Vascular Complications of Diabetes: Current Issues in Pathogenesis and Treatment

VASCULAR COMPLICATIONS OF DIABETES CURRENT ISSUES IN PATHOGENESIS AND TREATMENT

Editor Richard Donnelly MD, PhD, FRCP, FRACP Division of Vascular Medicine University of Nottingham The Medical School Derby DE22 3DT UK

Associate Edward Horton MD Editor Joslin Diabetes Center One Joslin Place Boston MA 02215 USA

VASCULAR COMPLICATIONS OF DIABETES CURRENT ISSUES IN PATHOGENESIS AND TREATMENT SECOND EDITION

Editor Richard Donnelly MD, PhD, FRCP, FRACP Division of Vascular Medicine University of Nottingham The Medical School Derby DE22 3DT UK

Associate Edward Horton MD Editor Joslin Diabetes Center One Joslin Place Boston MA 02215 USA

Supported by an Educational Grant by Eli Lilly & Co

Answers That Matter.

© 2005 by Blackwell Publishing Ltd Blackwell Publishing, Inc., 350 Main Street, Malden, Massachusetts 02148-5020, USA Blackwell Publishing Ltd, 9600 Garsington Road, Oxford OX4 2DQ, UK Blackwell Publishing Asia Pty Ltd, 550 Swanston Street, Carlton, Victoria 3053, Australia The right of the Author to be identified as the Author of this Work has been asserted in accordance with the Copyright, Designs and Patents Act 1988. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher. First published 2002 Second Edition 2005 Library of Congress Cataloging-in-Publication Data Vascular complications of diabetes: current issues in pathogenesis and treatment / edited by Richard Donnelly and Ed Horton.-- 2nd ed. p. ; cm. Includes bibliographical references and index. ISBN-13: 978-1-4051-2785-1 (alk. paper) ISBN-10: 1-4051-2785-6 (alk. paper) 1. Diabetic angiopathies. [DNLM: 1. Diabetes Complications. 2. Diabetic Retinopathy--etiology. 3. Protein Kinase C--adverse effects. 4. Vascular Diseases--etiology. WK 835 V3305 2005] I. Donnelly, Richard, 1960- II. Horton, Edward S. RC700.D5V375 2005 616.1'3--dc22 2005008488

ISBN-13: 978-1-4051-2785-1 ISBN-10: 1-4051-2785-6 A catalogue record for this title is available from the British Library Set in Branding Serif and Branding Sans Design and layout by Designers Collective Printed and bound in the USA by Walsworth Publishing Co., Marceline, Missouri Commissioning Editor: Alison Brown Development Editor: Claire Bonnett Production Controller: Kate Charman For further information on Blackwell Publishing, visit our website: http://www.blackwellpublishing.com The publisher’s policy is to use permanent paper from mills that operate a sustainable forestry policy, and which has been manufactured from pulp processed using acid-free and elementary chlorine-free practices. Furthermore, the publisher ensures that the text paper and cover board used have met acceptable environmental accreditation standards.

CONTENTS

List of contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .v Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .vi

SECTION I MICRO- AND MACROVASCULAR COMPLICATIONS OF DIABETES Chapter 1 The public health impact of the diabetes epidemic . . . . .3 Adrian R. Scott Chapter 2 Risk factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .13 Adrian R. Scott Chapter 3 Diabetic nephropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .23 Adrian R. Scott Chapter 4 Coronary heart disease and diabetes . . . . . . . . . . . . . . . . . . . . . .35 Adrian R. Scott Chapter 5 Diabetes and cerebrovascular disease . . . . . . . . . . . . . . . . . . . . .45 Adrian R. Scott Chapter 6 Erectile dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .51 Adrian R. Scott Chapter 7 Evidence-based interventions to prevent or retard vascular complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .59 Adrian R. Scott

SECTION II DIABETIC NEUROPATHIES Chapter 8 Classification and clinical features of neuropathy . . . . . . . . 79 Rayaz A. Malik Chapter 9 Pathophysiology of diabetic neuropathy . . . . . . . . . . . . . . . . . .85 Rayaz A. Malik Chapter 10 Epidemiology and natural history of DPN . . . . . . . . . . . . . . . . .91 Rayaz A. Malik Chapter 11 Detection/Screening/Assessment . . . . . . . . . . . . . . . . . . . . . . . . . .97 Rayaz A. Malik Chapter 12 Foot ulceration and Charcot arthropathy . . . . . . . . . . . . . . . . .105 Rayaz A. Malik

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CONTENTS

Chapter 13 Treatments options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .113 Rayaz A. Malik Chapter 14 Management guidelines for diabetic peripheral neuropathy and foot ulceration . . . . . . . . . . . . . . . . . . . . . . . . . . .121 Rayaz A. Malik

SECTION III DIABETIC RETINOPATHY AND ASSOCIATED OPHTHALMIC DISORDERS Chapter 15 Diabetic retinopathy: epidemiology and risk factors . . . .129 Hean-Choon Chen Chapter 16 Classification and diagnosis of diabetic retinopathy . . . . .139 Hean-Choon Chen Chapter 17 Diabetic maculopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .151 Hean-Choon Chen Chapter 18 Proliferative diabetic retinopathy . . . . . . . . . . . . . . . . . . . . . . . . .163 Hean-Choon Chen Chapter 19 Non-retinal diabetic ocular complications . . . . . . . . . . . . . . . .171 Hean-Choon Chen

