise programs is best handled by a discussion of what previous programs may have been lacking and starting anew, armed with the proper knowledge (i.e., goals and guidelines) to make it work. A reminder that it took some time to gain weight and/or become out of shape and that some results may be slow to realize is prudent. Impatience and faulty expectations are the seeds of doubt that allow other obstacles to grow. There is no way to remove all roadblocks to physical activity before they appear. A survey of nonexercisers regarding reasons for their inactive life-style is likely to yield a wide range of responses from “too tired” to “bad knees.” Table 5 lists some of the more frequent barriers to exercise. The health professional can play a critical role in the exercise program start-up and maintenance process by helping the patient identify the potential obstacles to success, and then assisting him/her with viable options to overcome those roadblocks. Table 6 lists 10 common barriers and possible solutions. Anticipating and preparing for obstacles to regular exercise improves the odds of success. However, barriers to physical activity are varied and unpredictable. Occasional crises and relapses should be expected, but not considered failures. Resume and/or modify activity as soon as each situation allows. The best advice is to be flexible, patient, and persistent.


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Table 5 Barriers to Exercise Time Convenience Support Enjoyment Self-esteem/confidence

Program direction Knowledge regarding exercise (myths) Being injury/illness-free Not a priority Program success

Regular physical activity is an essential part of any weight-management plan. Health improvements can be realized and maintained if consideration is given to individual needs and interests, as well as the setting of appropriate goals and exercise program guidelines. A discussion of potential roadblocks and options to overcome those barriers increases the probability that the aforementioned plans are carried out and the objectives met. In short, physical activity and exercise play a large role in the treatment of obesity. However, without proper eating habits, physical activity, and exercise, patients may never reach their full potential.

4. FUELING YOUR BODY FOR ACTIVITY AND WEIGHT MANAGEMENT Information abounds about supposed perfect diets that result in a quick and successful weight loss. However, these diets are typically difficult to maintain and many are unhealthful. Rather, life-style changes to acquire ongoing behaviors are the key. We recommend a life-style that includes a combination of healthy eating and exercise. Table 7 contains some guidelines that the health professional can provide to help patients develop an eating plan that will provide the necessary energy for exercise and still achieve their weight-loss goals. A successful weight-management effort includes eating well combined with physical activity. Physical activity requires adequate energy and nutrition from a variety of foods. Breaking free of diets that restrict foods and calories will allow the body to have what it needs to participate in a level of exercise required to meet weight-management goals.

5. CONCLUSION The health benefits of exercise include reduction in coronary heart disease risk factors, improved cardiovascular and respiratory function, reduced colon cancer risk, and enhanced psychological well-being. The first stage in the health professional’s role in treating obesity through physical activity, exercise, and proper nutrition is to explain the benefits of an active life-style. Knowledge alone, however, is not likely to lead to permanent life-style change. The second stage should focus on individualizing an exercise program to meet the person’s needs and interests. Roadblocks to positive behavior change can be avoided through a discussion of potential barriers. A combination of regular physical activity and sound eating habits is essential to enhance the chances for achieving a healthful weight. Most importantly, individuals should be encouraged to view physical activity as a permanent life-style behavior—a lifetime goal, not a 12-wk project. The recommendation to “be a tortoise, not a hare” will allow a modest, consistent effort over a long time to yield satisfying results.

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Table 6 Patient’s Barriers to Exercise and Possible Solutions Barrier 1: No time to exercise due to work and/or family obligations. Solutions: Exercise and socializing need not be mutually exclusive. Try exercising with family, friends, and co-workers to accomplish multiple objectives; schedule it into the day like any other appointment or meeting; exercise first thing in the morning before the day becomes too busy or fatigue becomes a factor. Barrier 2: Not convenient because of lack of fitness center, frequent travel, or vacation. Solutions: Because exercise minutes can have an accumulated effect, seek opportunities to incorporate physical activity into the daily routine. For example, take the stairs instead of the elevator or park further away from a destination; select health clubs that are on the way to and from work; choose activities like walking that can be done almost anytime or anywhere; inquire about workout facilities and/or nearby parks when making hotel arrangements. Barrier 3: Lack of support or too many distractions to stay committed. Solutions: The buddy system is very effective in keeping exercisers on track. Join a group or find a friend with similar goals; make an agreement to exercise. This helps to keep both parties honest when other options or diversions arise. Barrier 4: Boredom/lack of enjoyment makes exercise undesirable and easy to put off. Solutions: Make it fun! Read, listen to music/books on tape, watch TV or movies; change scenery and/or vary the routine; engage in conversation to pass the time. Barrier 5: Embarrassment from being out of shape, exercising in front of others and/or not having or being able to wear the right clothes. Solutions: Remind yourself who you are doing this for—you. Do not worry about competing with others, but instead concentrate on your goals. Find a friend with similar objectives for mutual encouragement; wear comfortable clothes; exercise at non-busy times in a fitness center if privacy is still an issue. Barrier 6: Lack of direction or structure in the exercise program. Solutions: Do not hesitate to seek assistance from qualified health professionals regarding exercise program development (goals and guidelines). After all, it is their job and there are no stupid questions where your health and fitness are concerned; check back with the exercise specialist periodically to update your goals and program as needed. Barrier 7: “No pain, no gain” (and other myths) make exercise less than appealing. Solutions: Again, discuss concerns and questions with a health professional to clear up misperceptions regarding exercise. For example, as stated earlier, even moderate intensity exercise can yield positive health results. In other words, it does not have to hurt to be effective. Barrier 8: Injury and/or illness will not allow for the development of a regular exercise program. Solutions: Listen to your body, and if frequent or chronic injuries occur, seek assistance from your physician or sports medicine specialist; vary the exercise routine to avoid overuse injuries; verify that the proper technique is being used during exercise; replace shoes if excessively worn; examine your daily life-style (i.e., sleep habits, physical and/or mental work environment, and diet patterns) for clues to possible causes of the problem(s). Barrier 9: Not a priority—too lazy and/or tired to exercise. Solutions: List the potential benefits to be gained from exercise and post them to remind you of your goals; low energy may be a sign that stamina needs improvement—exercising may decrease early or chronic fatigue and permit even more daily activity; keep a bag packed with exercise clothes by the door ready for the next day. Barrier 10: Lack of success in previous attempts, resulting in dissatisfaction and disenchantment with physical activity. Solutions: Consult a health professional regarding the setting and updating of appropriate goals, exercise guidelines, and program development; start slowly and increase activity gradually; keep an exercise log to review your accomplishments; seek periodic health and fitness assessments to measure progress; be patient, as results may take time to realize.


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Table 7 Guidelines for Helping Patients Develop an Eating Plan I. Use the Food Guide Pyramid to develop a low-fat and nutritious eating plan to support exercise Pearl: The body must have adequate fuel for exercise, even when weight loss is the goal. A minimum of six grains (three of those should be whole grains), a total of five fruits and vegetables, two servings from the dairy group, and two servings from the meat/protein group are recommended. II. Choose an eating plan based on generous amounts of fruits, vegetables, whole grains, beans, and legumes Pearl: Base meal plans on vegetables, grains, and legumes, such as stir-frys or casseroles, and add small amounts of meat or dairy foods as a complement. III. Minimize the use of sugar, salt or sodium, caffeine, and alcoholic beverages. Processed foods typically containing added sugar and salt are generally lower in nutritional value than their unprocessed counterparts. Pearl: When choosing fruits and vegetables, choose fresh or frozen. Read labels to be sure that they have no added sugar or salt. Find other ways to flavor food without adding salt or sugar to cooked foods. Limit consumption of caffeine-containing beverages to one or two a day, and before noon. Moderate consumption of alcoholic beverages to no more than one or two a day, and do not drink on an empty stomach. IV. Eat to fuel exercise; do not skip meals and snacks as a method to lose weight Pearl: Eat regularly, three to five times, throughout the day. Choose a variety of foods from the Food Guide Pyramid to make balanced meals and snacks that satisfy hunger and the energy needs for exercise. V. Do not make diets for weight loss a punishment that often ends in disappointment and failure Pearl: Consume an appropriate quantity and variety of foods to fuel your body for exercise. VI. Throw away lists of “bad” foods and “good” foods Pearl: Individuals should allow themselves the experience of pleasurable, guilt-free eating. They will feel better mentally and physically, remove the barriers to eating pleasure, and eliminate the feelings of deprivation. VII. Enjoy eating foods in a slow and relaxed manner. It takes at least 20 min for the feeling of satiety to be felt. Pearl: In a fast-paced society, slowing down to eat may be the only time out of the day an individual takes to relax. Eating should be a calm and relaxing experience. VIII. Maintain a gentle awareness about food choices Pearl: Limit fast foods and snacks to keep fat calories below 30% of the total diet. IX. Enjoy the flexibility of normal eating. On some occasions one may eat too much (holiday family meal). Physical hunger is the body’s response to not having been fed for several hours and is a painful feeling. Physical hunger is satisfied by any type of food that provides the body with needed energy. Pearl: Learn the difference between physical hunger, emotional hunger, and appetite. Eat in response to physical hunger and stop eating when that hunger is satisfied.

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ACKNOWLEDGMENTS We wish to acknowledge the research efforts of Amy Gibbs, an intern in the Center for Educational Services at The National Institute for Fitness and Sport. A special thanks to Cassie Stumpf for her organizational support and personal assistance. Their help was greatly appreciated and instrumental in writing this chapter.

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47. Poehlman ET, Melby CL, Badylak SF. Resting metabolic rate and postprandial thermogenesis in highly trained and untrained males. Am J Clin Nutr 1988; 47:793–798. 48. Poehlman ET, Melby CL, Badylak SF, Calles J. Aerobic fitness and resting energy expenditure in young adult males. Metabolism 1989; 38:85–90. 49. Hill JO, Heymsfield SB, McMannus C, DiGirolamo M. Meal size and thermic response to food in male subjects as a function of maximum aerobic capacity. Metabolism 1984; 33:743–749. 50. Bray G. Effect of caloric restriction on energy expenditure in obese subjects. Lancet 1969; 2:397–398. 51. Leibel RL, Rosenbaum M, Hirsch J. Changes in energy expenditure resulting from altered body weight. N Engl J Med 1995; 332:621–628. 52. Saris WH. The role of exercise in the dietary treatment of obesity. Int J Obesity 1993; 17(Suppl 1):S17–S21. 53. Geliebter A, Maher MM, Gerace L, Gutin B, Heymsfield SB, Hashim SA. Effects of strength or aerobic training on body composition, resting metabolic rate, and peak oxygen consumption in obese dieting subjects. Am J Clin Nutr 1997; 66:557–563. 54. Dempsey JA. Anthropometrical observations on obese and non-obese young men undergoing a program of vigorous physical exercise. Res Quart 1964; 35:275–287. 55. Dudleston AK, Benniou M. Effect of diet and/or exercise on obese college women. J Am Diet Assn 1970; 56:126–129. 56. Oscai LB, Williams BT. Effect of exercise on overweight middle-aged males. J Am Geriatr Soc 1968; 16:794–797. 57. Boileau RA, Buskirk ER, Horstman DH, Mendez J, Nicholas WC. Body compositional changes in obese and lean med during physical conditioning. Med Sci Sports Exerc 1971; 3:183–189. 58. Westerterp-Plantenga MS, Verwegen CR, Ijedema MJ, Wijckmans NE, Saris WH. Acute effects of exercise or sauna on appetite in obese and nonobese men. Physiol Behav 1997; 62:1345–1354. 59. Leon AS, Conrad J, Hunninghake DB, Serfass R. Effects of a vigorous walking program on body composition and lipid metabolism of obese young men. Am J Clin Nutr 1979; 33:1776–1787. 60. Pi–Sunyer FX. Effect of exercise on food intake. In: Hirsch J, Van Itallie TB, eds. Recent Advances in Obesity Research IV. John Libbey, London, 1985. 61. Anon. Physical activity and cancer. Physical Activity Fitness Res Digest 1995; 2(2):1–6. 62. Lew EA, Garfinkel L. Variations in mortality by weight among 750,000 men and women. J Chronic Dis 1979; 32:563–576. 63. Bernstein L. Henderson BE, Hanisch R, Sullivan-Halley J, Ross RK. Physical exercise and reduced risk of breast cancer in young women. J Natl Cancer Inst 1994; 86:1403–1408. 64. Sinyor D, Schwartz SG, Peronnet F, Brisson G, Seraganian P. Aerobic fitness level and reactivity to psychosocial stress: physiological, biochemical and subjective measures. Psychosom Med 1983; 45(3):205–217. 65. Keller S, Seraganian P. Physical fitness level and automatic reactivity to psychosocial stress. J Psychosom Res 1984; 28(4):279–287. 66. Tucker LA, Cole GE, Friedman GM. Physical fitness: a buffer against stress. Perceptual and Motor Skills 1986; 63:955–961. 67. Crews DJ, Landers, DM. A meta-analytic review of aerobic fitness and reactivity to psychosocial stressors. Med Sci Sports Exerc 1987; 19(5):S114–S120. 68. Brownell KD, Stunkard AJ. Physical activity in the development and control of obesity. In: Stunkard AJ, ed. Obesity. WB Saunders, Philadelphia, PA, 1980, pp. 300–324. 69. Horton ES. The role of exercise in the prevention and treatment of obesity. In: Bray GA, ed. Obesity in Perspective. Vol. 2, Part 1. DHEW Publication No. (NIH) 75–708. Washington, DC, US Government Printing Office, 1975, pp. 62–66. 70. Mahoney KB. Adipose cellularity as a predictor of responsiveness to treatment of obesity. Ph.D. dissertation. The Pennsylvania State University, 1977. 71. Wilson GT. Brownell KD. Behavior Therapy for Obesity: An evaluation of treatment outcome. Adv Behav Res Ther 1980; 3:49–86. 72. Mattsson E, Larsson UE, Rossner S. Is walking for exercise too exhausting for obese women? Int J Obes Relat Metab Disorders 1997; 21:380–386. 73. Rikli RE, McManis BG. Effects of exercise on bone mineral content in post menopausal women. Res Quart Exerc Sport 1990; 61:243. 74. Perri MG, Martin AD, Leermakers EA, Sears SF, Notelovitz M. Effects of group versus home-based exercise in the treatment of obesity. J Consult Clin Psychol 1997; 65:278–285. 75. American College of Sports Medicine. ACSM’s Guidelines for Exercise Testing and Prescription, 5th ed. Williams and Wilkins, Baltimore, MD, 1995:12–26,153–175. 76. Borg GAV. Psychophysical bases of perceived exertion. Med Sci Sports Exerc 1982; 14(5):377–381.

Chapter 14 / Behavioral Treatment of Obesity

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Behavioral Treatment of Obesity New Approaches to an Old Disorder

Thomas A. Wadden and David B. Sarwer 1. INTRODUCTION Behavior therapy has figured prominently in the management of obesity since Stuart’s (1) landmark report of this approach in 1967. Even today, with the promise of a new generation of antiobesity drugs, experts caution that medication must be combined with a comprehensive program of behavior modification, now frequently referred to as lifestyle modification (2,3). This caveat recognizes that our nation’s growing obesity problem is attributable primarily to changes in our daily eating and activity habits rather to changes in our gene pool. This chapter briefly discusses the goals and methods of behavioral treatment, the short- and long-term results of this approach, and innovative new applications of this therapy (see Table 1).

1.1. Treatment Philosophy: A Brief Overview Early behavior therapists held that obesity was a learned disorder that resulted from simply eating too much and exercising too little (1,4). Therapy helped patients unlearn maladaptive behaviors and acquire more appropriate ones. This simplistic view has been modified in light of findings that body weight is influenced by genetic, metabolic, and hormonal factors that elude voluntary control (5–7). Such factors clearly predispose some individuals to obesity and probably limit the lowest weights they can achieve. Obese individuals often greet news of genetic influences with dismay, concluding that there is little they can do to control their weight. Studies of laboratory animals, however, have revealed the importance of behavior in the presence of clear biological constraints. Sclafani and Springer (8), for example, have shown that the same animal will maintain either a lean or an obese weight, depending on the diet and exercise regimen provided. Thus, a rat deprived of its running wheel and fed a high-fat, high-sugar diet of supermarket foods will increase its weight by 30–40% and maintain the higher weight chronically, as long as the diet is provided (8). Animals with a genetic predisposition to obesity are even more responsive to changes in the environment (9). Obese individuals, like these laboratory animals, probably have a range of weights they can maintain (10). Genetic and metabolic influences may well set the range of possible weights, such that a person with a marked family history of obesity will never be thin. Eating and activity habits, however, probably determine the specific point within From: The Management of Eating Disorders and Obesity Edited by: D. J. Goldstein © Humana Press Inc., Totowa, NJ

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Part III / Treatment Table 1 Chapter Overview 1. Introduction 1.1. Treatment Philosophy: A Brief Overview 2. Behavioral Assessment 2.1. Biological Factors 2.2. Environmental Influences 2.3. Social–Psychological Status 2.4. Timing 3. Treatment Goals and Options 4. Cognitive Behavioral Treatment 4.1. Self-Monitoring 4.2. Problem-Solving 4.3. Nutrition 4.4. Stimulus Control 4.5. Slowing Eating 4.6. Cognitive Restructuring 4.7. Exercise 5. Short-Term Results of Treatment 5.1. Increasing Initial Weight Loss 5.1.1. Extending Treatment Duration 5.1.2. Very-Low-Calorie Diets 5.1.3. Portion-Controlled Diets 6. Long-Term Results of Treatment 7. New Goals of Obesity Treatment 7.1. Basis of New Recommendations 8. Improving Long-Term Weight Management 8.1. Long-Term Behavioral Treatment 8.1.1. Frequency of Follow-up 8.1.2. Size of W eight Losses 8.1.3. Delaying or Preventing Weight Regain 8.2. Long-Term Pharmacologic Treatment 8.2.1. Size of Weight Losses 8.2.2. Role of Behavioral Treatment 8.2.3. Combined Behavioral–Pharmacologic Treatment 9. Future Directions 9.1. Acceptance of Modest Weight Losses 9.2. Improving Body Image Attitudes 10.Summary

the range at which weight is regulated (10). The goal for individuals with a strong genetic predisposition to obesity is to adopt a low-fat and high-activity life-style that regulates weight at the low end of their possible weight range. As discussed later, we believe that this range is approximately 10%–15% of initial weight, such that a woman who now weighs 100 kg can probably reduce her weight to 85–90 kg (and maintain it there) by adopting a low-fat, high-activity life-style (11). She is unlikely, however, to maintain a weight of 70 kg, despite tenacious efforts.


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Table 2 Comprehensive Behavioral Assessment (BEST) B

E

S

T

Biological factors—helps in setting reasonable goal weight Family history Onset of obesity Weights at 5-yr intervals Dieting history Environmental influences Eating habits Physical activity Social–psychological status Mood Sleep Body image Self-esteem Satisfaction with family and work Temporal factors Motivating factors Life stressors

2. BEHAVIORAL ASSESSMENT Before beginning treatment, patients should have a comprehensive behavioral assessment to evaluate: (a) factors responsible for their obesity, (b) their psychosocial status, (c) goals and expectations of treatment, and (d) the timing of therapy (12). The assessment requires about 1 h and is best conducted by a mental health professional, although it can be conducted by physicians, nurses, or dietitians who have access to psychiatric consultation when needed. This assessment has been described previously (12) and is summarized only briefly here (Table 2). It covers four areas: (a) biological, (b) environmental, (c) social-psychological, and (d) temporal factors (i.e., BEST treatment).

2.1. Biological Factors Biological predisposition to obesity can be roughly gauged by inquiring about the patient’s age of onset and family history of obesity, as well as the individual’s dieting history and weights at 5-yr intervals (12). As a general rule, we find that our heaviest patients are positive for a family history of obesity, child–adolescent onset, and a marked history of weight loss and regain (i.e., weight cycling) (13). This information, in conjunction with body weights at various milestones, is useful for selecting weight-loss goals. Such individuals lose weight but rarely achieve the goal weights they desire (14). Thus, an individual who wishes to reduce to 80 kg is unlikely to do so, if the last time she weighed this amount was in the seventh grade. As a rule, the goal weight should be no lower than the lowest weight since age 21 that the patient has maintained for 1 yr or more without illness or dieting (12,15).

2.2. Environmental Influences Patients’ eating habits are best assessed by having them record their food and beverage intake for several days before the interview (12). The goal is to determine the general

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composition of the diet (particularly with regard to fat and sugar), the approximate calorie intake, and the individual’s pattern of eating. Patients should be instructed to consume their usual diet, although some dietary restraint may occur as a result of recording. Binge eating (see Chapter 11) should be assessed by asking whether the patient has occasions on which he/she eats, in a brief period of time, large amounts of food (i.e., which would be considered large by others) and feels out of control while doing so (16). Such behavior occurs in about 20–30% of obese individuals treated in specialty clinics but in only about 2% of the general population (17). Binge eating can be assessed by the Questionnaire on Weight and Eating Patterns (16) and treated, as discussed later, by methods including cognitive behavioral therapy and antidepressant medications. Obese binge eaters usually require more structure and emotional support during weight loss than do obese nonbingers. Exercise can be assessed by inquiring about the patient’s daily life-style activity (i.e., walking and stair use), as well as participation in recreational sports such as aerobics, tennis, swimming or bowling (12). Attitudes toward exercise also should be assessed. The above questions should reveal the relative contributions of overeating and inactivity to the individual’s obesity. Patients’ shame or embarrassment about their behavior should be greeted with reassurance that new eating and exercise habits can be learned. The most challenging cases are those in which patients report exemplary eating and activity habits and yet are substantially overweight. Assessment of resting energy expenditure is useful in such cases to verify the patient’s report of low-energy intake (18).

2.3. Social–Psychological Status About 25–35% of obese patients treated in university and hospital clinics suffer from depression or related disturbances that may require treatment (19). Thus, the practitioner should inquire about the patient’s mood, sleep, appetite, and enjoyment of activities. Paper-and-pencil tests such as the Beck Depression Inventory (20) provide an excellent method of screening. The presence of binge eating is a marker for dysphoria; obese binge-eaters consistently score higher in depression than do obese nonbingers (16,17). Mood should be assessed in the context of learning about the patient’s work, intimate relationships, current life goals, methods of coping, and general strengths and weaknesses (12). In addition, the practitioner should assess how weight has affected the patient’s psychosocial development, including body image and selfesteem. Particularly in persons with childhood onset of obesity, weight is likely to have been a source of frustration and sadness at many of life’s most important moments. Patients often are grateful for the chance to discuss these experiences with a concerned listener (21).

2.4. Timing The practitioner should also determine why the patient has decided to lose weight at this time (12). In most cases, patients have been overweight for many months, if not years, and something has prompted them to seek weight loss. The prompt, such as the discovery of a weight-related illness or a spouse’s urging, may be a source of distress and should be discussed with the patient. It is important to determine that the patient is motivated to lose weight rather than simply being told to do so by family members, an employer, or the family doctor.


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Patient and provider also should determine whether it is a favorable time to attempt weight loss. The patient should be relatively free of major life stressors for the next few months, given findings that the higher the stress level (i.e., new job, financial problems, family illness, etc.), the greater the likelihood of attrition from therapy (22). During difficult times, patients should strive to maintain their weight (neither gaining nor losing) and wait for a more favorable time to begin treatment.

3. TREATMENT GOALS AND OPTIONS The above assessment should conclude with a discussion of the patient’s goals of treatment and the extent to which they are realistic. We usually assess desired changes in four areas: (a) weight, (b) health and mobility, (c) appearance and body image, and (d) social life and self-esteem (see Appendix 1). Based on findings discussed in Subheading 5., we suggest that patients expect a weight loss of approximately 8%–10% of initial weight when treated by cognitive behavioral therapy and 10%–15% when treated by this therapy combined with medication (11). These losses are usually far smaller than those desired by significantly obese persons (23). To set realistic expectations, we usually indicate that a 10% weight-loss weight will improve many of the health complications of obesity (24) but may not enhance body image or psychosocial functioning to the extent desired. If further improvements in psychological status o4e desired, additional measures should be taken to achieve them, such as cognitive behavioral therapy for body-image disturbance (discussed later) or skills training to improve social life (12). Figure 1 presents a conceptual scheme for selecting treatment, based on the patient’s body mass index (weight in kg/height in m2) and the medical need for weight reduction, as judged by the presence of comorbid conditions or other risk factors. We believe that all persons with a body mass index (BMI) > 30 kg/m2 should first be treated by a comprehensive behavioral program combined with a 1200–1500-kcal/d balanced diet (as described in Subheading 4.) (25). Those unsuccessful with this approach may be treated, in addition, by pharmacotherapy or a portion-controlled low-calorie or very low-calorie diet. Severely obese patients, with a BMI > 40 kg/m2, have the option of gastric surgery (26). The next section describes a typical program of cognitive behavioral therapy combined with a 1200 to 1500-kcal/d diet.

4. COGNITIVE BEHAVIORAL TREATMENT Behavioral treatment relies on the functional analysis of behavior to identify events that are associated with inappropriate (as well as appropriate) eating, exercise, or thinking habits (27,28). The approach examines antecedents, behaviors, and consequences (ABCs). Once events such as emotional upset or television watching are reliably found to precede overeating, steps are taken to control or modify the antecedent events. The individual, for example, who overeats while watching TV would limit his eating to the kitchen or dining room and, thus, extinguish the association between eating and television. Eating behaviors also are targeted for change. One of the consequences, for example, of eating slowly is increased enjoyment of food and greater satiety. Thus, patients are instructed in techniques to slow their rate of eating. They also are taught how to control the emotional upset that results from overeating (and often leads to more eating).

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Fig. 1. A conceptual scheme showing a three-stage process for selecting a treatment for an individual. The first step, the Classification Decision, divides people into four levels based on body mass index (BMI). This level dictates which of four steps would be appropriate in the second stage, the Stepped-Care Decision. This indicates that the least intensive, costly, and risky approach will be used from among the treatment alternatives. The solid arrow between the boxes identifies the treatment most likely to be appropriate. The third stage, the Matching Decision, is used to make a final treatment selection, based on the assessment of the patient’s need for weight reduction, as judged by the actual presence of comorbid conditions or other risk factors. The arrow with open circles indicates a reduced need for weight reduction because of the absence of risk factors. The arrow with closed circles shows the more intensive treatment option, appropriate for persons with a significant comorbid condition. For example, many patients with a BMI of 27–29 kg/m2 do not have health complications. The appropriate treatment for such individuals would include a commercial program or a behavioral or self-help approach. By contrast, the practitioner may wish to 2 consider pharmacotherapy with an individual with a BMI of 29 kg/m who also has type II diabetes. Patients with significant psychiatric problems, or who want more support in changing diet and exercise habits, can be referred for adjunct care. Reprinted with permission of Thomas A. Wadden, PhD and Kelly Brownell, PhD.

Patients’ eating and exercise habits can be most effectively analyzed in individual treatment. Most weight-reduction therapy, however, is conducted in groups (27). Group treatment reduces the cost of therapy, which is not usually covered by insurance plans, and provides important social support. Treatment has been distilled into several principal components (described below) that are covered in treatment programs that usually last from 16–26 wk and are delivered to groups of 10–20 people. We recommend groups of 8–10 persons which meet for 60–90 min. This size ensures that all patients have a chance to talk.


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Patients are usually given a treatment manual, such as the LEARN Program for Weight Control (28), which provides weekly readings and homework assignments for adopting new behaviors. As such, treatment is very goal directed. But more than just providing assignments, treatment sessions are designed to help patients develop strategies to implement desired behaviors, as well as identify barriers to behavior change. Thus, treatment sessions are process oriented, which distinguishes them from lectureoriented presentations (12). The next section provides a brief overview of the principal components of treatment. Those wishing to use a behavioral approach are encouraged to obtain one of the detailed manuals, such as the LEARN Program (28).

4.1. Self-Monitoring Self-monitoring—the recording of one’s behavior—often is considered the cornerstone of behavioral treatment (27,29). Patients keep extensive records of their food intake (and physical activity) throughout treatment. In the initial weeks, they record daily the types, amounts, and caloric value of foods eaten. Armed with this information, they try to reduce hidden sources of fat and sugar from their diet and, thus, decrease their calorie intake by approximately 500–700 kcal/d. Record keeping is increased over time to include information about times, places, and feelings associated with eating (as shown in Fig. 2). These events are analyzed to determine precipitants of inappropriate eating and to plan interventions. Several correlational studies have shown that self-monitoring is associated with successful long-term weight control (30).

4.2. Problem-Solving Identification of appropriate dietary and exercise interventions is facilitated by the use of problem-solving skills (31). As applied to weight management, problem solving is used to: (a) define the weight- or eating-related problem, (b) generate possible solutions to the difficulty, (c) evaluate the solutions and then select the most appropriate one, (d) implement the new behavior, (e) evaluate the outcome, and (f) re-evaluate alternative solutions if the one selected is not successful (32). Effective problem solving correlates positively with the maintenance of weight loss (33).

4.3. Nutrition Patients in behavioral treatment are not prescribed a diet. Instead, they are asked to consume foods they like but to modify their diet so that it promotes weight control and cardiovascular health. To this end, patients are usually taught how to use the Food Guide Pyramid (34) and are encouraged to consume approximately 12% of calories from protein, no more than 30% from fat, and the remainder from carbohydrates. Women are frequently prescribed a daily calorie goal of approximately 1200 kcal and men a goal of 1500–1800 kcal. Patients have the option of monitoring their calorie intake, fat intake, servings from the Food Guide Pyramid, or combinations of these (28). Monitoring fat intake alone may result in a smaller weight loss than monitoring calories (35). Investigators had expected that reducing fat intake while allowing ad libitum consumption of carbohydrate would produce better long-term weight loss than conventional caloric restriction. However, two studies failed to support this hypothesis (35,36).

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Fig. 2. A daily log for recording foods and beverages consumed, physical activity, and thoughts and feelings related to weight control. (Reprinted with permission of Thomas A. Wadden, Ph.D).

4.4. Stimulus Control Stimulus-control techniques are designed to modify antecedents to eating. These interventions can be classified into five broad categories: (a) shopping prudently to keep problem foods out of the house, (b) storing foods properly to reduce incidental eating, (c) leaving food on the plate, (d) limiting times, places, and activities associated with eating, and (e) planning for social situations involving food (27,28). The benefits of stimulus control have not been demonstrated empirically but these procedures remain a part of treatment because of their intuitive appeal.


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4.5. Slowing Eating Patients are taught to slow their rate of eating to improve satiety and, thus, reduce food intake. Typical strategies include putting down utensils between bites, pausing during meals, counting bites, and chewing food thoroughly before swallowing (28,30). These techniques also may help patients enjoy their food more and, thus, counteract feelings of deprivation that often accompany caloric restriction. Empirical support for this intervention is limited to one study, but it did show that patients who ate more slowly lost larger amounts of weight (37).

4.6. Cognitive Restructuring Cognitive restructuring teaches patients to identify, challenge, and correct the negative thoughts that frequently undermine dieters. Such thoughts typically fall into one of three categories: (a) the impossibility of successful weight control, (b) unrealistic eating and weight-loss goals, and (c) self-criticism in response to perceived dietary lapses (12,28). Patients are taught to identify and improve their thinking by self-monitoring. They record the negative self-statements (i.e., thoughts) they had during an overeating episode or some other upsetting experience. Then, in treatment sessions, they examine the validity of irrational, self-critical thoughts and identify more appropriate, rational responses. These positive responses must be practiced repeatedly until they start to ring true. Cognitive restructuring has proven to be effective in the treatment of depression (38), bulimia nervosa (39), and other psychiatric conditions (40). Its efficacy, however, with obesity has not been adequately demonstrated. However, our clinical experience is that cognitive restructuring is a critical treatment component for obese patients with low selfesteem and/or a negative attributional style. It also is the most difficult component of treatment to implement successfully. Interested practitioners would benefit from attending a day-long workshop on cognitive therapy or otherwise obtaining formal training.

4.7. Exercise The above interventions have focused primarily on reducing energy (food) intake. Weight loss, however, also can be induced by increasing energy expenditure through increased physical activity. Brownell and Stunkard (41) have divided activity into two categories. Programmed activity consists of regularly scheduled bouts of physical exertion, which include sports such as running, swimming, cycling, and the ever-widening spectrum of aerobic workouts. Life-style activity, the second category, involves increasing energy expenditure during the course of the day by activities such as walking rather than riding, using stairs rather than escalators, and discarding energy-saving devices such as TV remote controls and extension telephones. (See Chapter 13 for strategies on encouraging exercise.) In the only comparisons of these approaches, Epstein and colleagues (42,43) found that in children, life-style activity was associated with better maintenance of weight loss than was programmed exercise. Most practitioners, however, encourage patients to increase both types of activity (12,28,31,44). Patients usually begin by walking two or three times a week for about 20 min at a time. Over 10–15 wk, they are encouraged to increase their walking (or other aerobic activity) to four or five times weekly for 40–45 min per bout. The eventual goal for life-style activity is to expend an extra 100 kcal/d (12,31).

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Adding exercise to a 1200-kcal/d diet marginally increases weight loss—perhaps by 2 kg—during a 12–20-wk program (45,46). (Most persons have to walk about 70 miles to burn just 1 kg of fat!) Thus, the weight-reducing benefits of exercise should not be overstated, lest patients grow disappointed by their results. The true benefits of exercise may reside in improving health and mood (47) and in facilitating the maintenance of weight loss (30). Numerous studies have found that persons who maintained their weight loss reported exercising regularly, whereas weight regainers did not (30,33,48). Reasons for this improved outcome are not entirely understood but have been attributed to the favorable effects of exercise on body composition and possibly resting metabolic rate, in addition to the increased energy expenditure during physical activity (49,50). The key therapeutic challenge is ensuring that patients continue to exercise following termination of formal treatment. Several randomized trials have shown that exercise adherence declines over time, an occurrence associated with eventual weight regain (31,46,51,52). Home-based exercise programs appear to be associated with better adherence and longterm weight loss than are clinic-based approaches. Participants appear to stop exercising when supervised programs end (53).

5. SHORT-TERM RESULTS OF TREATMENT The data in Table 3 show that patients currently treated by a comprehensive behavioral approach lose approximately 8.5 kg during 20 wk of treatment. The table summarizes the results of behavioral treatment from 1974 to 1995, as determined from randomized clinical trials published in four leading journals—Addictive Behaviors, Behaviour Research and Therapy, Behavior Therapy, and Journal of Consulting and Clinical Psychology. Studies were included in this table only if they were considered representative of behavioral treatment as typically practiced. Thus, for example, short-term studies that used computer-assisted therapy were not included (54,55). The table updates findings first reported by Brownell and Wadden in 1986 (56). A comparison of early (i.e., 1970s) and more recent studies (1991–1995) reveals that as treatment duration has increased, so has weight loss. Thus, for example, in 1974, treatment of 8.4 wk was associated with a mean loss of 3.8 kg, whereas therapy from 1991–1995 averaged 22.2 wk and produced a mean loss of 8.5 kg. The rate of weight loss has remained constant over time at about 0.4–0.5 kg/wk, suggesting that longer treatment, rather than the introduction of new treatment procedures (such as cognitive restructuring), is responsible for the greater weight loss. Low attrition rates, of less than 20%, indicate that the great majority of patients who begin treatment will benefit. Thus, treatment outcome has improved markedly since the late 1950s when Stunkard (57) so memorably summarized the results of that era: “Most obese persons will not stay in treatment. Of those who stay in treatment, most will not lose weight and of those who do, most will regain it” (p. 79).

5.1. Increasing Initial Weight Loss 5.1.1. EXTENDING TREATMENT DURATION Investigators have tried during the past decade to increase the size of initial weight losses, given that most patients remain obese even after “successful” behavioral treatment (see Table 3). Three approaches have been studied, the first of which was simply extending the length of treatment. Four long-term studies have revealed the limitations


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Table 3 Summary Analysis of Randomized Clinical Trials of Group Behavior Therapy for Obesity

Number of studies Sample size Initial weight (kg) Length of treatment (wk) Weight loss (kg) Loss per week (kg) Attrition (%) Length of follow-up (wk) Loss at follow-up (kg)

1974

1978

1985–1987

1988–1990

1991–1995

15 53.1 73.4 8.4 3.8 0.5 11.4 15.5 4.0

17 54.0 87.3 10.5 4.2 0.4 12.9 30.3 4.1

13 71.6 87.2 15.6 8.4 0.5 13.8 48.3 5.3

5 21.2 91.9 21.3 8.5 0.4 21.8 53.0 5.6

5 30.2 94.9 22.2 8.5 0.4 18.5 47.7 5.9

Note: The data are adapted and updated from ref. 56. All studies sampled were published in the following four journals: Addictive Behaviors, Behavior Therapy, Behaviour Research and Therapy, and Journal of Consulting and Clinical Psychology. All values, except for number of studies, are weighted means. Thus, studies with larger sample sizes had a greater impact on the mean values than did studies with smaller sample sizes. The five studies in the 1991–1995 analysis can be found in refs. 45, 59, 77, 118, and 119. In all studies, data are reported only for standard behavioral interventions.

of this approach. Wadden and colleagues (58) treated patients for 52 consecutive weeks by behavior therapy and a 1000–1200 kcal/d diet. Participants lost 11.9 kg during the first 26 wk, but only an additional 2.5 kg during wk 27–52. Perri and colleagues (59) reported comparable findings in a 40-wk study. Patients treated weekly for 1 yr by Wing and colleagues (60) lost 13.5 kg during the first 26 wk, but regained 2.1 kg during weeks 27– 52. Factors responsible for patients’ failure to continue to lose weight during extended treatment are poorly understood. Reductions in resting energy expenditure which slow weight loss are a probable factor (61,62), as is possible treatment burn-out, reflected by poor dietary adherence (63) and declining attendance of treatment sessions (51,60). Further study of these issues is required, but it is now clear that extending treatment does not yield weight losses of more than 12–15% of initial weight for the great majority of patients. 5.1.2. VERY LOW-CALORIE DIETS The second method of inducing larger losses has been the use of very low-calorie diets (VLCDs) providing 400–800 kcal/d. These diets are generally safe when used with carefully selected patients under appropriate medical supervision, although patients are at increased risk of developing gallstones (64–66). Nine randomized trials that have combined behavioral treatment with the use of a VLCD for 8 or more weeks have reported average weight losses of 14.2–21.8 kg, equal to reductions of approximately 15%–22% of initial weight (58,60,67–73). As discussed in a later section, patients typically regain 35–50% of their weight loss in the year following treatment. A majority, however, appear to maintain a loss of *5% of initial weight for 3 yr or more (74). 5.1.3. PORTION-CONTROLLED DIETS Portion-controlled diets also have been used to increase initial weight losses. Wadden and Bartlett (65) hypothesized that the greater than expected differences in weight loss between an 800 kcal/d VLCD and a 1000 to 1200 kcal/d diet of conventional foods was attributable to patients’ difficulties with the latter diet in measuring portion sizes and

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calculating calories. Obese individuals typically underestimate their calorie intake by 20–50% when consuming a conventional diet (75,76). VLCDs, by contrast, provide patients a portion-controlled diet with a known energy intake, factors that should facilitate adherence to a daily calorie goal (65). Jeffery and colleagues (77) have demonstrated the effectiveness of a portion-controlled diet in increasing weight loss. Subjects treated by a standard behavioral program (with a self-selected 1000-kcal/d diet) lost 7.7 kg during 6 mo. Those treated by the same program, but who also were given their breakfast and dinner meals 5 d/wk, lost a significantly greater 10.1 kg. In a follow-up study, these investigators showed that it was the provision of a structured meal plan, rather than the foods per se, that was responsible for the success of the portion-controlled diet (78). Thus, patients who were provided a meal plan that told them precisely what foods to purchase (and eat) lost 12.0 kg in 6 mo, whereas those instructed to consume a standard self-selected diet (of the same caloric value) lost a significantly smaller 8.0 kg. Patients given foods, in addition to the meal plan, lost 11.7 kg–a significantly greater loss than that produced by standard behavioral treatment but not by the provision of a meal plan alone. These findings are similar to those from a study of VLCDs. Patients who were provided a list of high-protein foods (i.e., lean meat, fish, and fowl) to purchase (and consume) lost similar amounts of weight as patients who were given a high-protein liquid diet (65). This set of findings supports many patients’ reports that they are successful, at least in the short term, with a “no-brainer” approach that eliminates food choices.

6. LONG-TERM RESULTS OF TREATMENT Data in Table 3 confirm a widely heard lament—that dieters regain their lost weight. In the studies from 1985 to 1995, patients treated by behavior therapy combined with a 1200-kcal/d diet regained approximately 30–35% of their weight loss in the year following treatment. Longer follow-up is associated with greater regain. Thus, 5 yr after treatment, Wadden and colleagues (69) found that subjects, on average, had returned to their baseline weight, findings consistent with those of other investigators (79). Weight regain is a problem regardless of the diet selected. Patients prescribed VLCDs have typically regained 35–50% of their weight loss in the year following treatment (58,60,67–73), whereas those in the two portion-control studies by Wing and Jeffery and their colleagues regained approximately 35–45% (77,78). Patients treated by the more conservative approach of reducing only fat intake (while allowing ad libitum intake of carbohydrates) have fared about the same. Those so treated by Schlundt and colleagues (35), as well as Jeffery and colleagues (36), lost 4.6 kg in 20–24 wk of treatment but maintained reductions of only 2.1–2.6 kg 1 yr after treatment. Somewhat more favorable results were reported by Pascale and colleagues (80).

7. NEW GOALS OF OBESITY TREATMENT These highly publicized long-term results have been taken as evidence that “diets don’t work” (81,82). This statement is correct if what is meant is that patients are expected to lose weight and maintain the loss for 5 or more years. However, few treatments for chronic conditions—including hypertension, diabetes, bulimia nervosa, or depression— enjoy such success. Moreover, the long-term benefits of obesity therapy should not be overlooked. Even with weight regain, a majority of patients maintain a 5% reduction


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in initial weight 1 or more years after treatment (11,74). Losses of this size are associated with improvements in weight-related health complications, including hypertension, diabetes, and hypercholesterolemia (24,83). These favorable findings have led prominent scientific bodies, including the Institute of Medicine, to recommend modest weight losses, as noted in the following statements: Many people are not sure how much weight they should lose. Weight losses of only 5-10 percent of body weight may improve many of the problems associated with overweight, such as high blood pressure and diabetes. Even a smaller loss can make a difference. (84, p. 111) Small weight losses, of as little as 10 to 15 percent of initial body weight, can generally help reduce obesity-related co-morbidities (e.g., hypertension, abnormal glucose tolerance, and abnormal lipid concentrations), decrease the risk of depression, and increase self-esteem. In many cases, the obese person finds that weight loss helps to resolve the symptoms of a co-morbidity or slow its progression. (85, p. 55) Successful long-term weight control by our definition means losing at least 5 percent of body weight ... and keeping it below our definition of significant weight loss for at least 1 year. (85, p. 55)

As seen in Table 3, behavioral treatment meets the Institute of Medicine’s criteria for successful long-term weight control. Patients, on average, reduce their initial weight by approximately 9% at the end of treatment and maintain a reduction of 6% 1 yr after treatment. Weight losses produced by behavioral treatment are clearly associated with improvements in cardiovascular risk factors, as recently demonstrated by Wing and Jeffery (86).

7.1. Basis of New Recommendations Two additional developments have led investigators to recommend weight loss, when only a decade ago there was significant debate about the wisdom of this recommendation, in view of high relapse rates (65). The first finding is the definitive evidence that excess weight is associated with increased morbidity and mortality. Manson and colleagues (87) have shown that persons with a BMI * 27 kg/m2 are at increased risk of coronary heart disease and other complications. Denial or minimization of obesity’s adverse health effects is no longer tenable. A second finding is that cycles of weight loss and regain (i.e., weight cycling) do not appear to be associated with the adverse effects previously hypothesized (88). Concern about the potential deleterious effect of weight cycling may have deterred many Americans from seeking weight loss. Figure 3 presents data for 12 women who lost 19 kg in 6 mo and then regained to their baseline weight over 3 yr (89). Weight cycling was not associated with long-term reductions in resting energy expenditure or fat-free mass, nor did it result in increased deposition of fat in the upper body—all three occurrences which had been feared. Additional studies have found that weight regain following intentional weight loss is not associated with significant adverse psychological effects (90–92), although it may be associated with an increased risk of binge eating (92). Other reports have cast doubt on its association with increased morbidity and mortality (93).

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Fig. 3. Measurement of resting energy expenditure (REE), body weight, fat-free mass (FFM), and body fat in 12 women before treatment, after a mean weight loss of 18.9 ± 2.6 kg, and following weight regain over an average period of 29.3 ± 5.0 mo. After full-weight regain, none of the values for REE, FFM, or body fat differed significantly from baseline values. (From ref. 89 and reproduced here with permission of John Wiley and Sons.)

8. IMPROVING LONG-TERM WEIGHT MANAGEMENT Maintaining weight loss remains the single greatest challenge for significantly obese patients and their practitioners. This problem may be ultimately solved by research on the genetics of obesity and body weight regulation, as exemplified by the discovery in the mouse of the ob gene (94) and its protein product, leptin (7). Even then, steps must be taken to prevent the development of obesity by reversing a national life-style that implicitly discourages physical activity (as a result of changes in home, school, and work environments) and explicitly encourages (through vast advertising budgets) the consumption of a high-fat, high-sugar diet. Until such discoveries and changes occur, practitioners must realize that obesity is a chronic condition that, like hypertension and diabetes, requires long-term care (24). Long-term behavioral treatment and long-term pharmacotherapy each have been shown to improve the maintenance of weight loss (11).

8.1. Long-Term Behavioral Treatment 8.1.1. FREQUENCY OF FOLLOW-UP A series of studies by Perri and colleagues have demonstrated the benefits of long-term behavioral treatment (31,46,95,96). Patients in a study who attended every-other-week


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group maintenance sessions for the year following weight reduction maintained 13.0 kg of their 13.2 kg end-of-treatment weight loss, whereas those who did not receive such therapy maintained only 5.7 kg of a 10.8 kg loss (31). Studies by Wadden et al. (58) and Wing et al. (60) also showed excellent maintenance of weight loss while subjects attended either weekly or biweekly follow-up sessions, following treatment with a 1200-kcal/d diet. Maintenance sessions appear to provide patients the support and motivation needed to continue to practice weight-control skills, which include keeping a diet diary, exercising regularly, eating a low-fat diet, and measuring and recording their weight at least once a week, if not more frequently (30). Of these, exercise may be the most important, given the numerous case reports and controlled trials that have shown its association with longterm weight reduction (30,33,48,50). Table 4 summarizes the results of four studies in which patients were treated for 1 yr or more by weekly or biweekly group behavioral treatment. Present data are insufficient to draw firm conclusions but suggest the need for at least every-other-week contact. Jeffery and colleagues (77) found that monthly visits failed to prevent weight regain in the year following treatment, despite the fact that subjects were also provided a highly structured meal plan during this time. Infrequent contact probably is not sufficient to sustain patients’ attention to and motivation for behavior change. 8.1.2. SIZE OF WEIGHT LOSSES Two additional points should be noted about long-term behavioral treatment, the first is that it does not appear to be as effective following a VLCD as following a 1200 kcal/d diet (31,58). In two separate studies, we found that patients treated by a VLCD who had lost 18–20 kg—roughly 20% of initial weight—regained more than 45% of their weight loss in the year following treatment, despite the provision of weekly or bi-weekly group treatment during this time (58,97). Agras and colleagues (67) recently reported similar findings. By contrast, patients in behavioral studies who lost 9-12% of initial weight by adhering to a 1200-kcal/d diet generally maintained their full weight loss as long as weekly or bi-weekly maintenance therapy was provided (see Table 4). It is not clear whether the poorer weight maintenance following a VLCD is attributable to the larger weight loss or to the consumption of a more restrictive diet. Regardless, the data indicate that, for a majority of patients, long-term behavioral treatment will facilitate maintenance of a 10% reduction but not a 20% reduction. The one possible exception to this conclusion is a report by Wing and colleagues (60) in which patients who completed two separate 3-mo cycles of a VLCD during the first 9 mo of treatment reduced their weight by approximately 18%. Patients, however, regained weight rapidly during the last 3 mo of this year-long program, despite the continued provision of weekly group treatment. 8.1.3. DELAYING OR PREVENTING WEIGHT REGAIN A final issue is that long-term behavioral treatment appears to delay rather than to prevent weight regain. When maintenance sessions are discontinued, patients typically regain weight. Thus, participants in Perri’s study (31) described earlier, regained an average of 3 kg in the 6 mo following completion of their year-long weight maintenance program. One year after completing a 52-wk behavioral program, persons treated by Wing et al. (60) regained approximately 4.8 kg of their 10.5-kg loss. These findings reveal the need for even longer-term care (i.e., beyond 1 yr) to support patients’ efforts to maintain healthy eating and exercise habits. Such therapy, however, is challenging;

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Table 4 Mean Percentage Reduction in Initial Weight for Patients Treated for 1 or More Years by Weekly or Bi-weekly Behavior Therapy Study Perri et al. (31)

a

N

25/19

Viegener et al. (96) 43/30

Wadden et al. (58)

21/17

Wing et al. (60)

48/41

Treatment Wk 1-20: LCDd + weekly group behavior therapy; wk 21–72: LCD + biweekly maintenance therapy wk 1-26: LCD + weekly group behavior therapy; wk 27-52: LCD + biweekly maintenance therapy wk 1-52: LCD + weekly group behavior therapy; wk 53-78: LCD + biweekly maintenance therapy Wk 1-52: LCD + weekly group behavior therapy

Maximum % lost during treatmentb

% Lost at c last visit

14% at wk 20

13% at wk 72

9% at wk 26

9% at wk 52

14% at wk 52

12% at wk 78

13% at wk 26

10% at wk 52

a N b

is the number of patients who began and completed treatment. Maximum percentage reduction in initial weight and the time at which it occurred. Percentages were calculated by dividing mean weight loss by patients’ mean initial weight; c Percentage reduction in initial weight at time that patients were assessed at the last weight-maintenance visit; d LCD = low-calorie diet (i.e., 1000–1500 kcal/d) of conventional foods.

patients’ attendance of group sessions declines over time, despite their acknowledgment of the need for continued care (58,60). Pharmacotherapy may provide assistance with this problem.

8.2. Long-Term Pharmacologic Treatment The pharmacologic treatment of obesity experienced a setback on September 15, 1997 when fenfluramine and dexfenfluramine were withdrawn from the market because of concerns that they were associated with valvular heart disease (98). Approximately 30% of patients in each of five clinical samples (treated for 6–24 mo) were found to have aortic regurgitation of mild or greater severity and/or mitral regurgitation of moderate or greater severity (98). The 30% incidence was so much higher than the expected rate of 1–5% that the drugs’ manufacturers felt compelled to remove the medications from the market. Studies are now underway to confirm the association between these agents and valvular heart disease and, if possible, to identify the mechanisms responsible. If fenfluramine and dexfenfluramine caused valvulopathy, then clearly they were the wrong medications with which to treat obesity. The fen-phen experience, however, showed that long-term pharmacotherapy may, indeed, be the right model of care for some obese patients, provided that safe and effective agents are found. Patients treated by Weintraub and colleagues by the combination of group behavior modification and fenphen lost approximately 16% of initial weight in the first 34 wk and maintained the majority of this loss at 3.5 yr, if they remained on medication (99). These results are superior to those typically achieved with behavior therapy alone.


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Despite the fen-phen setback, weight loss medications are likely to play an increasingly important role in the next decade. Sibutramine, a serotonin and norepinepherine reuptake inhibitor, was approved by the Food and Drug Administration (FDA) in November 1997 for “weight loss and the maintenance of weight loss” (100,101). Another medication—orlistat (Roche Laboratories, Nutley, NJ)—is under review by the FDA at the time of this writing (102). This agent, a pancreatic and gastric lipase inhibitor, partially blocks the absorption of dietary fat. The FDA’s approval of sibutramine implicitly recognizes that (1) obesity is a serious medical disorder rather than a problem of willpower and that (2) obesity requires long-term treatment, similar to other chronic disorders. The latter point should be underscored. Most significantly obese individuals will probably have to take weight loss medications long term. Otherwise, they are likely to regain their lost weight if medication is terminated (100,103), just as patients with controlled hypertension become hypertensive again when medication is withdrawn. Several excellent reviews of the pharmacologic treatment of obesity are available (104–106). Thus, the present discussion is limited to two issues: (a) the size of the weight losses to be expected with medication and (b) the relationship between behavioral and pharmacologic treatments. 8.2.1. SIZE OF WEIGHT LOSSES Table 5 summarizes the results of five studies, 1 yr or longer, that used dexfenfluramine (73,107), the fen-phen combination (99), Orlistat (101), or sibutramine (102). These investigations, which obtained the most favorable long-term results to date, found that patients reduced their initial weight by only 8–16%, even when maintained on medication for 3 yr or more, and even when patients remained significantly (i.e., they had more weight to lose). These are averaged data; some individuals lost larger amounts of weight. However, they were in the minority. These findings underscore the need to help patients set realistic weight loss goals, as discussed later. 8.2.2. ROLE OF BEHAVIORAL TREATMENT Pharmacologic treatment holds promise of facilitating long-term weight control for significantly obese persons in an efficient and relatively cost-effective manner. By contrast, long-term behavioral treatment is effective but is rarely provided outside of research and hospital clinics and, even then, is probably subscribed to by no more than 20% of persons who complete an initial weight-reduction program. Although pharmacotherapy could significantly improve the long-term treatment of obesity, it will probably be most effective when joined with a program of behavioral treatment. In fact, the five drug studies summarized in Table 5 all included the prescription of either a low-calorie or very low-calorie diet. In addition, patients in Weintraub’s study (99), which yielded the best results to date, participated in 14 2-h group behavior modification sessions during the first 34 wk of treatment, during which time they reached their maximum weight loss of 16% of initial weight. Failure to provide adequate behavioral counseling could result in substantially smaller weight losses. Thus, for example, Craighead and colleagues (103) found that patients who were provided 120 mg/d of fenfluramine but were seen only once a month for brief doctor visits lost only 6.0 kg (about 7% of initial weight) in 6 mo, whereas persons who received the same medication but in combination with weekly group behavior therapy lost 15.3 kg (about 16% of initial weight). Persons who were treated by group behavior

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Table 5 Mean Percentage Reduction in Initial Weight for Patients Treated by Weight-Loss Medication for 1 or More Years Study Andersen et al. (73) Guy-Grand et al. (107) James et al. (101) Jones et al. (102) Weintraub et al. (99)

a

Maximum % lost b during treatment

N

Treatment

21/17 404/254 g 23/14 93/150 62/58

VLCD or LCD + dF LCD + dF h LCD + orlistat LCD + sibutraminei LCD, group counseling, and fenfluramine (60 mg/d)– phentermine (15 mg/d)

d

e

f

15% at 26 wk 11% at 26 wk 9% at 28 wk 8% at 26 wk 16% at 34 wk 11% at 156 wk

% lost at c last visit 11% at 52 wk 10% at 52 wk 8% at 52 wk 7% at 52 wk 15% at 54 wk

a N b

shows number of patients who began and completed treatment. Maximum percentage reduction in initial weight and the time at which it occurred. Percentages were calculated, in some cases, by dividing mean weight loss by patients’ mean initial weight. Some values were presented in graphic form only and are, thus, estimated here. c Percentage reduction in initial weight at time that patients were last assessed while continuing to receive medication. d VLCD = very-low-calorie diet. e LCD = low-calorie diet. f dF = dexfenfluramine; all patients treated by dF received 30 mg/d. g 14 of 23 patients completed treatment but data presented are for all 23 patients using last-observation-carried forward analysis. h 120 mg TID. i 15 mg OD.

modification alone (without medication) lost 10.9 kg (about 11%). Thus, the combination of medication plus behavior therapy had additive effects that were superior to those of either therapy used alone. 8.2.3. COMBINED BEHAVIORAL-PHARMACOLOGIC TREATMENT We recently completed a 1-yr pilot study to determine whether behavioral counseling can be effectively delivered during brief physician office visits, using a structured protocol (108). To this end, 26 women with a mean age of 47.0 yr and weight of 96.7 kg were prescribed 60 mg/d of fenfluramine and 15 mg/d of phentermine, as well as a 1200-kcal/ d diet. In addition, all women were provided copies of the LEARN Program for Weight Control (28). Treatment differed in that half the women, assigned at random, attended weekly group behavioral sessions for the first 18 wk, every-other-week sessions for an additional 22 wk, and once monthly sessions for the last 12 wk (a total of 32 sessions over 52 wk). Participants in the other condition met individually with a physician for 15–20 min on each of 10 occasions (weeks 1, 2, 4, 6, 10, 18, 26, 34, 42, and 52). They, like the patients in group treatment, were given specific homework assignments to be completed before their next office visit. All participants were asked to keep records of their food intake and to begin a walking program. At the end of 1 yr, patients in both conditions had lost 14.0–15.5 kg—roughly 15% of initial weight. Thus, brief, structured office visits were as successful as more frequent group behavioral counseling in inducing and maintaining a significant weight loss. These data await replication and comparison with results of medication provided in a traditional outpatient practice (i.e., without a structured protocol). In addition, we will need to


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determine whether effective physician counseling can by provided in 10 min or less, given constraints imposed by managed care. However, these results suggest that primary care physicians can have a significant impact on the management of obesity by combining behavioral and pharmacologic therapies.

9. FUTURE DIRECTIONS This last section examines three new developments in the behavioral treatment of obesity: (a) binge eating in overweight persons, (b) patient acceptance of modest weight losses, (c) and the treatment of body-image dissatisfaction. The discussion of binge eating is very brief because there are several excellent reviews of the etiology, complications, and treatment of this disorder (17,109,110), as well as Chapter 11. Recent studies have shown that cognitive behavioral therapy, designed to help patients stop dieting (i.e., restricting their food intake) and correct self-critical thoughts about weight and shape, successfully reduced binge eating and depression (111,112). Patients, however, generally failed to lose weight, a puzzling occurrence in light of the reported reduction in bingeing. Thus, investigators currently are uncertain as how best to treat the three problems that usually afflict these patients—eating disorder, mood disturbance, and excess weight (associated with possible health complications). The problem is that caloric restriction is usually necessary to induce significant weight loss, but such restriction is thought to cause binge eating. One possibility is to treat the obesity first with diet and exercise and then once weight and health complications have improved, to use cognitive behavioral strategies to reduce binge eating. This approach might be more favorable than first having subjects stop binge eating, only then to resume dieting to lose weight. Such sequencing could reactivate binge eating. Other options include combining cognitive behavioral treatment with medication (113). Further study also is needed of traditional behavioral weight loss therapy, given Marcus’ (114) recent findings that patients treated by this approach showed improvements in mood and binge eating comparable to those of persons treated by cognitive behavioral treatment specifically designed for binge eating. In addition, patients treated by traditional therapy lost weight, whereas those treated by the other approach did not.

9.1. Acceptance of Modest Weight Losses Although there is remarkable consensus among obesity experts that patients should seek modest weight losses of 5–15% of initial weight, little is known about patient acceptance of this recommendation. Most patients enter treatment in pursuit of goal weights that are more influenced by appearance than health concerns. Moreover, there appears to be a striking gap between the weight losses patients desire and those they can actually achieve. This discrepancy was clearly revealed by a recent study by Foster and colleagues (23), who found that the mean reduction in body weight desired by 60 obese women (weight of 99 kg) was 32%. After 48 wk of treatment, patients’ mean weight loss was 16.3 kg (a 16.4% reduction). Thus, patients, on average, ended treatment only halfway to their goal weight. Twenty percent of patients achieved only a weight loss which they said before treatment they would consider “disappointing.” Fully 47% of participants did not even achieve a loss that they had defined before treatment as “disappointing.” These data suggest that significantly obese individuals will have trouble accepting health professionals’ recommendations of modest weight losses. Moreover, we believe

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that the discrepancy between the weight losses that subjects seek and those that they actually attain will predispose them to disappointment and eventual relapse, as a consequence of undermining their weight-related self-efficacy. In short, if patients complete treatment feeling that they have failed to reach their goals, they will have little motivation or confidence to undertake the more challenging task of maintaining their weight loss. These findings underscore the importance of practitioners carefully reviewing before treatment the patient’s expectations of weight loss (as shown in Appendix 1). The provider must clearly state what the patient can and cannot expect of treatment with regard to changes in weight, health complications, body image, and social functioning. Significantly obese individuals must ultimately be convinced that losing 10–15% of initial weight is a major success, even if they remain overweight after treatment. They should be informed at the outset that the goal of treatment is to improve their health and wellbeing and that weight loss cannot be expected to make them look like their favorite Hollywood star or to heat up their social life. Because a person’s satisfaction is usually determined by comparing what was obtained with what was expected, we believe that realistic expectations are critical to long-term weight control.

9.2. Improving Body Image Cognitive therapy has recently been used to help obese women cope with perhaps the principal complaint that motivates them to seek weight loss—negative body image. The treatment has been developed by Rosen and colleagues (115,116), in collaboration with Cash (117). Initially, patients are informed about the origins of body-image development and are shown how negative body-image attitudes are learned and maintained from cultural stereotypes and personal experience. Patients monitor situations in which they are self-conscious about their bodies and identify their self-critical statements at such times. In addition, they are taught to recognize and combat the prejudice and discrimination that are directed at obese individuals. Another intervention has patients practice a series of graded-exposure exercises in which they look at themselves in a full-length mirror at home. This exposure, which is designed to desensitize them to the sight of their own bodies (which they have been avoiding), is accompanied by cognitive restructuring in which patients replace negative self-descriptions (i.e., “look at that fat stomach”) with neutral statements (i.e., “my stomach is round”). Over time, patients also are asked to face feared body-exposure situations, such as wearing form-fitting clothes or a sleeveless blouse. They wear such clothes first at home, then in group sessions, and finally in the community. Patients also practice response prevention, for example, resisting the urge to check their appearance or to camouflage their shape. Obese persons so treated by Rosen and colleagues (115) in an eight-session program reported marked improvements in body image and global self-esteem. Participants, on average, did not lose weight—a finding that demonstrates that self-esteem can be separated from and enhanced independently of weight status. Fairburn (39) has used similar techniques in the treatment of bulimia nervosa to decrease the centrality of weight and shape in patients’ self-evaluations. Such body-image interventions would appear to hold great promise in the cognitive-behavioral treatment of obesity. They may help patients feel better about their appearance both during and after treatment, regardless of the amount of weight they have lost. The greatest contribution of bodyimage therapy may be in the maintenance of weight loss, although this hypothesis awaits empirical investigation.


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10. SUMMARY The behavioral treatment of obesity, now more than three decades after Stuart’s landmark report, continues to make progress in the induction and maintenance of weight loss, as well as in the treatment of obesity-related conditions, including binge-eating disorder and body-image disturbance. The wedding of behavioral and pharmacologic interventions during the next decade holds promise of significantly improving the management of this serious, refractory, and prevalent disorder.

ACKNOWLEDGMENTS Preparation of this chapter was supported by a National Institute of Mental Health Research Scientist Development Award (KO2-MH00702-08) and by grant DK50058-02, both to Dr. Wadden. Dr. Sarwer is supported by the Edwin and Fannie Gray Hall Center for Human Appearance.

APPENDIX 1 Goal-Setting Work Sheet for Weight Reduction Persons 30% or more overweight can use this work sheet before treatment to determine a realistic weight-loss goal and to assess the changes they anticipate with weight reduction. Patient and practitioner together should review the patient’s expectations to ensure that they are realistic.

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Copyright ®Thomas A. Wadden, Ph.D., 1996. Reprinted with permission of Thomas A. Wadden.


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Chapter 15 / Very-Low-Calorie Diets

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Very-Low-Calorie Diets Edward A. Mascioli

1. INTRODUCTION This chapter discusses very-low-calorie diets, their history, their definition, indications, contraindications, medical monitoring, side effects, and short- and long-term results (Table 1). From a popularity perspective they are past their peak. Nevertheless, they are still widely used and are very useful tools in the management of obesity.

1.1. DEFINITION Very-low-calorie diets are generally defined as containing 800 cal or less per day. They vary in form whether food or liquid meal replacement powders is used. They also vary with respect to protein intake and vitamin and mineral supplementation.

1.2. BRIEF HISTORY Very-low-calorie diets should be thought of as a useful tool to achieve rapid, yet generally safe, weight loss in patients who have medically significant degrees of obesity. As such, very-low-calorie diets have been used for many years. Early reports show that caloric intake of less than 400 cal per day with 50 g of protein with small amounts of fat and carbohydrates in outpatients achieved over 20 lb of weight loss within several weeks (1). Total water fasts produced rapid loss of weight, but unfortunately some of this weight loss was lean tissue. Often patients on a total fast were anorectic. In addition to loss of lean tissue, side effects included vitamin and mineral deficiencies and death. Because of these problems, as well as ventricular arrhythmias, which can occur from excessive cardiac muscle loss and electrolyte disturbances, total fasting was abandoned justifiably (2). Such problems with total fasting led to further development of very-low-calorie diets. Further work developing very low calorie diets (3–6) showed much better preservation of lean tissue when protein and micronutrients were supplied in the diet as compared with total fasting. Other work showed that 1.5 g of high-quality protein per kilogram of ideal body weight given to the dieting obese individual would achieve nitrogen equilibrium at 4 wk of dieting. This was an improvement of nitrogen economy as compared with a group of women fed equicalorically whose caloric delivery consisted of half protein and half carbohydrate (7). This work highlighted the necessity of providing adequate amounts of lean, high-quality protein. Clearly, although many patients diet with far less protein From: The Management of Eating Disorders and Obesity Edited by: D. J. Goldstein © Humana Press Inc., Totowa, NJ

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Mascioli Table 1 Very-Low-Calorie Diets: Chapter Overview 1. Introduction 1.1. Definition 1.2. Brief History 2. Varieties of Very Low Calorie Diets 2.1. Liquid Protein Diets Historic development 2.2. Very-low-Calorie Diet—Food Based 2.3. Protein-Sparing Modified Fast—Powder Based 3. Patient Selection 3.1. Indications 3.2. Contraindications 3.3. Patient Screening 4. Medical Monitoring 5. Side Effects 5.1. Physiology 5.2. Anorexia 5.3. Blood Sugar 5.4. Constipation 5.5. Uric Acid 5.6. Gallstones 5.7. Hair Loss 5.8. Metabolic Rate Changes 5.9. Blood Pressure 5.10. Lipid Levels 6. Food based versus Powder VLCD 7. Degree of Caloric Restriction 8. Weight Loss Effectiveness 9. Pharmacologic Therapy 10. Summary

intake especially when not medically supervised, the safety of this diet is probably due to its short-term nature. Clearly, anyone under medical supervision should be at or near 1.5 g of high quality protein per kilogram of ideal body weight ingested per day.

2. VARIETIES OF VERY-LOW-CALORIE DIETS 2.1. Liquid Protein Diets In the late l970’s, the over-the-counter availability of liquid protein products served as a significant barrier to further development and medical acceptance of very-lowcalorie diets. These products contained partially hydrolyzed collagen, which was variably supplemented with other amino acids to partially improve its amino acid profile for human nutrition. Additionally, these liquid protein products were significantly deficient in many essential vitamins and minerals. It was estimated that at least 100,000 people consumed these products as their only nutrition for at least 1 mo during 1977 and 1978. Fifty-eight deaths associated with the use of these products were reported to the Food and Drug Administration including 17 individuals who had been well without any comorbid conditions due to their obesity (8).


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Cardiac complications accounted for the deaths, which often occurred during fasting rather than during refeeding. Syncope was often observed and individuals who had electrocardiograms had characteristic findings. These findings had been demonstrated many years earlier in individuals starving themselves. The electrocardiographic features were a low QRS voltage and a prolonged QTc interval. From this, many patients developed ventricular arrhythmias that were particularly unresponsive to antiarrhythmic therapy. At autopsy, the hearts showed myocardial atrophy (9–13). Subsequent studies showed that cardiac rhythm remains normal during restricted diets when adequate attention is paid to protein intake as well as vitamin, mineral, and electrolyte supplementation (14,15). Other side effects do occur with these diets when appropriate nutrition is maintained. However, they are far less serious and generally either preventable or easily managed as discussed later in this chapter.

2.2. Food-Based Very-Low-Caloric Diet 2.2.1. PROTEIN-SPARING MODIFIED FAST A food-based very-low-calorie diet is the protein sparing modified fast, based on foods that are lean muscle meats. Generally, fish and poultry are the preferred sources. No other foods are prescribed. Carbohydrate intake is only limited to glycogen present in the meat; fat is similarly limited. Therefore, essentially patients receive most of their calories from protein, which is especially the case if lean protein foods are chosen such as poultry breast meat without skin or dry white meat fish without skin. Preparing the protein various ways is allowed as long as added oils and fats are not used. Other nutrients that are included are water of at least 2 L and salt because of the diuretic effect of a low carbohydrate intake. Generally, this is at least 2 L of non caloric beverages and 2 1/2 g of salt (1 g of sodium). In individuals with hypertension, titration of their antihypertensive medication needs to occur before supplemental salt is given. Also needed daily is potassium. Generally, this is prescribed at a dose of 25 mEq in a liquid form and as the bicarbonate salt. The form is liquid due to the small chance of intestinal perforation with potassium pills, especially in individuals with slower GI motility, which occurs in individuals who are fasting. The bicarbonate and citrate salts are used, as the provision of some base does lead to improved nitrogen and protein balance (16). Additionally, all vitamins and minerals are given in the form of a comprehensive multivitamin, multimineral tablet per day. Calcium supplements of at least 1000 mg as well as 300 mg of magnesium are also given.

2.3. Powder-Based Very-Low-Caloric Diets Powder-based very-low-calorie diets have been very popular in recent years, and although less used currently, they are still widely available. Under different brand names are powders in packets, which are generally protein powders based on milk protein. The amount of lactose in the products is variable as is carbohydrate. Generally, the amount of carbohydrate in these products is greater than that on the protein-sparing modified fast in that the caloric intake equals around 800 cal/day for the average dieter. One concern is the relative amount of protein in these preparations. Given that carbohydrates help spare protein, 1 1/2 g of protein per kilogram of ideal body weight per day for protein balance may not be necessary, but given the lessons of the past it is prudent to prescribe this amount of protein to every patient.

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Mascioli Table 2 Considerations for Very-Low-Caloric Diet Indications: Obesity, at least 20% over desirable weight Prior failure of conventional diets Commitment to adhere to an obesity treatment program

3. PATIENT SELECTION Because very-low-calorie diets can carry some medical risks, the degree of obesity in appropriate candidates should be kept in mind. This is generally defined as the individual being at least 30% overweight, although in 1985 a Consensus Development Conference on the Health Implications of Obesity through the National Institutes of Health concluded that a weight 20% above desirable warrants treatment (17). Merely ascribing risks from obesity resulting from overweight is simplistic. For consideration of treatment, overweight means having excessive adipose tissue and distribution of that excess fat. We know that individuals who have a greater waist-to-hip ratio have greater risks from their obesity given the same amount of overweight as compared with individuals whose fat is distributed in the lower body. This is discussed more fully in Chapter 10.

3.1. Indications Indications for consideration with a very-low-calorie diets include body weight greater than 20% over desirable; prior failure with more conventional, less restrictive diets, and the commitment to adhere to a comprehensive obesity program of which the very-lowcalorie diet is one part (Table 2).

3.2. Contraindications Contraindications to very-low-calorie diets include cerebrovascular disease, milder degrees of overweight, significant renal or hepatic disease, extremes of age, malignancy, type 1 diabetes mellitus, and recent myocardial infarction. Some of these contraindications are relative (Table 3).

3.3. Patient Screening Very-low-calorie diets should be considered medical treatment. Therefore, physiciansupervised care should be provided. Patient should undergo a complete medical history and physical examination before being placed on a very-low-calorie diet. The comorbid complications of obesity should be identified along with any medications that the patient may be taking. Individuals at less than medically significant degrees of overweight, or individuals with histories of eating disorders, anorexia nervosa, or bulimia nervosa, should be excluded. Laboratory screening should include a chemistry panel, lipid panel, complete blood count, and a resting electrocardiogram.

4. MEDICAL MONITORING Patients need to be seen frequently while they are on a very-low-calorie diet. To be on the safe side, patients should be seen weekly, especially if they are on any medications that may need to be adjusted because of weight loss and/or the medical practitioner is not


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Table 3 Contraindications to a Very-Low-Calorie Diet

Table 4 Risks and Benefits of Very-Low-Calorie Diets

Advanced age Cerebrovascular disease Less than 20% over desirable weight Significant renal or hepatic disease Malignancy Type I diabetes mellitus Recent myocardial infarction History of anorexia nervosa or bulimia nervosa

Side effects

Benefits

Anorexia Constipation Hypoglycemia Uric acid Gallstones Hair loss Orthostasis

Lowered: Blood glucose Blood pressure Lipid levels

fully experienced with very-low-calorie diets. Frequent visits also provide time for the patients to be treated with other facets of their program, such as exercise teaching, behavior modification and nutrition education. Electrolyte determination should be done weekly or biweekly initially. After one or two months, the interval may be lengthened if stable and the patient is compliant with all supplements. With excessive rates of weight loss, compliance (adequate protein intake, diuretic use) needs to be questioned and certainly blood testing and/or obtaining an electrocardiogram should be considered.

5. SIDE EFFECTS AND OTHER CHANGES OCCURRING DURING VERY-LOW-CALORIE DIETS Side effects, although common, are generally minor and do not require cessation of the very-low-calorie diet (see Table 4).

5.1. Physiology The physiology most important to understand on diets such as these is the lowered insulin level resulting from less intake of dietary carbohydrates. This in turn lessens water and sodium retention and diminishes blood pressure. Additionally catecholamine levels drop (18,19). Because of this diet-induced diuresis, diuretics should be stopped on initiation of the very-low-calorie diet. If the patient is on large amounts of diuretics, one needs at least to cut the dose substantially and watch these patients very carefully in terms of their rate of weight loss, blood pressure, and potassium levels. Administration of sodium in the from of a bouillon cube is recommended for all patients who are not on any antihypertensive medication initially. For patients who are on antihypertensive medications, a frequent assessment of their blood pressure and acute administration of bouillon if they become symptomatic or orthostatic is warranted, as well as decreasing their antihypertensive medications.

5.2. Anorexia Anorexia can occur during very-low-calorie diets. This condition is generally associated with a low and constant carbohydrate intake. If patients eat a greater amount of carbohydrates, although calorically minimal and transient, appetite can return for a few days. Also, the patient can undergo antidiuresis, resulting in a few pounds of weight gain. Understanding this physiology can be reassuring to the patient, and educational as well.

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5.3. Blood Sugar Elevated blood sugars generally respond quite nicely to a very-low-calorie diet. Individuals with type I diabetes mellitus are generally considered to be poor candidates for very-low-calorie diets because of their ongoing requirement for insulin; therefore it is necessary to have some dietary carbohydrate ingested daily for safety. However, for individuals with type II diabetes mellitus, a very-low-calorie diet can be remarkably therapeutic. Generally, in individuals who have been controlled with diet, no special precautions need to be taken. Type II individuals who are on oral hypoglycemic agents have their hypoglycemic agents generally stopped completely on initiation of the verylow-calorie diet. Some practitioners have stopped all insulin therapy on initiation of a very-low-calorie diet, although usually the starting dose is half the patient’s normal dose (20). Another stepwise approach would be to decrease the insulin dose in half and as long as the blood sugars remain less than 200 mg/dL, continue halving the insulin dose on subsequent days. When a total of 30 U of insulin per day is reached, cessation of insulin administration can occur generally quite safely. Patients are asked to measure their capillary blood sugar at least twice a day. If they cannot comply with this, then very-lowcalorie dieting or significant dieting in that particular patient needs to be seriously questioned. In a true type II diabetic patient, there should be no risk of ketoacidosis, especially if he or she is closely followed. An important aim of treating individuals with diabetes and very-low-calorie diets is the prevention of hypoglycemia. If hypoglycemia occurs, progression of the diet is interrupted and faith in the medical practitioner can be eroded and prevented from being further developed.

5.4. Constipation Constipation can occur because of the low-fiber content of these diets. This is generally treated with adequate amounts of sugar-free fiber preparations sold over the counter. Generally, frequency of defecation should be expected to decrease because of the much smaller amounts of food being ingested.

5.5. Uric Acid Because of the development of ketones, which compete with renal tubular excretion of uric acid, acute attacks of gout can be seen. In the author’s experience this is only seen in individuals who have had a history of gout in the past before the very-low-calorie diet. Conversely, if one has a history of gout and is placed on a very-low-calorie diet, one should expect precipitation of an acute gouty attack unless prophylaxis is undertaken. Administration of allopurinol generally works well. Therapy of acute attacks is routinely given. This competition of ketones for renal tubular excretion of uric acid generally occurs for 6 wk. Thereafter uric acid levels are related to body weight (21,22).

5.6. Gallstones It is clear that cholesterol gallstones are related to obesity (23). Obese patients have elevated cholesterol saturation in the initial weight-maintaining obese state. In obese individuals undergoing weight loss, the lithogenicity of bile is increased (24). In addition to increased bile cholesterol saturation, there is biliary stasis because of less fat intake. Both of these factors increase the chance of developing gallstones during weight loss. Studies done several years ago showed a high degree of cholesterol precipitation in


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individuals on very-low-calorie diets (25, 26). In the majority of patients these cholesterol crystals are asymptomatic. In some patients on refeeding, perhaps because of better gallbladder contraction, there is some abdominal cramping experienced on reinitiation of food ingestion. It is unusual for the stones to become symptomatic and warrant surgical treatment. Pharmacologically, prevention of these stones is partially successful with aspirin, or more completely with the bile salt ursodiol (25). Overall, as weight is related to the incidence of gallstones, weight loss leaves the patient at a lower risk for gallstone formation even though the patients passed through a transient period of increased risk.

5.7. Hair Loss Some patients experience hair loss, generally referred to as a telogen effluvium, which is seen 3 mo after the diet is initiated. Other causes for this type of hair loss include significant emotional distress, surgery, anesthesia, significant febrile illness, and pregnancy. Excessive hair loss is noted 3 mo after initiation of the diet when the patient is no longer losing weight or certainly not losing it rapidly. The exact mechanism of this effect is not fully appreciated, although it may be related to inadequate protein and micronutrient ingestion during dieting, at least in some patients. Most of the time the hair does grow back, although slowly in many patients due to the normal slow growth of hair (1 cm/mo).

5.8. Metabolic Rate Changes Metabolic rate varies with feeding. Whether eating below caloric needs or above them, metabolic rate tends to move in the direction of the caloric disturbance, i.e., increased metabolism with overeating and decreased metabolism with undereating, such that predicted weight changes are somewhat blunted (27,28). With weight loss, the mechanisms of decreased metabolic rate include a decrease in catecholamines and in triiodothyronine (T3). Additionally, diet-induced thermogenesis, a process of increasing energy expenditure due to eating, occurs less when dieting. Spontaneous physical activity is generally reduced as well. The quantitative reduction in resting metabolic rate on a very-lowcalorie diet is in a range of 20–25%. However, this is not permanent as is commonly believed. Metabolic rate does respond with an increase when the patient ingests more calories (29). The important therapeutic point to emphasize to the patient is that a history of repeated dieting in no way influences their metabolic rate on a permanent basis. Patients need to be taught that long-term dietary intake must diminish if weight that is lost is to be maintained unless exercise calories are increased significantly and permanently.