SECTION IV MECHANISMS OF HYPERGLYCAEMIA INDUCED VASCULAR DYSFUNCTION Chapter 20 Pathophysiology and potential targets for therapeutic intervention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .179 Richard Donnelly Chapter 21 Protein kinase C . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .189 Richard Donnelly Chapter 22 Protein kinase C activation and vascular permeability . . .197 Richard Donnelly Chapter 23 Role of protein kinase C activation in cardiovascular and renal complications of diabetes . . . . . . . . . . . . . . . . . . . . . .205 Richard Donnelly Chapter 24 Experimental pharmacology using isoform-selective protein kinase C inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .213 Richard Donnelly Chapter 25 Clinical trials with ruboxistaurin . . . . . . . . . . . . . . . . . . . . . . . . . .221 Richard Donnelly Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .226

LIST OF CONTRIBUTORS

Hean-Choon Chen FRCS, FRCOpath Consultant Ophthalmologist Derbyshire Royal Infirmary Derby, UK

Richard Donnelly MD, PhD, FRCP, FRACP Professor of Vascular Medicine University of Nottingham and Honorary Consultant Physician The Medical School Derby, UK

Rayaz A. Malik MB.ChB, PhD, MRCP Senior Lecturer and Consultant Physician Academic Department of Medicine Manchester Royal Infirmary Manchester, UK

Adrian R. Scott MD, FRCP Consultant Physician Diabetes Centre Northern General Hospital Sheffield, UK

v

PREFACE

Diabetes-related cardiovascular complications often cause premature mortality, as well as disabilities such as blindness, foot ulceration and amputation. The health care and social care costs of managing these complications are enormous, but new treatments, devices and clinical management protocols are steadily improving the longer term outcomes for people with diabetes. This second edition has been revised and updated to reflect state of the art clinical practice. In particular, a new section on diabetic neuropathy covers important aspects of screening and detection, diagnosis and management. The book is aimed at healthcare professionals involved in the assessment and surveillance of patients with diabetes complications, and the section on protein kinase C (PKC) explains the basis of a major new pathway responsible for hyperglycaemia-induced vascular injury. Recent clinical trials have suggested that inhibition of PKC-β is an effective therapeutic intervention for improving the symptoms and outcomes from diabetes-related complications. Richard Donnelly

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Vascular Complications of Diabetes: Current Issues in Pathogenesis and Treatment, Second Edition Edited by Richard Donnelly, Edward Horton Copyright © 2005 by Blackwell Publishing Ltd

SECTION I MICRO- AND MACROVASCULAR COMPLICATIONS OF DIABETES

Vascular Complications of Diabetes: Current Issues in Pathogenesis and Treatment, Second Edition Edited by Richard Donnelly, Edward Horton Copyright © 2005 by Blackwell Publishing Ltd

Adrian R. Scott MD, FRCP CHAPTER 1 THE PUBLIC HEALTH IMPACT OF THE DIABETES EPIDEMIC

INTRODUCTION The 21st century will see diabetes emerge as the world’s commonest chronic disease. Whilst the bulk of this will be type 2 diabetes (90%) the incidence has been rising in both types. The direct and indirect costs of diabetes and its complications, plus the associated reduction in quality and quantity of life, will have considerable economic consequences. This effect will be most noticeable in developing countries which are going to see a disproportionate increase in the prevalence of diabetes over the next few decades. It has been estimated that the worldwide prevalence of diabetes will double between 1990 and 2010. Epidemiological studies in the USA have shown that the number of people with known diabetes has increased from around 1.5 million in 1958 to 10.5 million in 1998. Most states in the US report a prevalence of over 8% and this fails to take into account those people with undiagnosed diabetes. Most screening studies indicate that at least 50% of people found to have diabetes were silently undiagnosed for sometime.

THE NATURAL HISTORY OF TYPE 1 DIABETES Although onset is predominantly in childhood or young adulthood, a significant proportion will be diagnosed over the age of 30 years. The peak ages for onset, however, are around puberty and between 4–6 years old. Life expectancy is reduced, though there is some evidence that this is improving. The British Diabetic Association Cohort study (1972–1993), a prospective follow-up of insulin-treated patients with diabetes diagnosed under the age of 30, showed increased mortality at all ages. Avoidable metabolic complications such as hypoglycaemia and diabetic ketoacidosis accounted for most of the excess mortality among those under 30 years but after 20 years of diabetes the impact of atherosclerotic macrovascular complications steadily increases. The prognosis is particularly disturbing for children diagnosed with type 1 diabetes under the age of 10 years; previous reports have indicated that 60% were dead within 40 years of diagnosis. With increasing duration of diabetes, the prevalence of retinopathy, nephropathy and neuropathy is highest in those with poor glycaemic control and lowest in those with good control. The Diabetes Control and Complications Trial (DCCT 1995) established quite clearly that good glycaemic control in type 1 diabetes can reduce the incidence and progression of microvascular complications but the risk of a vascular event increases with duration of diabetes and the presence of nephropathy.

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SECTION I • MICRO- AND MACROVASCULAR COMPLICATIONS OF DIABETES

The DCCT was under-powered, and the patients too young, to be sure if improved glycaemia reduced the risk of macrovascular complications, however, the trend was for good control to be associated with a reduction in vascular events.

EPIDEMIOLOGY OF TYPE 1 DIABETES The worldwide variation in incidence is considerable though the pattern of presentation is similar. The incidence is showing signs of increasing at all ages but most noticeably in the under 5s. In under 16s, Northern Europe (Finland, Scotland, Sweden) has the highest rates with up to 30–35 cases per 100,000 of the population aged 7.0 > 11.1

Impaired Glucose Tolerance (IGT): Fasting (if measured) and 2hr post glucose load

< 7.0 and > 7.8

Impaired Fasting Glycaemia (IFG): Fasting

> 6.1 and < 7.0

And (if measured) 2hr post glucose load

< 7.8

Normal Fasting Plasma Glucose (FPG)

< 5.6

For epidemiological or population screening purposes, the fasting or 2hr value after 75g oral glucose may be used alone. For clinical purposes, the diagnosis of diabetes should always be confirmed by repeating the test on another day unless there is unequivocal hyperglycaemia with acute metabolic decompensation or obvious symptoms.