5.9. Blood Pressure Blood pressure responds quite well to very-low-calorie diets. Approximately threefourths of obese hypertensive individuals will normalize their blood pressure with weight loss without continuation of antihypertensive medications (30,31).

5.10. Lipid Levels Lipid levels also change with dieting. Triglyceride levels are more sensitive than cholesterol levels. Triglycerides respond early and usually consistently to weight loss (22). Cholesterol levels are more variable. There is a drop in all fractions of cholesterol during the first several weeks of a fast. In many individuals, however in spite of continued weight loss, these levels can increase. When maintenance of a reduced weight occurs, blood cholesterol levels in the majority of patients are lower than when they started (33).

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6. FOOD-BASED VS POWDER VERY-LOW-CALORIE DIETS Which form the food is in for optimal effectiveness is a reasonable question. A study done for 4 wk looking at patient acceptability of a food-based, protein-sparing modified fast versus a powder-based diet generally showed that individuals on the food-based, very-low-calorie diet reported less hunger and preoccupation with food than those on the liquid preparation (34). A second study done with diabetic subjects receiving 800-cal diets of either allliquid supplement or liquid supplement in addition to one food-based meal per day were compared. This study showed equivalent efficacy between the two regimens through 12 wk (35).

7. DEGREE OF CALORIC RESTRICTION WARRANTED A recent study evaluated whether the degree of caloric restriction or the form of nutrition was more important (36). Patients were randomized to receive liquid formula diets at either 420, 660, or 800 cal/day. In these three groups there were no differences in terms of diet acceptability, symptoms, mood, weight loss or body composition changes. This emphasizes the notion that putting people on a significantly restricted diet as compared to their normal intake is the most important aspect of the diet. The difference between 400 and 800 cal of intake is far smaller than the difference between the patient’s normal intake, which is generally 2000–3000 cal/day and the intakes on these liquid supplements. Therefore, the changes in weight loss were not predictable on the basis of the calories ingested (i.e., the 400-cal group did not lose a significantly greater amount than the other groups).

8. WEIGHT LOSS EFFECTIVENESS Very-low-calorie diets are generally the most effective method for obtaining shortterm weight loss. Generally 40–50 lb for women and 50–60 lb of weight loss for men have been reported by different groups (37–39). These losses usually occur over 3–4 mo of dieting and are substantial improvements over other methods of dieting. Maintaining this weight loss is clearly a major challenge. Patients who receive behavior modification during their weight loss fare better than those who are just given the diet alone. At 1 yr follow-up, two-thirds of the lost weight is regained in a group given diet alone, whereas generally one-third is regained in a group receiving behavior modification (38,39). Other follow-up at 2 1/2 yr showed that medically significant weight loss of at least 10%, which was achieved by 90% of the cohort initially, was maintained by 33% (35). In one study, average initial weight loss was 21.4 kg with maintained weight loss on average for the entire group at 30 mo of 6.5 kg (40). Follow-up at more distant times (5 yr) showed that as a group the cohort had regained all of their weight. Exercise was clearly associated with better weight maintenance. Patient selection may play a role. Patients who are in very-low-calorie diet programs have failed to achieve lasting weight loss maintenance at least four or five times prior to their current very-low-calorie diet attempt. Results in this group could be expected to be less successful than those who are dieting for the first time. Support for this comes from a survey based on place of employment done several years ago (41). The subjects were interviewed for a history of obesity. In this survey, over half of the group with a history of obesity had achieved a loss of at least 10% from their heaviest weight and a weight no


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more than 10% above desirable for their height and gender and maintained this weight loss for several years. These optimistic data are clearly not the norm in the obesity literature. Subjects in obesity treatment studies are overrepresented by individuals with prior failures. Therefore we should be aware of a prior weight loss history in evaluating chances for individual patients success (41).

9. PHARMACOLOGIC THERAPY AND VERY-LOW-CALORIE DIETS Pharmacologic intervention for maintenance of weight loss after very-low-calorie diets has shown early promise. Pharmacological agents for weight loss are discussed in Chapter 16. Their use in clinical practice is summarized in Chapters 20 and 21. A recent study of people who had lost weight on a very-low-calorie diet and then randomizing them either to placebo or dexfenfluramine treatment showed weight loss maintenance in the drug treatment group as compared to weight regain in the nondrug treatment group (42). Similar results were shown for fluoxetine (43).

10. CONCLUSION Very-low-calorie diets are very effective tools for the short-term treatment of obesity. When done in a medically monitored setting by medical practitioners familiar with their use, physiology, indications, contraindications, side effects, and benefits, these diets can be very effective in achieving large amounts of medically significant weight loss in a few months. Maintaining this weight loss becomes the paramount therapeutic goal. Inclusion of the very-low-calorie diet in a comprehensive obesity treatment program that also incorporates nutrition education, exercise training, and behavior modification is essential for responsible use (44). Additionally, the use of pharmacologic agents to enhance weight loss maintenance is a promising avenue.

REFERENCES 1. Evans FA, Strang JM. The treatment of obesity with low caloric diets. JAMA 1931;97:1063–1069. 2. Johnson D, Drenick EJ. Therapeutic fasting in morbid obesity: Long-term follow-up. Arch Intern Med 1977;137:1381–1382. 3. Apfelbaum M. The effects of very restrictive high protein diets. Clin Endocrinol Metab 1976;5:417–430. 4. Bistrian BR, Winterer J, Blackburn GL, et al. Effect of a protein-sparing diet and brief fast on nitrogen metabolism in mildly obese subjects. J Lab Clin Med 1977;89:1030–1035. 5. Genuth SM, Castro JH, Vertes V. Weight reduction in obesity by outpatient semistarvation. JAMA 1974; 230:987–991. 6. Vertes V, Genuth SM, Hazelton IM. Supplemented fasting as a large-scale outpatient program. JAMA 1977;238:2151–2153. 7. Hoffer LJ, Bistrian BR, Young VR, et al. Metabolic effects of very low calorie weight reduction diets. J Clin Invest 1984;73:750–758. 8. Sours HE, Frattali VP, Brand CD, et al. Sudden death associated with very low-calorie weight reduction regimens. Am J Clin Nutr 1981;34:453–461. 9. Brown JM, Yetter JF, Spicer MJ, Jones JD. Cardiac complications of protein sparing mod)fied fasting. JAMA 1’378;240:120–122. 10. Lantigua RA, Amatruda JM, Biddle TL, et al. Cardiac arrhythmias associated with a liquid protein diet for the treatment of obesity. N Engl J Med 1980;303:735–738. 11. Singh BN, Gaarder TD, Kanegae T, et al. Liquid protein diets and torsade de pointes. JAMA 1978;240:115–119. 12. Michiel RR, Sneider JS, Dickstein RA, et al. Sudden death in a patient on a liquid protein diet. N Engl J Med 1978;298:1005–1007.

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13. Garnett ES, Barnard DL, Ford J. et al. Gross fragmentation of cardiac myofibrils after therapeutic starvation for obesity. Lancet 1969;1:914–916. 14. Phinney SD, Bistrian BR, Kosinski E, et al. Normal cardiac rhythm during hypocaloric diets of varying carbohydrate content. Arch Intern Med 1983;143:2258–2261. 15. Amatruda JM, Biddle TL, Patton ML, Lockwood DH. Vigorous supplementation of a hypocaloric diet prevents cardiac arrhythmias and mineral depletion. Am J Med 1983;74:1016–1022. 16. Gougeon-Reyburn R, Marliss EB. Effects of sodium bicarbonate on nitrogen metabolism and ketone bodies during very low energy protein diets in obese subjects. Metabolism 1989;38:1222–1230. 17. National Institute Health Consensus Development Panel on the Health Implications Consensus of Obesity. Health implications of obesity: National Institutes of Health Development Conference Statement. Ann Intern Med 1985;103(6 Suppl, Part 2):1073–1077. 18. Sigler MH. The mechanism of the natriuresis of fasting. J Clin Invest 1975;55:377–387. 19. De Haven J, Sherwin R, Hendler R, Felig P. Nitrogen and sodium balance and sympatheticnervous-system activity in obese subjects treated with a low-calorie protein or mixed diet. N Engl J Med 1980;302:477–482. 20. Henry RR, Schaeffer L, Olefsky JM. Glycemic effects of intensive caloric restriction and isocaloric refeeding in noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 1985;61:917–925. 21. Lecoq FR, McPhaul JJ Jr. The effects of starvation, high fat diets, and ketone infusions on uric acid balance. Metabolism 1965;14:186–197. 22. Nicholls A, Scott JT. Effect of weight loss on plasma and urinary levels of uric acid. Lancet 1972;2:1223–1224. 23. Maclure KM, Hayes KC, Colditz GA, et al. Weight, diet, and the risk of symptomatic gallstones in middle-aged women. N Engl J Med 1989;321:563–569. 24. Bennion LJ, Grundy SM. Effects of obesity and caloric intake on biliary lipid metabolism in man. J Clin Invest 1975;56:996–1011. 25. Broomfield PH, Chopra R. Sheinbaum RC, et al. Effects of ursodeoxycholic acid and aspirin on the formation of lithogenic bile and gallstones during loss of weight. N Engl J Med 1988;319:1567–1572. 26. Liddle RA, Goldstein RB, Saxton J. Gallstone formation during weight-reduction dieting. Arch Intern Med 1989;149:1750–1753. 27. Welle SL, Amatruda JM, Forbes GB, Lockwood DH. Resting metabolic rates of obese women after rapid weight loss. J Clin Endocrinol Metab 1984;59:41–44. 28. Landsberg L, Young JB. Fasting, feeding and regulation of the sympathetic nervous system. N Engl J Med 1978;298:1295–1301. 29. Wadden TA, Foster GD, Letizia K.A, Mullen JL. Long-term effects of dieting on resting metabolic rate in obese outpatients. JAMA 1990;264:707–711. 30. Kirschner MA, Schneider G, Ertel NH, Gorman J. An eight-year experience with a very low calorie formula diet for control of major obesity. Int J Obes 1988;12:69–80. 31. Reisin E, Abel R, Modan M, et al. Effect of weight loss without salt restriction on the reduction of blood pressure in overweight hypertensive patients. N Engl J Med 1978;298:1–6. 32. Ellis RW, Darga LL, Lucas CP. The short- and long-term effects of a low-fat, cholesterol-free, hypocaloric diet on serum triglyceride and cholesterol distribution in severely obese humans. Int J Obes 1987;11:29–40. 33. Wood PD, Stefanick ML, Dreon DM, et al. Changes in plasma lipids and lipoproteins in overweight men during weight loss through dieting as compared with exercise. N Engl J Med 1988;319:1173–1179. 34. Wadden TA, Stunkard AJ, Brown L, Brownell KD, Day SC. A comparison of two diet very low calorie diets: Protein sparing modified fast vs protein formula liquid diet. Amer J Clin Nutr 1985;41:533–539. 35. Anderson JW, Brinkman-Kaplan V, Hamilton CC, et al. Food-containing hypocaloric diets are as effective as liquid - supplement diets for obese individuals with NIDDM. Diabetes Care 1994;17:602–604. 36. Foster GD, Wadden TA, Peterson FJ, Letizia KA, Bartlett SJ, Conill AM. A controlled comparison of three very-low calorie diets: Effects on weight, body composition, and symptoms. Am J Clin Nutr 1992;55:811–817. 37. Palgi A, Read JL, Greenberg I, et ,al. Multidisciplinary treatment of obesity with a protein-sparing mod)fied fast: results in 668 outpatients. Am J Public Health 1985;75:1190–1194. 38. Hovell MF, Koch A, Hofstetter CR, et al. Long-term weight loss maintenance: Assessment of a behavioral and supplemented fasting regimen. Am J Public Health 1988;78:663–666. 39. Wadden TA, Stunkard AJ. Controlled trial of a very low calorie diet, behavior therapy, and their combination in the treatment of obesity. J Consult Clin Psychol 1986;54:482–488.


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40. Flynn TJ, Walsh MF. Thirty month evaluation of a popular very low calorie diet program. Arch Fam Med 1993;2:1042–1048. 41. Schachter S. Recidivism and self-cure of smoking and obesity. Am Psychol 1982;37:436–444. 42. Finer N, Finer S, Naoumova RP. Drug Therapy after very low-calorie diets. Amer J Clin Nutr 1992;56:1955–1985. 43. Goldstein DJ, Wilson MG, Hill LA. Fluoxetine therapy in weight maintenance post VLCD. Obes Res 1996;4:200. 44. National Task Force on the Prevention of and Treatment of Obesity. Very Low Calorie Diets. JAMA 1993;270:967–974.

Chapter 16 / Pharmacologic Therapy of Obesity

16

213

Pharmacologic Therapy of Obesity George A. Bray

1. INTRODUCTION This chapter provides physicians with guide to current and potential drugs used for the treatment of obesity, excluding agents being developed based on molecular technologies. The molecular basis of obesity is summarized in Chapter 18. Following a brief historical review, the evolution of drug treatment is described, followed by a discussion of the medications currently used as well as those in development (Table 1). The final section focuses on the clinical settings in which medications may be indicated and criteria for selecting patients. WARNING: Most available drugs for treating obesity are “scheduled” by the Drug Enforcement Agency. These “schedules” and Food and Drug Administration (FDA) guidelines are used by state regulatory agencies to regulate medical practice. Use of any scheduled drug in a manner different from these regulations, regardless of what is reasonable medical practice or in the best interest of patients, can result in criminal prosecution for a felony violation. If convicted, you can go to jail or have your license suspended. If you intend to use these drugs, check the regulations of your state licensing board.

2. EVOLUTION OF DRUG TREATMENT 2.1. Historical Review Thyroid extract was the first drug used for the treatment of obesity (1), and its use continued for nearly 100 years after its introduction in 1893. However, thyroid hormones are not indicated for the treatment of obesity unless the patient is hypothyroid. In the 1920s, dinitrophenol was introduced for the treatment of obesity after it was noted that textile workers lost weight when exposed to this drug (1). Dinitrophenol uncouples oxidative phosphorylation and its use was discontinued because of serious side effects, including neuropathies and cataracts. In 1937, amphetamine (_-methyl-`phenethylamine) was introduced for the treatment of obesity (2). For the next 30 yr, a variety of medicines, including amphetamine, thyroid hormone, and digitalis, were used individually and in combination in a variety of different colored pills for which the name “rainbow pills” was coined. These combinations were discontinued following the report of several deaths associated with their use in the United States (3). This mayhem, accompanied by the significant abuse potential for dextroamphetamine, led to a marked From: The Management of Eating Disorders and Obesity Edited by: D. J. Goldstein © Humana Press Inc., Totowa, NJ

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214


Table 1 Chapter Overview 1. Introduction 2. Evolution of Drug Treatment 2.1. Historical Review 2.2. Mechanisms for Treatment of Obesity 2.2.1. Models 2.2.2. Mechanisms 2.2.2.1. Food Intake Adrenergic Receptors Serotonin Receptors Histamine Receptors GABA Receptors Peptides 2.2.2.2. Nutrient Partitioning 2.2.2.3. Thermogenesis 3. Drugs Approved by the FDA for Clinical Use in the Treatment of Obesity 3.1. Drugs Affecting Food Intake 3.1.1. Noradrenergic Drugs that Release Norepinephrine or Block Its Reuptake into Neurons 3.1.1.1. Chemistry 3.1.1.2. Pharmacology 3.1.1.3. Efficacy 3.1.1.4. Safety of Appetite Suppressants 3.1.2. Noradrenergic Drugs that Act as _-1-Adrenergic Agonists 3.1.2.1. Chemistry 3.1.2.2. Pharmacology 3.1.2.3. Efficacy 3.1.2.4. Safety of Appetite Suppressants 3.1.3. Serotonergic Drugs 3.1.3.1. Chemistry 3.1.3.2. Pharmacology 3.1.3.3. Efficacy 3.1.3.4. Safety 3.1.4. Stepped or Combination Therapy 4. Areas of New Drug Development 4.1. Drugs that Suppress Food Intake 4.1.1. Sibutramine: An Amine Reuptake Inhibitor 4.1.2. Antagonists of Opioid Receptors 4.1.3. Biguanides 4.1.4. _-2-Adrenergic Antagonists 4.1.5. Peptides 4.1.5.1. Cholecystokinin 4.1.5.2. Neuropeptide Y 4.1.5.3. Leptin (ob Protein) 4.1.5.4. Bombesin 4.1.5.5. Enterostatin Agonists 4.1.5.6. Sugar Acids 4.2. Nutrient Partitioning 4.2.1. Preabsorptic Nutrient Partitioning (Nutrient Availability) 4.2.1.1. Inhibitors of Gastric Emptying 4.2.1.2. Inhibitors of Carbohydrate Digestion


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Table 1 (continued) 4.2.1.3. Inhibitors of Fat Digestion or Absorption Cholesytramine Orlistat Pseudonutrients 4.2.2. Post Absorptive Effectors of Nutrient Partitioning 4.2.2.1. Growth Hormone 4.2.2.2. Testosterone 4.2.2.3. Glucocorticoids 4.2.2.4. Other Steroids 4.2.2.5. Lipid Modulators 4.2.3. Thermogenic Drugs 4.2.3.1. Adrenergic Drugs 5. Drugs Previously Used But Not Approved or Recommended 5.1. Thyroid Hormone 5.2. Dextroamphetamine, Methamphetamine, and Phenmetrazine 5.3. Human Chorionic Gonadotropin 5.4. Dinitrophenol 5.5. Digitalis 6. Use of Drugs in the Clinical Treatment of Obesity 6.1. Realities of Treatment 6.2. Evaluation of the Obese Patient 6.2.1. Classification 6.2.2. Measurement 6.2.3. Clinical Evaluation 7. Summary

decrease in the use of drugs in the treatment of obesity. Over the next 25 yr, the use of drugs in the treatment of obesity gradually regained acceptability and there appeared to be institutionalization of this with the approval of dexfenfluramine in the United States. The acceptability of medical treatment for obesity was set back again by the withdrawal of fenfluramine and dexfenfluramine after identification of apparent treatment-induced cardiac valvulopathy. Nevertheless, the marketing of sibutramine and the marketing of orlistat (Xenical®, Hoffmann LaRoche, Nutley, NJ) suggests that this has been a further temporary setback for medicinal treatment of obesity. One goal of this chapter is to put the current use of these and related medications as a treatment for obesity into a modern perspective.

2.2. Mechanisms for Treatment of Obesity 2.2.1. MODELS The past 25 yr have seen substantial strides in unraveling the mechanisms by which obesity might be treated. Several models have helped to provide a framework for understanding obesity and its treatment (4,5). In this discussion, a feedback model for control of nutrient intake and metabolism will be used (4–7). This model consists of a controlled system, the body, which includes digestion, absorption, storage, and metabolism of carbohydrate, fat and protein; a central control system in the brain; the afferent neural and hormonal signals that tell the brain about the state of the body; and the efferent motor,

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Part III / Treatment Table 2 Mechanisms that Reduce Food Intake System Noradrenergic

Serotonergic

Dopaminergic Histaminergic

Mechanism

Examples

_-1 Agonist _-2 Antagonist `-2 Agonist a Stimulate NE release Block NE reuptake 5-HT 1B or 1C Agonist Stimulate 5-HT release Block reuptake D-2 Agonist H-1 Antagonist

Phenylpropanolamine Yohimbine Clenbuterol Phentermine Mazindol Metergoline Fenfluramine Fluoxetine Apomorphine Chlorpheniramine

a

NE-norepinephrine.

autonomic, and hormonal controls that regulate food intake and the “metabolic state” of the body (6). In addition to such models, the molecular understanding of obesity has been rapidly progressing and is providing an even greater understanding of the mechanisms involved in obesity (see Chapter 18). 2.2.2. MECHANISMS 2.2.2.1. FOOD INTAKE Three different mechanisms can be used to classify treatments for obesity. The first mechanism is the regulation of food intake. Any agent that can reduce food intake has potential for treatment of obesity. Table 2 lists a number of receptor systems in the central nervous system that are known to reduce food intake or body weight. ADRENERGIC RECEPTORS Stimulation of _-1-adrenergic receptors decreases food intake (8). Conversely, _-1adrenergic antagonists used to treat hypertension can increase food intake and body weight (9). Stimulation of _-2-adrenergic receptors (e.g., by clonidine) in the paraventricular nucleus of animals will increase food intake, particularly the intake of carbohydrates (10). Yohimbine, an _-2-adrenergic antagonist, blocks this effect of clonidine and in one clinical trial has been shown to reduce weight gain in women (11). Stimulation of `-adrenergic receptors in the perifornical area decreases food intake. The inhibition of norepinephrine reuptake and release of norepinephrine from nerve endings are two mechanisms by which the `-2-adrenergic receptors are activated by many appetite-suppressing drugs. If `-adrenergic receptors are involved in feeding, blockade of these receptors with `-adrenergic blocking drugs might increase food intake and weight gain. A small weight gain has been seen in post-myocardial-infarction patients treated with propranolol (12). Dopaminergic receptors may also be involved in modulation of food intake, as shown by the fact that sulpiride, an antagonist to dopamine D1 receptors, can increase food intake. The dopaminergic receptors may also be involved in hedonic responses to food and this may account for the abuse potential of some appetite-suppressing drugs (13).


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SEROTONIN RECEPTORS Serotonin receptors also have significant effects on food intake (14). Cyproheptadine, a serotonin (5-HT) antagonist, significantly increases food intake and body weight and stimulation of the 5-HT1A receptors increases food intake (15). In contrast, drugs acting on the 5-HT1B/1D or 5-HT2C serotonin receptors (MCPP, CIN57493, quipazine, and MK212) decrease food intake (14). The racemic mixture of fenfluramine (d,l-fenfluramine = Pondimin®) acts to enhance serotonin release, accounting for a significant part of its appetite-suppressant effect. (The FDA has withdrawn Pondimin from the marketplace.) Partial blockade of serotonin reuptake by fenfluramine and more complete blockade by fluoxetine (Prozac®, Lovan®, Eli Lilly, Indianapolis IN) and sertraline (Zoloft®, Pfizer, New York, NY) may account for the appetite-suppressant effects of these drugs (14). Other antidepressants that increase food intake, such as amitriptyline, may also act by blocking these serotonin receptors. HISTAMINE RECEPTORS Experimentally, histamine receptors in the central nervous system have been implicated in the feeding system (16). Blockade of the histamine receptors with _-fluromethylhistidine, clorpheniramine, or meperamine can decrease food intake. Some of the weak neuroleptics such as chlorpromazine, thioridazine, and mesoridazine may increase body weight by acting on histamine receptors as well as on serotonin receptors. GABA RECEPTORS Receptors for gamma amino butyric acid (GABA) may increase or decrease food intake, depending on the site of action in the brain (17). When GABA agonists are injected into the ventromedial hypothalamus, food intake is increased. In contrast, injection of GABA agonists into the lateral hypothalamus decreases food intake. Bicucculine, a drug which blocks GABA receptors, also can decrease food intake, providing further evidence that these receptors may play a physiological role in modulating food intake. PEPTIDES Several neurotransmitter peptides affect food intake by acting on specific receptors. Endogenous and exogenous opioids are potent stimulators of feeding (18). Dynorphin, acting primarily through kappa receptors, stimulates food intake when injected directly into the hypothalamus. Naloxone, an opioid antagonist, has been shown to decrease food intake in man and animals (19). Neuropeptide-Y (NPY) and galanin (GAL) both increase food intake but their effect on the intake of macronutrients is very different (20). When animals are given a choice of individual macronutrients, NPY increases carbohydrate intake with little effect on the intake of other macronutrients, whereas galanin primarily increases the intake of fat. Several other peptides listed in Table 3 also affect intake of specified nutrients (21). 2.2.2.2. NUTRIENT PARTITIONING A second major mechanism for modulating body fat stores is through control of “nutrient partitioning” (22). Nutrient partitioning refers to channeling or guiding dietary nutrients toward protein accretion and growth, milk synthesis and lactation or fat storage. During growth, ingested nutrients such as protein are shunted toward linear growth rather than storage. As growth plateaus, nutrient partitioning into protein vs fat stores shifts toward fat storage. The degree of nutrient partitioning differs among individuals who are

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Table 3 Approved Appetite-Suppressing Drugs DEA schedule

Trade names

t1/2 (h)

Tablet size 25 or 50 mg before breakfast 35 mg before meals or 105 mg (slow release)

218

III

Didrex

6–12

Phendimetrazine

III

Anorex; Adilpose; Bontril; Melfiat-105; Obalan; Prelu-2; Plegine; Statobex; Wehless; and others

5–12

Diethylpropion (Amfepramone)

IV

Tenuate; Tepanil generic

4–6

Mazindol

IV

10

Phentermine hydrochloride

IV

Mazanor Sanorex Fastin; Ionamin; Phentrol; Adipex-P Obermine, and generic Ionamin and generic Dexatrim; Acutrim

Phentermine resin IV Phenylpropanolamine Not scheduled Serotonin–norepinephrine reuptake inhibitor Sibutramine IV

Meridia; Reductil

12–24

25 tab before meals 75 mg in AM (slow release) 1 mg before meals 2 mg before meals 8, 15, 18.75, 30, and 37.5 mg

25–150 70–210

75 75 1–3 15–37.5

7–24

15 and 30 mg 25 or 75 mg

25–75

2–14

5.10, 15 mg once daily

5–15

Note: Schedule II drugs have not been included because they are not approved by the FDA for treating obesity.


Noradrenergic agents Benzphetamine

Daily dose range (mg)


219

overfed (23), suggesting that drugs and techniques that modify nutrient partitioning have potential value in the treatment of obesity. The growth hormone directs nutrients toward linear growth and milk production. In adults, growth hormone shifts the partitioning of nutrients toward protein and away from fat. Gonadal hormones, particularly testosterone, are potent nutrient-partitioning agents. Gonadal hormones enhance protein storage and decrease fat storage, and is most evident at the onset of puberty. Adrenal glucocorticoids also may affect nutrient partitioning and fat distribution by enhancing protein catabolism and increasing fat storage primarily in the central or abdominal region. Finally, `-adrenergic drugs, particularly `-2- and/or `-3-adrenergic agonists, can enhance protein synthesis and reduce fat storage (24). 2.2.2.3. THERMOGENESIS Thermogenesis is a third mechanism for modulating fat stores. There are three components to thermogenesis: (1) resting metabolic rate, (2) facultative and nonfacultative thermogenesis in response to nutrients, and (3) physical activity. Thyroid hormones are the original thermogenic drugs (1). Deficiency of thyroid hormone reduces metabolic rate, and hyperthyroidism increases metabolic rate. Because thyroid hormones can increase the loss of protein and calcium from the body (25), they generally should not be used to treat obesity. Several other hormones are thermogenic. The growth hormone is a nutrient-partitioning agent that is calorigenic in normal and obese humans and produces a shift in nutrient storage from fat to protein (26). Androgenic and anabolic steroids also are thermogenic and enhance nitrogen retention. Some adrenergic agonists also are thermogenic. Norepinephrine and epinephrine are known to increase the metabolic rate. Ephedrine, a synthetic noradrenergic drug, is thermogenic in normal and obese subjects and has been used therapeutically to treat obesity (27). Terbutaline is a `-2-adrenergic agonist developed for treatment of respiratory symptoms, which is thermogenic and induces weight loss (28). Several synthetic, thermogenic drugs recently have been developed (see Subheading 4.2.3.). Whether the shift from fat to protein storage and the thermogenic effects of these compounds are separable is unclear from the present literature.

3. DRUGS APPROVED BY THE FOOD AND DRUG ADMINISTRATION FOR CLINICAL USE IN THE TREATMENT OF OBESITY 3.1. Drugs Affecting Food Intake 3.1.1. NORADRENERGIC DRUGS THAT RELEASE NOREPINEPHRINE BLOCK ITS REUPTAKE INTO NEURONS 3.1.1.1. CHEMISTRY The chemical structure of the currently marketed drugs, including fenfluramine, which was recently withdrawn from the market, approved for the treatment of obesity, is shown in Fig. 1. This includes two compounds from Schedule III and four compounds in Schedule IV. All of the currently available drugs, except mazindol, are derivatives of `-phenethylamine. Four types of chemical modification were used to reduce the abuse potential, while retaining the appetite suppressing effect. Most of these drugs probably act by releasing norepinephrine from stores in presynaptic vesicles. Norepinephrine, in

OR

220


Fig. 1. Formulas for drugs approved for the treatment of obesity.

turn, reduces food intake by acting on `-adrenergic receptors in the perifornical hypothalamus. As such, appetite suppressants have chemical similarities with norepinephrine and epinephrine. Mazindol, on the other hand, is a tricyclic compound and not a derivative of `-phenethylamine. Mazindol probably acts by blocking the reuptake of norepinephrine into presynaptic terminals, thus increasing the interneuronal concentration of norepinephrine to act on `-adrenergic receptors. However, mazindol’s basic effects are similar to those of the `-phenethylamine derivatives. 3.1.1.2. PHARMACOLOGY Appetite suppressant drugs bind to hypothalamic receptors and the potency of this binding is highly correlated with their suppression of appetite (29). The primary pharmacological effects of these drugs are on the central nervous system, on the cardiovascular system, and on peripheral metabolism. All appetite-suppressant drugs produce central excitation, manifested clinically as difficulty in sleeping and in some individuals as nervousness. This effect is most obvious shortly after the drug is administered and decreases substantially with continued use. To a variable extent, these drugs may also increase heart rate and blood pressure. A slight elevation in blood pressure is seen mainly with amphetamine, however, this effect is usually short lived and not clinically significant. Metabolic effects also have been observed with some of these drugs including increased lipid mobilization in vitro and enhanced glucose uptake. Clinical studies of the available appetite suppressants are cited in Table 3.


221

3.1.1.3. EFFICACY The largest review of effectiveness for noradrenergic appetite-suppressing drugs was conducted by the FDA in the early 1970s (30). There were 210 double-blind studies, which included 4543 patients treated with active drug and 3180 patients treated with placebo. The studies lasted from 4 to 20 wk. In more than 90% of the studies, the active drug produced more weight loss than placebo. In 40% of the 160 trials comparing placebo with active drugs, the patients receiving the active drug lost significantly more weight than those receiving placebo. After 4 wk of therapy, the dropout rate for patients on active drugs was 24.3% compared to 18.5% for patients receiving placebo. Forty-four percent of patients on active drugs lost 0.45 kg/wk (1 lb/wk) compared with only 26% of patients receiving placebo. In this study, 2% of patients receiving active drugs lost more than 1.4 kg/wk (3 lb/wk) compared to 1% with placebo. Average weight loss for patients taking the drug was 0.25 kg/wk (0.56 lb/wk) more than those receiving placebo at the end of 4 wk of therapy. Lumping all patients together at their final weights, the patients taking the active drug lost approximately 0.25 kg/wk (0.56 lb/wk) more than those taking placebo (30). Studies comparing one active drug with another failed to show any significant advantage for one compound. Trials with noradrenergic appetite-suppressing drugs have been carried out for up to 60 wk (Table 4). Several points are worth examining in this table. First, there was considerable variation among studies in the amount of weight loss that occurred during the treatment with active drugs. Second, regardless of the length of study, which lasted up to 60 wk, the drug-treated patients almost always lost more weight than the placebo-treated patients. Third, there was no obvious advantage in terms of weight loss per week among drugs when studies lasting up to twenty weeks are separated from those beyond 20 wk. Fourth, there is no obvious difference between medications and their relative effectiveness. The reason for this lack of difference is apparent in examining the data presented in Fig. 2 (1). This is a study in which 30 patients in the drug treated group and 15 patients in the placebo group all remained in treatment for the entire 20 wk. The drug-treated patients lost more weight than the placebo-treated group, but that the rate of weight loss declined and appeared to be reaching a plateau. This plateau effect has been observed in studies with noradrenergic appetite-suppressant drugs that last more than 5 mo. This effect is consistent with a feedback model where the drug serves to modify a comparator and lead to an alteration in the “set point” or comparator properties of the system in much the same way as a thermostat would accomplish this for heating or cooling a house. 3.1.1.4. SAFETY OF APPETITE SUPPRESSANTS The appetite suppressing drugs have a number of side effects which are summarized relative to placebo in Table 5 (31). Among the noradrenergic drugs, insomnia and dry mouth are the most common side effects. Other responses tend to be less common and none are serious. The safety of appetite-suppressant drugs has been the subject of considerable discussion. Griffiths et al. (32), using baboons as subjects, examined the reinforcing properties of intravenous preparations of several appetite-suppressing drugs and compared these effects to the potency of each drug to reduce food intake. The ratio of anorexiant dose to reinforcing dose, a measure of abuse potential, is shown in Fig. 3 for several drugs. At one extreme are diethylpropion and amphetamine. At the other extreme are fenfluramine

222

Table 4 Drug Treatment of Obesity Drug

a

Schedule IV Diethylpropion

Mazindol 222

Duration (wk)

75 (slow release) 75 (slow release) 25 thrice daily 75 (slow release) 25 thrice daily 25 thrice daily 25 thrice daily 25 thrice daily 2 1 thrice daily 1 thrice daily 1 thrice daily 1 thrice daily 1 thrice daily 1 thrice daily 2 2 2 2 1 thrice daily 2 4 1 2

6 12 12 25 12 12 14 — 12 6 6 12 12 6 6 12 12 12 12 8 12 20 6 8

No. of patients Drug Placebo 28 21 41 9 22 20 30 17 50 18 15 14 32 15 15 20 40 27 19 13 19 28 15 21

28 20 33 4 18 17 30 43 21 12 12 33 15 15 20 20 24 23 13 23 28 15 21

Mean weight change (kg) Drug Placebo –1.9 –6.6 –9.1 –11.7 –4.4 –6.8 –3.1 –6.0 –8.6 –2.3 –5.1 –8.5 –6.4 –5.2 –4.0 –6.9 –8.4 –8.4 –1.4 –5.2 –5.0 –1.9 –2.6 –15.7

–0.9 –4.5 –4.5 –1.6 –1.6 –4.4 –6.1 –4.4 –5.4 –0.5 –1.2 –2.4 –2.6 –2.3 –1.0 –1.6 –1.1 –6.6 –0.3 –3.8 –3.6 +0.7 –1.0 –11.6

Weight change (kg) drug–placebo 1.0 2.6 4.6 10.1 2.8 2.4 –3.0 1.6 3.2 1.8 3.9 6.1 3.8 2.9 3.0 5.3 7.3 1.8 1.1 1.4 1.4 2.6 3.6 4.1

Diet restriction 1200–1500 kcal Restricted 100 kcal “Strict” 100 kcal 100 kcal — — 600 kcal 1000 kcal None None 1000 kcal None None 1200 kcal 1000 kcal 1000 kcal Restricted 1200 kcal 2.3–4.5 kcal/kg 1000–1200 kcal None 260 kcal

Year 1971 1974 1975 1975 1975 1975 1978 1978 1973 1973 1973 1973 1974 b 1975 1975 1975 1975 1975 1975 1975 1975 1976 1976 1977


Dose (mg)

9 9 14 6 12 16 16 14 6 24 24 36 36

20 20 39 72 114 21 19 30 78 34 20 19 14

97 20 twice daily 20 twice daily 40 twice daily 20–40 40 Clortermine 50 50 Phendimetrazine 105 c Schedule II Amphetamine 5 thrice daily 5 thrice daily 5 thrice daily Phenmetrazine 75 (slow release) 25 thrice daily Unscheduled PPA 20 (fast acting) plus 55 (slow acting)

8 6 6

50 78 76

Phentermine

223

Schedule III Benzphetamine Chlorphentermine

20 39 28 114 16

6 6 4 12 12

38 39 7 (studies) 18 (studies) 36

12 6 12 6 6

14 20 32 53 14

12

53

29 77 32 20 11 11 50

–5.0 –3.4 –3.8 –3.0 –4.2 –9.2 –8.8 –7.3 –3.8 –5.3 –10.0 –12.2 –13.0 –1.9 –6.6 –9.1 –11.7 –4.4 –6.8 –6.0 –6.0 –8.6 –2.3 –5.1 –8.5 –6.4 –5.2 –4.0 –6.9 –8.4 –84

–4.5 –4.5 –2.7 –0.77 –1.2 –5.2 –5.2 –1.8 –1.5 –1.5 –4.4 –4.8 –4.8 –0.9 –4.5 –4.5 –1.6 –1.6 –4.4 –4.4 –4.4 –5.4 –0.5 –1.2 –2.4 –2.6 –2.3 –1.0 –1.6 –1.1 –66


2 2 1 thrice daily 2 2.11 30 (resin complex) 30 (resin complex) 30 30 30 30 30 30

0.5 –1.1 1.1 3.0 3.0 4.0 3.6 5.5 2.3 3.8 5.6 7.4 8.2

Behavior mod. Behavior mod. Behavior mod. None None 9–10.2 kcal/lb 9–12.2 kcal/lb 1000 1000 None Individual diet 1000 1000

1977 1977 1978 1977 1985 1972 1972 1974 1975 1977 1977 1968 1968

1.0 2.6 4.6 10.1 2.8 2.4 1.6 1.6 3.2 1.8 3.9 6.1 3.8 2.9 3.0 5.3 7.3 1.8

1200–1500 kcal Restricted 1000 kcal “Strict” 1000 kcal 1000 kcal — — 600 kcal 1000 kcal None None 1000 kcal None None 1200 kcal 1000 kcal 1000 kcal

1971 1974 1975 1975 1975 1975 1978 1978 1973 1973 1973 1973 1974 1975b 1975 1975 1975 1975

223

(continued)

224

Table 4 (continued) Drug

Dose (mg)

a

Fluoxetined

25 thrice daily with caffine 25 thrice dily 75 65

Duration (wk)

No. of patients Drug Placebo

224

4

33

2 2 8

70 51,36 50

60 10 20 40 60 60 60

24 8 8 8 8 52 52

24 131 131 131 131 14

60 60

52 6

11 11

Fluoxetine is not approved for treatment of obesity.

–1.4 –5.2 –5.0 –14.8 –1.9 –2.6 –15.7 –5.0 –3.4 –3.8 –3.0 –4.2 –9.2 –7.3 –3.8 –5.3 –10.0 –12.2 –13.0 placebo.

–0.3 –3.8 –3.6 –10.5 +0.7 –1.0 –11.6 –4.5 –4.5 –2.7 –0.77 –1.2 –5.2 –1.8 –1.5 –1.5 –4.4 –4.8 –4.8

Weight change (kg) drug–placebo 1.1 1.4 1.4 4.3 2.6 3.6 4.1 0.5 –1.1 1.1 3.0 3.0 4.0 5.5 2.3 3.8 5.6 7.4 8.2

Diet restriction

Year

Restricted 1200 kcal 2.3–4.5 kcal/kg 800–1200 kcal 1000–1200 kcal None 260 kcal Behavior mod. Behavior mod. Behavior mod. None None 9–10.2 kcal/lb 1000 1000 None Individual diet 1000 1000

1975 1975 1976 1976 1976 1976 1977 1977 1977 1978 1977 1985 1972 1974 1975 1977 1977 1968 1968


a Schedule categories provided by the Drug Enforcement Agency. b Cross-over study: same 15 patients first received drug and then received c Schedule II drugs are not approved for treatment of abesity. d

Mean weight change (kg) Drug Placebo


225

Fig. 2. Effect of biphetamine or placebo on body weight. There were 30 patients in the drugtreated group and 15 in the placebo-treated group, all of whom remained in treatment for the entire 20 wk. (Adapted from ref. 4.)

and phenylpropanolamine. Although the ratio of appetite-suppressant dose to reinforcing dose is of some utility in predicting abuse potential, it does not always correlate with clinical experience. For example, diethylpropion has been widely used as an appetitesuppressing drug, yet there are few episodes of misuse. However, diethylpropion’s appetite suppressant to reinforcing ratio in baboons is greater than amphetamine or phenmetrazine, both of which are classified in Schedule II. There is no indication for use of drugs in Schedule II for treatment of obesity. Drugs in Schedule IV are obviously preferred, but drugs in Schedule III also have a low abuse potential. 3.1.2. NORADRENERGIC DRUGS THAT ACT AS _-1-ADRENERGIC AGONISTS Phenylpropanolamine is only approved drug in this class. 3.1.2.1. CHEMISTRY Phenylpropanolamine (Propadrine or PPA) is a series of isomers of pseudo and norpseudo ephedrine (33). The name phenylpropanolamine in the United States and the same name in Europe or Australia may be different chemical isomers. This difference introduces confusion in interpreting some of the clinical literature, as some of the isomers of phenylpropanolamine are considerably more effective in suppressing appetite than others (33). 3.1.2.2. PHARMACOLOGY In animal studies, phenylpropanolamine reduced food intake by acting on _-1-adrenergic receptors located in the paraventricular nucleus (8). 3.1.2.3. EFFICACY Phenylpropanolamine is used as both a nasal decongestant and a weight-control drug (33). A summary by Weintraub of five trials of phenylpropanolamine vs placebo, is

226

Table 5 Side Effects of Various Anorexiant Drugs Compared with Those of Placebo Drugs

a

Amphetamine /methamphetamine Phenmetrazine Phendimetrazine Benzphetamine Phentermine Chlorphentermine Clortermine Diethylpropion Mazindol Fenfluramine Placebod Fluoxetine 60 mg

Headache

Insomnia

Nervousness

Dizziness

Weakness or fatigue

2.2

6.9

2.1

6.3

0.9

1.2

38

0.9 0 —c — 1.6 1.7 1.2 0.8 1.15 3.4 0.6

6.5 4.6 2.1 3.2 6.2 7.8 0.9 4.8 1.4 1.8 2.7

5.5 1.4 7.4 — 0.9 1.1 1.2 1.3 0.7 3.6 1.3

5.6 6.6 2.2 1.6 3.1 1.2 0.7 3.1 1.0 1.0 1.6

1.3 — 0 — 0.8 0.8 0.8 0.9 1.0 2.8 n.o

0.4 0.9 0 1.0 — — — 0.4 3.2 1.1 —

5 — — — — — — 0 — 0.1 —

Depression Tremor

2.8

Anxiety

2.2

Rise in blood presure Tachycardia 30 1.7 — — — — — — — — 0.3 — Part III / Treatment

(continued)

Amphetamine /methamphetamine Phenmetrazine Phendimetrazine Benzphetamine Phentermine Chlorphentermine Clortermine Diethylpropion Mazindol Fenfluramine d Placebo Fluoxetine 60 mg

Palpitations

Dry mouth

Nausea

Abdominal discomfort

Constipation

Diarrhea

Edema

Polyuria or frequency


Drugsa

Drowsiness

Sweating

4.2

1.4

b

25

1.6

1.8

0.9

2.7

—

—

20 — 0.7 — — — — 16 — 0.1 —

3.8 4.6 1.7 0 3.7 3.4 1.2 3.5 3.0 3.1 0.8

3.3 — 2.0 2.7 2.3 1.1 3.2 3.4 1.1 1.4 2.9

0.4 2.5 3.0 — — — 1.3 0.6 — 2.7 —

1.6 1.8 — — 2.5 2.5 1.8 0.9 — 3.7 1.8

— — — — — — — — 7.2 0 2.0

2.3 — — — b 5.0 b 2.6 — — — 1.8 —

1.8 b

0 b 9.5 — — — — — b 3.3 b 1.5 0 —

a

The data given for each drug are expressed as the ratios of the percentage of drug subjects compared to the percentage of placebo subjects reporting each side effect. The placebo data represent the percentage of placebo subjects reporting each side effect. (From Br J Psychiat 143:77–86.) b Percentage of patients reporting the symptom. c Data were not sufficient to make comparisons possible. d Placebo-treated patients also experienced dysuria (0.3%) and chills (0.1%). Source: Compiled by the author. Data derived from publications referenced in Bray GA The obese patient. In: Major Problems in Internal Medicine, Vol. 9. WB Saunders, Philadelphia, PA, 1976.

227

228


Fig. 3. Anorectic-reinforcement ratio. Effect of various anorexiant drugs on food intake and reinforcing potential. The lower the number the smaller the reinforcing potential relative to food intake. (Adapted from ref. 32.)

shown in Table 6 (34). The mean weight loss for relatively short-term drug trials with PPA is 0.23 kg/wk. Phenylpropanolamine thus produces significantly more weight loss than placebo, but the magnitude of this weight loss is smaller than with the noradrenergic drugs already discussed. 3.1.2.4. SAFETY Two major concerns have been raised about phenylpropanolamine. The first is the potential for this drug when combined with caffeine to serve as a “lookalike” drug in illicit trade. For this reason, the combination of phenylpropanolamine and caffeine is no longer allowed in legitimate sales. The second concern is that phenylpropanolamine may increase blood pressure. The literature is conflicting but suggests that high doses (above 75 mg) of the drug can increase blood pressure, but if used according to directions, this is a minor problem (35). 3.1.3. SEROTONERGIC DRUGS 3.1.3.1. CHEMISTRY Fenfluramine is a `-phenethylamine and is chemically related to the noradrenergic drugs in Fig. 1. Pharmacologically, however, the substitution of a trifluromethane group in the meta position on the phenyl ring alters the function of this drug dramatically (14). 3.1.3.2. PHARMACOLOGY Fenfluramine does not deplete norepinephrine but alternatively acts to increase serotonin concentration in the neuronal cleft by partially inhibiting reuptake of serotonin as well as releasing serotonin from nerve endings. The nor-fenfluramine metabolite, produced by de-ethylation of fenfluramine, is a serotonin agonist. The increased serotonin in the neuronal cleft is believed to reduce food intake. Of the two isomers in the racemic mixture of fenfluramine, the d-isomer (dexfenfluramine) appears to

Study (date)

229

Hoebel et al. (1975b) Sebok (1977b ) Nobel and Kalkhof (1981) Nobel and Respess (1981) Settel (1965) Schteingart (1992) Greenway (1989)

Daily dosage (mg) Single Total

Study design

Comparison agent

Crossover

Placebo

25

75

2

Parallel

Placebo

50

100

Parallel

Placebo

75

Crossover

Placebo

Crossover

Study length (wk)

No of subjects (dropouts) PPA Placebo

Weight loss (gain) (kg/wk) PPA Placebo

6

70 total completed 36 (6) 36 (12)

0.46 0.32 0.47

0.28 (0.05) 0.27

75

6

120 (1)

123 (8)

0.73

0.45

50

50

6/–a

173 (68)

88 (36)

0.67

0.47

Placebo

25

75

3/3

42 (12)

Total

0.67

0.32

Parallel

Placebo

75

75

6

51 (15)

50 (23)

0.43

0.18

Parallel

Placebo

75

75

12

50 (5)

48 (8)

0.23

0.10


Table 6 Clinical Trials of Phenylpropanolamine Alone

a

First six weeks only of study analyzed (as parallel group study). Source: Compiled by the author.

229

230


be the anorectic compound (14); the l-fenfluramine appears to act on the dopaminergic system. Fenfluramine is metabolized to an active metabolite with a similar half-life to the parent compound. 3.1.3.3. EFFICACY The clinical efficacy of d,l-fenfluramine has been demonstrated in studies of short and long duration. The data from the International Dexfenfluramine Trial (INDEX) are shown in Fig. 4 (36). Seven European centers participated in the INDEX trial of dexfenfluramine, which enrolled 418 placebo-treated and 404 drug-treated patients. In a manner similar to that observed in other studies, the INDEX trial showed that the patients remaining in treatment lost significantly more weight than those on placebo. Weight loss plateaued at approximately 6 mo and was better maintained for the remaining 6 mo in the drug-treated patients than in those receiving placebo. Not all patients responded to this drug. If a patient does not respond by 4 mo, they are unlikely to respond if the drug is continued and it would be wise to discontinue it. Data from a number of studies are available with fluoxetine (Prozac; Lovan), a drug approved for treating depression but not obesity. No clinical trials for weight loss have been reported for the antidepressant sertraline (Zoloft). In a clinical trial with fluoxetine, 10, 20, 40, 60, or 80 mg/d lasting up to 8 wk, the drug produced a dose-dependent weight loss (37). Fluoxetine has been shown to be significantly better than placebo in a number of studies. The study by Darga et al. (38) (Fig. 5) showed that weight loss with fluoxetine was maximal at 12–16 wk and was significantly greater in drug-treated than in placebotreated patients. After 16 wk, however, the drug-treated patients regained weight even though continuing to take the medication. This weight gain was accompanied by an increased variance in body weight, indicating that some patients regained more weight, whereas others maintained their weight loss. 3.1.3.4. SAFETY Racemic fenfluramine and its d-isomer dexfenfluramine are not addicting. The Drug Abuse Council had unanimously recommended removing fenfluramine and its isomers from the schedule because there is no evidence of drug abuse prior to the surfacing of the issue of cardiac valve problems associated with their use. The profile of side effects for this compound versus the noradrenergic compounds is shown in Table 6. Dry mouth and insomnia occur with both groups. Diarrhea is seen with fenfluramine, whereas constipation is seen with noradrenergic drugs. There have been several isolated reports of pulmonary hypertension, which is rare and reversible in most patients (39). In a case-control study, the prevalence of this rare complication was estimated to be between 1 in 20,000 and 1 in 100,000. There are also reports of cardiac valvular lesions that recently led the FDA to withdraw fenfluramine and dexfenfluramine from marketing (40,41). A number of side effects have been reported with fluoxetine. In general, they are minor and tend to subside with continued treatment (Table 6). 3.1.4. STEPPED OR COMBINATION THERAPY As noted earlier, at least two mechanisms mediate the clinically effective appetitesuppressing drugs, one involving noradrenergic receptors and a second involving serotonergic receptors. Because a plateau in weight loss is observed with both types of drugs, the potential for achieving a greater weight loss or reduced side effects by using a combination of noradrenergic and serotonergic drugs has been evaluated by Weintraub and

a

Drug

d,l-Fenfluramine

231

Fenfluramine plus phentermine a Dexfenfluramines

Dose (mg) 20 twice daily 40 20 thrice daily 60 (extentabs) 60 twice daily 60 (pacaps) 60 (pacaps) 60 (pacaps) 60 (pacaps) 60 (pacaps) 60 20 40 60 60, 15 15 twice daily 15 twice daily 30 twice daily 15 twice daily 15 twice daily

Duration (wk) 6 6 12 12 16 12 24

52 10 36 36 36 28 12 12 12 52 24 26

No. of patients Drug Placebo 44 23 56 60 11 18 25 32 (behavior mod.) 23 (combined) 21 26 16 8 9 62

43 43 58 11 22 10

21 25 13

59

19 (hospital) 20 (hospital) GP26 GP24 64 69 295 268 19 23

Mean weight loss (kg) Drug Placebo

Net weight loss (kg)

Diet restriction


Table 7 Drug Treatment of Obesity

Year

2.4 1.7 6.6 4.7 5.8 3.0 14.5 10.9

0.3 0.3 2.5 2.5 9.4 0.0 6.0 6.0

2.1 4.1 4.1 2.2 3.6 3.0 8.5 4.9

None None None None 1000–1800 kcal None 1000–1200 kcal 1000–1200 kcal

1975 1975 1976 1976 1976 1988 1981 1981

15.3 0 5.9 11.9 12.7 10.6 14.3

6.0 3.0 3.3 9.5 9.5 9.5 4.6

9.3 3.0 2.6 2.4 3.2 1.1 9.7

1000–1200 kcal Dietary advice 18–20 kcal 1200 kcal 12 kcal 1200 kcal

1981 1983 1983 1985 1985 1985 1992

2.8 5.3 8.1 9.8 6.2 5.8

1.7 1.4 3.5 7.2 2.6 2.9

4.5 3.9 4.6 2.6 3.6 8.7

Counseling Counseling 16 kcal/kg >400 kcal/d 1200–1500 kg Calories by 24–40%

1985 1985 1988 1989 1990 1988

a

Not approved in the United States.

231

232


Fig. 4. Dexfenfluramine completers analysis. Baseline N df = 404; placebo = 418. Effect of treatment with dexfenfluramine or placebo on body weight. This year-long trial was conducted in 24 centers. Approximately half of the patients who began the trial remained in treatment at the end of the year. Drug-treated patients lost significantly more weight than those treated with placebo. (Adapted from ref. 36.)

Fig. 5. Effect of treatment with fluoxetine or placebo on body weight. The weight loss of the drugtreated group reached a nadir 29 wk after beginning the drug and tended to regain weight thereafter. (Adapted from ref. 38.)

his colleagues (42). Their first trial showed that a combination of phentermine and d,l-fenfluramine used at half-maximal doses produced as much weight loss as either drug at maximal dose, but was accompanied by fewer side effects. This was followed by a 4-yr trial using a combination of phentermine and d,l-fenfluramine (43). Figure 6 shows the weight loss during the first double-blind phase of this trial (43). During the first 6-wk, lead-in period, all patients were treated with a combination of behavior modification,


233

Fig. 6. Effect of combination treatment with fenfluramine and phentermine. During the 6-wk run-in period, both groups were treated with diet, exercise and behavior modification. Patients were randomized using minimization techniques to assure a close match at the start of the double-blind period. During the double-blind period, the placebo-treated patients lost almost no additional weight, whereas the drug-treated patients plateaued at a significantly lower weight. (Adapted from ref. 42.)

exercise, and individual nutritional counseling. Subjects were randomized into drug- or placebo-treatment groups at the end of the 6-wk lead-in period, using techniques to make the groups comparable. Thus, at the beginning of the first double-blind drug trial, the placebo- and drug-treated patients had similar weights. Little additional weight was lost by the placebo-treated group during the ensuing 28 weeks. The mean overall weight loss in the placebo-treated group from the beginning of the lead-in period to week 32 was 4.6 kg. In contrast, the fenfluramine-treated group continued to lose weight with an average weight loss of 15.6 kg over 32 wk. Nearly half of the patients in this drug study had an initial and sustained therapeutic benefit (43). Continuous therapy was more effective than intermittent therapy. Patients receiving active drugs continued to respond over the entire 3.5 yr. When the drug was withdrawn after 3.5 yr, patients regained weight, proving once again that drugs do not work when not taken. No serious side effects were observed in this study. Additional studies using combined therapy in different doses are clearly indicated. The clinically relevant conclusions from this study are summarized in Table 8.

4. AREAS OF NEW DRUG DEVELOPMENTS 4.1. Drugs That Suppress Food Intake 4.1.1. SIBUTRAMINE: AN AMINE REUPTAKE INHIBITOR In contrast to all the other sympathomimetic drugs in Table 3, sibutramine has been extensively evaluated in several multicenter trials lasting 6–12 mo. In a clinical trial

234

Part III / Treatment Table 8 Conclusions from the Study of Combined Drug Treatment for Obesity 1. 2. 3. 4. 5. 6. 7. 8. 9.

Anorexiants improve weight loss. Effects last more than 3.5 yr. No evidence of nontherapeutic use or abuse. Some patients received little benefit. Continuous therapy was better than intermittent therapy. Weight loss goal of 15% below baseline. Anorexiants did not impair behavior modification. Partial tolerance to adverse effects of dry mouth and sleep disturbances. Weight loss raised high-density lipoprotein cholesterol and lowered triglycerides. Source: ref. 41.

lasting 8 wk, sibutramine was found to produce dose dependent weight loss with doses of 5 and 20 mg/d. Three clinical trials are included in the package insert (44–46). They were conducted in men and women ages 18–65 with a BMI between 27 kg/m2 and 40 kg/ m2. In one trial enrolling 456 patients, 56% of those who stayed in the trial for 12 mo lost at least 5% and 30% of the patients lost 10% of their initial body weight while taking the 10 mg dose (46). In a dose-ranging study of 1047 patients lasting 6 mo, 67% achieved a 5% weight loss and 35% lost 10% or more (44). They showed a dose-related reduction in body weight and body fat. Data from this trial on over 1000 patients are shown in Fig. 7. There is a clear dose-response during treatment for 24 wk and regain of weight when the drug was stopped indicating that the drug remained effective. Nearly two-thirds of the patients treated with sibutramine lost more than 5% of their body weight from baseline and nearly one-third lost more than 10%. The year-long trial showed that 10 and 15 mg doses produced significantly greater weight loss than placebo but that these doses were not different from one another. In a third trial, in patients who initially lost weight on a very low calorie diet before being randomized, sibutramine produced additional weight loss, whereas the placebo-treated patients began to regain. Lipids and uric acid were reduced across all trials in relation to the weight loss. The medication will be available in 5, 10, and 15 mg doses; 10 mg/d as a single daily dose is the recommended starting level with titration up or down based on response. Doses above 20 mg/d are not recommended. Of the patients who lost 4 lb in the first 4 wk of treatment, 60% achieved a weight loss of more than 5%, compared with less than 10% of those who did not lose 4 lb in 4 wk. Combining data from the total of 11 studies on sibutramine showed a weight-related reduction in triglyceride, total cholesterol, and LDL-cholesterol and a weight loss-related rise in HDL-cholesterol. 4.1.2. ANTAGONISTS OF OPIOID RECEPTORS Naloxone and naltrexone rapidly reduce food intake in human subjects (18). However, three clinical trials with naltrexone, a long-lasting derivative of naloxone, showed that doses ranging from 50 to 300 mg/d administered for 8 wk did not have a significant effect on body weight except for the female cohort in one of the three studies (47–50). 4.1.3. BIGUANIDES Metformin, which was recently been approved by the FDA to treat non-insulin-dependent (type II) diabetes mellitus, produced weight losses ranging from 2.3 kg (5 lb) in 7 mo to 6.0 kg (13.2 lb) at the end of the period of observation, which lasted, in some cases, up to 2 yr (51).


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Fig. 7. Effect of sibutramine on body weight.

4.1.4. _-2 ADRENERGIC ANTAGONISTS Clonidine is an _-2-adrenergic agonist that stimulates food intake in experimental animals (52); thus, a blockade of _-2-adrenergic receptors might reduce food intake. Yohimbine, an _-2-adrenergic blocking drug, showed no effect in two studies of males (53– 54), but in one study with females there was a significant weight loss in the yohimbine-treated subjects (52). Yohimbine also has been reported to reduce local fat deposits when applied topically in a cream (54). Further studies of _-2-adrenergic blocking drugs may be warranted. 4.1.5. PEPTIDES 4.1.5.1. CHOLECYSTOKININ A number of neuropeptides are known to decrease or increase food intake (18,21). Agonists to the peptides that decrease food intake and antagonists to those that increase food intake offer viable strategies to develop new drugs to treat obesity. Cholecystokinin (CCK) suppresses food intake when administered peripherally. In clinical studies, the infusion of cholecystokinin prior to ingestion of a meal reduces food intake by producing early satiety in both lean and obese subjects (53–57). Antagonists to the CCK receptors (Devazepide and L-365, 260) increase food intake in experimental animals, suggesting a functional role for CCK (58). Cholecystokinin agonists are being developed for potential clinical use in the treatment of obesity (59). None of the other anorectic peptides have yet to spawn potentially viable drugs. 4.1.5.2. NEUROPEPTIDE Y Antagonists to neuropeptide Y (NPY) or to galanin may be particularly interesting because they might affect the intake of specific macronutrients. NPY, which has at least five different receptors, strongly stimulates carbohydrate intake. A NPY1,5 antagonist is in development, but no publications reporting on its effects in humans are available.

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Galanin, on the other hand, stimulates the intake of fat. The nutrient specificity of these peptides makes them good candidates for future research. 4.1.5.3. LEPTIN (OB PROTEIN) This gene product, whose defect produces obesity in the ob/ob (obese) mouse, and has been shown to reduce food intake in these ob/ob mice and in animals that became obese eating a high-fat diet (see Chapter 18 for further discussion). This peptide, which contains 167 amino acids, may prove to be a useful therapeutic tool. 4.1.5.4. BOMBESIN Bombesin is a tetradecapeptide derived from frog skin that has been shown to influence food intake as well as produce hypothermia and hyperglycemia. In clinical studies, peripheral administration of bombesin produced a dose-dependent reduction in food intake. Studies in experimental animals suggest that the bombesin receptors may be the neuromedin-B receptors, as a combination of neuromedin-B and a gastrin releasing peptide (GRP) can reduce food intake. 4.1.5.5. ENTEROSTATIN Enterostatin is the signal pentapeptide produced when procolipase, a pancreatic acinar cell enzyme, is secreted into the intestine. This pentapeptide has two structures across most mammalian species. They are Val-Pro-Asp-Prp-Arg (VDPDR) or Al_-Pro-GlyPrp-Arg (APGPR). In a variety of experimental animals, enterostatin was shown to selectively reduce fat intake without influencing either carbohydrate or protein intake. In one clinical study, enterostatin at doses of 4 and 16 mg given intravenously to obese healthy volunteers was without effect on food intake. 4.1.6. SUGAR ACIDS A number of small sugar acids and lactones have been reported to either increase or decrease food intake in experimental animals. No clinical studies with these derivatives are reported yet (60).

4.2. Nutrient Partitioning 4.2.1. PREABSORPTIVE NUTRIENT PARTITIONING (NUTRIENT AVAILABILITY) Several approaches have been used to alter nutrient availability by altering digestion and absorption in the gastrointestinal tract, leading to nutrient partitioning of ingested food between absorption and excretion. 4.2.1.1. INHIBITORS OF GASTRIC EMPTYING A delay in gastric emptying might reduce food intake by increasing stomach volume and signaling early satiety. (-D-)-Threo-chlorocitric acid reduced body weight experimentally in association with delayed gastric emptying (61). Clinical trials on this compound are suggestive, but the development of this drug may have been terminated because no recent studies have been published. 4.2.1.2. INHIBITORS OF CARBOHYDRATE DIGESTION Amylase inhibitors from natural sources (Jack beans), _-glucosidase inhibitors or disaccharidase inhibitors such as acarbose, miglitol, and AO128 (62) have reduced the digestion of starch and disaccharides such as maltose, lactose, and sucrose. Of these


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compounds, the disaccharidase and sucrase inhibitors will reduce digestion of disaccharides to their monosaccharides, thus reducing absorption. The effect is dose dependent and at larger doses large quantities of carbohydrates reach the colon, where they serve as substrates for bacteria, which may result in bloating and intestinal discomfort. Excessive flatulence is a clinical side effect for both disaccharide and sucrose inhibitors. Below these doses, the digestion curve is flattened making these drugs potentially useful in treatment of diabetics. Clinical studies have yet to show any significant effect of these drugs on body weight. 4.2.1.3. INHIBITION OF FAT DIGESTION OR ABSORPTION CHOLESTYRAMINE Cholestyramine binds bile acids and disrupts micelle formation, thus providing one approach to inhibiting triglyceride digestion. At high doses, cholestyramine leads to increased fecal fat loss. Two clinical trials with cholestyramine failed to show any significant effect on weight loss at nearly maximally tolerated doses (1), and no recent trials have been reported. The antibiotic neomycin reduces fat absorption but has deleterious effects on the intestinal mucosa (1). A third agent in this group is perfluorooctyl bromide, a contrast medium for gastrointestinal (GI) X-rays, which blocks absorption of all macronutrient classes in experimental animals. No clinical trials have been published with this agent. ORLISTAT (XENICAL) Pharmacology. Orlistat (formerly called tetrahydrolipstatin) is a potent selective inhibitor of pancreatic lipase and reduces intestinal digestion of fat. The drug has a dosedependent effect on fecal fat loss, increasing it to about 30% on a diet that has 30% of energy as fat. Orlistat has little effect in subjects eating a low-fat diet as might be anticipated from the mechanism by which this drug works. Efficacy. Five long-term clinical trials with orlistat lasting 6 mo–2 yr have been published or presented in abstract form (63–67). The results of one of the 2-yr trials is shown in Fig. 8 (13). The trial consisted of two parts. In the first year patients received an hypocaloric diet calculated to be 500 kcal/d below their requirements. During the second year the diet was calculated to maintain weight. At the end of year 1 the placebotreated patients lost 6.5% of their initial body weight in year 2 than those receiving placebo. An analysis of quality of life in patients treated with orlistat showed improvements over the placebo group in spite of the concerns about gastrointestinal symptoms. Safety. Orlistat is not absorbed to any significant degree and its side effects are thus related to the blockade of triglyceride digestion in the intestine. Fecal fat loss and related GI symptoms are common initially, but subside as patients learn to use the drug. Some patients also need supplementation with fat-soluble vitamins, which can be lost in the stools. Absorption of other drugs does not seem to be significantly affected by orlistat. PSEUDONUTRIENTS Artificial sweeteners, indigestible fibers, and fat substitutes all fall in this group. Saccharin, cyclamates, aspartame, and acesulfame-K are the currently available artificial sweeteners. One trial with aspartame (68) showed that substitution of aspartame for sucrose caused weight loss in women but not men. The use of various fibers such as guar, mucilage, pectin, and chitosan to treat obesity is based on the hypothesis that nondigestible bulking agents would reduce food intake, absorption, or both. Efficiency of clinical trials with fiber are variable.

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Microparticulate Protein. Two fat substitutes are available. One of these is a microparticulate protein which has the feel of fat on the tongue. Because it is a protein, it cannot replace fats in cooking but has been used as a fat substitute in foods such as ice cream. It has 4 kcal/g as compared to 9 kcal/g for fat. Olestra. A second pseudofat is olestra. It is a mixture of penta-, hexa-, and hepta-esters of sucrose, which cannot be hydrolyzed by pancreatic lipase. Depending on the nature of the free fatty acids incorporated into olestra, its melting point and “taste feel” can be altered. Substitution of olestra for triglyceride in the diet decreases the digestible fats and, thus, has potential use for reducing caloric intake. Studies in normal-weight men show complete caloric compensation within 24 hr when olestra is covertly substituted in the breakfast meal (69). Two clinical studies in obesity evaluated the effectiveness of olestra on weight loss. In one study, olestra reduced weight, and in the other study, it did not. When olestra replaced 30% of the fat in the diet of healthy men for 14 days, they continued to eat the same quantity of food but lost weight because they did not compensate for the reduced available energy intake (70). The available data indicate that olestra is safe (71) and it was recently recommended for approval by the FDA as a food additive. 4.2.2. POSTABSORPTIVE EFFECTORS OF NUTRIENT PARTITIONING 4.2.2.1. GROWTH HORMONE Growth hormone (GH) is thermogenic in humans (26). Treatment with GH will increase the amount of lean tissue and decrease the amount of fat in hypopituitary human subjects. Conversely, the reduction of growth hormone after treatment of acromegaly is followed by an increase in body fat, particularly visceral fat (72). Several clinical studies were conducted with growth hormone in obesity (1,73,74), but its potential role is unclear because it produces acromegaly as a side effect. 4.2.2.2. TESTOSTERONE The increase in upper abdominal obesity and visceral fat in women is associated with an increased level of free testosterone and a decreased level of sex-hormone-binding globulin (SHBG) (75). In males, however, there is an inverse relationship between testosterone and central fat (76). Noting this relationship, Marin and colleagues conducted two studies looking at the effects of replacement with testosterone on regional fat distribution in men (76). The first study used testosterone undecanoate, which is absorbed via the lymphatic system in chylomicrons. In subsequent studies, they have used testosterone delivered via a transdermal patch (77). In both double-blind randomized clinical studies, Marin et al. demonstrated that testosterone significantly decreased visceral fat in males whose circulating testosterone was at the lower limits of normal. Dihydrotestosterone, an androgenic metabolite of testosterone involved in gonadal development, did not effect visceral fat (78). 4.2.2.3. GLUCOCORTICOIDS An increase in central fat deposition and an increase in catabolism of skin, muscle, and bone are characteristic of Cushings syndrome (adrenal hyperfunction) and treatment is with high doses of glucocorticoids (79). Addison’s disease (adrenal insufficiency) is associated with loss of body fat. Glucocorticoids are essential for the development of obesity in animals (80) and blockade of glucocorticoids with RU-48A will reverse one type of experimental obesity (81). Clinically, overactivity of the hypothalamic–pituitary–adrenal axis has been suggested as a central factor in the metabolic syndrome associated with increased visceral fat (82).


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4.2.2.4. OTHER STEROIDS Megestrol acetate (Megase®) increases food intake and fat storage in women with breast cancer (83,84) and this may involve hypothalamic neuropeptide Y (NPY) (83), reinforcing the role of steroids in obesity (83,84). Treatment with glucocorticoids produces a central form of fat storage and enhanced protein breakdown. Recently, dehydroepiandrosterone (DHEA), a major secretory steroid from the adrenal gland, was shown to decrease body fat in several models of obesity (85). However, clinical studies did not show a decrease in body fat in obese patients (86). 4.2.2.5. LIPID MODULATORS Several mechanisms might be probed to induce metabolic alteration in nutrient partitioning. Modulation of fat storage and breakdown offer possibilities of modifying nutrient flux. Because _-2-adrenergic receptors reduce lipolysis, _-2-adrenergic antagonists might enhance lipolysis (49). Modulation of the adenosine receptors is a second potential approach for enhancing lipolysis. Metformin, discussed in Subheading 4.1.3., might fit in this category because its mechanism of action is through channeling peripheral use of glucose. 4.2.3. THERMOGENIC DRUGS 4.2.3.1. ADRENERGIC DRUGS `-2 and/or `-3 adrenergic drugs are thermogenic and increase body protein and decrease body-fat content in mice, rats, pigs, sheep, and cattle (87). Several thermogenic `-3 adrenergic drugs were assessed in early clinical trials (88). A SmithKline Beecham compound, BRL-26830A, is the most extensively studied (89,90). In two studies published only in abstract, there was no significant weight loss. In one long-term clinical trial, the drug was significantly more effective than placebo (90). Its major side effect was the development of mild tremors due to `-2-adrenergic effects of this compound. Three other compounds, one from the Imperial Chemical Industries (now Zeneca, London, UK) (ICI D-7114), one from Hoffmann LaRoche (Nutley, NJ) (Ro16-8714), and one from Lederle (Wyeth-Ayerst, Philadelphia, PA) (CL-346,216), were also assessed in clinical trials. The Roche compound increased energy expenditure in lean and obese subjects but has not been studied further. The ICI compound, although effective in increasing thermogenesis in animals, was apparently without effect when administered to human volunteers (Arne Astrup, MD, personal communication). CL-346,216 was assessed in brief clinical trials, but the data are not published. Terbutaline, a `-2-adrenergic drug used to treat asthma, was found to be thermogenic and produced weight loss (28).

5. DRUGS PREVIOUSLY USED BUT NOT APPROVED OR RECOMMENDED 5.1. Thyroid Hormone Thyroid hormone, originally introduced into the treatment of obesity in 1893 (1), is not recommended in the treatment of obesity, except in the clinically hypothyroid patient.

5.2. Dextroamphetamine, Methamphetamine, and Phenmetrazine These Schedule II appetite-suppressant drugs (1) have significant drug-abuse liability. None of these three drugs should be used to treat obesity.

5.3. Human Chorionic Gonadotropin Nearly 40 yr ago, injections of human chorionic gonadotropin (HCG) were given to human subjects after it was observed that treatment of adolescents with Frohlich’s syn-

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drome showed altered fat deposition during treatment with HCG. Four double-blind, randomized, clinical trials with HCG injections compared with placebo showed no significant differences (91). Thus, there is no evidence that HCG injections are effective in treating obesity.

5.4. Dinitrophenol Dinitrophenol uncouples oxidative phosphorylation, increases body temperature and is thermogenic. Because of severe side effects, including neuropathy, hepatic damage, and cataracts, the drug should not be used to treat obesity (1).

5.5. Digitalis Anorexia and nausea are side effects of treatment with digitalis. For these reasons, it was temporarily used to treat obesity (3), but because of the narrow range between therapeutic and toxic doses, digitalis should only be used to treat congestive heart failure (1).

6. USE OF DRUGS IN THE CLINICAL TREATMENT OF OBESITY 6.1. Realities of Treatment There are a number of realities about the treatment of obesity with drugs or other modalities (see Chapters 20 and 21). First, obesity is a chronic relapsing disease that has many causes. In most obese patients, a clear etiologic diagnosis is usually not possible. There are genetic factors: cases of neurologic disorders with obesity as a consequence, cases of endocrine disease which produce obesity, and cases in which drug treatment leads to obesity. Because of its chronic nature and usually unknown etiology, cure of obesity is rare, but palliation is a realistic goal. Weight loss occurs with most treatments and except for surgery or very low-calorie diets, it is usually slow, meaning 0.5–1.0 kg/wk. Regaining body weight is common after a weight-loss program is terminated, and in contrast to the relatively slow rate of weight loss, weight regain may be rapid. A regain in weight after termination of treatment with the drugs is often described as a failure of the drugs. A more appropriate interpretation is that medications do not work if not taken. This is true of medications for the treatment of obesity just as it is for medications used to treat hypertension, diabetes, heart disease or asthma (92). Compliance with medication for treating obesity suffers from problems associated with all drugs, including remembering to take doses, concerns about side effects, and so forth.

6.2. Evaluation of the Obese Patient 6.2.1. CLASSIFICATION The classification that I propose for evaluating the patient with obesity is adapted from a classification used for heart disease. It involves three components: (1) an anatomical classification, (2) an etiologic classification, and (3) a functional classification (Table 9). An anatomic classification can be based on either the number of adipocytes or on the distribution of body fat. The major emphasis should be on distribution of body fat. In many obese people, whose problem begins in childhood, the number of adipocytes may be increased twofold to fourfold, with the normal range being (20–60) × 109 fat cells. Individuals with increased numbers of fat cells have hyperplastic obesity, which is to be distinguished from the hypertrophic form of obesity, in which the total number of


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Table 9 Classification of Obesity I. Anatomic classification A. Microscopic 1. Fat cell size 2. Fat cell number B. Macroscopic 1. Total body fat 2. Subcutaneous fat distribution 3. Visceral fat 4. Abnormal or unusual fat deposits II. Etiologic classification A. Hypothalamic B. Endocrine C. Dietary D. Physical inactivity E. Genetic F. Drug induced G. Unknown III. Functional Classification A. Degree of risk estimated from body mass index and fat distribution

Class 1 2 3 4 5

Grade

BMI

0 1 2 2 3

20 ) 25 25 ) 30 30 ) 35 35 ) 40 >40

Circumference of waist (cm) M 100 F >70 71–90 >90 VL L M H VH

L M H VH VH

M H VH VH VH

Note: VL = very low; L = low; M = Moderate; H = high; VH = very high.

B. Associated risks 1. High blood pressure (systolic > 140; diastolic >90 mm Hg) 2. Insulin resistance or diabetes (glucose [mg/dL] ⫼ insulin [µU/mL] [G/I] >6) 3. Total cholesterol ⫼ HDL-C (females >5.0; males 6.0) 4. LVH by electrocardiogram 5. Sleep apnea or high PaCO2 6. Hirsutism or high luteinizing hormone/follicle-stimulating hormone ratio 7. Smoking 8. Restrained eaters 9. Low physical activity

adipocytes is normal but the size of individual fat cells is increased. Generally, all obesity is associated with an increase in the size of adipocytes, but only the markedly obese individual has an increase in the total number of fat cells. Individuals who are 75% or more overweight almost always have an increase in the number of fat cells. Thus, markedly overweight individuals have hypercellular obesity, whereas those with modest degrees of obesity may be hypercellular but are more likely to have hypertrophic obesity.

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Table 10 Methods of Estimating Body Fat and Its Distribution Method

242

a

Ease of use

Accuracy

Measures regional fat

$ $ $ $$

Easy Easy Easy Moderate

High Low Moderate Moderate

No Yes Yes Yes

$$ $$$

Moderate Difficult

High High

No No

$$ $$$ $$$$ $$$ $$ $$

Moderate Moderate Difficult Moderate Easy Difficult

High High High High High High

No No No No No No

$$$ $$$$ $$$$ $$$$

Easy Difficult Difficult Difficult

High High High High

No Yes Yes No

$ = low cost, $$ = moderate cost, $$$ = high cost, $$$$ = very high cost.


Height and weight Skinfolds Circumferences Ultrasound Density Immersion Plethysmograph Heavy water Tritiated Deuterium oxide, or heavy oxygen Potassium isotope (40K) Total-body electrical conductivity (TOBEC) Bioelectric impedance (BIA) Fat-soluble gas Absorptiometry (Dual energy X-ray absorptiometry = DEXA; dual-photon absorptiometry = DPA Computed tomography (CT) Magnetic resonance imaging (MRI) Neutron activation

a

Cost


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The duration of weight loss that follows successful dietary treatment of obesity is shorter and the rate at which weight is regained is more rapid in individuals with hypercellular obesity as compared to those with hypertrophic obesity. The distribution of adipose tissue or body fat can be divided into three components. The first is the percentage of body fat. The second is the distribution of fat into either upper-segment android or male-type obesity where fat is primarily on the trunk and shoulders as opposed to lower body, and gynoid or female-type obesity in which the primary fat deposits are located on the thighs or hips. In women with upper-segment body-fat distribution, compared to women with lower body-fat distribution but of total similar body-fat levels, there is impairment of glucose tolerance and substantially increased insulin secretion following an oral glucose load. Women with upper-body obesity also show an increased circulating level of free testosterone, reduced levels of SHBG, increased insulin resistance and reduced hepatic clearance of pancreatic insulin. Men with upper-body obesity often have lower levels of testosterone, which has prompted studies using testosterone to reduce upper body fat in men. The third component of fat is visceral fat. This intr_-abdominal depot increases with age and carries the highest risk for developing cardiovascular and other disease consequences. 6.2.2. MEASUREMENT Obesity or fatness can be measured by a number of techniques. A summary of these methods is shown in Table 10, which lists the various methods and provides an estimate of cost and difficulty as well as whether the method can measure body-fat distribution. For epidemiologic studies, fat is usually estimated using skinfold measurements. When the body mass index (BMI) is above 30 kg/m2, skinfold measurements and BMI are almost superimposable. The sum of the triceps plus subscapular skinfold greater than 45 mm in males and 65 mm in females can be used to define obesity. Where measurements of body fat are available, a body fat above 25% for males and above 33% for females also can define obesity. In addition to measurements of body fatness, regional fat distribution plays an important role in predicting health risks. Regional fat distribution can be estimated by several techniques. A computed tomographic (CT) scan or a magnetic resonance imaging (MRI) scan, at the level of the L-4/L-5 intervertebral space, is the most accurate but also the most expensive. The ratio of the circumference of the waist to the circumference of the hips has been widely used in epidemiologic studies, but this is no better and may be worse than the waist circumference alone. Ratios for waist to hip above 0.80 in women and above 0.95 in men put individuals in the high-risk category. A waist circumference above 100 cm (40 in.) in men and above 95 cm (39 in.) in women also puts them in the high-risk category. The ratio of skinfolds on the trunk to that on the limbs and the sagittal diameter are two other techniques for estimating central fat. Widely accepted standards for fat distribution do not exist. 6.2.3. CLINICAL EVALUATION Because all treatments for obesity entail some risk, it is important to decide whether drug treatment is appropriate for the risks involved (93). To do this requires an assessment of the risk associated with total fat and fat distribution in relation to the risks of treatment. Two variables can be used to make this assessment. The first is the body mass index, and the second is the distribution of body fat (Fig. 8).