Table 1.1 Criteria for the diagnosis of diabetes mellitus (WHO classification 1999). Note that the American Diabetes Association defines IFG as FPG 5.6–6.9 mmol/l. People with IFG and IGT are considered to have “pre-diabetes”. An OGTT (75g) may be indicated in people with IFG if considered at high risk of diabetes.

clinical practice the ADA recommended using fasting glucose testing alone, and the use of the two hour oral glucose tolerance test (OGTT) was not recommended. Subsequent investigations have shown that fasting and two hour glucose criteria do not identify the same group of individuals. The DECODE study, which combined the results of 13 prevalence studies in nine European countries, found that there was a distinct sex difference in the prevalence of diabetes, impaired fasting glucose (IFG) and impaired glucose tolerance (IGT). Undiagnosed diabetes and IFG were more common in men than in women at 30–69 years of age. IGT was higher in women than in men and was particularly high in the over 70s. In the USA, the NHANES III study (2000), confirmed that diagnosed diabetes is most prevalent in the middle-aged (6%) and elderly (11%) compared to only 1.5% of 18–44 year olds (Fig. 1.1). The incidence is increasing in childhood and is related to obesity.

CHAPTER 1 • THE PUBLIC HEALTH IMPACT OF THE DIABETES EPIDEMIC

Impaired fasting glucose Undiagnosed diabetes Diagnosed diabetes

Age-standardized per cent

25

20

15

10

5

0

NonNonMexican Hispanic Hispanic American white black

NonNonMexican Hispanic Hispanic American white black

Men

Women

Fig 1.1 Prevalence of diabetes, impaired fasting glucose, and impaired glucose tolerance in US adults: From the Third National Health and Nutrition Examination Survey 1988–1994. Diabetes Care 1998; 21: 518–524.

THE COST OF DIABETES There is considerable morbidity associated with diabetes and calculating the cost can at best be an imprecise estimate. Diabetes is the leading cause of blindness, end-stage renal failure and lower-extremity amputation. People with diabetes experience high rates of macrovascular complications at least twice that of those without diabetes. In the UK, estimates of the cost of diabetes were first attempted in 1989 using 1984 data and this suggested that 4–5% of all UK healthcare expenditure went on people with diabetes. More recent data suggest the figure is more like 8%, and that one third of total expenditure on diabetes is spent on those aged 0 to 24 years. Based on 1999 figures, it was estimated that it might cost £100 million, in England alone, to implement the findings of the UKPDS, in terms of intensive treatment of glycaemic control and blood pressure. The difficulties, however, are that it is difficult to cost episodes in patients with multiple pathologies and coding has been shown to under-

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SECTION I • MICRO- AND MACROVASCULAR COMPLICATIONS OF DIABETES

record secondary diagnoses such as diabetes. Most economic assessments concentrate on direct costs, though clearly indirect costs, such as time off work, and intangible costs, such as what might have been, will inflate the figures considerably. Surveys from the USA suggest that health care expenditure was over $11,000 per year per person with diabetes compared to $2,600 for people without diabetes. Over 60% was due to inpatient hospitalization. Nevertheless, there are effective strategies for the prevention or delay of complications associated with diabetes and both the DCCT in type 1 diabetes and the UKPDS in type 2 diabetes has demonstrated the effectiveness of intensification of treatment. An economic model has been used to analyse the costs of DCCT, enabling calculation of the costs of preventing end-stage complications. The model predicted that intensive therapy would result in approximately 15 years free from the first major complications of type 1 diabetes and additional years of life free from blindness, ESRF and lower-extremity amputation (Fig. 1.2). It was projected that intensive therapy would prolong life by about 5 years and the cost was approximately $29,000 per year of life gained. Similar economic modeling has looked at the cost-effectiveness of ‘comprehensive’ or intensive care of type 2 diabetes (Table 1.2). Such models are predicting the likelihood of complications developing in a diabetic population. One such model suggests that with standard care (non-intensive) over a life-time, 19% of subjects would become blind, 17% would develop ESRF and 16% would require lower-extremity amputation. With intensification of glucose control these figures could be reduced by up to 75% (but with no effect on cardiovascular outcome), with increased survival by 1.3 years. The average lifetime cost was $40,000 more than with standard care. Of course, these models are limited because they have only looked at the cost and benefits of intensification of glycaemic control and clearly there are many other interventions available to reduce macrovascular risk. These somewhat daunting economic assessments of diabetes care can be viewed from different perspectives. For politicians and public health specialists, it provides an incentive to invest now in primary prevention of type 2 diabetes, as treatment costs are unsustainable given the epidemic of diabetes that is sweeping the developed and developing worlds. For clinicians, the challenge is to develop cost-effective strategies and deliver high quality diabetes services that reach the majority rather than the minority. Examples of affordable interventions with proven benefits are: comprehensive eye-screening; ensuring everyone at high vascular risk receives low dose aspirin; and annual foot assessments, but these are not made available to all people with diabetes, even in the more affluent societies. The pharmaceutical industry must not forget that it remains part of the society in

(b)

Cumulative incidence of ESRD (%)

(a)

Cumulative incidence of blindness (%)

CHAPTER 1 • THE PUBLIC HEALTH IMPACT OF THE DIABETES EPIDEMIC

(c)

30 Standard care Comprehensive care 20

10

0 0

8

16

24

32

40

48

56

64

0

8

16

24

32

40

48

56

64

0

8

16

24

32

40

48

56

64

30

20

10

0

Cumulative incidence of IEA (%)

30

20

10

0 Years after diagnosis of diabetes

Fig. 1.2 For people receiving standard care, the model predicts sharply increasing cumulative incidence of complications, including blindness (a), ESRD (b), and lowerextremity amputation (LEA) (c) with increasing duration of type 2 diabetes. The model predicted a substantially lower incidence of these long-term complications with a program of comprehensive care. Eastman, et al. Diabetes Care 1998; 21 (Suppl 3): C19–C24.

9

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SECTION I • MICRO- AND MACROVASCULAR COMPLICATIONS OF DIABETES

Predicted reduction in life time costs of end-stage complications through comprehensive care for type 2 diabetes Cost elements

Standard care

Present value costs (3% discount rate) General and diabetes-related medical care ($) 32,365 Eye disease ($) 3,128 Renal disease ($) 9,437 Neuropathy/lower-extremity amputations ($) 4,381 New coronary heart disease ($) 13,458 Total costs ($) 62,769 QALY (undiscounted) 16.04 QALY (discounted 3%) 11.43 Life-years (undiscounted) 17.05 Incremental cost/QALY gained —

Comprehensive care Difference

58,312 1,536 960

25,947 (1,592) (8,477)

1,469 14,414 76,922 18.03 12.30 18.37 —

(2,912) 956 13,922 1.9 0.87 1.32 16,002

Table 1.2 Predicted reduction in life time costs of end-stage complications through comprehensive care for type 2 diabetes. Data are averages per person per life time. Cost savings are indicated in parentheses.

which it operates and has a social responsibility. The challenge is to develop and market safe therapies which generate enough profit to encourage future shareholders to invest, but not so much that only the wealthy can afford them.

CHAPTER 1 • THE PUBLIC HEALTH IMPACT OF THE DIABETES EPIDEMIC

CURRENT ISSUES •

•

•

•

Population screening for type 2 diabetes is not widespread and may not be cost-effective but targeted opportunistic screening of high risk individuals (such as women with prior gestational diabetes, first degree relatives, high-risk ethnic groups, the obese) will identify 70% of those with undiagnosed diabetes. With the increase of obesity in childhood this may mean screening young people in their teens if they are from a family in which type 2 diabetes is common. Finnish and American randomized studies have demonstrated that interventions such as weight loss and exercise programs in patients with impaired glucose tolerance have a role in delaying or preventing the progression to frank diabetes by over 50%. Metformin used in this context reduces progression from IGT to diabetes by 30%. Studies of the early use of insulin sensitizers in IGT are ongoing. The epidemic of obesity affects all ages and consequently the emergence of type 2 diabetes in childhood is increasingly apparent. The prognosis is likely to be particularly bad in this age group and a high incidence of nephropathy and early onset cardiovascular disease is to be expected in South Indians, Maori and other indigenous populations. Effective prevention and treatment strategies for obesity are urgently required. Studies from the UK have shown that simple messages such as discouraging intake of high sugar carbonated drinks can reduce the development of excess weight gain and obesity in adolescents. Scandinavian countries have introduced bans on television advertising to children for ‘energy-rich/nutrition-poor’ (junk) foods and New Zealand is trying to introduce a ‘fat-tax’ which would tax snack foods and soft drinks.

FURTHER READING DCCT research group. Resource utilization and costs of care in the DCCT. Diabetes Care 1995; 18:1468–1478. Haffner SM, Stern MP, Hazuda HP, Pugh JA, Patterson JK. Hyperinsulinaemia in a population at high risk for non-insulin dependent diabetes mellitus. N Engl J Med 1986; 315: 220–224. Rubin RJ, Altman WM, Mendelson DN. Health care expenditures for people with diabetes mellitus, 1992. J Clin Endocrinol Metab 1994; 78: 809A–809F. The Worldwide Burden of Diabetes. Proceedings of a workshop. Phoenix, Arizona, USA. Diabetes Care 1998; 21: Suppl 3. Tuomilehto J, Linström J, Eriksson JG et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001; 344: 1343–50.

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Vascular Complications of Diabetes: Current Issues in Pathogenesis and Treatment, Second Edition Edited by Richard Donnelly, Edward Horton Copyright © 2005 by Blackwell Publishing Ltd

CHAPTER 2 RISK FACTORS

Adrian R. Scott MD, FRCP

INTRODUCTION Prior to the use of glycosylation products such as glycosylated haemoglobin and fructosamine in the late 1970s, estimates of glucose control relied on selfreported urine tests, random blood sugars measured in the outpatient setting and other surrogate measures such as frequency of hypoglycaemia, or measurement of 24 hour urinary glucose excretion. Despite these difficulties, the association between duration of diabetes, the degree of hyperglycaemia and the severity of microvascular and neuropathic complications had long been observed in both type 1 and type 2 diabetes. It was also clear that the relationship between glycaemic control and macrovascular disease was not straight forward since people with mild degrees of hyperglycaemia such as those with impaired glucose tolerance had twice the risk of developing coronary heart disease as those with normal glucose tolerance. In addition, the association of diabetes (particularly type 2) with multiple vascular risk factors such as hypertension and dyslipidaemia was apparent but it has taken until this last decade or so to realize that it is the interaction of these factors that so alters risk and that each must be viewed in this context, not in isolation. This chapter looks at the influence of hyperglycaemia and other factors on the development of microvascular and macrovascular complications.