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Fig. 8. European multicenter orlistat study.

There is a curvilinear relationship between BMI and mortality that is often described as “J” or “U” shaped. Underweight individuals may have an increased risk for respiratory disease, tuberculosis, digestive disease, and some cancers. For overweight individuals, the risks are cardiovascular disease, gallbladder disease, high blood pressure, and diabetes (see Chapter 22 for a review of the epidemiologic studies related to the risks of obesity). Body weights associated with a body mass index of 20–25 kg/m2 are good weights for most people. When the body mass index is below 18 kg/m2 or above 27 kg/m2, risk increases in a curvilinear fashion. Individuals with a body mass index between 25 kg/m2 and 30 kg/m2 in men of any age and between 25 and 30 kg/m2 for women under 35 or between 27 and 30 kg/m2 in women over 35 may be described as having low risk. Individuals with a BMI between 30 kg/m2 and 35 kg/m2 have moderate risk, whereas those with a body mass index between 35 kg/m2 and 40 kg/m2 are at high risk, and those with a BMI above 40 kg/m2 have very high risk from their obesity. The relative risk is shifted by a number of factors including smoking, hypertension, elevated total or LDL cholesterol and reduced HDL cholesterol. It is clear from epidemiological data that increased abdominal and particularly visceral fat carries increased risks. The top percentile in abdominal fat distribution nearly doubles the risk of mortality and morbidity from heart disease, diabetes, and hypertension. This extra risk is observed in men and women and rises sharply for the top 10th percentile of abdominal fat distribution. When the difference in fat distribution is corrected, the excess mortality observed between men and women is largely, if not completely, eliminated. The risk associated with excess central accumulation of fat probably reflects the increase in visceral fat. Abnormal glucose tolerance, hypertension, and hyperlipidemia are more closely associated with the amount of visceral fat than with total body fat. The sagittal diameter has been proposed as a way to estimate visceral fat, but


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at the present time, the only reliable way to determine visceral fat is with a CT or MRI scan. When newer, less expensive methods become available, this will be an important clinical advance.

7. SUMMARY This review has dealt with an evaluation of currently available medications used in the treatment of obesity and the new areas in which agents are being developed. For a variety of reasons, the currently available drugs are probably not used effectively in treatment of obesity. This is suggested particularly by the long-term trial recently published by Weintraub and his colleagues. The use of drugs should be combined with an effective treatment program, and if they are to be used for “more than a few weeks,” unless the FDA discontinues this restriction, an outline of the treatment plan and an informed consent by the patient should be obtained and the local licensing authority should be notified of the intent to use drugs for long-term treatment.

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Chapter 17 / Practical Aspects of Obesity Treatments

17

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Practical Aspects of Obesity Treatments Combination Therapies

Richard L. Atkinson

1. INTRODUCTION: OBESITY AS A DISEASE With the realization that obesity is a disease not a psychological problem, the horizons of obesity treatment have widened. The concept of drug treatment of obesity has gained more widespread acceptance, and the most recent and exciting developments in obesity treatment have involved the use of drugs as an integral component. This chapter will review the concept of obesity as a disease and discuss the integration of the standard treatment of obesity, including diet, exercise (see Chapter 13), and behavior modification (see Chapter 14), with single drugs or combinations of drugs, as a potentially more effective regimen for the long-term maintenance of weight loss (Table 1). Obesity is a disease characterized by an excess accumulation of adipose tissue (see discussion of the etiologies of obesity in Chapter 8). Recent research has identified several single-gene defects that cause obesity in animals, and analogues of these genes are found in humans (see Chapter 18). Bouchard and colleagues (1) have identified more than 130 genes and gene markers that are associated with obesity and may contribute to the etiology of obesity in humans and animals. Thus, obesity is a syndrome or a collection of diseases all characterized by excess adipose tissue (see Chapter 10). The 1990 National Health and Nutritional Evaluation Survey III (NHANES III) used a definition of obesity as a body mass index (BMI: weight in kg/height in m2) of 27.8 kg/ m2 for men and 27.3 kg/m2 for women (2). This study found that 31.4% of men and 35.3% of women were obese by these definitions (see Chapter 9). More recent analyses show that the figure has risen, and about 35% of all American adults are obese (3). Older beliefs that obesity was simply due to a failure of willpower or a lack of selfdiscipline are no longer tenable (see Chapter 22). However, the fact that the prevalence of obesity increased by about 30% in the decade from 1980 to 1990 (2) means that genetics are not the only factor. Because it is not possible that the gene pool changed in one decade, this mandates that factors in the environment must play a major role in the development of obesity. Most scientists in the field now believe that obesity is a combination of a genetic predisposition for obesity that is brought out by environmental factors. From: The Management of Eating Disorders and Obesity Edited by: D. J. Goldstein © Humana Press Inc., Totowa, NJ

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Atkinson Table 1 Overview of Chapter 1. Introduction: Obesity As A Disease 2. Necessity for Long-Term Treatment and Experience with Standard Therapy 3. Rationale for Combining Therapies 4. Rationale for Use of Obesity Drugs 5. Classification of Obesity Drugs 6. Indications and Contraindications for Obesity Drugs 7. Single Drugs for Obesity 8. Combination Drug Therapy for Obesity 8.1. Ephedrine Combination 8.2. Phenylpropranolamine and Benzocaine 8.3. Fenfluramine and Phentermine 8.4. Fluoxetine and Phentermine 9. Practical Aspects of Drug Therapy 9.1. Need for Education and A Nutrition “Team” 9.2. Side Effects and Adverse Events 9.3. Drug Regimens and Administration 10. Summary and Conclusions

Currently, it is not possible to manipulate the genes for obesity, but the environment certainly can be manipulated. The genetic contribution to obesity helps explain why medical treatment of obesity, consisting of diet, exercise, and behavior modification, has had a poor long-term success rate. Only a long-term, comprehensive program of life-style modification appears to increase the success rate, and few people are able to consistently modify their behavior lifelong. Although surgical treatment of obesity has a good success rate, it is reserved for massively obese individuals and, therefore, is not an option for the average overweight person.

2. NECESSITY FOR LONG-TERM TREATMENT AND EXPERIENCE WITH STANDARD THERAPY Because obesity is a disease with an underlying genetic component, it must be considered a chronic disease. Chronic diseases require chronic treatments, and when the treatment stops, the disease comes back. Many patients, and even many health care professionals, look for short-term solutions. They do not understand the necessity for lifelong intensive treatment. Massively obese patients who meet the criteria for obesity surgery achieve long-term weight loss in a good percentage of cases, as the effects of the surgery are permanent. For the remainder of less obese patients, some form of medical treatment is the only option. Behavioral treatments produce satisfying initial weight loss in the majority of patients, but long term weight maintenance is much more critical and is more difficult to achieve. Routine medical treatment of obesity consisting of nutrition education, behavior modification, exercise therapy, and activity training has a failure rate of greater than 95% over 5–10 yr when treatment is not continued (4–7). Even with surgery for obesity, weight is regained if the surgical procedure is reversed. This discouraging information points out the absolute necessity of continual treatment over the lifetime of an obese person with the methods currently available.


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3. RATIONALE FOR COMBINING THERAPIES Unfortunately, obesity is like most chronic diseases, and single treatments are often ineffective. The general lack of success with nonpharmacologic treatment has been noted earlier, and the disappointing results with drug treatment alone will be described below. These observations suggest that obesity treatment should mimic treatments of other chronic diseases. If a single intervention is not effective, combinations of therapies should be instituted. The remainder of this chapter will address the use of drugs, alone or in combination, combined with standard therapy. There is hope that if sufficient combinations are evaluated, the majority of obese patients may achieve sustained weight loss.

4. RATIONALE FOR USE OF OBESITY DRUGS Although diet, exercise, and behavior modification of life-style can be successful, the necessity to not eat when hungry and to eat less palatable foods when highly palatable foods are available wears thin with time. Also, dramatic increases in exercise and activity levels are difficult to sustain. The genetic predisposition to obesity mandates that obese people cannot behave as thin people do and become thin; they have to do more. The ob/ ob mouse and Zucker obese rat are models for obese humans. If these animals are pair fed to lean littermates, they remain obese (8). To weigh the same as their lean littermates, they have to eat half of what their lean littermates eat. Similar, although perhaps not as drastic, requirements undoubtedly are present in humans. It is almost impossible to continue such restricted behavior indefinitely with the American environment that is so conducive to eating high-energy, high-fat foods excessively. It has been amply shown that obese people do not continue diet, exercise, and behavior modification regimens lifelong. Obesity drugs are a more passive way of changing the physiology of obesity. By definition, effective drugs change the biochemistry of the body. As described below, most of the obesity drugs continue to be effective as long as they are taken.

5. CLASSIFICATION OF OBESITY DRUGS With the exception of sibutramine, which was approved for marketing in early 1998, all obesity drugs on the market are off patent. There are two main types of obesity drugs currently available: serotonergic agonists and adrenergic agonists, as listed in Table 2. All of the adrenergic agonists are scheduled by the Drug Enforcement Agency (DEA), with the exception of phenylpropanolamine, which is an over-the-counter agent. There is never an occasion to use obesity drugs in Schedule II, and little reason to use drugs in Schedule III. The adrenergic agonists that are used most frequently by prescription in the United States are phentermine, mazindol, and diethylpropion, all of which are DEA Schedule IV. Phenylpropanolamine is the most commonly used drug for obesity and is present in a large number of over-the-counter diet aids. All of these drugs were approved by the FDA many years ago and were expected to be used only briefly (12 wk or less). The two serotonin agonists previously approved for the treatment of obesity were d,l-fenfluramine, the racemic mixture, and dexfenfluramine, the pure dextro isomer (Table 2). These drugs were withdrawn from the market because of cardiovascular side effects. Although they are not approved for the treatment of obesity, many physicians have used fluoxetine, sertraline, and other antidepressant agents with serotonin reuptake inhibition activity for weight reduction (Table 2).

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Atkinson Table 2 Categories of Obesity Drugs and DEA Schedules: 1. Adrenergic agonists a. II: amphetamine, methamphetamine, phenmetrazine b. III: benzphetamine, chlorphentermine, chlortermine, phendimetrazine c. IV: diethylpropion, mazindol, phentermine a d. OTC: phenylpropanolamine, ephedrine, and caffeine 2. Serotonin agonists a. IV: d,l-fenfluramine, d-fenfluramine b. Not scheduled: fluoxetinea, sertralinea 3. Combined adrenergic and serotonergic agonist: IV: sibutramine c a 4. Drugs affecting absorption: orlistat , acarbose a Not currently marketed b Marketing suspended. c

approved for the treatment of obesity.

Currently experimental, not FDA approved.

Sibutramine is a reuptake inhibitor of both serotonin and norepinephrine, so it acts as an agonist for both (9). It has minimal dopamine agonist activity and does not appear to have abuse potential, but has been assigned as a Schedule IV drug by the DEA and FDA. The combination of ephedrine and caffeine, with or without the addition of aspirin, has been used in Europe and is reported to produce weight loss (11,12). Methylxanthines (caffeine, theophylline, theobromine, etc.) and/or aspirin potentiate the effects of ephedrine and increase weight loss and metabolic rate by slowing the degradation of norepinephrine (11–14). Ephedrine–caffeine stimulates norepinephrine secretion. Caffeine enhances norepinephrine activity by inhibiting phosphodiesterase, the enzyme that metabolizes cyclic AMP, through which norepinephrine acts. Aspirin enhances norepinephrine activity by inhibiting adenosine, which is involved in norepinephrine inactivation. The combination may be associated with increases in heart rate, blood pressure, and metabolic rate (11–14). The increases in heart rate and blood pressure associated with ephedrine–caffeine appear to be short-lived, but the effect on thermogenesis persists (12). Orlistat is a new agent that is under review by the FDA and probably will be released to the market. Orlistat acts by inhibiting intestinal lipase, thus blocking the digestion and absorption in the small intestine of about one-third of dietary fat ingested (15,16). The portion of dietary fat not absorbed passes through to the colon and is metabolized and utilized by colonic bacteria or is excreted. Orlistat does not have prolonged activity and must be taken with a meal to be effective. Acarbose, an amylase inhibitor that blocks complex carbobydrate absorption (17), has just been approved for use in the treatment of diabetes in the United States. Acarbose has been shown to be ineffective in the treatment of obesity when used as a single agent, although anecdotal reports suggest that it occasionally may produce modest additional weight loss when used in combination. Acarbose is a good choice for the obese, non-insulin-dependent diabetic for its action to improve glucose tolerance, decrease insulin resistance to potentially produce some weight loss. There are a number of other potential drugs that may eventually be useful for the treatment of obesity, such as gut peptides, neurotransmitter agonists or antagonists, and beta-3 agonists (18). None are currently near submission to the FDA for use in humans. Leptin is in clinical trials and may potentially be a new drug in the intermediate future.


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Table 3 Criteria for Use of Obesity Drugs: 1. Criteria for usea a. BMI > 27 kg/m2 2 b. BMI > 25 kg/m , if complications present c. Age > 18 yr, < 65 yr 2. Contraindications or cautions for use a. Pregnancy or lactation b. Unstable cardiac disease c. Uncontrolled hypertension d. Other drug therapy, if incompatible e. Severe psychiatric disorder or anorexia (contraindication or caution) f. Presence of any severe systemic illness (caution) g. Closed-angle glauccma (caution) a

Criteria of the North American Association for the Study of Obesity; the FDA criteria are a BMI of > 30 without complications of obesity and > 27 with complications.

6. INDICATIONS AND CONTRAINDICATIONS FOR OBESITY DRUGS As noted earlier, treatment of obesity with drugs will only be effective if the drugs are continued indefinitely. Therefore, obesity drugs must be used carefully and only with appropriate indications. Table 3 lists some of the criteria commonly used to determine who should take obesity drugs. The practice of giving obesity drugs to individuals who are only modestly overweight should be deplored. The weight criteria listed (e.g., a body mass index [BMI] of 27 or above) were recommended by a panel of experts convened by the North American Association for the Study of Obesity (19). Any use of obesity drugs in individuals who weigh less than this should be very carefully documented. The FDA criteria for use of obesity drugs is a BMI of 30, and many investigators favor this more conservative criterion. Whatever the criteria selected, these are only guidelines. There may be potentially mitigating factors that might justify use in individuals below the cutoffs. These may include complications of obesity such as hypertension, diabetes, and hyperlipidemia. The presence of excess intra-abdominal fat, or visceral obesity, is a major risk factor for diabetes, heart disease, and strokes (20). Visceral obesity with a BMI below 27– 30 can be documented with magnetic resonance imaging (MRI) or a computed tomography (CT) scan. Individuals who have a history of a BMI greater than 27–30 in the past but who have been able to maintain weight loss with difficulty may be considered for treatment with obesity drugs. It makes no sense to have such individuals regain their weight before they become eligible for treatment with obesity drugs. Finally, some patients have significant psychological concerns regarding excess body weight. The physician should carefully evaluate such patients before prescribing obesity drugs to determine if there is any evidence of eating disorders. In some cases, referral for psychological or psychiatric counseling to deal with these concerns may be a better choice than prescription of obesity drugs.

7. SINGLE DRUGS FOR OBESITY A large number of studies have evaluated the treatment of obesity with a single drug. The vast majority of these studies were for brief periods of time, most commonly about

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Atkinson Table 4 Studies of Long Term Weight Loss with Obesity Drugs 1 yr weight change (kg) Placebo Diethylpropion Mazindol Fenfluramine Dexfenfluramine

Fluoxetine

0.5 -10.2 — -4.5 -7.2 -2.7 -4.6 +0.6 -4.5 -1.5

Obesity Drug -8.9 -14.2 -12.0 -8.7 -9.8 -5.7 -5.2 -13.9 -8.2 -2.3

Source: ref. 23.

12 wk. Scoville (21) summarized over 200 studies of single agents and concluded that obesity drugs were poorly effective, because weekly weight loss was only about 0.5 lb greater on drug than on placebo. Silverstone (22) compared several drugs with placebo and noted weight losses that were statistically significant differences with all drugs as compared to placebo, but, again, the differences were small. Goldstein and Potvin (23) evaluated all of the studies in the literature that lasted longer than 6 mo. At 1 yr, average weight losses were highly variable across drugs and placebo among studies and ranged from 2.3 to 14.2 kg (Table 4). Losses with mazindol were greatest at 14.2 and 12.0 kg. Fluoxetine produced weight losses of 2.3–3.9 kg. Losses with fenfluramine and dexfenfluramine varied from 5.2 to 9.8 kg. For some of the studies with larger weight losses, the placebo groups also had very good weight loss. This may be attributed to the addition of the combination of diet, exercise, and behavior modification that often are a part of these protocols. Thus, the protocols were not a pure test of drug vs placebo. If the individual studies are evaluated, the range of weight losses is quite large. One explanation for these data is that people with greater weight losses were more attentive to reduction of energy intake and to exercise. However, there may be some people who are more sensitive to obesity drugs and could be classified as ‘’responders.” Goldstein et al. (24) attempted to identify factors that would predict success upon treatment with fluoxetine and found a series of variables that gave significant results. However, the variation was large and the variables nonspecific, so that the formula has little clinical usefulness. Additional studies are indicated to determine if clinically useful predictors can be identified.

8. COMBINATION DRUG TREATMENT FOR OBESITY Drugs are used for most acute or chronic diseases. For such diseases, if one drug does not completely alleviate the problem, a second, third, or more are added. The use of combinations of drugs for obesity has been surprisingly sparse. The only combinations of drugs that have been used for obesity are ephedrine–methylxanthines–aspirin, phenylpropanolamine–benzocaine, fenfluramine–phentermine, and fluoxetine–phentermine (11,12,25–32). The data from these studies are described in the following subsections.


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8.1. Ephedrine combinations The combination of ephedrine with caffeine and/or aspirin results in fat loss with preservation of lean body mass (11). Long-term data with the combination of ephedrine and caffeine or aspirin are very sparse. Toubro et al. (12) compared placebo, ephedrine alone (60 mg/d), caffeine alone (600 mg/d), and the combination of ephedrine and caffeine over a period of 24 wk in 180 subjects. None of the substances caused weight loss alone, compared to placebo, but the combination produced significant weight loss. The study was extended for another 26 wk in an open-label study on 99 of the subjects. The mean weight loss of about 16 kg persisted for 50 wk in the 99 of 180 subjects who completed the protocol. Daly et al. (11) treated a small number of subjects in an openlabel study for periods of up to 26 mo and noted persistent modest weight loss. There has been little prescription of this combination of drugs by physicians in the United States, but there is a large business in these agents in health food stores and other commercial distributors. Most of the preparations of this combination are sold as “supplements,” generally in the form of extracts. Because the food supplement industry is essentially unregulated in the United States, companies may make extracts of natural products and sell them almost indiscriminately. The ma huang plant contains ephedra, the “natural” form of ephedrine. Caffeine is extracted from coffee beans or other similar products. Finally, salicylic acid may be extracted from willow bark. The combination of these three extracts is effective in producing significant weight loss, but batch-to-batch variations may introduce problems. If a batch contains greater quantities of one or more of the active ingredients, this may produce symptoms or side effects. Conversely, lower strengths may reduce effectiveness and induce the patient to take greater quantities. This may be dangerous if a weak batch is followed by a potent batch. Physicians and other health professionals should inquire about the use of such preparations when taking a history from obese patients and warn the patients of the potential problems.

8.2. Phenylpropanolamine and Benzocaine A single study exists of the use of phenylpropanolamine (PPA) and benzocaine in combination (25). Benzocaine is a local anesthetic agent contained in some over-the-counter weight reduction aids that are reputed to ‘’numb the taste buds.” Greenway (25) found that the combination of PPA and benzocaine was no more effective than placebo in an 8-wk trial, so this combination cannot be recommended for clinical use.

8.3. Fenfluramine and Phentermine Although fenfluramine and dexfenfluramine are no longer on the market, the results of using this combination for obesity are instructive. Weintraub et al. (26) compared full doses of fenfluramine (120 mg/d) or phentermine resin (30 mg/d) alone with the combination of these two agents in half-strength each (60 mg and 15 mg, respectively). Weight loss on this combination (phen-fen) was similar to that on full doses of the other two drugs, and there were fewer side effects with the combination. In a seminal study that has profoundly changed the perception of obesity treatment, Weintraub (27) kept 121 subjects on the combination of phentermine resin and fenfluramine for up to 3.5 yr. All subjects were treated with diet, exercise, and behavior modification. At 60 wk, patients on continuous treatment had lost 15.8 kg. The design of the study called for some subjects to go on and off the drug several times. These subjects gained weight off drugs and lost weight when drugs were reinstituted. In general, significant weight loss persisted as long

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as the drugs were given, although the average weight loss declined over time. When subjects discontinued medications at the end of the study, weight gain back to baseline levels was rapid. There have been few other published studies with phen-fen. Atkinson et al. (28) reported 1 yr weight loss of about 17 kg in patients treated with 60 mg/d of fenfluramine and 18.75–37.5 mg/d of phentermine HCl. Reductions in systolic and diastolic blood pressures in hypertensive patients of about 28 mm Hg and 17 mm Hg, respectively, were noted. In subjects with elevated levels, serum cholesterol and triglycerides fell 27 mg/dL and 79 mg/dL, respectively (28). As described in detail in Subheading 9., fenfluramine and dexfenfluramine were reported to cause cardiac valve lesions and were removed from the market.

8.4. Fluoxetine and Phentermine Dhurandhar and Atkinson (32) reported in abstract form that the combination of fluoxetine (20–60 mg/d) and phentermine hydrochloride (18.75–37.5 mg/d) produced significant weight losses that were similar to those produced by the combination of fenfluramine (20–60 mg/d) and phentermine HCl (18.75–37.5 mg/d).

9. PRACTICAL ASPECTS OF DRUG THERAPY 9.1. Need for Education and a Nutrition “Team” The weight losses described earlier with use of single drugs or combinations of drugs demonstrate that most obese patients will not attain “ideal” body weight nor the weight they desire (33). Foster et al. (33) had patients describe their expectations at the start of treatment and noted that almost half of their patients did not even achieve a weight loss that they considered “disappointing” at baseline. If drugs alone are used, weight losses are likely to be smaller than if drugs are combined with diet, exercise, and behavior modification. Most physicians do not have enough time to provide the education necessary on diet, exercise, and behavior modification. Simply writing a prescription is fast, but it is not in the best interests of the patient. Therefore, it is optimal to develop a team of physician and one or more allied health professionals such as a dietitian, nurse, exercise physiologist, and so forth, to provide the education and psychological support necessary to achieve and maintain the greatest weight loss of which a particular individual is capable. In the absence of such allied health professionals, physicians should assess community resources such as commercial weight-reduction programs and self-help groups such as TOPS and Overeaters Anonymous. Some commercial programs are expensive and provide little education, so the physician has an obligation to investigate the adequacy of any program before referring the patient there. The self help groups are helpful in providing group support and may provide very good information on diet and exercise, depending on the participants and group leaders.

9.2. Side Effects and Adverse Events The practice of writing a prescription without additional education or without adequate follow-up is inadequate care, not only because success rates may be lower but because obesity drugs are associated with side effects that require careful follow-up. The most common and/or serious side effects and adverse events of obesity drugs are listed in Table 5. Most side effects occur early in the course of treatment and improve or resolve within


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Table 5 Potential Side Effects and Adverse Events Resulting from Obesity Major Primary pulmonary hypertension Abnormalities of cardiac valves Minor Dry mouth Fatigue Hair loss Altered mental function Constipation Sleep disturbances Abnormal menses Headache Blurred vision GI disturbance Sweating Altered sex drive

the first month. Dry mouth is common and often persists, as does fatigue or asthenia. Sleep disturbances, such as insomnia, drowsiness, and vivid dreams, tend to resolve. Gastrointestinal (GI) disturbances occur, such as diarrhea, particularly with serotonin agonists, and constipation with adrenergic agonists. It is important for patients to drink large amounts of water to help constipation and because sweating is another side effect that may contribute to dehydration. Because patients may not be hungry, they also may neglect to drink adequate fluids. The three most bothersome adverse events that may occur with obesity drugs are altered mental functioning, abnormalities of cardiac valves, and primary pulmonary hypertension. About 18% of patients treated with phen-fen complained of loss of concentration, mental fuzziness, or short-term memory loss (28). This complaint rarely was sufficiently severe to require cessation of drug treatment, and function returned to normal shortly after discontinuation of the drugs (28). Primary pulmonary hypertension (PPH) is a much more serious complication that has been reported in conjunction with the use of obesity drugs. In the 1960s, aminorex fumurate, a drug used for weight control, was reported to increase the risk of PPH (34). More recently, there have been a number of cases of PPH reported in patients on treatment with obesity drugs (34,35). A case-control study in Europe identified 95 cases of PPH with a screening of over 300 hospitals (35). Dexfenfluramine was associated with the greatest number of cases, but all types of obesity drugs were implicated (35). The authors concluded that the risk of PPH with prolonged use (more than 3 mo) was about 1 per 20,000 patients. The study was criticized (36,37) regarding the appropriateness of the control group. Obesity itself is associated with an increased incidence of PPH, but obesity drug treatment, particularly with fenfluramine and dexfenfluramine, appears to confer a greater risk. Prospective studies are needed to assess the risk with the obesity drugs remaining on the market. In the interim, physicians should be highly alert to the appearance of undue fatigue, new onset of dyspnea on minimal to modest exertion, or other symptoms of pulmonary and right-sided heart failure. The 5 yr mortality of PPH is over

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Atkinson Table 6 Philosophy For Use Of Obesity Drugs 1. Start at a low to very low dose. 2. Increase the dosage when a plateau is reached. 3. Reduce the dose to previous level if an increase does not cause more weight loss. 4. Discontinue if a drug does not appear effective. 5. Use the lowest maintenance dose possible. 6. Add additional drugs as needed. 7. Use clinical judgement to determine if side effects require cessation.

50%, and the only successful treatment of progressive disease is heart–lung transplant. The risk of PPH alone is sufficient reason to deny obesity drugs for trivial weight loss. Cardiac valve lesions, predominantly insufficiency of aortic and mitral valves, were reported by Connolly et al. (38) with the use of the phen-fen combination. Subsequent reports to the FDA identified about 91 additional individuals with cardiac abnormalities on echocardiogram, about 30% of the total (39–41). These reports were uncontrolled, so it is difficult to determine the true incidence. Oral presentations at scientific meetings suggest that same investigators are finding rates of about 30–35% of former users of fenfluramine or dexfenfluramine have valve lesions, whereas others find minimal or no relationship. Large-scale studies are in progress to address these questions.

9.3. Drug Regimens and Administration There are few data to guide physicians as to the optimal drug regimen to use in a given patient. It is very clear that different people respond differently to the combination of obesity drugs, diet, and exercise. It also is clear that sensitivity to dosage of drugs varies widely. In their study on the combination of diet, exercise, phentermine, and fenfluramine, Weintraub et al. (26,27) showed that most subjects lost weight with low doses of phentermine and fenfluramine. In subjects who did not lose well initially, increasing the dosage to full levels did not cause additional weight loss. A reasonable philosophy for use of obesity drugs is summarized in Table 6 (see also Chapter 20). Because obesity drugs may have adverse effects, it is important to use them only when indicated and to use the lowest dose that will give maximum weight loss with tolerable side effects. By starting at a low dose, some of the side effects may be avoided. Most patients will need more than one drug for maximal weight loss, but it may be reasonable to start with only one drug to determine if the patient is highly sensitive and will do well with only one drug. Additional drugs are added as necessary. If an increase in dosage does not cause additional weight loss, the dosage should be reduced. If a new drug does not contribute to reducing weight or complications, it should be discontinued. The physician must use clinical judgment to determine if a given patient should discontinue one drug or all drug therapy. Often patients are reluctant to discontinue drugs, even in the face of significant side effects, because the drugs are effective and weight regain is highly likely with cessation of drug therapy.

10. SUMMARY AND CONCLUSIONS Obesity is a complex syndrome that requires complex treatment. Obesity rarely may be treated with only one form of therapy. All patients need the underlying basic treat-


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ments of diet, exercise, and behavior modification for a healthy life-style. When these fail, obesity drugs may be considered. Single-drug therapy or low-dose combination drug therapy has been very helpful in producing sustained weight loss, but with the expectation that the drugs will be needed lifelong. There are significant side effects with obesity drugs, so they should only be used for significant obesity. Almost never is there an indication for temporary treatment with obesity drugs. Careful follow-up is needed, and because obesity treatment requires a great deal of patient education, it is best done with a team of at least one allied health professional such as a dietitian, nurse, exercise physiologist, or other educator. The optimal regimen for each patient will differ, and until additional research is done, choosing a regimen is a matter of trial and error.

REFERENCES: 1. Chagnon YC, Perusse L, Bouchard C. The human obesity gene map the 1997 update. Obesity Res 1998; 6:76–92. 2. Kuczmarski RJ, Flegal KM, Campbell SM, Johnson CL. Increasing prevalence of overweight among US adults. JAMA 1994;272:205–211. 3. Kuczmarski RJ, Carroll MD, Flegal KM, Troiano RP. Varying body mass index cutoff points to describe overweight prevalence among U.S. adults: NHANES III (1988 to 1994). Obesity Res 1997;5:542–548. 4. Andersen T, Stokholm KH, Backer OG, Quaade F. Long-term (5-year) results after either horizontal gastroplasty or very-low calorie diet for morbid obesity. Int J Obes 1988;12:277–284. 5. Wadden TA, Sternberg JA, Letizia KA, Stunkard AJ, Foster GD. Treatment of obesity by very low calorie diet, behavior therapy, and their combination: a five year perspective. Int J Obes 1989;13 (Suppl 2):39–46. 6. Perri MG. Improving maintenance of weight loss following treatment by diet and lifestyle modification. In: Wadden TA, VanItallie TB, eds. Treatment of the Seriously Obese Patient. Guilford, New York, 1992, pp. 456–477 7. Wilson GT. Behavioral treatment of obesity: thirty years and counting. Adv Behav Res Ther 1993;16:31–75. 8. Coleman DL. Obese and diabetes: two mutant genes causing diabetes-obesity in mice. Diabeltologia 1979; 14:141–148. 9. Ryan DH, Kaiser P, Bray GA. Sibutramine: a novel new agent for obesity treatment. Obes Res 1995;3 (Suppl 4):553S–559S. 11. Daly PA, Krieger DR, Dulloo AG, Young JB, Landsberg L. Ephedrine, caffeine and aspirin: safety and efficacy for treatment of human obesity. Int J Obes 1993;17 (Suppl 1):S73–S78. 12. Toubro S, Astrup AV, Breum 1., Quaade F. Safety and efficacy of long-term treatment with ephedrine, caffeine, and an ephedrine/caffeine mixture. Int J Obes 1993;17 (Suppl 1):S69–S72. 13. Dulloo AG. Ephedrine, xanthines and prostaglandin-inhibitors: actions and interactions in the stimulation of thermogenesis. Int J Obes 1993;17 (Suppl 1):S35–S40. 14. Arner P. Adenosine, prostaglandins and phosphodiesterase as targeted for obesity pharmacotherapy. Int J Obes 1993;17 (Suppl 1):S57–S59. 15. Drent ML, van der Veen EA. First clinical studies with orlistat: a short review. Obesity Res 1995;3 (Suppl 4):623S–625S. 16. James WP, Avenell A, Broam J, Whitehead J. A one year trial to assess the value of orlistat in the management of obesity. Int J Obesity 1997;21 (Suppl 3):S24–S30. 17. Berger M. Pharmacological treatment of obesity: digestion and absorption inhibitors—clinical perspective. Am J Clin Nutr 1992;55:318S–319S. 18. Bray GA. Pharmacologic treatment of obesity: symposium overview. Obes Res 1995;3 (Suppl 4):415S–417S. 19. Pi-Sunyer X. Guidelines for the approval and use of obesity drugs. Obes Res 1995;3:473–478. 20. Kissebach AH, Vydelingum N, Murray R, et al. Relation of body fat distribution to metabolic complications of obesity. J Clin Endocrinol Metab 1982;54:254–260. 21. Scoville BA. Review of amphetamine-like drugs by the Food and Drug Administration. In: Vol. II, Bray GA, eds. Obesity in Perspective. Fogarty International Center for Advanced Studies in the Health Sciences, Series on Preventive Medicine, Washington, DC, US Government Printing Office, 1976, pp. 441–443.

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22. Silverstone T. Appetite suppressants: a review. Drugs 1992;43:820–836. 23. Goldstein DJ, Potvin JH. Long-term weight loss: the effect of pharmacologic agents. Am J Clin Nutr 1994;60:647–657. 24. Goldstein DJ, Rampey AH Jr, Roback PJ, Wilson MG, Hamilton SH, Sayler ME, Tollefson GD. Efficacy and safety of long-term fluoxetine treatment of obesity—maximizing success. Obes Res 1995;3 (Suppl 4):481S–490S. 25. Greenway FL. Clinical studies with phenylpropanolamine: a metaanalysis. Am J Clin Nutr 1992;55 (1 Suppl):203S–205S. 26. Weintraub M, Hasday JD, Mushlin AI, Lockwood DH. A double blind clinical trial in weight control: use of fenfluramine and phentermine alone and in combination. Arch Intern Med 1984;144:1143–1148. 27. Weintraub M. Long-term weight control: The National Heart, Lung, and Blood Institute funded multimodal intervention study. Clin Pharmacol Ther 1992;51:581–646. 28. Atkinson RL, Blank RC, Schumacher D, Dhurandhar NV, Ritch DL. Long term drug treatment of obesity in a private practice setting. Obes Res 1997;5:578–586. 29. Hartley GG, Nicol S, Halstenson C, Khan M, Pheley A. Phentermine, fenfluramine, diet, behavior modification, and exercise for treatment of obesity. Obes Res 1995;3 (Suppl 3):340s. 30. Dhurandhar NV, Blank RC, Schumacher D, Ritch DL, Chan E, Reig TS, et al. Combination drug treatment of obesity in women of different ages. Obes Res 1995;3 (Suppl 3):341S. 31. Dhurandhar NV, Blank RC, Schumacher D, Ritch DL, Chan E, Reig TS, et al. Racial differences in response to combination drug treatment of obesity. Obes Res 1995;3 (Suppl 3):405s. 32. Dhurandhar NV, Atkinson RL. Comparison of serotonin agonists in combination with phentermine for treatment of obesity. FASEB J 1996;10:A561 33. Foster GD, Wadden TA, Vogt RA, Brewer G. What is a reasonable weight loss? Patients’ expectations and evaluations of obesity treatment outcomes. J Consult Clin Psychol 1997;65 (1):79–85 34. Brenot F, Herve P, Petitpretz P, Parent F, Duroux P, Simonneau G. Primary pulmonary hypertension and fenfluramine use. Br Heart J 1993;70:537–541. 35. Abenhaim L, Moride Y, Brenot F, et al. Appetite-suppressant drugs and the risk of primary pulmonary hypertension. N Engl J Med 1996;335:609–616. 36. Manson JE, Faich GA. Pharmacotherapy for obesity—do the benefits outweigh the risks? N Engl J Med 1996;335:659–660. 37. Dhurandhar NV, Atkinson RL. Appetite-suppressant drugs and primary pulmonary hypertension. N Engl J Med 1997; 36:511. 38. Connolly HM, Crary JL, McGoon MD, Hensrud DD, Edwards BS, Edwards WD, et al. Valvular heart disease associated with fenfluramine-phentermine. N EngL J Med 1997;337:581–588. 39. Cannistra LB, Davis SM, Bauman AG. Valvular heart disease associated with dexfenfluramine. N Engl J Med 1997;337:636. 40. Graham DJ, Green L. Further cases of valvular heart disease associated with fenfluramine–phentermine. N Engl J Med 1997; 337:635. 41. Kurz X, Van Ezmen A. Valvular heart disease associated with fenfluramine–phentermine. N Engl J Med 1997; 337:1772–1773.

Chapter 18 / Genetics and Potential Treatments for Obesity

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Genetics and Potential Treatments for Obesity David J. Goldstein and Jose F. Caro

1. OVERVIEW—DAVID J. GOLDSTEIN During the last 5 years, the information on the genetic contributions toward obesity has increased exponentially. In this chapter, Caro discusses our recent understanding regarding leptin, the Ob protein which is produced in the adipocyte and signals the brain regarding energy needs, and the leptin receptor to which the Ob protein binds. He further mentions other work in the area of the genetics of obesity. There is another aspect of the genetics of obesity which may help in understanding future developments in this area conceptually. Much obesity occurs in environments in which food is plentiful. Clearly, when members of native populations come to the United States, their levels of obesity increase significantly. This has been explained by the evolutionary or “thrifty” gene hypothesis (1). This hypothesis was developed to explain the development of hypertension in certain populations as it related to “salt-sparing” (2– 4). It also was used to explain the predisposition toward non-insulin-dependent diabetes mellitus (5,6) or other diseases that are thought to be rare historically (7). Work underway at this time is identifying genes that have been proposed based on such studies that contribute to obesity in certain families or populations. Much of this work is as yet unconfirmed, but we can expect some of these candidate genes to be targets for future therapeutic intervention. This chapter establishes a background for interpreting and evaluating this work.

REFERENCES 1. Rett K, Wiclmayr M, Mehnert H. What is the clinical significance of insulin resistance. J Cardiovasc Pharmacol 1992; 20:S22–S266. 2. Wilson TW, Grim CE. Biohistory of slavery and blood pressure differences in blacks today. A hypothesis. Hypertension 1991; 17:I122–I128. 3. Blaustein MP, Grim CE. The pathogenesis of hypertension: black–white differences. Cardiovasc Clin 1991; 21:97–114. 4. Weder AB, Schork NJ. Adaptation, allomentry, and hypertension. Hypertension. 1994; 24:145–156. 5. Turner RC, Levy JC, Clark A. Complex genetics of type 2 diabetes: thrifty genes and previously neutral polymorphisms. Q J Med 1993; 86:413–417. 6. Wendorf M. Archaeology and the “thrifty” non insulin dependent diabetes mellitus (NIDDM) genotype. Adv Perit Dial 1992; 8:201–207. 7. Brown G, Nesse R. Evolutionary Concepts in Medicine. From: The Management of Eating Disorders and Obesity Edited by: D. J. Goldstein © Humana Press Inc., Totowa, NJ

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Part III / Treatment Table 1 Chapter Overview 1. Overview 2. Introduction: Obesity as a “Complex Disease” 3. Rodent Models of Obesity 3.1. Leptin, Neuropeptide Y, and `-3-Adrenorgic Receptors 3.2. Parabiotic Experiments 3.2.1. Obesity Resulting from Destruction of the Ventromedial Hypothalamus 3.2.2. Genetic Obesity 4. The ob Gene 5. The Leptin Receptor 6. Abnormalities in the Human Leptin and the Leptin Receptor 7. Other Human Targets 8. Conclusion: Applicability to Treatments

2. OBESITY AS A COMPLEX DISEASE—JOSE F. CARO This chapter summarizes the present knowledge about the genetics of obesity and the implication for therapies (Table 1). Obesity is a “complex disease” similar to type II diabetes, hypertension and ischemic heart disease. These are among the most common disorders of Western civilization. In many respects, obesity is the worst of the complex diseases, because its presence increases the prevalence and severity of the others (1). Complex diseases arise from the multifaceted interaction of the environment and multiple genes. The inheritance of these diseases is different from the classic (mono)genetic diseases. First, no simple Mendelian mode of transmission is apparent. Second, the severity of the disease shows quantitative, unimodal variation, rather than a dichotomous distribution. Therefore, the phenotype of complex diseases reflects the multifactorial effect of all contributing genes (polygenic) and all environmental factors (2). What is the evidence for environmental and hereditable influences on the development of obesity? Probably the best are two simple observations: (a) The prevalence of obesity in America was less than 15% in 1900. Today, it is more than 30%. It is clear that in 100 yr, the gene pool of the human population did not change dramatically. What has changed is the environment. We have moved from a “lean environment” to an “obese environment.” (b) The twins studies of Stunkard et al. (3) fully support the influence of genetics in obesity. The intrapair correlation coefficients of the values for body mass index of 154 pairs of identical twins reared together was similar (0.74) to that of 93 pairs of identical twins reared apart (0.70). The characteristics of complex diseases render the hunt for genes contributing to these diseases a major challenge.