HYPERGLYCAEMIA In a prospective personal series of 4,400 patients with diabetes, observed between 1947 and 1973, Pirart showed that poor glycaemic control was clearly related to a higher prevalence of retinopathy, nephropathy and neuropathy compared with patients with better control. With the discovery of glycosylated haemoglobin the association between long-term hyperglycaemia and complications was confirmed. Retinopathy and microalbuminuria are good markers of microvascular disease and indicative of a generalized vasculopathy. The numerous studies that have looked at the relationship between glycaemic control and both the onset and progression of microvascular complications have produced remarkably consistent results. For example, The Berlin Retinopathy Study was an observational report on children and adolescents with type 1 diabetes who were followed between 1977 and 1993. At that time Berlin was politically and geographically isolated and most young people with type 1 diabetes were followed up by a single centre. Glycosylated haemoglobin (HbA1C) was available from 1980 onwards and urine for microalbumin was tested from 1987 onwards. Data has been published on 346 patients (190 males) who were followed up to the age of 18–22 years. The rate of onset of

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SECTION I • MICRO- AND MACROVASCULAR COMPLICATIONS OF DIABETES

background retinopathy rose with increasing HbA1C from 0.7 events per 100 patient years in the group with a long-term HbA1C of < 7% to 7.3 events per 100 patient years when the long-term HbA1C was > 11%. The incidence of retinopathy increased steeply when the HbA1C was above 9% (Fig. 2.1) and was similar to the results seen in the Diabetes Control and Complications Trial (DCCT). Surprisingly, glycaemic control did not appear to influence the time to development of retinopathy, except in those with very poor control (HbA1C >13%). In all other groups the median time to onset of background diabetic retinopathy was approximately 12 years. Patients with microalbuminuria, however, developed retinopathy after a mean of 11.5 years compared to 14.7 years in those with normoalbuminuria. The chance of remaining free from background retinopathy after 12 years was < 25% in patients with microalbuminuria compared to 81% in patients without microalbuminuria. In the DCCT study 1,441 highly selected patients aged 13–39 years were randomly assigned to intensive or conventional treatment. Approximately half of those randomized had been selected as free of retinopathy and with normal urinary albumin excretion. The other half had mild to moderate retinopathy and urine albumin excretion 1.5 × 103 5 100 4 1.4 × 104 1

Table 24.1 Tabulated IC50 values (i.e. concentrations in nM required to achieve 50% inhibition of enzyme activity) for ruboxistaurin and the non-specific PKC inhibitor, staurosporine, with respect to each PKC isoform and related intracellular kinases. Adapted from Science 1996; 472: 728–731.

CHAPTER 24 • EXPERIMENTAL PHARMACOLOGY USING ISOFORM-SELECTIVE PKC INHIBITORS

new vessel formation. Thus, blocking VPF-mediated retinal permeability is a prime target for therapeutic amelioration of diabetic maculopathy. Studies in rats have clearly shown that intravitreal administration of VPF increases vitreous fluorescein leakage, and that pretreatment of these animals for one week with ruboxistaurin 25 mg/kg/day via oral administrattion ameliorated VPF and phorbol ester-induced vitreous fluorescein leakage (Fig. 24.2). Furthermore, whereas control rats showed a two-fold increase in vitreous fluorescein leakage after intravitreal VPF administration, rats pretreated with the PKC-β inhibitor showed no difference in basal vitreous fluorescein leakage but there was a 96% reduction in VPF-induced vitreous fluorescein leakage (Fig. 24.2). Increased retinal permeability is a hallmark of neovascularization within the diabetic eye, as well as being a sight-threatening pathological entity even in the absence of new vessel formation. These experimental data have shown that oral administration of ruboxistaurin is well tolerated and considerably

P = 0.015

P = 0.043

Vitreous fluorescein leakage (arbitrary units)

20

10

0 0 0

2 0

0 25

2 VPF (ng/eye) 25 PKC-β inhibitor (mg/kg rat/day)

Fig. 24.2 Oral administration of the PKC-β inhibitor, ruboxistaurin, to normal rats prevents the increase in vitreous fluorescein leakage following intravitreal injection of VPF. Adapted from Diabetes 1997; 46: 1473–1480.

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SECTION IV • MECHANISMS OF HYPERGLYCAEMIA INDUCED VASCULAR DYSFUNCTION

attenuates VPF-mediated retinal permeability. Furthermore, diabetes is characterized by an increase in retinal mean circulation time (MCT), and oral treatment with ruboxistaurin for two weeks in STZ-diabetic rats reduced retinal MCT, as measured by video fluorescein angiography (Fig. 24.3). This experimental data has now been confirmed in phase II clinical trials in which ruboxistaurin administration for one month produced significant improvements in retinal blood flow and MCT among 27 diabetic patients (chapter 25). Larger, multicentre clinical trials are in progress.

(a)

(b) 0.5

*

4

§

§ 2

0

0

(c) 20 *

15 10

+ +

+ +

+ +

0.3 0.2 0.1 1.0

10

+ +

1.5

5 0

* 0.4

0 1.0 10 0 0.1 Dose of ruboxistaurin (mg/kg) (d) 2

0.1

MCT (s)

GFR (ml/min)

+

Filtration fraction (GFR/RPF)

6

Urinary AER (mg/day)

216

§ 1

§

§

0.5

0

0

10

0

0

0.1

1.0

10

Dose of ruboxistaurin (mg/kg)

Fig. 24.3 Effect of oral dosing with ruboxistaurin on renal and retinal vascular function in non-diabetic (●) and STZ-diabetic (●) rats. Untreated diabetic animals show increases in glomerular filtration rate (GFR), renal filtration fraction (GFR corrected for renal plasma flow, RPF), urinary albumin excretion rate (AER) and retinal mean circulation time (MCT). Oral treatment with ruboxistaurin 0.1–10 mg/kg/day ameliorated these renal and retinal haemodynamic abnormalities. Science 1996; 272: 728–731.