3. RODENT MODELS OF OBESITY The lessons learned from monogenetic lesions leading to obesity in rodents plus a better understanding of energy metabolism in humans should provide very powerful tools toward a rational candidate gene approach (4).


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Table 2 The Clinical Appearance (Phenotype), Mode of Inheritance, and Molecular Defects Due to Monogenic Lesions (Genotypes) in Obese Rodents Genotype ob db fa fat Agouti

tubby

Phenotype

Mode of Inheritance

Severe obesity; hyperglycemia Severe obesity; hyperglycemia Severe obesity; hyperglycemia Gradual obesity; hyperglycemia Yellow coat; gradual obesity

Autosomal; recessive Autosomal; recessive Autosomal; recessive Autosomal; recessive Autosomal; dominant

Mild obesity; hyperinsulinemia

Autosomal; recessive

Molecular defect Two different mutations in the ob gene which result in absent leptin production Mutation in the leptin receptor Mutation in the leptin receptor Mutation in carboxypeptidase E, which processes neuropeptides such as NPY Overexpression of the novel agouti protein, a potent melanocortin receptor antagonist Sequence not reported yet, but may be the sulfonylurea receptor

3.1 Leptin, Neuropeptide Y, and `-3-Adrenergic Receptors Table 2 illustrates some of the recent discoveries in rodent models of obesity. Investigations into the molecular mechanism leading to obesity in the ob/ob mouse (5) and the db/db mouse (6–8) are of great importance because they resulted in the discovery of leptin (Greek root, leptos, meaning thin) and the leptin receptor in the hypothalamus (9), respectively. It is now possible to integrate these two discoveries with the previous knowledge of body-fat regulation as shown in Fig. 1. The regulation of body weight is depicted as a closed-loop system. Figure 1 shows that any increases in fat stores results in increased production of leptin by the white adipose tissue (10). Leptin, the afferent signal of the loops, circulates in the blood in remarkable proportion to total-body fat stores (11). The receiver of the leptin signal that analyzes the fat-derived signal is the brain. Parenteral administration of recombinant leptin in mice potently reduces body weight by decreasing food intake and increasing energy expenditure (12–14). Very small concentrations of centrally administered recombinant leptin produces the same effect (12). Figure 1 proposes that circulating leptin crosses the blood-brain barrier and/or the blood–cerebrospinal fluid (CSF) barrier through a specific transporter. Leptin then binds to its receptor in the hypothalamus, probably in the arcuate nuclei, and modulates certain unidentified neurocircuits and neurotransmitters to stimulate the efferent system of the loop. It is likely that neuropeptide Y (NPY) plays an important role in the system. Stephens et al. (15) have recently demonstrated that chronic leptin administration decreases hypothalamic NPY mRNA in the ob/ob mouse. Furthermore, leptin directly suppresses NPY release from isolated perfused normal-rat hypothalamus (15). Neuropeptide Y-ergic neurons of the hypothalamic arcuate nuclei that project to the paraventricular and dorsomedial nuclei control energy balance by stimulating feeding and inhibiting thermogenesis. Activation of the afferent loop by the brain decreases appetite, increases activity, and increases thermogenesis–the result of which is negative energy balance and restoration of fat stores to normal (16).

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Fig. 1. Relation between percent body fat and serum leptin in humans.

How a decrease in NPY results in the regulation of appetite and activity is not known. The increase in thermogenesis is likely the result of increased sympathetic outflow that ultimately activates the release of norepinephrine from sympathetic nerve terminals that reactivate the `-3-adrenergic receptors in brown adipose tissue. When norepinephrine binds to the `-3-adrenergic receptors on fat cells, it increases their metabolic rate by increasing the expression of the gene that encodes uncoupling protein. This protein that is present in the inner membrane of the mitochondria then releases energy from fatty acid as heat (17). From the previous discussion, it appears that NPY is the leptin transducer system. However, this simple idea may prove to be far from true. It is likely that a fundamental physiological function, such as maintenance of energy balance, is regulated by a multidimensional system with overlapping control pathways of closed- and open-loop systems.

3.2 Parabiotic Experiment Mutations or disregulations in any of the key steps of the closed-loop system of body weight regulation depicted in Fig. 1 could contribute to the development of obesity in humans. Because of the crucial role that leptin plays in this loop, it is appropriate to briefly review the experiments that led to our current incomplete understanding of body-weight regulation as shown in Fig. 1. Parabiotic studies contributed to early understanding of the genes contributing to obesity. In parabiosis, two rodents are surgically joined by suturing their skin together after making an incision through the skin of both rodents. This permits transfer of low-


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molecular-weight substances form one rodent to the other. If both animals lack the ability to make a hormone to inhibit feeding, they both become obese. If both animals lack a receptor to recognize a hormone that inhibits feeding, they both become fat. If these two are joined to each other, the receptor-deficient animal would overproduce the hormone, suppressing the appetite of the hormone-deficient animal. 3.2.1. OBESITY RESULTING FROM DESTRUCTION VENTROMEDIAL HYPOTHALAMUS It was in 1958 that Hervey first demonstrated the presence of a hormone that regulated body weight by interacting with the hypothalamus (17). G. C. Kennedy had suggested 5 yr earlier that the site of this hormone production was adipose tissue (18), giving birth to the lipostatic theory of body-weight control. The experiment performed by Hervey (17) is one of the best examples from the golden days of physiology. The production of obesity by the destruction of the ventromedial hypothalamus (VMH) in a member of a parabiotic rat pair led to death by starvation in the unlesioned animal. Hervey proposed that a circulating satiety factor was produced by the lesioned parabiont as body fat accumulated. This animal was rendered insensitive to this factor by VMH destruction. Thus, the unlesioned parabiont became hypophagic in response to the high level of the satiety signal transmitted across the parabiotic union. Parabiosis poses a barrier to the exchange of short-lived circulating hormones such as the gastrointestinal hormones cholecystokinin, bombesin, insulin, glucagon, glucagon like peptides, and so forth. It is clear now that Hervey’s factor is leptin. Also, as proposed by Hervey, leptin is not a gastrointestinal-terminating (satiety) signal because its concentration does not increase postprandially in humans (19).

OF THE

3.2.2. GENETIC OBESITY Parabiosis experiments performed in animals with genetic obesity are also an important part of the history of leptin. Hausberger reported in 1958 (20) that nonobese mice suppressed the weight gain of ob/ob mice in parabiosis; that is, the normal mouse produced the substance that was lacking in the ob/ob mouse and that suppressed eating. Hansberger interpreted this result to indicate that “this type of obesity is caused by the lack of a factor which can be transmitted by successful parabiosis.” This prediction was correct, the ob/ob mouse does not produce leptin (5). The genetic mechanism of obesity in the db/db mouse and the fa/fa rat was predicted to be different from that in the ob/ob mouse because instead of the normal rodent preventing weight gain in the obese rodent, the normal rodent died of starvation. Coleman and Hummel (21) reported in 1969 that lean mice in parabiosis with obese db/db littermates died of starvation. Harris and co-workers found the same with fa/fa rats (22). These results, which were strikingly similar to those obtained by Hervey (17), using rats VMH lesioned, suggested that db/db and fa/fa animals became obese due to central nervous system insensitivity to the circulating satiety factor now known to be leptin. Again, these predictions were correct. The db/db mouse (6,7) and the fa/fa rat (8) were recently found to have mutations in the leptin receptor (9), which render them insensitive to leptin.

4. THE ob GENE The positional cloning of the mouse obese (ob) gene by Zhang et al. (5) was the beginning of what will be known as the “fat years” of obesity research and one of the best

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examples of modern endocrinology in action. Zhang et al. (5) reported in 1994 that they had identified the gene responsible for obesity in one of the most intensively studied genetic rodent models of obesity, the ob/ob mouse, homozygous for a mutant form of the obese (ob) gene. The mouse ob gene encodes a 4.5-kb adipose tissue messenger RNA with a highly conserved 167 amino acid open reading frame. The predicted amino acid sequence is 84% identical between human and mouse and has features of a secreted protein. A nonsense mutation in codon 105 was found in the original congenic C57BL/6J ob/ob mouse strain, which expressed a 20-fold increase of abnormal ob mRNA. A second mutation was found in the co-isogenic SM/Ckc-+ob21/ob21 mouse; this mutation must be in the promoter region of the ob gene, because it prevents the synthesis of ob mRNA (5). The structural organization of the human (23) and mouse (24) obese gene is at hand. The human ob gene spans ~20 kb and contains three exons separated by two introns. The first intron, ~10.6 kb in size, occurs in the 5' untranslated region, 29 basepair (bp) upstream of the ATG start codon. The second intron 2.3 kb in size is located at glutamine + 49. By the fluorescence in situ hybridization technique, the ob gene was assigned to human chromosome 7q31.3. Leptin structural defects in humans are extremely rare (27). These will be discussed further in Subheading 5. Most important for the understanding of leptin metabolism is the emerging knowledge of the sequence, regulation, and activity of the ob gene promoter (25–27). Such understanding is important, as the quantity of leptin is important in appetite regulation, and the amount of and circumstances governing leptin production ultimately are governed by the ob gene promoter. Like other adipocyte genes that are transcriptionally activated by CCAAT/enhancer binding protein a (C/EBPa) during preadipocyte differentiation, expression of the mouse ob gene is immediately preceded by the expression of C/EBPa. Although the 5' flanking region of the mouse ob gene contains several consensus C/EBPa binding sites, only the proximal region between nucleotides –58 and –42 relative to the transcriptional start site appears to be functional (25). Peroxisome proliferator activated receptor g2 (PPARg2) is also involved in regulation of leptin production. PPARY2 plays an important role in initiating transcription of adipocyte genes during differentiation. Preliminary attempts to locate a PPARg2 binding site or to demonstrate transcription of the obese promoter by PPARg2 have been unsuccessful (25). It is possible that (1) a PPARg2 enhancer lies outside of the promoter sequences analyzed thus far, (2) the PPARg2 binding site does not conform to the classical sequence motifs, (3) a direct effect of PPARg2 can only be demonstrated if the promoter is activated by another transcription factor such as C/EBPa, or (4) the effect of PPARg2 is indirect.

5. THE LEPTIN RECEPTOR The major question to answer relates to the mechanism of leptin action. This is of paramount importance because human obesity is characterized by hyperleptinemia; that, is the amount of leptin is, on average, proportionate to body mass index (11). Because the expected response to an elevation in leptin is decreased caloric intake and increased energy expenditure, it appears that most obese humans are insensitive to their endogenous leptin production. Thus, to understand human obesity relatively, we need to understand the causes of this insensitivity.


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Table 3 Studies of Leptin and Leptin Receptor in Humans Candidate Leptin (ob gene) Coding region mRNA expression Circulating leptin Brain leptin transport Leptin receptor Coding region mRNA expression

Findings

Ref.

No mutations found in ~400 humans except for two related children with severe obesity Increased in proportion to adipose tissue mass Increased in proportion to adipose tissue mass Saturable transport probably normal in obesity

10,27–29,30

No mutations in 15 human hypothalamus No difference between lean and obese subjects

37 37

10,31,32 11,33 34–36

The first step to understanding leptin action has been completed. Tartaglia et al. (9) discovered the leptin receptor. The leptin receptor belongs to the class I cytokine receptor family. Indeed, the primary structure of leptin is unique, but the secondary structure resembles that of a cytokine (26). The leptin receptor has an extracellular binding domain of 840 amino acids, a transmembrane domain of 34 amino acids, and a variable intracellular domain. Beyond Lys 889, which includes 29 amino acids of the intracellular domain, the leptin receptor splices into 3 forms with totally different intracellular domains and a fourth soluble form. A short leptin receptor, named Ob Ra, has a 34 amino acid intracellular domain and it is believed to function as a transporter. A long leptin receptor, named Ob Rb, has a 304 amino acid intracellular domain and it is believed to function as the first leptin-signaling step. In fact, the long intracellular domain contained putative motifs for Janus protein–tyrosine kinase (JAK) and signal transducers and activators of transcription (STAT) binding. JAK and STAT are key steps for cytokinine class I receptor signaling (26). Another leptin receptor, named Ob Rc, with an intracellular domain of 32 amino acids may also function as a transporter (7). Finally, a receptor named Ob Re is identical to the others upstream to Histadine 796, at which point the nucleotide sequences diverge with a total of 808 amino acids (7). Thus, this receptor is the shortest without a transmembrane domain and, therefore, predicts a soluble receptor (7). An unexpected finding is the wide distribution of the different leptin receptor isoforms. They are not located in the hypothalamus only, but have a wide distribution in the brain, choroid plexus, liver, lungs, heart, kidney, testes, adipose tissue, spleen, and so forth (7,9). To ascertain the role of leptin in all these tissues will certainly be a fertile area of investigation.

6. ABNORMALITIES IN HUMAN LEPTIN AND THE LEPTIN RECEPTOR Table 3 summarizes the initial work testing the hypothesis that abnormalities in leptin or the leptin receptor could be involved in the mechanism of obesity in humans. However, this work has not indicated that structural defects in either leptin or the leptin receptor are significant contributors to human obesity. The sequence of the ob gene coding region has been studied by three different groups of investigators (27–29). More than 400 human ob

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cDNAs have been studied. All of them proved to be normal, except for one in which a first base substitution (G to A) was detected that changed a valine to a methanine at position 94 (27). This amino acid substitution appears to have no effect on activity, as the amount of immunoreactive circulating leptin in the patient was consistent with the degree of obesity. Thus, mutations in the coding region of the ob gene appear to be extremely rare in human obesity (27). Furthermore, the amount of normal ob mRNA in adipose tissue and the amount of circulating leptin are in remarkable proportion to the amount of adipose tissue (11). Because the expected response to elevation in leptin is decreased caloric intake and increased energy expenditure, it appears that most obese humans are insensitive to their endogenous leptin production. However, as shown in Fig. 1, there may be intravascular defects that render leptin defective, such as leptin antibodies, leptin antagonists, and leptin-binding proteins, which may prevent free leptin interaction with its target tissue. These possibilities are currently being explored in different laboratories. One such exploration is investigating the role of binding proteins in human obesity. Leptin enters the brain by a saturable system (34). In human obesity, the high circulating leptin concentration saturates this transport system (35,36). The efficiency of leptin uptake is much lower in obese individuals (35,36). Thus, leptin transport into the brain may be a rate-limiting step for leptin action. Consequently, severe hyperleptinemia may not be equated to leptin receptor resistance in all cases. Another approach is investigations of the leptin receptor (Table 3). Leptin receptor gene expression in lean vs obese individuals was examined by measuring the incorporation of radiolabeled downstream primer into an ~800 bp polymerase chain reaction (PCR) product (37). There was neither a difference in the amount of leptin receptor mRNA between the lean and obese groups nor a correlation between leptin receptor gene expression and body mass index. No difference in the size of the cDNA product from lean and obese individuals was observed, ruling out the presence of alternative splicing in obese humans as observed in db/db mice (37). Subjects were screened for potential sequence variations in the leptin receptor cDNA product. Although for most subjects, most regions of the leptin receptor were identical, suggesting that the leptin receptor transcripts were derived from a single species of mRNA, however, some single-base substitutions were identified in leptin receptor cDNA. One such substitution of adrenosine (A) to guanine (G) at position 668 of the leptin receptor cDNA substitutes glutamine for arginine at the position of 223 of the leptin receptor protein and generates a restriction site for Hpa II (a restriction enzyme) that leaves the cDNA confirming the substitution. All but one subject in this study carried this substitution in their leptin receptor DNA. Sequence variations were detected in two other areas of the leptin receptor. No relationship between any of the sequence variations and the lean or obese phenotypes could be established (37). This suggests that structural defects in the leptin receptor may have little contribution in human obesity.

7. OTHER HUMAN TARGETS In addition to the hereditability of excess body weight and regional fat distribution, the work of Bouchard and co-workers has clearly suggested hereditability of energy intake, energy expenditure, and the propensity toward being spontaneously active (2). Therefore, brown adipose tissue and, more specifically, the `-3-adrenergic receptor gene, has been considered as a candidate gene for the hunt for the cause of obesity. Recently, a replacement of tryptophan by arginine at position 64 of the protein in the first intracellular


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loop of the receptor has been demonstrated (37–39). However, it appears that this particular mutation in the `-3 receptor is not a major determinant of obesity or upper-body fat, although it may be involved in the earlier onset of type II diabetes (40). Other studies with reasonable candidates genes, such as tumor necrosis factor-_, the uncoupling protein, Na-K ATPase, glucose transporter-1, and so forth, have been reviewed recently (2). For the most part, this important work has not been revealed an explanation for the majority of human obesity. 8. CONCLUSION: APPLICABILITY TO TREATMENTS The discovery of leptin at the end of 1994 initiated what will be known as the “fat years” of obesity research. There is no question that this field is ready for major advances. The human genome project is on schedule and an extensive knowledge of all human chromosomes should be on hand soon. Panels of families with obesity are currently being assembled, phenotyped and DNA banked in an effort to define the molecular and genetic bases of obesity. There is no question that the syndrome of obesity will be defined as a collection of different diseases with distinct genetic abnormalities by the beginning of the upcoming millennium. Such new knowledge should provide powerful biological tools to prevent, reverse, and, ultimately, cure obesity. Figure 1 provides sites for the development of new drugs for the treatment of obesity. Leptin or leptin analogues will be logical drugs to be tested. Although obese patients have leptin resistance, patients with type II diabetes are also insulin resistant, and insulin is still the best therapy for many of them. Agents that increase the sensitivity of the brain to endogenous leptin production would certainly be of great value. Likewise, as shown in Fig. 1, agents that decrease NPY or NPY receptor antagonists could have an important place in the treatment of obesity. Finally, agents that increase thermogenesis, such as `-3-adrenergic agonists, might also play a rational role in obesity therapy. The good news is that all of these compounds, and others, are already in place, although at different stages of research development. However, even when these drugs are available, they are unlikely to be fully effective unless the individual and society take responsible steps to modify the “environment,” a key deleterious element in all “complex” diseases of today.

REFERENCES 1. Kahn RC. The role of obesity in diabetes mellitus. Curr Opin Endo Diabetes 1996; 3:1–2. 2. Bouchard C. The genetics of obesity in humans. Curr Opin Endo Diabetes 1996; 3:29–35. 3. Stunkard AJ, Sorensen TIA, Hannis C, Teasdale TW, Chakraborty R, Schull WJ, et al. An adoption study of human obesity. N Engl J Med 1986; 314:193–198. 4. Wilkinson WO. The genetic basis of obesity in rodents. Curr Opin Endo Diabetes 1996; 3:24–28. 5. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman J. Positional cloning of the mouse obese gene and its human homologue. Nature 1994; 372:425–432. 6. Chen H, Charlat O, Tartaglia LA, Woolf EA, Weng X, Ellis S, et al. Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Cell 1996; 84:491–495. 7. Lee GH, Proenca R, Montez JM, Carroll KM, Darvishzadeh JG, Lee JI, et al. Abnormal splicing of the leptin receptor in diabetic mice. Nature 1996; 379:632–635. 8. Chua SC, Chung WK, Wu-Peng XS, Zhang Y, Lui SM, Tartaglia L, et al. Phenotypes of mouse diabetes and rat fatty due to mutation in the Ob (leptin) receptor. Science 1996; 271:994–996. 9. Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, Devos R, et al. Identification and expression cloning of a leptin receptor, OB-R. Cell 1995; 83:1263–1271. 10. Considine RV, Nyce MR, Allen LE, Morales LM, Triester S, Colberg J, et al. Evidence against either a premature stop codon or the absence of ob gene in mRNA in human obesity. J Clin Invest 1995; 95:2986–2988.

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11. Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med 1995; 334:292–295. 12. Campfield LA, Smith FJ, Guisez Y, Devos R, Burn P. Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks. Science 1995; 269:546–549. 13. Pelleymounter MA, Cullen MJ, Baker MB, Hecht R, Winters D, Boone T, et al. Effects of the obese gene product on body weight regulation in ob/ob mice. Science 1995; 269:540–543. 14. Halaas JL, Gajiwala KS, Maffei M, Cohen SL, Chait BT, Rabinowitz D, et al. Weight reducing effects of the plasma protein encoded by the obese gene. Science 1995; 269:543–546. 15. Stephens TW, Basinski M, Bristow PK, Bue-Valleskey JM, Burgett SG, Craft L, et al. The role of neuropeptide g in the antiobesity action of the obese gene product. Nature 1995; 377:530–533. 16. Dryden S, Williams G. The role of hypothalamic peptides in the control of energy balance and body weight. Curr Opin Endo Diabetes 3:51–58, 1996. 17. Hervey GR. The effects of lesions in the hypothalamus in parabiotic rats. J Physiol 1959; 145:336–352. 18. Kennedy GC. The role of depot fat in the hypothalamic control of food intake in the rat. Proc Roy Soc (Lond) 1953; 140:578–592. 19. Sinha MK, Ohannesian JP, Heiman ML, Kriaciunas A, Stephens TW, Magosin SA, et al. Nocturnal rise of leptin in lean, obese and non-insulin dependent diabetes mellitus subjects. J Clin Invest 1996; 97:1344–1347. 20. Hausberger FX. Parabiosis and transplantation experiments in hereditarily obese mice. Anat Rec 1958; 130:313. 21. Coleman DL, Hummel KP. Effects of parabiosis of normal with genetically diabetic mice. Am J Physiol 1969; 217:1298–1304. 22. Harris RB. Role of set point theory in regulation of body weight. FASEB J 1990;4:3310–3318. 23. Isse N, Ogawa Y, Tamura N, Masuzaki H, Mori K, Okazaki T, et al. Structural organization and chromosomal assignment of the human obese gene. J Biol Chem 1995; 270:27,728–27,733. 24. He Y, Chen H, Quon MJ, Reitman M. The mouse obese gene. J Biol Chem 1995; 270:28,887–28,891. 25. Hwang CS, Mandrup S, MacDougald OA, Geiman DE, Lane MD. Transcriptional activation of the mouse obese (Ob) gene by CCAAT/enhancer binding protein _. Proc Natl Acad Sci USA 1996; 93:873–877. 26. Kishimoto T, Taga T, Akira S. Cytokine signal transduction. Cell 1994; 76:253–262. 27. Considine RV, Considine EL, Williams CJ, Nyce MR, Zhang PL, Opentanova I, et al. Mutation screening and identification of a sequence variation in the human Ob gene coding. Biochem Biophys Res Commun 1995;220:735–739. 28. Niki T, Mori H, Tamori Y, Kishimoto-Hashiramoto M, Ueno H, Araki S, et al. Molecular screening in Japanese and Asian Indian NIDDM patients associated with obesity. Diabetes 1996; 45:675–678. 29. Maffei M, Stoffel M, Barone M, Moon B, Dammerman M, Ravussin E, et al. Absence of mutations in the human ob gene in obese/diabetic subjects. Diabetes 1996; 45:679–682. 30. Montague, CT, Farooqu, Sadaf I, Whitehead P, Jonathan P. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 1997; 387:903–908. 31. Lonnquist F, Arner P, Nordford L, Schalling M: Overexpression of the obese (Ob) gene in adipose tissue of human obese subjects. Nature Med 1: 950–953, 1995. 32. Hamilton BS, Paglia D, Kwan AYM, Deitel M. Increased obese mRNA expression in omental fat cells from massively obese humans. Nature Med 1995; 1:953–956. 33. Lallone R, Ranganathan S, Kern PA, Friedman JM. Leptin levels in human and rodent: measurement of plasma leptin and Ob RNA in obese and weight-reduced subjects. Nature Med 1995; 1:1155–1161. 34. Banks WA, Kastin AJ, Huang W, Jaspan JB, Maness LM. Leptin enters the brain by a saturable system independent of insulin. Peptides 1996; 17:305–311. 35. Schwartz MW, Peskind E, Raskind M, Boyko EJ, Porte D. Cerebrospinal fluid leptin levels: Relationship to plasma levels and to adiposity in humans. Nat Med 1995; 2:589–593. 36. Caro, JF, Kolaczynski JW, Nyce MR, Ohannesian JP, Opentanova I, Goldman WH, et al. Decreased CSF/ serum leptin ratio in human obesity: a possible mechanism for leptin resistance. Lancet 1996; 348:159. 37. Considine RV, Considine EL, Williams CJ, Hyde TM, Caro JF. The hypothalamic leptin receptor in humans: identification of incidental sequence polymorphisms and absence of the db/db mouse and fa/ fa rat mutations. Diabetes 1996; 19:992. 38. Walston J, Silver K, Bogardus C, Knowler WC, Celi FS, Austin S, et al. Time of onset of non-insulindependent diabetes mellitus and genetic variation in the `3 adrenergic receptor gene. N Engl J Med 1995; 333:343–347.


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39. Widen E, Lehto M, Kanninen T, Walston J, Shuldiner AR, Groop LC. Association of a polymorphism in the b3 adrenergic receptor gene with features of the insulin resistance syndrome in Finns. N Engl J Med 1995; 333:348–351. 40. Clement K, Vaisse C, Manning BSJ, Basdevant A, Guy-Grand B, Ruiz J, et al. Genetic variation in the `3 adrenergic receptor and an increased capacity to gain weight in patients with morbid obesity. N Engl J Med 1995; 333:352–354.

Chapter 19 / Surgery in the Management of Severe Obesity

19

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Surgery in the Management of Severe Obesity Peter N. Benotti

1. INTRODUCTION This chapter describes the indications for referral for surgery for obesity and postsurgical management (Table 1). Obesity is a problem that is increasing in this country. Approximately 12 million people in the United States are severely overweight. Of these, approximately 3–4 million are so severely obese that their health and well-being are affected by their obesity (1–4). Comorbid conditions that cause early death or disruption of the quality of life in the severely obese include hypertension, hypertrophic cardiomyopathy, hyperlipidemia, diabetes, certain cancers, cholelithiasis, obstructive sleep apnea, hypoventilation, degenerative arthritis, and psychosocial impairments (5). During the past 20 years, as surgery has slowly evolved and taken its place in the armamentarium for obesity care, there has been little documented long-term efficacy of diet, behavior, or other modalities directed at the care of the severely obese. Only two clinical trials looking at behavior modification in a total of 101 obese subjects demonstrate a 4-yr weight loss of 30% of excess weight (6), and a 10-yr weight loss of between 10 and 20 kg in 49 patients (7). There is no long-term data beyond 4 yr available supporting medical therapy for weight reduction in the severely obese. The large number of patients whose health is threatened by severe obesity, coupled with the lack of available alternative therapies for these patients, has resulted in the emergence of surgery as the only therapy offering a meaningful potential for durable long-term weight control.

2. THE EVOLUTION OF SURGERY The original operative procedure developed approximately 20 yr ago was the jejunoileal bypass, which was designed to provide controlled malabsorption. The procedure creates a markedly shortened small intestine by the anastomosis of 40 cm of proximal jejunum to 10 cm of terminal ileum (8–10). The majority of the jejunum and ilium were defunctionalized and not exposed to the direct fecal stream. This operation did result in significant long-term weight control for 80–85% of patients (11). Unfortunately, major nutritional, metabolic, and ano-rectal problems were not uncommon (12). In addition, structural abnormalities in the liver developed in 29% of patients and frank cirrhosis developed in 7–10%, causing significant late morbidity and mortality (13). The potential From: The Management of Eating Disorders and Obesity Edited by: D. J. Goldstein © Humana Press Inc., Totowa, NJ

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Part III / Treatment Table 1 Chapter Overview 1. 2. 3. 4. 5.

Introduction The Evolution of Surgery Indications for Surgery Referral Complications of Surgery Results of Obesity 5.1. Analysis of Results 6. Late Complications 7. Risk–Benefit

for life-threatening liver insufficiency and the inability to predict its occurrence has eliminated the clinical use of this procedure (14,15). In the early 1980s, Mason observed that significant weight loss consistently occurred after subtotal gastrectomy in patients with peptic ulcer disease. He and other investigators then began preliminary experiments involving the creation of small gastric pouches and narrowed gastric pouch emptying configurations in small numbers of morbidly obese patients (16,17). These preliminary trials demonstrated that these procedures could be performed safely and that weight loss could be achieved without major dangerous late sequelae. Subsequent investigators in efficacy studies with adequate numbers of patients applied these procedures involving the creation of small gastric pouches with narrowed outflow stomas to a more diverse group of morbidly obese patients, with similar results (18–23). Finally, the newly developed gastric partitioning operation for obesity was compared with a standard medical modified-fast regimen in a randomized, controlled trial that documented the superiority of gastric surgery as compared to diet therapy in the long-term management of severely obese patients (24). As a result of a 1991 National Institutes of Health Consensus Conference, surgery officially became part of the armamentarium for those caring for severely obese patients (25). The two operative procedures currently recognized by the 1991 NIH Consensus Conference are vertical banded gastroplasty and gastric bypass operation. The vertical banded gastroplasty restricts food intake primarily by limiting gastric reservoir volume (Fig. 1). The small 15- to 20-cm3 gastric reservoir created by stapling techniques sits parallel to the lesser curvature of the upper stomach and empties through a narrow channel on the lesser curvature into the remaining stomach. The emptying channel is reinforced with prosthetic material so as to ensure a channel circumference of 4.5–5 cm. This operation is attractive because it preserves gastroduodenal continuity and avoids the potential for malabsorption and micronutrient deficiency. The gastric bypass operation is also designed to restrict gastric reservoir capacity by the creation of a 15- to 20-cm3 stapled gastric pouch. In contrast to the gastroplasty, however, the newly constructed pouch is connected by a 10-mm anastomosis to a Roux-en-Y jejunal limb, bypassing the distal stomach, duodenum, and very proximal jejunum (Fig. 2). With this operation, gastric restriction is combined with the emptying of semiparticulate gastric contents in unregulated fashion into the jejunum. Thus, restriction of gastric reservoir volume is combined with varying degrees of malabsorption or maldigestion. In addition to the above-mentioned operations, Scopinaro and co-workers have continued to advocate the concept of malabsorption with the biliary pancreatic bypass


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Fig. 1. The vertical banded gastroplasty procedure. A 20-cm3 gastric reservoir created along the lesser curvature of the upper stomach empties into the remaining stomach through a narrow banded channel. (Reprinted by permission of the publisher from Benotti, The role of gastric surgery in the multidisciplinary management of severe obesity. Am J Surg 169:361–366. Copyright 1995 by Exerpta Medica Inc.)

operation (26,27). In this procedure, bile and pancreatic juice draining into the duodenum are diverted to the ileum via a long Roux-enY limb. In addition, either the stomach is partitioned with staples or the distal stomach is resected (Fig. 3). Although this procedure results in excellent weight loss, it has not been used widely in the United States because of greater nutritional and metabolic risks. The weight loss following biliopancreatic bypass has stimulated many bariatric surgeons to experiment by increasing the Rouxen-Y limb lengths in conjunction with gastric bypass surgery to improve long-term results and yet maintain safe and healthy weight control (28). In general, as Roux-en-Y limb lengths increase, weight loss increases in direct relationship to potential nutritional and metabolic sequelae.

3. INDICATIONS FOR SURGERY REFERRAL The NIH Consensus Conference established the following indications for surgery in the severely obese patient. Definitions of severe or morbid obesity includes a weight that is twice or 100 lb over desirable weight or body mass index over 40 kg/m2. Surgery is indicated for the otherwise healthy severely obese patient who has failed attempts at medical weight reduction. Surgery is also indicated in the severely obese patient whose life is threatened by significant obesity-related comorbidity. The traditional age limits for patients have been 18–55 yr. However, there is now evidence that selected patients above the age of 55 years do very well following this surgery (29). In contrast, there are only

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Fig. 2. The gastric bypass operation. A 20-cm3 proximal gastric pouch is connected by a 10 to 12 mm anastomosis to a Roux-en-Y jejunal limb. (Reprinted by permission of the publisher from Benotti, The role of gastric surgery in the multidisciplinary management of severe obesity. Am J Surg 169:361–366. Copyright 1995 by Exerpta Medica Inc.)

anecdotal reports of successful gastric surgery for obesity in adolescence, and thus the efficacy of surgery in these patients remains controversial. Contraindications to surgery for severe obesity include a history of psychosis, substance abuse, and major organ dysfunction (Table 2).

4. COMPLICATIONS OF SURGERY Gastrointestinal surgery for the severely obese is technically demanding because the massively expanded fat mass causes technical and exposure problems during surgery. The increased complication rates related to all types of abdominal surgery in the obese have been well documented (30,31). As with other technically demanding operative procedures, the increased experience with gastric surgery for obesity has resulted in a gradual reduction in complication rates to acceptable levels. The operative mortality associated with gastric surgery for severe obesity is 0.3–1.6%. The serious infectious complications involving anastomotic leaks, abscess, and peritonitis occur in 1.6–2.3% of patients. Other complications include deep venous thrombosis (0.35%), pulmonary embolism (0.3%), subphrenic abscess (0.09%), and wound infections (5%) (32–34). Although these are significant risks, they compare favorably with the long-term risks of conservative therapy for severe obesity.


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Fig. 3. The biliopancreatic bypass. The stomach is either partitioned or the distal stomach is resected. A gastroileostomy is performed. The alimentary limb is connected to the biliopancreatic limb by an enteroenterostomy. (Reprinted by permission of the publisher from Scopinaro, Biliopancreatic diversion for obesity at eighteen years. Surgery 119:261–268. Copyright 1996 by Mosby–YearBook, Inc.)

Table 2 Indications for Surgical Therapy • • • •

Severe obesity: weight twice or 100 lb above desirable body weight Failed attempts at medical weight reduction Ages 18–55 Absence of psychosis, major substance abuse, or major organ dysfunction

5. RESULTS OF OBESITY SURGERY Weight loss has been the traditional criterion used to assess efficacy of surgery for severe obesity. The exact methodology for expression of weight-loss results is controver-

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Fig. 4. Weight loss 60–96 mo after Roux-en-Y gastric bypass as reported in three large series with good follow-up. Weight is recorded as a percentage of ileal body weight (䊕 = Benotti et al. [35]; 䊉 = MacDonald and Pories [36]; 䊏 = Linner [37]). (Reprinted by permission of the publisher from Benotti, The role of gastric surgery in the multidisciplinary management of severe obesity. Am J Surg 169:361–366. Copyright 1995 by Exerpta Medica Inc.)

Fig. 5. Weight loss after vertical banded gastroplasty. The results are taken from three large series where weight is reported or could be calculated as a percentage of desirable weight. (䊕 = MacLean et al. [38]; 䊉 = Mason [34]; 䊏 = Yale and Weiler [39]). (Reprinted by permission of the publisher from Benotti, The role of gastric surgery in the multidisciplinary management of severe obesity. Am J Surg. 169:361–366, Copyright 1995 by Exerpta Medica Inc.)


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sial, and this has complicated the comparison among the large number of published longterm trials of weight loss following obesity surgery. Weight has been expressed as absolute weight in pounds or kilograms, percentage of excess weight, percentage of desirable body weight, and, infrequently, as the body mass index (weight in kilograms divided by the height squared in meters). The weight loss after either of the gastric operations is most rapid during the first 12 mo postoperatively. Subsequently, weight tends to stabilize, with a slight tendency toward late weight regain. The experience of several large obesity surgery centers with Roux-en-Y gastric bypass is summarized in Fig. 4. These large series are selected because they involve good long-term follow-up in a large number of patients. The sequential weight information in these series is expressed in reference to ideal body weight. Similar weight-loss curves have been reported by a number of other surgical centers with weight expressed as percentage of excess weight or absolute weight. Postoperative weight plateaus during the second and third postoperative year at an average of 30–40% above ideal weight (35–37). The weight changes following vertical banded gastroplasty are more modest (Fig. 5). After 12 mo, weight tends to plateau at approximately 60–70% above desirable (34,38,39).

5.1. Analysis of Results Numerous clinical trials have been published confirming durable weight control following gastric operations for severe obesity. Nevertheless, lack of uniformity concerning the reporting of sequential weight-loss results complicates the comparison of results from different obesity centers (40–42). In addition, all patients’ results are pooled and average weights are plotted in relation to time after surgery. Most published series do not separate the weight-loss results for severely obese and superobese patients. The results summarized are taken from a large series with good follow-up in which weight was recorded as percentage of desirable or where the published data allow recalculation to this reference standard (Figs. 4 and 5). These results consistently demonstrate a 10–20% better average weight loss with gastric bypass vs gastroplasty (Figs. 4 and 5) (31,35,39). This finding has been confirmed in prospective controlled trials comparing the two operations (43– 49). Possible explanations for the greater weight loss with gastric bypass include the additive effects of restriction of gastric volume and some degree of maldigestion or malabsorption. In addition, the phenomenon of “dumping” related to unregulated emptying of simple carbohydrates into the jejunum may exert feedback by reducing caloric intake and changing food preferences. Finally, the greater incidence of mechanical pouch emptying complications with the purely restrictive procedures results in a change in eating behavior toward the ingestion of high-caloric liquids, which empty more rapidly and yet provide some element of satiety. Comparative studies suggest that the incidence of mechanical and digestive symptoms tends to be less after the gastric bypass operation. The revision rate following gastroplasty approaches 20%, the indications being relative weight loss failure and/or major digestive symptoms (48–50). There are numerous published trials with good follow-up demonstrating satisfactory 5-yr weight control following gastric surgery for severe obesity. In addition, there are fewer reports of similar results with follow-up extending to 12-yr. If surgical failure is defined as failure to lose 30–50% of excess weight at 5 yr, the estimated failure rate after gastric surgery is between 10% and 20%. The published revision rate following gastroplasty approximates 20% (50).

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It is interesting to note that the surgical results have been universally criticized because of the relative lack of long-term weight-control data. However, the vast majority of published medical behavioral and pharmacologic clinical trials have follow-up measured in months. Only two trials with a small number of patients have published 4-yr results (6,7). There continues to be a lack of significant data confirming that any conservative approach to severe obesity has any long-term effect.