CHAPTER 24 • EXPERIMENTAL PHARMACOLOGY USING ISOFORM-SELECTIVE PKC INHIBITORS

Further experimental studies have shown that diabetes-induced reductions in Na+/K+-ATPase and Ca2± -ATPase in the retina are mediated, in part, via PKC-β activation. Oral administration of ruboxistaurin normalizes Na+/K+-ATPase activity in retinal microvessels (Fig. 24.4).

PKC-β INHIBITION AND EXPERIMENTAL NEPHROPATHY The early stages of diabetic renal disease are characterized by glomerular hyperfiltration, mesangial expansion and microalbuminuria. Hyperglycaemiainduced de novo synthesis of DAG, coupled with activation of PKC, especially PKC-β, affects the structural and functional changes in the kidney via several different mechanisms involving various phosphorylation substrates of PKC. For example, mesangial expansion has been attributed, in part, to PKC-mediated increases in transforming growth factor-β (TGFβ) gene expression, activation of cytosolic phospholipase A2 and inhibition of Na+/K+-ATPase activity.

40

#

35

Na+/K+-ATPase activity

30 25 *

20 15 10 5 0 Normal

Diabetes

Diabetes + ruboxistaurin

Fig. 24.4 Oral treatment with the PKC-β inhibitor ruboxistaurin, reverses diabetesrelated reductions in Na+/K+-ATPase activity in retinal microvessels. Adapted from Diabetes 1998; 47: 464–469.

217 217

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Experimental studies with ruboxistaurin have shown that, following oral administration for eight weeks to STZ-diabetic and non-diabetic rats, urinary albumin excretion rate (AER) and glomerular hyperfiltration were significantly reduced (Fig. 24.3). Interestingly, higher doses of the PKC-β inhibitor (1–10 mg/kg/day) were required to inhibit diabetes-mediated PKC activation in the kidney compared with the retina (0.1 mg/kg/day). In addition, treatment with ruboxistaurin had no significant effect on GFR and filtration fraction in non-diabetic animals (Fig. 24.3). Among diabetic rats, however, the dose-response curve for ruboxistaurin in normalizing GFR paralleled its inhibitory effect on PKC activity.

Renal protection with aminoguanidine and angiotensinconverting enzyme inhibition (ACE-I) involves normalization of glomerular PKC activity In experimental models of diabetic renal disease, e.g. the STZ-diabetic rat, it is well established that ACE-Is and aminoguanidine retard the structural and functional abnormalities characteristic of diabetic nephropathy, particularly with respect to reducing urinary AER. The exact mechanisms by which these therapeutic interventions work is not entirely clear, but recent work by George Jerums and colleagues has shown that glomerular PKC activity levels are normalized in STZ-diabetic rats during experimental treatment with aminoguanidine and the ACE-I, ramipril. Thus, diabetes-related increases in glomerular PKC activity may serve as an important common pathway by which metabolic and haemodynamic factors contribute to the initiation and progression of diabetic renal disease. Existing renoprotective agents, e.g. ACE-Is, may slow the progression of nephropathy, in part, by normalizing diabetes-induced increases in glomerular PKC activity.

EFFECTS OF RUBOXISTAURIN IN EXPERIMENTAL DIABETIC NEUROPATHY Various pathways have been implicated in the pathogenesis of diabetic neuropathy, including increased polyol pathway activity, enhanced non-enzymatic glycation and PKC activation. In addition, neural ischaemia is thought to play an important role in diabetic nerve injury, in part via PKC activation which impairs vasodilation and increases vasoconstrictor pathways in the endoneurial microvasculature. In experimental STZ-diabetic rats, motor nerve conduction velocity and sciatic nerve blood flow are reduced. Treatment with ruboxistaurin ameliorated these abnormalities via mechanisms attributable to prevention of neural ischaemia (Fig. 24.5).

CHAPTER 24 • EXPERIMENTAL PHARMACOLOGY USING ISOFORM-SELECTIVE PKC INHIBITORS

Velocity (m/s)

65

control level

60

55

0.0

0.1

0.3

1.0

10.0

25.0

Dose (mg/kg)

Fig. 24.5 Ruboxistaurin improves sciatic nerve conduction velocity in experimental models of peripheral neuropathy. A dose-related effect is illustrated.

CLINICAL IMPLICATIONS OF AN ORALLY ACTIVE PKC-β INHIBITOR, RUBOXISTAURIN Extensive experimental studies have shown that ruboxistaurin selectively inhibits PKC-β in retinal, neural, renal and vascular tissues following oral administration without any significant adverse effects. The encouraging tolerability profile of ruboxistaurin is no doubt attributable to its pharmacological specificity for PKC-βI and PKC-βII. The animal studies have convincingly shown that, following chronic oral treatment, ruboxistaurin ameliorates the early increases in retinal blood flow, glomerular filtration rate and renal and retinal permeability. This data opens the possibility of a new and exciting pathway for therapeutic intervention in the earliest stages of diabetic microvascular disease. In particular, such an approach would be unique in offering protection against the development and progression of retinopathy and nephropathy via a mechanism that is independent of (and complementary to) glucose or blood pressure reduction. Thus, in clinical practice, PKC-β inhibition would be used as an adjunct to all existing therapies for the prevention of diabetic vascular complications. Large multicentre clinical trials are on-going not only in diabetic retinopathy and renal disease but also in patients with other diabetic complications, e.g. erectile dysfunction and diabetic neuropathy.

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CURRENT ISSUES • Ruboxistaurin is a unique orally active PKC inhibitor which is highly specific for the PKC-β isoforms. Following oral administration to STZdiabetic rats, ruboxistaurin prevented diabetes-related increases in retinal and renal PKC activity in parallel with amelioration of glomerular hyperfiltration, microalbuminuria and increased retinal blood flow. • Ruboxistaurin shows an excellent tolerability profile in experimental diabetic animals, no doubt reflecting its specificity for inhibiting only two out of twelve PKC isoforms. Furthermore, in non-diabetic animals (in which there is no augmentation of PKC activity) ruboxistaurin has no significant effects on retinal or renal haemodynamics. Thus, the compound seems to be highly specific for PKC-β and only achieves therapeutic effects in experimental studies in which diabetes-related increases in PKC are present. • Large multicentre clinical trials with ruboxistaurin are on-going to assess its efficacy and safety in patients with diabetic retinopathy and peripheral neuropathy. In due course further studies will be established to define the role of this compound in other diabetes complications, including nephropathy and erectile dysfunction.

FURTHER READING Aiello LP, Bursell SE, Clermont A et al. Vascular endothelial growth factor-induced retinal permeability is mediated by protein kinase C in vivo and suppressed by an orally effective β-isoform-selective inhibitor. Diabetes 1997; 46: 1473–1480. Ishii H, Jirousek MR, Koya D et al. Amelioration of vascular dysfunction in diabetic rats by an oral PKC-β inhibitor. Science 1996; 272: 728–731. Kowluru RA, Jirousek MR, Stramm L et al. Abnormalities of retinal metabolism in diabetes or experimental galactosemia: V relationship between protein kinase C and ATPase. Diabetes 1998; 47: 464–469. Nakamura J, Kato K, Hamada Y et al. A protein kinase C-β-selective inhibitor ameliorates neural dysfunction in streptozotocin-induced diabetic rats. Diabetes 1999; 48: 2090–2095.

Vascular Complications of Diabetes: Current Issues in Pathogenesis and Treatment, Second Edition Edited by Richard Donnelly, Edward Horton Copyright © 2005 by Blackwell Publishing Ltd

CHAPTER 25 Richard Donnelly MD, PhD, FRCP, FRACP CLINICAL TRIALS WITH RUBOXISTAURIN INTRODUCTION Ruboxistaurin is the first molecule in an exciting new class of PKC-β‚ specific inhibitors which ameliorate the structural and functional vascular abnormalities associated with hyperglycaemia in humans and experimental animals. A series of detailed molecular and experimental studies were conducted to document the effects of ruboxistaurin in retinal, neural and endothelial tissues. These were followed by a series of multicentre clinical trials to evaluate longer term efficiency and safety in patients with diabetes related complications. The design and execution of these trials has posed considerable challenges, and many of these trials are still ongoing. There are, however, a number of encouraging results already in the public domain from phase II studies.

RUBOXISTAURIN IMPROVES ENDOTHELIAL DYSFUNCTION Diabetes is associated with endothelial dysfunction, and hyperglycaemia impairs the endothelial-dependent vasodilator response to acetylcholine. In a placebo controlled, double blind crossover study in healthy volunteers, there was evidence that ruboxistaurin improved forearm blood flow in response to incremental arterial infusions of the endothelium-dependent vasodilator methacholine under hyperglycaemic conditions (Fig. 25.1). Thus, this novel experimental study has confirmed that inhibition of PKC-β in healthy volunteers prevents the reduction in endothelium-dependent (nitric oxide mediated) vasodilation induced by acute hyperglycaemia.

CLINICAL TRIALS OF RUBOXISTAURIN IN DIABETIC RETINOPATHY Experimental studies have shown that ruboxistaurin inhibits hyperglycaemia-induced PKC activation in the retina (Fig. 25.2). In addition ruboxistaurin prevents neovascularization in a porcine model of retinal vein occlusion (Fig. 25.3). These experimental data provide encouraging evidence that PKC-β‚ inhibition might have a favourable effect on macular oedema formation and new vessel formation (two sight threatening complications) in patients with diabetic retinopathy. The clinical development of ruboxistaurin began with phase I tolerability and pharmacokinetic studies in healthy volunteers, followed by phase II efficacy studies in patients with diabetes. In patients with type 1 or type 2 diabetes and minimal or no evidence of diabetic retinopathy, ruboxistaurin increased retinal blood flow in a dose-dependent manner, maximal after 32 mg daily for

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Euglycaemia Hyperglycaemia p = 0.08

p = 0.001

Placebo

Ruboxistaurin

Forearm blood flow (ml / dl / min)

3

2

1

0

Fig. 25.1 Forearm blood flow in healthy volunteers during euglycaemia and hyperglycaemia after pretreatment with ruboxistaurin or placebo. The PKC-β‚ inhibitor improved the endothelial-dependent vasodilator response to methacholine under conditions of high glucose. Adapted from Beckman et al. Circulation Research 2002; 90: 107–111.

20

PKC activity (pmo/min/mg of protein)

222

Nondiabetic Diabetic 15

10

5

0 0

0.1

10.0

Ruboxistaurin (mg/kg/d)

Fig. 25.2 Ruboxistaurin attenuates the increase in retinal PKC activity in experimental rats with diabetes.

CHAPTER 25 • CLINICAL TRIALS WITH RUBOXISTAURIN

4

Neovascularization score

p = 0.03 3

2

1

0 Placebo

Ruboxistaurin 1 mg/kg/d, po

Fig. 25.3 Ruboxistaurin prevents neovascularization in a porcine retinal vein occlusion model of new vessel formation.

Extent of MCT abnormality at endpoint

1.2 1.0 0.8 0.6 0.4 0.2 0.0 Placebo

16 mg/d

32 mg/d

Fig. 25.4 Phase II study of ruboxistaurin in patients with type 1 or type 2 diabetes and retinopathy. In a double blind, placebo controlled study for four weeks, ruboxistaurin decreased mean retinal circulation time, i.e. improved retinal blood flow. Adapted from Aiello et al. Diabetes 1999; 48: A19.