6. LATE COMPLICATIONS Careful nutritional and metabolic monitoring of postoperative patients is essential in order to allow for safe and healthy weight control. This is consistent with the NIH Consensus Conference Development Statement, which emphasizes the importance of a multidisciplinary approach involving surgeons, behaviorists, and dietitians for the perioperative management of severely obese patients (25). Postoperative food aversion resulting in rapid and unsupervised weight loss in the uninformed patient will result in a risk for nutrient deficiencies with resultant clinical syndromes. Micronutrient deficiencies with associated hematologic or neurologic consequences occasionally occur following gastric surgery for obesity (51). Reductions in levels of iron and Vitamin B-12 occur in 36–70% of patients, whereas low folate levels occur in 30–45% (52,53). Actual clinical deficiency states associated with these micronutrients are much less common (12–25%) (51,54–56). Because reductions in the level of micronutrient carrier proteins are common during the period of rapid weight loss, this may contribute to the measured low levels of these specific nutrients and not necessarily imply a deficiency state (57). As a result of the preservation of gastroduodenal continuity with the vertical banded gastroplasty, micronutrient abnormalities are less common following this procedure (58). Neurologic syndromes ranging from peripheral neuropathy to encephalopathy have also been described, complicating gastric surgery for obesity (59–62). Fortunately, these are very rare and tend to occur only in those patients with protracted vomiting and/or maladaptive eating behavior who consume an inadequate diet without nutritional monitoring (51). Vomiting and maladaptive eating may occur in up to 20–30% of patients. The etiology is complex and is a function of eating behavior, emotional instability, slow pouch emptying, and, on occasion, structural failures of operation. These patients usually respond to multidisciplinary care, consisting of stress management, alterations in lifestyle, and changes in eating behavior provided in the context of support groups, by experienced nutritionists, behaviorists, and, occasionally, psychiatrists. The majority of patients, when advised about the critical importance of inadequate diet and the potential for deficiency states, respond favorably. Persistent vomiting or other digestive symptoms following gastric surgery occurs in 5–15% of patients. These patients require fluoroscopic or endoscopic examination of the surgical area in the stomach (63). Marginal ulcer will be detected in approximately 7% of patients (48,49,64). Leaks in the gastric staple line can occur in 5–20% of patients. Staple-line leaks can predispose to weight-loss failure and/or marginal ulceration. Marginal ulcer occurring in association with a staple-line leak usually does not respond to antacid therapy and requires surgery. This is thought to be related to the potential for the entire acidity of the parietal cell mass to come in contact with the small gastrojejunal anastomosis. After gastric surgery for obesity structural problems that cause significant gastrointestinal symptoms constitute an indication for revisional surgery. Revisional


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surgery after gastroplasty is necessary in up to 20% of patients (50). Revision following gastric bypass occurs in approximately 10% (49,65).

7. RISK-BENEFIT The relatively low operative risk, the absence of major undesirable late sequelae, and the potential health benefit afforded by durable weight control are factors which continue to support the role for gastric surgery in the management of severe obesity. As a result of the recent NIH Consensus Development Conference in 1991, the surgical community has focused its attention on the long-term health benefits of surgical weight loss. Until recently, the major variable addressed in all of the clinical trials was weight loss. Recent interest in outcome has focused attention on the association between weight loss following surgery and improvement or resolution of obesity-related comorbidity. Obesity-related comorbid conditions were resolved in 91% of a series of 45 superobese patients undergoing Roux-en-Y gastric bypass studied at 2 yr (28). In another series of 479 severely obese patients undergoing gastric surgery, 21% had non-insulin requiring diabetes and an additional 13% has impaired glucose tolerance. In 95% of the diabetic patients, carbohydrate metabolism returned to normal following weight loss associated with gastric bypass (66). These same investigators demonstrated excellent long-term improvement in glucose tolerance following gastric bypass, such that significant numbers of patients are able to discontinue insulin therapy (67). Several published surgical series have documented major resolution or improvement in obesity-related hypertension following gastric surgery (68,69). Noninvasive cardiac-imaging studies have demonstrated that left ventricular fractional shortening velocity and left ventricular internal dimensions improve following weight loss associated with gastric surgery for severe obesity (70). This and other preliminary evidence suggests that systolic function in these patients may improve following surgical weight loss. In addition, reductions in left ventricular wall and intraventricular septal thickness occurred following gastric surgery for severe obesity (71,72). Severely obese patients commonly have abnormal elevations in triglycerides and reduction in high-density lipoprotein cholesterol levels. Postoperatively, with weight loss, especially in women, high-density lipoprotein cholesterol, total cholesterol, and triglyceride levels improve (73). These improvements in lipid levels are sustained during long-term followup after obesity surgery (74). Major improvements in respiratory comorbidity have also been demonstrated by a number of investigators (75–79). Improvements in sleep apnea as well as any other parameters of pulmonary function occur in conjunction with weight loss in as many as 90% of patients (76). Increases in PaO2 and decreases in PaCO2, as well as reduction in sleep apnea index and improvement in lung volumes and flow rates, occur (77,78). Reduction in previously elevated pulmonary artery pressures occurs in conjunction with surgical weight reduction in patients with obesity hypoventilation (79). A major source of significant obesity-related disability is a result of chronic pain and limited mobility secondary to severe degenerative arthritis involving weight-bearing joints. One of the gratifying aspects of obesity surgery is the major improvement in this disability, which almost always accompanies surgical weight loss. Weight reduction following gastric surgery for severe obesity seems to favorably effect nearly all of the life-threatening comorbid problems plaguing these patients. Lon-

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gitudinal studies are now in progress to definitively confirm the overall feeling in the surgical community that surgical weight control results in improved health for these patients (80). At the present time, surgery remains the only treatment option affording severely obese patients a reasonable chance at durable weight control. Optimization of the results of surgery and better preparation and selection of patients for surgical therapy requires a multidisciplinary approach with input from physician, dietitian, behaviorist, and surgeon. Areas of active investigation that will improve the long-term results in surgery include identification of patients with major disorders of eating behavior and assessing the impact of adjuvant behavioral and pharmacologic therapy in conjunction with surgery. In addition, the surgical community continues to strive for improved results by studying division of the stomach as opposed to simple stapling and lengthening the Roux-en-Y limbs to increase the potential for weight loss.

REFERENCES 1. Abram S, Johnson C. Prevalence of severe obesity in adults in the United States. Am J Clin Nutr 1980; 33:364–369 2. National Center for Health Statistics, Najjar MF, Rowland M. Anthropometric reference data and prevalence of overweight, United States. 1976–1980. Vital Health Stat 11. No. 238. 1987; Oct; (238):1–73. 3. Najjar MF, Kuczmarski RJ. Anthropometricmetic data and prevalence of overweight for Hispanics: 1982–1984. National Center for Health Statistics. Vital Health Stat 11. 1989 Mar; (239):1–106. 4. Kuczmarski RJ. Prevalence of overweight and weight gain in the United State. Am J Clin Nutr 1992; 55:4955–5025. 5. NIH Consensus Development Panel. NIH Consensus Development Panel on the health implications of obesity. Ann Intern Med 1985; 103:981–1073. 6. Bjorvell H, Rossner S. Long term treatment of severe obesity: four year follow up of conbined behavior modification program. Br Med J 1985; 291:379–382. 7. Bjorvell H, Rossner S. A ten year follow up of weight change in severely obese subjects treated in a behavioral modification-like program Int J Obes 1990; 14:88 (Abstract). 8. Payne JH, DeWind LT, Commons RD. Metabolic observations in patients with jejunocolic shunts. Am J Surg 1963; 106:273–289. 9. Salmon PA. The results of small intestine bypass operations for the treatment of obesity. Surg Gynecol Obstet 1971; 132:965–979. 10. Scott HW, Dean R, Shull HJ, et al. New considerations in use of jejunoileal bypass in patients with morbid obesity. Ann Surg 1973; 177:723–735. 11. Bray GA, Barry RE, Benfield JR, Catelnuovo-Tedesco P, et al. Intestinal bypass operation as a treatment for obesity. Ann Intern Med 1976; 85:97–109. 12. Requarth JA, Burchard KW, Colacchio TA, et al. Long-term morbdity following jejunoileal bypass. Arch Surg 1995; 130:318–325. 13. Hocking MP, Duerson MC, O’Leary JP, et al. Jejunoileal bypass for morbid obesity Late follow-up in 100 cases. N Engl J Med 1983; 308:995–999 14. Griffen W, Bivins BA, Bell RM. The decline and fall of the jejunoileal bypass 1983; 157:301–308 15. Baddelay RM. An epilogue to jejunoileal bypass. World J Surg 1985; 9:842–849. 16. Mason EE, Ito C. Gastric Bypass in obesity. Surg Clin North Am 1967; 47: 1345–1351. 17. Halverson JD, Zuckerman GR, Koehler RE, Gentry K, Michael HEB, DeSchryver-Keeskemet K. Gastric bypass for morbid obesity; a medical-surgical assessment. Ann Surg 1981; 194:152–160. 18. Mason E. Gastroplasty. In: Griffin WO, Printen KJ, eds. Surgical Management of Morbid Obesity, Marcel Dekker, New York, NY, 1987. 19. Linner JH. Surgery for Morbid Obesity. Springer-Verlag, New York, NY, 1984. 20. Lechner GW, Callender AK. Subtotal gastric exclusion and gastric partitioning: a randomized prospective comparison of 100 patients. Surgery 1981; 90:637–644. 21. Thompson WR, Amaral JF, Caldwell MD, Martin HF, Randall HT. Complications and weight loss in 150 consecutive gastric exclusion patients. Am J Surg 1983; 146:602–612.


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22. Griffin WO, Bivins BA, Bell RM, Jackson KA. Gastric bypass for morbid obesity. World J Surg 1981; 5:817–822. 23. Buckwater JA, Herbst CA. Perioperative complication of gastric restrictive operations. Am J Surg 1983; 146:613–618. 24. Andersen T, Backer OG, Stokholm KH, Quaade F. Randomized trial of diet and gastroplasty compared with diet alone in morbid obesity. N Engl J Med 1984; 310: 351–356. 25. NIH Consensus Development Panel. National Institutes of Health Consensus Development Conference Statement. Gastrointestinal surgery for severe obesity. Ann Intern Med 1991; 115:956–961. 26. Scopinaro N, Gianetta E, Civalleri D, et al. Two years of clinical experience with biliopancreatic bypass for obesity. Am J Clin Nutr 1980; 33:506–514. 27. Scopinaro N, Gianneta E, Gian Franco A, et al. Biliopancreatic diversion for obesity at eighteen years Surgery 1996; 119:261–168. 28. Brolin, RE, Kenler HA, Gorman JH, et al. Long limb gastric bypass in the superobese. Ann Surg 1992; 215:387–395. 29. MacGregor AMC, Rand C. Gastric surgery in morbid obesity: outcome in patients aged 55 years and older. Arch Surg 1993; 128:1153–1157. 30. Pasulka PS, Bristrian BR, Benotti PN, et al. The risks of surgery in obese patients. Ann Intern Med 1986; 104:540–546. 31. Kral JG. Morbid obesity and related health risks. Ann Intern Med 1985; 103:1043–1046. 32. Yale CE. Gastric surgery for morbid obesity. Complications and long-term weight control. Arch Surg 1989; 124:941–946. 33. Poires WJ. The surgical approach to morbid obesity. In: Sabiston DC, ed. Textbook of Surgery: The Biologic Basis of Modern Surgical Practice. WB Saunders, Philadelphia, PA, 1991, pp. 851–866. 34. Mason EE, Maher JW, Scott DH, et al. Ten years of vertical banded gastroplasty for severe obesity. Prob Gen Surg 1992; 9:280–289. 35. Benotti PN, Hollingsworth J, Mascioli EA, et al. Gastric restrictive operations for morbid obesity. Am J Surg 1989; 157:150–155. 36. MacDonald KG, Pories WJ. Roux gastric bypass or vertical banded gastroplasty. Prob Gen Surg 1992; 9:321–331. 37. Linner JH. Results of gastric reduction surgery In: Linner JH, ed. Surgery for Morbid Obesity. SpringerVerlag, New York NY, 1984, pp. 127–132. 38. MacLean LD, Rhode B, Forse RA. Late results of vertical banded gastroplasty for morbid obesity. Surgery 1990; 107:20–27. 39. Yale CE, Weiler SJ. Weight control after vertical banded gastroplasty for morbid obesity. Am J Surg 1991; 162:13–18. 40. Rheinhold RB. Critical analysis of long-term weight loss following gastric bypass. Surg Gynecol Obstet 1982; 155:385–393. 41. Brolin RE, Kenler HA, Gorman RC, et al. The dilemma of outcome assessment after operations for morbid obesity. Surgery 1989; 105:337–346. 42. Brolin RE. Critical analysis of results: weight loss and quality of data. Am J Clin Nutr 1992; 55:577S–581S. 43. Sugarmen HJ, Kellum JM, Engle KM, et al. Gastric bypass for treating severe obesity. Am J Clin Nutr 1992; 55:560S–566S. 44. Hall JC, Watts JM, O’Brien PE, et al. Gastric surgery for morbid obesity. The Adelaide Study. Ann Surg 1990; 211:419–427. 45. Freeman JB, Burchett HJ. A comparison of gastric bypass and gastroplasty for morbid obesity. Surgery 1980; 88:433–444. 46. Laws HL, Piantadosi S. Superior gastric reduction procedure for morbid obesity. A prospective randomized trial. Ann Surg 1998; 192:334–336. 47. Pories WJ, Flickinger EG, Meelheim D, et al. The effectiveness of gastric bypass over gastric partition in morbid obesity. Consequences of distal gastric and duodenal exclusion. Ann Surg 1983; 196:389–399. 48. MacLean LD, Rhode BM, Forse RA, et al. A gastroplasty that avoids stapling in continuity. Surgery 1993; 113:380–388. 49. MacLean LD, Rhode BM, Samalis J, et al. Results of surgical treatment of obesity. Am J Surg 1993;165:155–162. 50. MacLean LD, Rhode B, Forse RA. Late results of vertical banded gastroplasty for morbid obesity. Surgery 1990; 107:20–27.

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51. Halverson JD. Metabolic risk of obesity surgery and long-term follow up. Am J Clin Nutr 1992; 55:602S–605S. 52. Amaral JF., Thompson WE, Caldwell MD, et al. Prospective hematologic evaluation of gastric exclusion surgery for morbid obesity. Ann Surg 1985; 201:186–193. 53. Halverson JD. Micronutrient deficiencies after gastric bypass for morbid obesity. Ann Surg 1986; 52:594–598. 54. Schilling RD, Goltdes PN, Hardie GH. Vitamin B 12 deficiency after gastric bypass surgery. Ann Intern Med 1984; 101:501–502. 55. Crowley LV, Olson RW. Megaloblastic anemia after gastric bypasss for obesity. Am J Gastroenterol 1983; 78:406–410. 56. Crowley LV, Seay J. Mullin G. Late effects of gastric bypass for obesity. Am J Gastroenterol 1984; 79:850–860. 57. Golner BB, Reinhold RB, Reinhold RB, Jacob A, et al. The short- and long-term effect of gastric partitioning surgery on serum protein levels. J. Am Coll Nutr 1987;6:279–285. 58. Printen KJ, Halverson JD. Hemic micronutrients following vertical banded gastroplasty. Am Surg 1988; 54:267–268. 59. Feit, H, Glasberg M, Ireton C, et al. Peripheral neuropathy and starvation after gastric partitioning for morbid obesity. Ann Intern Med 1982; 96:453–455. 60. Haid RW, Guttmann L, Crosby TW. Wernicke–Korsakoff encephalopathy after gastric plication. JAMA 1982;247:2566–2567. 61. Abranel JM, Berginer VM, Asmani A, et al. Neurologic complications after gastric restriction surgery for morbid obesity. Neurology 1987; 37:196–200. 62. Griffen WO, Young VL, Stevenson CC. A prospective comparison of gastric and jejunoileal bypass procedures for morbid obesity. Ann Surg 1977; 186:501–509. 63. Scarpa E, Negri M, Halpern Z, et al. Endoscopic diagnosis and management of complications after vertical banding gastroplasty. Endoscopy 1988; 201:11–12. 64. Brolin RE. Healing of the stapled stomach in bariatric operations. Surgery 1993; 113:484–490. 65. Schwartz R, Simpson W, Strodel WE, Simpson WS, Griffen WO Jr. Gastric bypass revisions: lessons learned from 920 cases. Surgery 1988; 104:806–812. 66. Pories WJ, MacDonald KG, Morgan EJ, et al. Surgical treatment of obesity and its effects on diabetes: 10 year follow up. Am J Clin Nutr 1992; 55:582S–585S. 67. Pories WJ, MacDonald K, Flickinger EG, et al. Is type II diabetes mellitus (NIDDM) a surgical disease? Ann Surg 1992; 215:633–643. 68. Foley EF, Benotti PN, Borlase B, et al. Impact of gastric restrictive surgery on hypertension in the morbidly obese. Am J Surg 1992; 163:294–297. 69. Carson JL, Ruddy ME, Duff AE, et al. The effect of gastric bypass surgery on hypertension in morbidly obese patients. Arch Intern Med 1994; 154:193–200. 70. Alpert MA, Amolak S, Terry BE, et al. Effect of weight loss on cardiac chamber size, wall thickness and left ventricular function in morbid obesity. Am J Cardiol 1985; 55:783–786. 71. Alaud-Din A, Meterissan S, Lisbona R, et al. Assessment of cardiac function in patients who were morbidly obese. Surgery 1990; 108:809–820. 72. Benotti PN, Bistrian B., Benotti JR, et al. Heart disease and hypertension in severe obesity: the benefits of weight reduction. Am J Clin Nutr 1992; 55:586S–590S. 73. Gleysteen JJ, Barbariak JJ. Improvement in heart disease risk factors after gastric bypass. Arch Surg 1983; 118:681–684. 74. Gleysteen JJ, Barboriak JJ, Sasse EA. Sustained coronary-risk factor reduction after gastric bypass for morbid obesity. Am J Clin Nutr 1990; 51:774–778. 75. Charuzi I, Paretz L, Peiser J, et al. Bariatric surgery in morbidity obese sleep apnea patients: short- and long-term follow up. Am J Clin Nutr 1992; 55:594S–596S. 76. Sugerman HJ, Fairman RP, Sood RK, et al. Long-term effects of gastric surgery for treating respiratory insufficiency of obesity. Am J Clin Nutr 1992; 55:597S–601S. 77. Sugerman HJ, Fairman RP, Baron PL, et al. Gastric surgery for respiratory insufficiency of obesity. Chest 1986; 90:81–86. 78. Charuzi I, Ovnat A. Peiser J, et al. The effect of surgical weight reduction on sleep quality in obesityrelated sleep apnea syndrome. Surgery 1985; 95:535–538. 79. Sugerman HJ, Baron PL, Fairman RP, et al. Hemodynamic dysfunction in obesity hypoventilation syndrome and the effects of treatment with surgically induced weight loss. Ann Surg 1988; 207:604–613. 80. Sjostrom L, Larsson B, Backman L, et al. Swedish obese subjects (SOS). Recruitment for an intervention study and a selected description of the obese state. Int J Obes 1992; 16:465–479.

Chapter 20 / Treating Obesity in the Physician’s Office

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Treating Obesity in the Physician’s Office David J. Goldstein, Ronald S. Rogers, Richard A. Lutes, and Roy C. Blank

OVERVIEW—DAVID J. GOLDSTEIN Disordered eating is among the most common behaviors with clinical consequence seen in developed countries. In addition, the prevalence of the established eating disorders (i.e., bulimia nervosa and anorexia nervosa) and obesity is increasing. The factors which may contribute to the increase in vulnerability to disordered eating and thus contribute to this increase in prevalence include improvements in food availability, increasing societal pressure toward restrained eating and fat avoidance, and individual genetic susceptibility. One additional feature the eating disorders have in common is multimodal therapy (Table 1). The initial steps in this therapy are thorough medical and dietary assessments, often coupled with behavioral psychotherapy or other behavioral intervention. When this is insufficient, pharmacologic therapy, often with serotonergic agents, may also be employed.

1. GROUP SUSCEPTIBILITY RELATED TO FOOD VARIETY, AVAILABILITY, AND PREOCCUPATION—THRIFTY GENE HYPOTHESIS Although food variety, availability, and preoccupation is increasing, society is placing increased emphasis on leanness as an ideal. In developed countries, food, particularly high-fat food, is abundant and inexpensive. If we consider the possible evolutionary advantage of primitive human’s storage of energy as fat for enhancing survival, then a preference for calorically dense foods would be a particularly advantageous characteristic to possess during seasons of scarce food and periods of famine. An individual with surplus fat stores would presumably be more likely to survive than others who lacked this attribute. It is theoretically attractive to propose that such evolutionary traits persist in modern humans as a taste preference for high-fat foods, despite changed environmental circumstances. In other words, this food preference is no longer necessary for survival, since periods of starvation rarely serve as a correcting mechanism to reduce weight in the developed world. This is not unlike similar evolutionary (or thrifty gene) hypotheses (1) developed to explain the salt-sparing metabolism resulting in hypertension (2–4), or the From: The Management of Eating Disorders and Obesity Edited by: D. J. Goldstein © Humana Press Inc., Totowa, NJ

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Table 1 Chapter Overview 1. Overview—David J. Goldstein 1.1. Group Susceptibility Related to Food Variety, Availability, and Preoccupation —Thrifty Gene Hypothesis 1.2. Restraint of Food Intake 1.3. Underlying Individual Susceptibility 2. Patient Perspectives of Obesity Treatment—Ron Rogers 2.1. Introduction 2.2. Obese Patient-Health Care Provider Relationship 2.3. Patient Perspectives 3. Clinical Experience in the Primary Physician's Office I: Use of Combination Therapy —Richard A. Lutes 4. Clinical Experience in the Primary Physician's Office II: Use of Combination Therapy —Roy C. Blank 4.1. Introduction 4.2. The Program 4.3. Case History 4.4. Treatment Program and Clinical Course 4.5. Summary 5. Maximizing the Benefits of Pharmacologic Therapy—David J. Goldstein 5.1. Introduction 5.2. When and How Should Treatment Be Initiated? 5.3. Monitoring Treatment 5.4. Maintenance and Renewal

predisposition toward non-insulin-dependent diabetes mellitus (5,6) or other modern diseases which are thought to be more rare historically (7). Because of a preference for high-fat foods and because these are typically the least expensive and most abundant foods in our culture, lower socioeconomic groups are especially susceptible to obesity. Indeed, the epidemiology of obesity in the United States would support this view. In addition, wide varieties of foods are readily available due to improvements in food preservation such as canning, freezing, or freeze drying and to rapid transportation of foods which once would only have been available seasonally in limited geographic areas. This increased availability and selection of food as well as advertising has focused our attention on food taste rather than survival as a motivator of intake. The great number of food purveyors, the popularity of recipe books, and a shift toward the use of food as a form of social entertainment attests to this change in focus. All of these factors encourage increased food intake. At the same time, the advent of industrialized society has resulted in a reduction in activity level. We drive rather than walk, and increasing numbers of us have sedentary work settings. At the same time, society increasingly emphasizes lean muscularity or frank thinness as the optimal ideal for physically attractiveness. This is particularly true for women who are objectified in media with this physique. Thus, although women have become, on average, heavier, the idealized shape preference as evidenced by Playboy centerfold and beauty pageant contestant measurements has become more slender (8). A similar trend is occurring for males who are increasingly portrayed as very lean but heavily muscled.


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2. RESTRAINT OF FOOD INTAKE A conflict between appetite and image has developed. Relatively few individuals are able to biologically regulate their food ingestion to maintain an optimal ideal weight, although this does occur in a small subset of the population. Others are able to regulate their ingestion through the use of regular dietary restraint (9). These individuals have learned what they can eat to maintain their weight and consciously exert continuous dietary restraint to attain this goal (9). These habitual dieters have established a life-style which permits them to maintain their goal weight. I hypothesize that for these individuals their goal weight is not at great divergence from the weight they would attain if they did not exert such restraint. This does not preclude the possibility that many of these individuals have disordered eating due to improper food choices. Most who are obese attempt to control weight with frequent on again–off again dieting and attempt to restrain from overeating, but periodically lose control. Indeed, recent data suggest that some individuals periodically binge eat (binge-eating disorder). Others compensate by increasing their exercise levels to accommodate their increased intake.

3. UNDERLYING INDIVIDUAL SUSCEPTIBILITY Finally, others who have difficulty accepting their real or perceived overweight have a propensity for the development of learned behaviors designed to control their weight (10). Individuals with bulimia nervosa often attempt to restrain their ingestion of food, but periodically lose control. At these times, they rapidly ingest large quantities of food (binge eating). Subsequently, they may “compensate” for their binge eating through the use of purging strategies, such as the use of vomiting, laxatives, diuretics, and exercise to forestall the effects of the binge. Individuals with anorexia nervosa have a distorted perception of their body image, resulting in the fixed belief that they are overweight even when emaciated. They substantially restrain their intake and may also use purging behaviors to further reduce their caloric intake. The disordered eating by these groups not only involves alteration of total caloric intake but also the development of disrupted food preference patterns (9,11). Many of these patients have limited food choices, eat unusual combinations of foods, and may also have other unusual eating habits. Ultimately, this leads to nutritional disturbances (12) which may further exacerbate the eating disorder. Early identification of patients at risk for eating disorders would be especially beneficial so that early intervention may help prevent the full development of these conditions before they are more resistant to therapy (13). It has been suggested that all of these patient groups may have a metabolic susceptibility which predisposes to the development of their eating disorder. As a common intermediate, disorders of serotonin neurotransmission appear to influence these conditions and their comorbidities (14–16). As might therefore be predicted, serotonergic agents have been shown to exert positive effects on the clinical course of these eating disorders. This does not necessarily imply that disorders of serotonin metabolism are primary because these agents do not invariably and permanently correct the conditions. Alternatively, pharmacotherapy may correct the underlying propensity, but may not be able to reverse the developed behaviors. Patients with these disorders may have developed disordered eating behaviors to compensate for the underlying metabolic defect. At times, these compensatory behaviors, although possibly beneficial in the short term, may,

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in the longer-term, exacerbate the metabolic process involved, further disrupting the eating behaviors. Behavioral intervention may therefore improve the condition, but may or may not correct the underlying biology propensity. To get closer to the metabolic cause of the eating disorders, we need to understand more about the sequencing of the behaviors that result in these disorders. For the present, a balanced multifactorial approach continues to offer the greatest benefit.

REFERENCES 1. Rett K, Wiclmayr M, Mehnert H. What is the clinical significance of insulin resistance. J Cardiovasc Pharmacol 1992; 20:S22–S26. 2. Wilson TW, Grim CE. Biohistory of slavery and blood pressure differences in blacks today. A hypothesis. Hypertension 1991; 17:I122–I128. 3. Blaustein MP, Grim CE. The pathogenesis of hypertension: black-white differences. Cardiovasc Clin 1991; 21:97–114. 4. Weder AB, Schork NJ. Adaptation, allometry, and hypertension. Hypertension. 1994; 24:145–156. 5. Turner RC, Levy JC, Clark A. Complex genetics of type 2 diabetes: thrifty genes and previously neutral polymorphisms. Q J Med 1993; 86:413–417. 6. Wendorf M. Archaeology and the “thrifty” non insulin dependent diabetes mellitus (NIDDM) genotype. Adv Perit Dial 1992; 8:201–207. 7. Brown G, Nesse R. Evolutionary Concepts in Medicine. 8. Garner DM, Garfinkel PE, Schwartz D, Thompson M. Cultural expectations of thinness in women. Psychological Reports 1980; 47:483–491. 9. Hetherington MM, Rolls BJ. Eating behavior in eating disorders: response to preloads. Physiol Behav 1991; 50:101–108. 10. Zerbe KJ. Anorexia nervosa and bulimia nervosa. When the pursuit of bodily “perfection” becomes a killer. Postgrad Med 1996;99:167–169. 11. Rolls BJ, Andersen AE, Moran TH, McNelis AL, Baier HC, Fedoroff IC. Food intake, hunger and satiety after preloads in women with eating disorders. Am J Clin Nutr 1992; 55:1093–1103. 12. Rock CL, Vasantharajan S. Vitamin status of eating disorder patients: relationship to clinical indices and effect of treatment. Int J Eat Disord 1995; 18:257–262. 13. Kreipe RE. Eating disorders among children and adolescents. Pediatr Rev 1995; 16:370–379. 14. Jimerson DC, Lesem MD, Kaye WH, Hegg AP, Brewerton TD. Eating disorders and depression: is there a serotonin connection? Bio Psychiatry 1990; 28:443–454. 15. Leibowitz SF. The role of serotonin in eating disorders. Drugs 1990; 39:33–48. 16. Jimerson DC, Lesem MD, Hegg AP, Brewerton TD. Serotonin in human eating disorders. Ann N Y Acad Sci 1990; 600:532–544.

PATIENT PERSPECTIVES OF OBESITY TREATMENT—RON ROGERS I’m fat, but I’m thin inside. Has it ever struck you that there’s a thin man inside every fat man, just as they say there’s a statue inside every block of stone? George Orwell, Coming Up for Air, 1939.

As Orwell suggests, many obese people seek to find the thin person inside their metaphorical block of stone. Obese patients often consult health care providers to help them achieve their weight-loss goals. To maximize obesity treatment, the health care professional must seek to understand their patient’s prior experiences, interests, and needs. In short, the health care provider must understand the patient’s perspective. The purpose of this section is to introduce the obese patient’s viewpoint.

1. INTRODUCTION Today in the United States, 66% of adults aged 20 yr and older, and 25% of children and adolescents in the United States suffer from obesity. The economic and health con-


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Table 1 Labels Associated with Fat Phobia Label Fat people have poor hygiene. Fat people are undisciplined. Fat people have emotional problems. Fat people are stupid.

Components Smell bad, sweaty, dirty, sloppy Pitiful, no self-control, no willpower, over-eat, inactive, disgusting, unambitious, unattractive Insecure, depressed, low self-esteem, miserable, moody Not artistic, uncreative, stupid, unitelligent

sequences of this phenomenon are staggering. In the United States the cost of obesity exceeds $100 billion (1). Moreover, obesity is linked to 300,000 deaths annually (1). At the same time, “American medicine is evolving to refocus health care providers’ regard for the patient’s viewpoint (2).” This professional evolution involves a dynamic shift from provider-centered care to patient-centered care. In the provider-centered paradigm, the provider fears turning over control to the patients because they lack the knowledge or desire to manage their own health care. In the provider-centered paradigm, patients often view health care providers as parental figures. Although this approach may work for some patients, most patients view this “do as I say” attitude as unlikely to promote understanding and trust. In the patient-centered paradigm, the physician shares control of the patient’s medical care. Health care providers who treat obesity should shift to the patient-centered paradigm because once a patient has a bad experience with a provider, he or she is likely to avoid professional health care for obesity and is more likely to enroll in do-it-yourself programs (e.g., Overeaters Anonymous) or nonclinical programs (Weight Watchers©). Although these programs may work for the mildly obese, they are often ineffective for the severely obese patient who is at high risk for obesity-related morbidity and mortality.

2. OBESE PATIENT–HEALTH CARE PROVIDER RELATIONSHIP Obese patients want doctors to understand their experiences with existing treatments, to accept new ideas, and to involve them in decision making. Health care providers often focus on the physical aspect of medical care, spending little time on the person. Moreover, providers are often uncomfortable managing the personal aspects of obesity and are sometimes uncomfortable with the patients themselves. This phenomenon is know as fat phobia. Fat phobia is a pathological fear of fatness often manifested as negative attitude and stereotypes about fat people (3). Fat phobia occurs when patients are labeled based on their size alone. Labels that are often unnecessarily assigned to obese people because of fat phobia are listed in Table 1. Among health care workers, fat phobia is not atypical as the health care providers’ views of obesity often mirror the views of the lay public; that is, health care providers believe that obesity is due to willful misconduct—eating too much and exercising too little (3). The net effect of these views is that obese people are discriminated against in receiving appropriate treatment of their disease. As with any chronic illness, obesity involves all aspects of the person, not merely the body. When coming in for office visits, obese patients commonly bring a history of unhappy experiences with health care providers. Health care providers should listen to understand these experiences before developing a treatment strategy. By attempting to

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first understand the patient concerns, the provider creates a therapeutic alliance with the patient. Consider the following scenarios. Scenario 1. Joan is 5 ft. 4 in., weighs 300 lb., and is 30-yr-old. She walks into her doctor’s office for a routine visit. As she enters the waiting area, she notices that none of the chairs are large enough for her to sit in comfortably, so she stands. A nurse leads Joan to an empty examining room. Inside, the nurse struggles to place a blood pressure cuff that is obviously too small around Joan’s arm, making her uncomfortable. Then, the nurse instructs Joan to step onto the scale. Joan politely refuses to comply with the nurses’ request. The nurse curtly replies that she’s under orders to measure her weight and again tells Joan to step on the scale. Joan asks the nurse if it’s necessary, and the nurse replies, “I’ll ask the questions.” Scenario 2. As a preteen, Renée was treated with amphetamines and low-calorie diets. One doctor visit resulted in Renee taking 15 amphetamine pills per day. When she complained of nausea and headaches, the doctor told her that she had an ulcer and discontinued the medication. As a teenager, Renée suffered from verbal, mental, and physical abuse by schoolmates and family, stemming from her obesity. She attended diet group meetings such as Overeaters Anonymous and Weight Watchers but saw little benefit. As an adult, Renée considers each tomorrow worse than today—bringing increased mental and physical abuse—but she never sees tomorrow as the start of better times. Situations like Joan’s and Renée’s occur too often and effectively alienate obese patients from seeking professional health care.

3. PATIENT PERSPECTIVES The following question was posted on several obesity-related support groups such as the one labeled alt.obesity.support on the Internet. “If you could teach doctors anything about treating obese patients, what would you teach them (4)?” These support groups were created by obese people and for obese people to exchange information about all aspects of obesity. Table 2 lists some responses to the above question. It is evident from the comments in Table 2 that obese patients perceive fat phobia among health care providers. For example, several of the responses refer to patients being criticized for their weight; others refer to experiences where health care providers did not have equipment that is properly sized for obese patients. The above comments reflect several patient perspectives and serve as reality links to patients’ wants and needs. To effectively implement a patient-centered health care paradigm providers’ attitudes should be congruent with patients’ wants, needs, and preferences (4).

4. IMPROVING OBESITY TREATMENT Health care providers should provide obese patients with consistent care, be honest, and provide information that is easy to understand. Moreover, the success of weighttreatment programs should be based on patients’ overall health rather than by their effects on weight-loss alone (4). Table 3 provides some specific suggestions for improving the patient-provider relationship. Table 3 is not an exhaustive list of treatment improvements, but is designed to nudge the provider toward the patient-centered health care paradigm. In fact, implementing patient-centered health care offers providers a unique opportunity to develop innovative methods for improving obesity treatment.


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Table 2. Comments from Patients on Internet Obesity Support Groups in 1996 I don’t think doctors have a clue how to deal with us. Medical intervention fails almost all the time and doctors don’t like to fail, so they usually either don’t treat us or tell us to go on a diet. They know that won’t work but that makes us the failures, not them, in their eyes.—M.A. Do not worry about your patients’ weight, care about their health!—E.J. We DO need chairs/tables that are comfortable in the waiting and examining rooms. We DO need personnel who are respectful. We DO need examining gowns that fit accordingly. We DO need tact, respect, care, and for Gods sake, a little humor about things, once in a while. NOT to be treated like slabs of meat.—T.D. Don’t always lecture [obese patients] on their weight. Obese patients are very aware of the condition, and criticism and negative comments from a doctor do not help. Also, have the larger size blood pressure cuffs available and using them without comment is needed. Makes the obese patient feel the doctor is prepared to treat them as they are.—Nemmy Obesity is not a character flaw of weakness, it is a medical condition. Don’t patronize or condescend to your patients. Respect their intelligence and give them enough information to allow them to make informed choice about their health care. If you plan to treat obesity, please, please, please familiarize yourself with recent developments and new paradigms in the field. Don’t assume that one treatment will work for everyone, monitor your patient’s progress on any regimen and adjust as necessary. Low fat; low carbohydrate; moderate fat, carbohydrate and protein; protein sparing modified fast; they all have their place, but will not all work on everyone. If you don’t have time to research them all yourself, hook up with a good, knowledgeable, open-minded dietitian.—J.S. When a patient first comes to you, ask whether they wish to be treated for obesity. If they say no, do not push. If weight is related to problems they present, tell them so, but treat the problems as you would treat them in a thin person. Do not push weight loss as a treatment unless they want it. Do not dispense unsafe and ineffective treatments. Know the medical research on obesity, including research that shows 95% of people who lose weight gain it all back, losing weight rapidly is dangerous, obesity per se is not bad for your health, and that there is no proof that losing weight (as opposed to being naturally thin) improves your health long-term.—S.J. Treat overweight patients just as you would any other patient. If your patient is happy at their present weight, don’t insist they lose weight.—M.T.

CONCLUSION The goal of this chapter is to provide insight into the obese patient’s perspective of professional health care and to recommend some methods for improving the obese patient-health care provider relationship. Fundamental to improving this relationship is acquiring the motivation to understand the patient before prescribing treatment and avoiding fat-phobic prejudices. Consider the whole individual and do not measure success based only on net weightloss but rather the patient’s overall health. Additionally, equip waiting and examining rooms with chairs and diagnostic tools designed to accommodate the obese patient. Other chapters of this book will address medical interventions and technological advancements for treating obesity. Although these interventions are important medical tools, nothing will promote a stronger patient-provider alliance and sense of trust than understanding the patients’ perspectives.

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Part III / Treatment Table 3. Practical Suggestions for Improving Obesity Treatment 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

Provide chairs in the waiting room to accommodate large-size individuals. Have adequate sized hospital gowns. Have large blood pressure cuffs. Provide truthful, unambiguous and balanced information. Do not make the patient feel guilty. Consider the patient’s wishes and seek feedback. Treat health first and obesity second. Provide sufficient information and clarify expectations of treatment for obesity. Help patients identify weight-loss goals. Listen actively and empathetically.

REFERENCES 1. Stern JS, Thomas PR. 1995. A commentary on weighing the options: criteria for evaluating weightmanagement programs. Obes Res 1995; 3(6):589–590. 2. Laine C, Davidoff F. 1996. Patient-Centered Medicine. JAMA 1996; 275(2):152–156. 3. Robinson BE, Bacon JG, O’Reilly J. 1993. Fat phobia: Measuring, understanding, and changing antifat attitudes. International Journal of Eating Disorders 14(4): 467-80. 4. Rogers RS, Goldstein DJ. 1996. Obese Patient Perspective Questionnaire posted on the Internet.

CLINICAL EXPERIENCE OF OBESITY TREATMENT IN A PRIMARY CARE PHYSICIAN’S OFFICE—RICHARD A. LUTES The following case history illustrates the dilemma of the primary care physician when presented with the “diabesity” syndrome (1).

1. INTRODUCTION Mary S. is a 62-yr-old black female accompanied by her slim 60-yr-old husband, Jim, to their first office visit with me. Her chief complaints are “change in insurance and needs med refills.” Mary is 68 in. tall and weighs 308 lb. Jim has uncomplicated hypertension and wants a refill of nifidepine. Mary has diabetes, leg and back pain, swelling in her legs, morning headaches, shortness of breath, wheezing at night, and fatigue. Her husband reports that she snores loudly and stops breathing at night. Her medications include humulin N insulin 50 U twice per day, amitryptiline 50 mg at bedtime for leg pain and daily morning headaches, propranolol LA 80 mg per day and hydrochlothiazide 25 mg every morning for hypertension, ibuprofen 600 mg four times daily for pain, and glyburide 10 mg every morning for diabetes. She also takes an overthe-counter inhaler for wheezing and has been on prednisone several times for “bad asthma attacks.” She has gained 60 lb. since she quit smoking and started insulin shots 2 yr ago. She wants help to lose weight. She “can’t get around anymore.” She asks for samples because of financial difficulties.

Obesity is a killer disease (2). Hippocrates taught that corpulence is not only a disease but a harbinger of others. Gordon and Kannel analyzed the Framingham data and wrote that physicians should treat obesity promptly when it appears with the sense of urgency seen when a patient presents with a lump in the breast (3). Consensus guidelines advise


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primary care physicians to screen patients for excessive weight as part of the periodic health evaluation (4–6). The diabesity syndrome is characterized by hypertension, non-insulin-dependent diabetes, dyslipidemia, upper-body obesity, and atherosclerotic cardiovascular disease, also known as syndrome X, discussed in Chapter 10. The treatment of diabesity frustrates many primary care physicians (7). The paradox of two patients sharing the same environment but with dichotomous body somatotypes is intriguing because it suggests differences in genetic backgrounds.

2. WHY ISN’T OBESITY URGENTLY TREATED? Obesity is not urgently treated by primary care physicians for numerous reasons (see Chapter 12). Many insurance companies do not reimburse physicians for obesity treatment. Some physicians have viewed obesity as a social problem or as a moral failing of their patients (8). Surveys of physicians identify a notable number of physicians who have stereotypical or negative attitudes toward obese patients (9,10). Many physicians are frustrated by the lack of treatment success and are unmotivated to address weight concerns (11) or choose to ignore obesity (12). Obesity treatment has even been suggested as harmful to patients (13). Fearful of possible negative effects of obesity treatment, some physicians discourage dieting or other weight loss attempts. Although obesity has been classified as a chronic disease by the National Institutes of Health in 1985, it currently allocates only about $0.50 per obese patient in the United States for research to fight this epidemic (14). Obese patients often require more care, are harder to examine, have more difficult veins to access, and probably have more office visits than leaner counterparts their age. Obesity remains a daunting task for the primary care physician to treat because there are no long-term cures. Obesity is a chronic disease that needs continuity of care like other chronic diseases (15). The primary care physician is in the optimal position to initiate treatment of obesity and to facilitate long-term follow-up care. Weight control is the cornerstone of treatment for many diseases in medicine, yet there are no reported controlled studies investigating weight loss on a low-calorie diet through a primary care doctor’s office (16).

3. PATIENT VIEWPOINT Many obese patients suffer low self-esteem and decreased quality of life (17). Rand showed that many former morbidly obese patients, who were successfully maintained for 3 yr after obesity surgery, would rather have a major handicap such as blindness, deafness, or be an amputee than be obese again (18). Moreover, none of these patients would rather have a million dollars than reclaim obesity. Many obese people perceive discrimination (19). The doctor is often viewed as a benevolent, wise authority figure who is there to help. The doctor must empathize with the difficulty the patient has in maintaining a lower body weight than may be genetically feasible. The patient arrives seeking help and expecting help. The doctor’s duty is to help the patient problem solve. The patient should understand that he or she will not be abandoned regardless of treatment results.

4. THE “TEACHABLE” MOMENT The doctor should be alert for the teachable moments when a patient may be motivated to attempt weight loss. These may include when a close family member has developed

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a significant medical problem such as diabetes, stroke, or heart attack. Other teachable moments include sick office visits for obesity-related disabling illnesses such as knee pain, low back pain, or new-onset diabesity. The primary care physician should be empathetic and understand the emotional pain of the clinically severe obese patient. At the first follow-up visit, Mary asked me for help in trying to lose weight. She has seen a dietitian several times but has only lost 20 lb. Mary curtails activity because of fatigue. She is always hungry. She usually skips breakfast. She wonders if her metabolism is slow. She has a hard time avoiding sweets because they make her mood better. She cooks for her husband who eats the same food she does. He can eat ice cream every night and not gain weight. She does not want to deprive him but has a hard time resisting temptation. She poignantly tells me it is not fair that she has had to struggle all her life with weight control, and Jim can eat anything he wants.

During a routine office visit a doctor can initiate a discussion about weight concerns. Primary care physicians will find patients in varying stages of motivation regarding implementing healthier life styles. These stages of change include precontemplation, contemplation, preparation, action, and maintainance (20). Only a small percentage of patients at risk are prepared to take action on their problem behaviors.

4.1. Assessing Readiness and Motivation Questionnaires such as the Diet Readiness Test, the General Well Being Schedule, and other assessment instruments (21) can be used to assess motivation and readiness for action toward changing life-style modifications. Also, case-finding instruments such as the Beck or Zung depression inventories may be used to diagnose concurrent psychological conditions that may affect weight therapy. Binge-eating disorders can be screened by using the Questionnaire on Eating and Weight Patterns—Revised (22). A history of sexual, emotional, or physical abuse may also contribute to weight problems.

4.2. Understanding the Patient Patients fill out a detailed obesity evaluation questionnaire that asks about weight at certain ages or at life milestones such as marriage, graduation, and childbirth. Activity patterns, meal-eating patterns, emotional factors, and perceived family support are evaluated. The patient completes these questionaires prior to the physician seeing the patient so that the physician can more efficiently address weight problems and stay on schedule. I reviewed Mary’s lab tests from recently obtained records. She had a total cholesterol of 264 mg/dL, high-density lipoprotein (HDL) cholesterol of 28 mg/dL, fasting triglycerides of 350 mg/dL, and a calculated low-density lipoprotein (LDL) cholesterol of 166 mg/dL. Hepatic tests included a GGT twice normal, alkaline phosphatase twice normal, AST twice normal, ALT three times normal, and a LDH that was slightly elevated. Serum creatinine was 1.0 mg/dL, serum glucose was 180 mg/dL, and there was no proteinuria by dipstick.

Evaluate obesity-associated disease symptoms (see Chapter 9) by asking a review of systems, and obtain routine lab work to evaluate common comorbid problems like hypothyroidism, hyperlipidemia, nonalcoholic steatohepatitis (23), and diabetes. Perform an overnight dexamethasone suppression test if Cushing’s syndrome is suspected. Prescribe 1 mg


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of dexamethasone for the patient to take at 11 P.M. and draw a plasma cortisol level the next morning at 8 A.M. A cortisol level less than 5 essentially rules out hypercortisolism (24). On physical examination Mary gets on the exam table with some difficulty due to pain in her hips and back. She has fairly large hands with some furrowing of skin on her knuckles. Neck exam reveals no thyromegaly or jugular venous distention, but the posterolateral neck folds have a discernible hyperpigmentation that is also present in the axillary folds. There is mild pitting edema of the legs and ankles. Mary has decreased lumbosacral range of motion and decreased sensation of her feet with absent ankle deep tendon reflexes bilaterally. The remainder of the physical examination is unremarkable or compromised by adipose tissue.

The physical examination is usually unrevealing, but targeted findings specifically sought for include the enlarged parotid glands, fine lanugo hair, yellow skin, and dental erosions seen in binge-eating disorder. Look for a high arched palate and uvular hypertrophy seen in sleep apnea, and search for hirsuitism and acanthosis nigricans often seen in the insulin-resistance syndromes (25). Obesity is associated with a higher incidence of cancers, but the excess fat makes physical examination of palpable masses difficult. Look for common comorbid disease physical examination manifestations such as signs of congestive heart failure, diabetes, skin infections, and target organ damage secondary to hypertension. I rarely find a palpable goiter contributing to obesity. Although hepatic steatosis is common, I rarely find enlargement of the liver on physical examination. The primary care physician should assess visceral fat stores that are linked to dangerous cardiovascular risk factors. A family physician group in Ohio recently reported visceral fat obesity is underdiagnosed by conventional body-mass index (weight in kilograms divided by meters squared) measurements (26). Recent reports suggest that visceral fat obesity can be easily assessed by measuring the waist circumference midway between the lowest rib and the iliac crest (27). The abdominal sagittal diameter measured by computer tomography (CT) scan correlates well with visceral fat obesity (28). Lars Sjostrom has described a technique of having patients lie supine with a carpenter’s level placed on the abdomen at the iliac crest (29). The sagittal diameter is measured as the distance from table to the horizontal level after a normal breath expiration. These easily performed office measurements have better correlation with visceral fat obesity than more commonly recommended measurements such as body-mass index or waist-hip ratio (30). However, some insurance companies request body-mass index values and percentage of ideal body weight to determine coverage for weight management programs. Significant risks increase with a waist circumference >102 cm (40 in.) in a man or greater than 88 cm (35.6 in.) in a woman. An abdominal sagittal diameter greater than 25 cm (10 in.) is more likely associated with atherogenic metabolic disturbances in the aforecited studies. It is likely that the most practical assessment for busy primary care physicians is the waist circumference.

5. LEVELS OF CARE The level of the primary care physician’s involvement in treatment of obesity varies. Levels of involvement can be defined. Level 1 treatment consists of case finding with minimal dietary advice. Level 2 care includes case finding, limited assessment, and referral to dietitians or self-help groups such as Weight Watchers or TOPS (Take Off

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Pounds Sensibly). Level 3 treatment is defined as case finding, limited assessment, and initiation of treatment in the doctor’s office. This may include dietary counseling by office staff, coordination of treatment plans with other health professionals such as dietitians or psychologists, and scheduled follow-up office visits to ascertain treatment results. Level 4 care includes case finding, nutritional assessment including anthropometric measurements, in-office dietary counseling, and initiating behavior modification techniques. The primary care physician promotes exercise and schedules frequent follow-up office visits to monitor therapies. The doctor will probably use patient self-monitoring records such as food and exercise diaries. The doctor will feel comfortable in helping the patient problem solve some difficulties of weight management. The primary care physician may enlist the involvement of other family members. Level 5 care involves a lot of commitment by the primary care physician and office staff. A comprehensive program for the treatment of obesity consists of dietary counseling, behavior modification techniques, exercise prescription, and frequent follow-up office visits. Group sessions make level 5 care more feasible economically. Special dietary approaches such as the use of very-low-calorie diets may be used. This level of treatment may use a variety of health care professionals including dietitians, physicians, exercise physiologists, psychologists, and an empathetic office staff. Most level five treatment programs currently are hospital based because of the quantity and intensity of services required. I record obesity on the periodic health evaluation record as a chronic disease problem. This implies that obesity be addressed at sick visits as with other chronic problems. Primary care physicians can follow weights, body-mass indices, and waist circumferences on flowcharts. This may involve labeling the patient as ill when they may feel well. Labeling patients with hyperlipidemia has not been found to be harmful (31). Having obesity on the chronic problem list allows me to address long-term control at periodic office visits as a goal even if cure cannot be achieved. Even modest weight losses that are maintained can have significant health benefits (32). Long-term continuity of care can help decrease the morbidity of chronic stable disease (33). The concept of medical nutritional therapy has been recently advocated by the American Diabetes Association (34). The physician serves as leader of the medical nutritional therapy team. The previous concepts of American Diabetes Association exchange diets have been modified in favor of target diets based on laboratory and physiological values (35). Therefore, it is helpful to explain to patients what these target values are. I tell patients I like to get the HDL or “healthy” cholesterol as high as possible and the LDL or “lousy” cholesterol as low as possible. Target values for fasting and postprandial blood sugars are given to patients. Information about home blood pressure monitoring helps the patient look at comorbid conditions rather than absolute weight as treatment goals. I discuss the importance of abdominal fat as a risk factor for cardiovascular disease. Pateints can measure their waists and correlate weight loss with notches on their belts. This allows the doctor to monitor progress in visceral fat obesity inches lost rather than just pounds lost. Garrow has advocated giving patients a nonexpandable waist cord to monitor on a regular basis as a check on when to be remotivated to reinstate vigorous weight management measures (36). I changed Mary’s medication from propranolol to captopril. Furosemide was instituted and hydrochlorthiazide and amitrytiline were discontinued. Ibuprofen was changed to


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acetaminophen 1000 mg four times a day to decrease liver and kidney problems. Discussion with the patient regarding decreasing the insulin dosage was met with some resistance. Mary returned one month later wheezing at night and short of breath. Clinically she was in congestive heart failure. An outpatient cardiac echocardiogram was technically compromised by excessive weight but revealed hypokinesis of the inferior ventricular wall. The consulting cardiologist declined to offer cardiac catherization because of technical problems related to her heavy weight and added digoxin to her regimen. Mary returned 2 wk later stating that she had increased her insulin dosage to 80 U twice a day and her home blood glucose values are running in the 300 range. Mary is upset that she cannot control her blood sugar and complains of increasing hunger.

The primary care physician should be aware of medications that can aggravate obesity. Tricyclic antidepressant medications significantly lower metabolic rate and increase preferences for sweets (37). The selective serotonin reuptake inhibitors are better choices for treating depression in the obese patient as several studies show antiobesity effects (38). Periactin and buspirone stimulate the serotonin receptors that increase appetite and can worsen obesity (39). Beta adrenergic blockers impair glucose uptake by muscles and inhibit lipolysis (40). Lithium causes weight gain as do the neuroleptic drugs used for schizophrenia (41). Hyperandrogenic states in women cause visceral fat obesity, but paradoxically hypoandrogenic states in men are associated with visceral fat obesity (42). Therefore antiandrogen drugs like cimitidene may be obesogenic in males if used long term. Prednisone causes visceral fat obesity by inducing lipoprotein lipase activity in abdominal fat. Some medications have beneficial effects such as phenylpropanolamine (43). Alpha1 adrenergic antagonist agents such as doxazosin and prazosin increase sensitivity to insulin and favorably affect lipoproteins (44). This probably results from vasodilatation caused by alpha-1 adrenergic blockade. Pindolol may be the best beta adrenergic receptor-blocker to use in obese patients since it antagonizes the serotonin receptor which promotes feeding and has lesser effects on decreasing fat metabolism than other beta adrenergic receptor-blocking drugs. Insulin also is potentially obesogenic as it tends to make people hungry and decreases lipolysis. Reversal of glucose toxicity may require insulin to normalize glucose in type II diabetes mellitius (45). Metformin may be useful in these patients, as it decreases hepatic glucose output rather than stimulates insulin secretion (46). Acarbose has been recently introduced and may allow the primary care physician alternatives to insulin for treatment of the diabesity syndrome (47). Another approach to control glucose toxicity rapidly is to utilize a very-low-calorie diet regimen (48). I use a modified lean meats approach described by Bistrian (49). I modify this very low calorie diet approach by adding 10 oz of fruit juice and minimal calorie vegetables. Although the very-low-calorie diet regimens have been criticized in the past, research has shown them to be safer than prescribing diuretics (50). The American Dietetic Association has recommended that very-low-calorie diets only be undertaken with the supervision of a multidisciplinary health team with monitoring by a physician and nutrition counseling by a registered dietitian (51). I feel that short-term use of very-low-calorie-diets by primary care physicians comfortable with fasting physiology can be very beneficial in ameliorating the glucose toxicity of the diabesity syndrome (see Chapter 10).

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6. OBESITY TREATMENT PROGRAM 6.1. Dietary Record I initiate obesity treatment by reviewing the obesity evaluation questionnaire the patient has completed. I then ask the patient to complete a 7-d dietary record on which the patient records usual food intake, estimated amounts of food consumed, ratings of hunger, ratings of mood, and places where food is eaten. This is the first step of behavior modification. I ask the patient to eat the way they normally eat and not to go on a restricted diet. Completing the food diary helps the patient learn about food cues. Obese patients do not estimate well the amount of food they consume (52). If the patient returns the dietary record completed, I feel the patient is motivated to address lifestyle modification factors contributing to obesity. Completing the food diary often enlightens the patient about unconscious eating behaviors. Patients discover problem times of the day when hunger peaks, and I help the patient modify eating patterns. The dietary record is helpful to the dietitian if a referral is made. Some patients have access to computerized dietary programs that are very useful. Often patients find it helpful to carry small notebooks or index cards to record dietary intake contemporaneously, and then they transfer information to the permanent record at the end of the day.

6.2. Emotions and Behaviors I approach obesity similar to other common problems I face in the office. I adapt the BATHE approach to the psychobiological needs of patients that Stuart and Lieberman have promulgated (53). Background is prodded by the question, “What is going on in your life?” Affect is ascertained by “How do you feel about that?” Trouble is evaluated by the question, “What troubles you about that?” Handling is “How are you handling that?” Empathy is denoted by the statement akin to “that must be difficult for you.” I focus on the strengths and successes of the patient and encourage self-help and selfresponsibility. The primary care physician must not be judgmental when patients fail to have success. Berating a patient for failure to stick to a low-calorie diet is usually counterproductive. I focus on the behavior of the patient that is potentially correctable rather than on what the scales reflect. Long-term weight maintenance is attributed to certain behaviors (54). These include regular daily exercise that need not be aerobic but rather sustained over fairly long time periods. Self-monitoring records of diet and activity are important. Positive attitudes and absence of significant family and job problems help promote success. Regular contact with a maintenance support group was important. Frequent contact with the primary care physician may be the strongest predictor of success (55).

6.3. Continuity, Interest, Support, Availability, and Empathy Primary care physicians are in an ideal situation to treat obesity because the attributes of continuity of care and low cost are common to a primary care physician’s practice. Dietitians and established weight management programs also can provide long-term continuity of care. The key principles of continuity, interest, support, availability, and empathy are critical for success. Psychosocial stresses may need to be addressed. Many patients do well with weight management until a significant stress sabotages the treatment program. The therapist must help the patient through the crisis period and try to keep the patient on track. Kayman


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has reported that weight loss maintainers approach problem solving more directly rather than emotionally (56). Referral to mental health counselors may be beneficial in some cases, but many patients can be supported by scheduling more frequent office visits where empathetic support and counseling are given. Teaching basic problem-solving attitudes and confronting skills is within the purview of many primary care physicians.

6.4. Diet What kind of dietary advice should be given to patients? Most authorities recommend a low-fat diet that is high in fiber. Some evidence points to obesity as being more prevalent in genetically predisposed individuals who are slow fat oxidizers (57). However, genes are not always destiny. It is possible to overcome genetically disadvantaged thrifty genes by intense life style modification, but it is extraordinarily difficult in our society. Despite the total fat intake going down in our society, the incidence of obesity is climbing and total calorie consumption is increasing as more carbohydrate calories are consumed (58). Some patients have the mistaken belief that because there is minimal fat in food, they can eat unlimited quantities. The fundamental laws of thermodynamics still apply. I do not recommend just a balanced deficit diet because it can be moderate to high in fat that is potentially atherogenic for many patients. I give handouts available from various sources on nutrition label reading, high-fiber foods, and low-fat foods. I recommend books, videotapes, and magazines available in bookstores and public libraries that contain sound nutritional advice. Most patients benefit from a referral to a registered dietitian. The dietitian can work with a patient’s lifestyle and can spend more time to individualize a diet than I can typically provide. Often insurance considerations regarding reimbursement for nutritional counseling limit ideal care.

6.5. Exercise Exercise is a dirty word to some overweight patients. Obese patients often relate horror stories of lifelong clumsiness, orthopedic injuries, and ridicule because of their body size. Many are understandably self-conscious about being seen in health clubs, gyms, and swimming pools. I often substitute the word activity for exercise in my follow-up office visits with patients. This euphemism seems less threatening to many obese patients. I try to emphasize increasing daily activity and explain that all activity adds up over time. I encourage patients to incorporate sustained levels of activity into their daily lives. I explain that fidgeting burns calories at rest, and I discuss the concept of spontaneous physical activity. Many obese patients are underactive, and patients have to discover ways to expend energy in their daily activities. Exercise helps cardiovascular endurance even if no weight is lost. Losing weight is more difficult as more weight is lost because of the increased efficiency of muscle movement and the lesser energy costs of moving a lower body weight. I explain that lean body mass is proportional to metabolic rate. Musclebuilding exercises help increase lean body mass, which results in a higher metabolic rate.

6.6. Office Setting Yanovski offers the primary care physician practical approaches to the evaluation and treatment of obese patients in the office setting (59). The primary care physician’s office should be a fat-friendly place (see Chapter 20). The patient’s weight should be obtained privately and discreetly, as many patients are sensitive about this issue. Medical assis-

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tants should know how to weigh a patient who weighs more than the upper limits of the balance beam scales. This method is easily done by taping an additional weight such as scissors to the end of the balance beam. The difference in body weight of an office staff member before and after adding the additional weight to the balance beam is measured, recorded, and used at future weighings. This difference is added to the modified balance beam weight obtained on the very heavy person who can now be successfully weighed. Waiting room chairs should be armless and strong enough to support the very large patient. Appropriate-sized drapes should be available. At least one exam room with a sturdy exam table accommodating very large persons should be present. Large vaginal speculums and other large-size medical equipment such as thigh blood pressure cuffs contribute to optimal efficiency of practice.

6.7. National Resources An excellent resource for the primary care physician is the Weight-Control Information Network (WIN) (60). WIN is a national source of information on weight control, obesity, and weight-related nutritional disorders for health professionals and the public. WIN answers written and telephone inquiries from doctors and the public. WIN provides fact sheets and pamphlets, journal article reprints, position papers by the National Task Force on Prevention and Treatment of Obesity, and literature searches of a weight-control subfile of the Combined Health Information Database. Self help groups such as TOPS and Weight Watchers are well established and useful for many patients. Established in 1948 as a nonprofit weight support organization, TOPS asks its members to have physician-recommended weight goals. Members attend weekly meetings and strive to achieve within a 10-lb range of the physician-recommended goal weight. TOPS recognizes its successful members at area, state, and national meetings. Its maintenance group is KOPS (Keep Off Pounds Sensibly). Members are eligible for KOPS status by staying at goal weight for 13 wk. Weight Watchers is a self-help group familiar to many doctors with similar weekly meetings, minimal dues, and low-fat commercial food products. The general approach I described will help mollify the weight-related comorbities of some patients. However, many patients will have difficulties incorporating these treatment approaches into their busy lifestyles. Doctors often resort to specific medical treatments for obesity-related medical conditions. It is often easier to start pharmacotherapy for hypertension, hyperlipidemia, and the diabesity syndrome than it is to aggressively use nonpharmacologic life-style modification techniques that are labor intensive to teach.

6.8. Role of Pharmacotherapy Pharmacotherapies for the foregoing conditions are well accepted by the medical community and insurance industry. It is curious that pharmacotherapy for the underlying problem of obesity associated with these medical conditions has not been accepted (61). Perhaps this reflects a bias that obesity is somehow a moral failing of patients rather than a complex genetically influenced disease. If primary care physicians could control visceral fat obesity, many prescriptions for treatment of obesity related comorbid conditions could be eliminated. Patients are increasingly asking if there is medication to help weight loss. Until very recently diet pills have been looked on with reluctance because of abuses of amphetamines in previous decades. As a result of these misuses of diet pills, state medical boards have significantly restricted the prescriptions of anorectic medications. The use of phentermine and fenfluramine, and the introduction of new agents will likely signal a paradigm shift in attitudes regarding pharmacotherapy for obesity.


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The stimulant medications may have added side effects in obese patients with significant comorbid conditions. Hypertension may be aggravated, sleep apnea can be worsened, or psychological distress could potentially result. The substance abusers in our society will misuse many products so it is not surprising that some will try to exploit unwary physicians. Drugs such as fenfluramine that have no abuse potential still have been tightly regulated. Pharmacologic agents that have similar chemical structures to amphetamine such as fenfluramine despite having very different biologic effects have been found guilty by association. Weintraub’s placebo-controlled study presented some hope that pharmacotherapy may be a useful adjunct to standard obesity treatment (62). Weintraub has shown that combination therapy with phentermine and fenfluramine is safe and clinically effective up to 3.5 yr. This limited study has engendered interest in long-term pharmacotherapy as a reasonable adjunctive approach to the treatment of obesity. The North American Association for the Study of Obesity has promulgated a positon paper recommending guidelines for the approval of antiobesity drugs (63). Clinical trials with larger numbers of patients are being conducted to determine safety and efficacy of long-term antiobesity pharmacotherapy. As a clinician participating in one of these trials, I was impressed that combinations of phentermine and d,l-fenfluramine are effective in helping reduced obese patients maintain weight lost for periods exceeding 2 yr. This combination of antiobesity medications was generally well tolerated with minimal treatment emergent side effects (64) until its implication in causing cardiac valvulvar disease. I am wary of the possible drug interactions and side effects that may only be seen after a larger number of patients have been treated. The serotonin syndrome associated with dual use of two serotonin drugs is potentially problematic (65). Many doctors and patients are not aware of the serotonergic nature of many commonly used medications such as dextromethorphan and demerol. Caution must be employed when prescribing serotoninactive medications such as fenfluramine with other serotonin drugs. I wrote Mary’s insurance company requesting approval for coverage for a comprehensive obesity treatment program approach, as she had failed to improve her medical problems. Her blood sugar control was worse despite increasing doses of insulin. She was willing to try a very-low-calorie diet regimen with medical supervision. Mary was on furosemide three times per day and continued to have edema and intermittent congestive heart failure symptoms. She was unable to increase her activity levels significantly because of her orthopedic and cardiovascular limitations. She asked me to write her insurance company to request coverage for a weight management program.

6.9. Role of Managed Care Organizations Managed care organizations are having a larger impact on the practice of medicine. Patients will likely be changing insurance companies frequently over the next 5 yr. I feel that managed care organizations will eventually be supportive of aggressive primary prevention of risk factors for disease. Many insurance companies currently limit obesity treatment from coverage. I think the most successful managed care organizations will likely be ones that can invest resources to prevent disease and keep people healthier rather than just treat the expensive consequences of diseases.

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Many managed care organizations currently are striving to be successful by decreasing hospital days and shifting this care to the home. Obesity contributes to more complicated medical problems requiring hospitalization and therefore would ideally be prevented. Control of obesity remains a formidable problem. The doctor’s office of the future may employ group sessions where common life-style problems such as smoking cessation, stress reduction, nutrition, prenatal care, and weight management are addressed. The economic costs of obesity are huge (66). Our challenge as health professionals is to develop better treatment for obesity and other life-style influenced medical problems. This remains a daunting task.

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24. Crapo L. Cushing’s syndrome: a review of diagnostic tests. Metab 1979; 28:955–977. 25. Matsuoka LY, Gavin JR, Kupchella CE, Dietrich JG. Acanthosis nigricans, hypothyroidism, and insulin resistance. Am J Med 1986; 81:58–61. 26. Logue E, Smucker WD, Bourguet CC, and the Nutrition, Exercise, and Obesity Reasearch Group. Identification of obesity: waistlines or weight? J Fam Pract 1995; 41:357–363. 27. Lean MEJ, Han TS, Morrison CE. Waist circumference as a measure for indicating need for weight management. Br Med J 1995; 311:158–161. 28. Pouliot MC, Despres JP, Lemieux S, Moorjani S, Bouchard C, Tremblay A, et al. Waist circumference and abdominal sagittal diameter: best simple anthropometric indexes of abdominal visceral adipose tissue accumulation and related cardiovascular risk in men and women. Am J Cardiol 1994; 73:460–468. 29. Sjostrom CD, Hakangard AC, Lissner L, Sjostrom L. Body compartment and subcutaneous adipose distribution—risk factor patterns in obese subjects. Obes Res 1995; 3:9–22. 30. Egger G. The case for using waist to hip ratio measurements in routine medical checks. Med J Aust 1992; 156:280–285. 31. Irvine MJ. Is knowing your cholesterol harmful? J Clin Epidemiol 1994; 47:131–145. 32. Goldstein DJ. Beneficial effects of modest weight loss. Int J Obes 1992; 16:397–415. 33. Amsterdam EA, Helfand M, Schnitzer TJ, Weir GC, Young CD. Following the patient with chronic stable disease. Patient Care 1995; 29:22–42. 34. American Diabetes Association. Nutrition recommendations and principles for people with diabetes. Diabetes Care 1994; 17:519–522. 35. Franz MJ, Horton ES, Bantle JP, Beebe CA, Brunzell JD, Coulston AM, et al. Nutrition principles for the management of diabetes and related complications. Technical review. Diabetes Care 1994; 17:490–518. 36. Garrow JS, Webster JD. Long-term results of treatment of severe obesity with jaw wiring and waist cord. Proc Nutr Soc 1986; 45:199A. 37. Fernstrom MH. Drugs that cause weight gain. Obes Res 1995; 3(suppl 4):435S–439S. 38. Goldstein DJ, Rampey AH, Roback PJ, Wilson M, Hamilton SH, Sayler, Tolefson GD. Efficacy and safety of long-term fluoxetine treatment of obesity—maximizing success. Obes Res 1995; 3(suppl 4):481S–490S. 39. Dourish CT. Multiple serotonin receptors: opportunities for new treatments for obesity? Obes Res 1995; 3(suppl 4):449S–462S. 40. Reaven GM, Lithell H, Landsberg. Hypertension and associated metabolic abnormalities—the role of insulin resistance and the sympathoadrenal system. N Eng J Med 1996; 334:374–381. 41. Editorial. Drugs causing weight gain. Br Med J 1974; 1:168. 42. Marin P. Testosterone and regional fat distribution. Obes Res 1995; 3(Suppl 4):609S–612S. 43. Schteingart DE. Effectiveness of phenylpropanolamine in the management of moderate obesity. Int J Obes 19992;16:487–493. 44. Shieh S-M, Sheu WH-H, Shen D-C, Fuh MM-T, Chen Y-DI, Reaven GM. Glucose, insulin, and lipid metabolism in doxazosin-treated patients with hypertension. Am J Hypertens 1992;5:827–831. 45. Rossetti L, Giaccari A, DeFronzo RA. Glucose toxicity. Diabetes Care 1990; 13:610–630. 46. Bailey CJ. Biguanides and NIDDM. Diabetes Care 1992; 15:755–772. 47. Coniff RF, Shapiro JA, Seaton TB, Hoogwerf BJ, Hunt JA. A double-blind placebo-controlled trial evaluating the safety and efficacy of acarbose for the treatment of patients with insulin-requiring type II diabetes. Diabetes Care 1995; 18:928–931. 48. Henry RR, Gumbiner B. Benefits and limitations of very low calorie diet therapy in obese NIDDM. Diabetes Care 1991; 14:802–823. 49. Bistrian BR. Clinical use of a protein-sparing modified fast. JAMA 1978; 240:2299–2301. 50. Wadden TA, Stunkard AJ, Brownell KD. Very low calorie diets: their efficacy, safety, and future. Ann Intern Med 1983; 99:675–684. 51. American Dietetic Association. Very-low-calorie weight loss diets. J Am Diet Assoc 1990; 90:722–726 (editorial). 52. Lichtman SW, Pisarka K, Berman ER, et al. Discrepancy between self-reported and actual caloric intake and exercise in obese subjects. N Engl J Med 1992; 327:1893–1898. 53. Stuart MR, Lieberman JA. Finding time for counseling in primary care. Patient Care 1994; 28:118–129. 54. Depue JD, Clark MM, Ruggiero L, Medeiros ML, Pera V. Maintainance of weight loss: a needs assessment. Obes Res 1995; 3:241–248. 55. Perri MG, Nezu AM, Patti ET, McCann KL. Effect of length of treatment of weight loss. J Consult Psychol. 1989;57:450–452.

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56. Kayman S, Bruvold W, Stern JS. Maintainance and relapse after weight loss in women: behavioral aspects. Am J Clin Nutr 1990; 52:800–807. 57. Ravussin E, Lillioja S, Knowler WC, Christin L, Freymond D, Abbott WGH, Boyce V, Howard BV, Bogardus C. Reduced rate of energy expenditure as a risk factor for body-weight gain. N Engl J Med 1988; 318:467–472. 58. Allred JB. Too much of a good thing? An overemphasis on eating low-fat foods may be contributing to the alarming increase in overweight among United States adults. J Am Diet Assoc 1995; 95:417,418. 59. Yanovski SZ. A practical approach to treatment of the obese patient. Arch Fam Med 1993; 2:309–316. 60. The Weight-Control Information Network, 1 Win Way, Bethesda, MD 20892-3665. Phone: 301-9511120; Fax: 301-951-1107; Internet: [email protected] 61. Bray GA. Use and abuse of appetite—suppressant drugs in the treatment of obesity. Ann Int Med 1993; 119:707–713. 62. Weintraub MW. Long-term weight control: the National Heart, Lung, and Blood Institute-Funded Multimodal Intervention Study. Clin Pharmacol Ther 1992; 51:581–585. 63. Guidelines for the approval and use of drugs to treat obesity. A position paper of the North American Association for the Study of Obesity. Obes Res 1995; 3:473–478. 64. Atkinson RL, Blank RC, Loper JF, Schumacher D, Lutes RA. Obes Res 1995; 3(suppl 4):497S–500S. 65. Mills K. Serotonin syndrome. Amer Fam Phys 1995; 52:1475–1482. 66. Wolf AM, Colditz GA. The cost of obesity. Pharmacoeconomics 1994; 5(suppl 5):34–37.

CLINICAL EXPERIENCE IN THE PRIMARY PHYSICIAN'S OFFICE II: USE OF COMBINATION THERAPY—ROY C. BLANK The objective of this section is to provide practice guidelines to using pharmacological therapy as part of a weight-loss program by describing a specific case history. The treatment of obesity in the traditional office setting remains an ineffectual approach to a major health problem. There are several possible explanations for this (see Chapter 12). Central to the issue is the lack of nutrition education in US medical schools. This basic component of medical care does not receive adequate emphasis in the medical school curriculum. Physicians are taught the complications of obesity, yet lack an understanding of the pathophysiology and dynamics of this disease. The relationship between eating disorders such as binge-eating and obesity is virtually unknown. Unfortunately, many physicians also share the prejudices and negative attitudes of society toward the obese (see Chapter 12). Previous controversial treatments have dampened physician’s willingness to treat the obese patient. Effective treatment is often elusive and the support necessary for comprehensive therapy is difficult to provide in the primary care office. In the face of these difficulties, the treatment of obesity has drifted away from the doctor’s office to the welcoming arms of commercial ventures. The major health concern in our country is largely treated in the shopping mall. With the increased recognition of obesity as a chronic medical illness, this trend is now changing. The driving force for this change in attitude was Weintraub’s seminal study that demonstrated long-term successful treatment of obesity with the regimen of phentermine and fenfluramine (1).

1. THE PROGRAM The promising results of Weintraub’s report prompted initiation of a long-term study of phentermine and fenfluramine in a private practice setting. In conjunction with the University of Wisconsin, 2000 patients were evaluated in an open-label study. The initial group of patients were in their third year of treatment. At the onset, patients were seen in an internal medicine office. Patient care is now provided in a free-standing clinical nutrition center. The following observations and recommendations are based on this clinical experience and serves as a model for pharmacotherapy of obesity.


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The appropriate management of obesity calls for a change in the mind-set of most physicians. Obesity is a multifactorial illness that requires attention to the same principles of management as other chronic disease processes. Each patient deserves a complete history, physical examination and laboratory evaluation. Analysis of these data permits an identification of the possible cause of obesity, the severity of the process, and the presence of any comorbid conditions. Treatment and disease process are then matched in a comprehensive therapeutic plan (2). Merely providing a prescription without a thorough appraisal of the patient is inappropriate.

2. CASE HISTORY The following case history and treatment plan demonstrate an approach to the management of an obese patient. Decision points are identified and comments are provided in italics. Patient Characteristics. S.J. is a 28-yr-old female who presents for the treatment of obesity. Social History. She is single with no children. She does not smoke, consume alcohol, or have a history of substance abuse. She is employed as a bank manager and denies undo stress from her employment. Although no problems are identified in this patient, the social history may provide clues that would help direct therapy. Particularly, if problems such as alcohol abuse are uncovered, treatment for obesity may be delayed and appropriate intervention provided. During times of undo stress or excessive change, treatment for obesity may be appropriately postponed. Questioning should determine whether family members are supportive of the effort to lose weight. Family History. Both parents are obese. Her father has hypercholesterolemia, diabetes mellitus and underwent coronary artery bypass surgery at age 48. Noting this positive family history increases the need to exclude comorbid conditions in this patient. The early onset of cardiac disease in her family places her in a higher risk category for future cardiac events. Past History. Her major health problem has been obesity since childhood. Repeated attempts to lose weight failed to achieve long-term benefit. She has a history of hypertension treated with medication. There is no history of diabetes mellitus and she is not aware of her cholesterol level. She denies a history of clinical depression. There has been no previous surgery. Medications include a calcium channel blocking agent for her blood pressure. From this information, the need for attention to her blood pressure is obvious. Initial treatment with anorectic medications should not aggravate this problem. As she loses weight, dosage adjustments for her blood pressure medication may be necessary. Review of Systems. A complete review of systems is relatively unremarkable. She does experience shortness of breath with moderate exertion. This symptom has developed with her progressive weight gain. Within the review of systems, certain questions are particularly relevant to the obese patient. These patients are approached in the same fashion as a patient with any other chronic medical illness. A thorough review of systems is required to properly evaluate patients receiving obesity treatment. One line of questioning should evaluate problems that complicate obesity. A careful cardiopulmonary history is needed. Questions regarding daytime somnolence, excessive snoring, or apneic episodes are

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indicated in each patient to screen for sleep apnea. Problems such as dyspepsia due to reflux may also be identified. Questions may be posed to discover problems that interfere with treatment. Evaluating current symptoms of depression, anxiety, and bipolar disorder is imperative, particularly because some medications utilized for obesity treatment may negatively impact psychiatric problems. Finally, questions may uncover potential etiologies for obesity. A change or abnormality in a woman’s menstrual cycle or a history of abnormal body hair growth may serve as a clue for endocrine abnormalities. Nutrition History. She has been overweight since childhood, with a progressive weight gain since she was 18-yr-old. Progressive weight gain represents an increased risk factor for future problems from obesity (3). Numerous prior weight-loss programs and self help attempts to lose weight have been unsuccessful. She has lost weight with a very low-calorie diet (VLCD), but regained it after a few months of treatment. Discreet episodes of binge-eating have not been a problem. There is no prior history of bulimia. Often she skips breakfast and lunch and consumes most of her calories in the evening. She labels herself a compulsive eater and feels that food is controlling her life when she loses control over her eating and food choices. She describes a high level of hunger, but sometimes continues to eat even though she is not really hungry. A detailed history of eating behavior provides insight into possible causes of obesity. This patient demonstrates a frequently described pattern of eating observed in obese patients. The increased hunger and lack of control over eating often improves with anorectic agents. Long-term success with VLCD would not be expected. She rarely exercised at any time in her life. Her therapeutic plan calls for intensive education regarding exercise and the development of an individualized plan (see Chapter 13). Physical Exam. Height 5 ft. 7 in.; weight, 340 lb.; body mass index (BMI) 52 (weight in kilograms, height in meters squared); waist–hip ratio, .95. Analyzing the BMI and waist–hip ratio is the first step in stratifying the patient’s risk from obesity. Although the BMI is not a precise measure of total body adiposity, as athletes or muscular individuals may have a BMI considered in the obese range, it provides some guidance related to health risk. Body fat may range from 10% to 31% with a BMI of 27 kg/m2 (3). Nonetheless, a BMI greater than 27 kg/m2 is associated with an increased health risk. Recent studies suggest an increased mortality as BMI exceeds 19, with the rate of risk climbing more rapidly with a BMI beyond 25–27 (4). This patient’s waist–hip ratio greater than 0.8, indicates upper body or central obesity, strongly associated with metabolic derangements such as insulin resistance, hypertension, lipid abnormalities, and hyperuricemia (5). Although a higher waist–hip ratio indicates individuals at higher risk for morbidity, lower waist–hip ratios are not completely benign in an obese individual. Young and Gelskeey recently showed that noncentrally obese subjects had mean blood pressure, lipid and glucose values that were significantly more unfavorable when compared to the nonobese (6). Blood pressure, 128/82; pulse 76. Examination of the head, eyes, ears, nose, and throat is negative. Her neck is supple with no thyromegaly. Cardiovascular exam reveals no murmurs or gallops. There is no neck vein distention and no edema. Peripheral pulses are normal. Her abdomen is markedly obese. Hair distribution is normal and there are no


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pigmented striae. Her extremities reveal no clubbing, cyanosis, or edema. Neurological examination is negative. Examination of the skin reveals acanthosis nigracans. A thorough physical exam is indicated at the outset of therapy for all obese patients. The finding of acanthosis nigracans suggests the likelihood of insulin resistance. There are no findings on her exam to indicate endocrine abnormalities such as Cushing’s disease. Laboratory. Glucose, 138 mg/dL (65–110); SGOT, 51 U/L (

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