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one month (Fig. 25.4). Having confirmed the basic safety and tolerability of ruboxistaurin, and demonstrated that it has pharmacodynamic activity on retinal blood flow, large multi-centre clinical trials were initiated to evaluate the safety and efficacy of the treatment in larger patient groups during longer term administration (two to four years). The PKC-diabetic retinopathy study (DRS) and the PKCdiabetic macular oedema (DME) study were the first international randomized, placebo controlled trials to assess whether oral treatment with ruboxistaurin will delay progression in patients with moderate to severe non-proliferative diabetic retinopathy at base-line, including progression from non-clinically significant to clinically significant macular oedema (CSMO). The results for approximately 1,000 patients followed for an average of 36–46 months will be announced soon. The clinical trials of ruboxistaurin in diabetic retinopathy have two key objectives. First, to determine if oral treatment with ruboxistaurin over three years will reduce progression of diabetic retinopathy or the need for laser photocoagulation in patients with moderately severe to very severe non-proliferative diabetic retinopathy in at least one eye. Second, to determine if all treatment with ruboxistaurin in patients with mild to moderate non-proliferative diabetic retinopathy and non-visually threatening diabetic macular oedema will delay development of clinically-significant macular oedema or the need for laser photocoagulation. The clinical trials with ruboxistaurin use 7-field stereoscopic fundal photographs and measurements of visual acuity as markers of drug efficacy.

CLINICAL TRIALS OF RUBOXISTAURIN IN DIABETIC PERIPHERAL NEUROPATHY A number of large phase III clinical trials are in progress to evaluate the effects of ruboxistaurin on various unpleasant symptoms of diabetic neuropathy and longer term outcomes in relation to nerve function and neurophysiological endpoints. These trials use a combination of symptom scores and nerve function measurements to assess efficacy.

CLINICAL TRIALS OF RUBOXISTAURIN IN OTHER DIABETESRELATED COMPLICATIONS Further clinical trials are in progress to evaluate the effects of ruboxistaurin on renal function and proteinuria, and on endothelial function in relation to lower limb ischaemia and macrovascular end-points.

CHAPTER 25 • CLINICAL TRIALS WITH RUBOXISTAURIN

CURRENT ISSUES • The results of large multicentre clinical trials of ruboxistaurin in patients with diabetic retinopathy and neuropathy are eagerly awaited in 2005–7. • As a completely novel drug, ruboxistaurin has posed unique challenges to the design and execution of international clinical trials in diabetes complications. • The safety and tolerability profile of ruboxistaurin is very encouraging. It is suitable for once-daily oral administration and has no adverse effects on immune function. • There are still some unanswered questions about the optimal dose of ruboxistaurin for each potential indication.

FURTHER READING Aiello LP, Bursell S, Devries T. Protein kinase C beta selective inhibitor Ruboxistaurin ameliorates abnormal retinal haemodynamics in patients with diabetes. Diabetes 1999; 48: A19. Aiello LP, David MD, Sheetz MJ. The PKC Inhibitor Diabetic Retinopathy Study Group. Design, baseline patient characteristics and high prevalence of severe to very severe nonproliferative diabetic retinopathy (NPDR) in the Protein Kinase C Diabetic Retinopathy Study (PKC-DRS). Diabetes 2002; 51 (suppl2): A209. Demolle D, de Suray JM, Onkelinx C. Pharmacokinetics and safety of multiple oral doses of LY333531, a PKC beta inhibitor, in healthy subjects. Clin Pharm Ther 1999; 65: 189. Demolle D, de Suray JM, Vandenhende F, et al. Ruboxistaurin single escalating oral dose study in healthy volunteers. Diabetologia 1998; 41: (Suppl 1): A354. Donnelly R, Idris I, Forrester J. Protein Kinase C inhibition and diabetic retinopathy: a shot in the dark at translational research. Br J Ophthalmol 2004; 88: 145–151.

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Vascular Complications of Diabetes: Current Issues in Pathogenesis and Treatment, Second Edition Edited by Richard Donnelly, Edward Horton Copyright © 2005 by Blackwell Publishing Ltd

226

INDEX aminoguanidine 86, 114, 124, 186–7 renal protection 218 amitriptyline 116, 125 A amputation 17, 35, 70 ACE inhibitors 28, 40, 49 diabetic foot 105, 106, 107, 125 myocardial infarction 63–4 lower limb 7, 8, 9, 18, 61, 67 neuropathy 115, 124 smoking 67 renal protection 218 anaemia 24, 33, 186 retinopathy 134 angiography 26, 39, 43, 61, 66 versus beta-blockers 63 fluorescein 102, 153, 154, 155, 156, 174 acetyl-L-carnitine 124 angioplasty 40, 42, 44, 62, 66 acetylcholine 207, 221 diabetic foot 107 acetylcysteine 26 angiotensin receptor antagonists 30, 70 actin 199, 200 angiotensin-converting enzyme inhibitors see acupuncture 118 ACE inhibitors acute sensory neuropathy 80 ankle reflex 79, 80, 81, 122, 125 adenosine 53, 100, 101 anti-arrhythmics 117 adenosine diphosphate 209 anti-oxidants 114 advanced glycated haemoglobin (Hb-AGE) 186 anti-platelet therapy 43 advanced glycation end-products (AGE) 86–7, anticoagulation 61 114, 179–87, 184 anticonvulsants 116–17, 117, 125 and age-adjusted death rate 180 antihypertensive agents 29, 32, 49, 73 cataract 172 erectile dysfunction 54 cross-linking 185 nephropathy 28–9 formation 183 antioxidants 30 harmful effects 185 apomorphine 55 inhibitors of 114 Appropriate Blood Pressure Control in Diabetes and oxidative stress 200 (ABCD) trial 87 receptors 185–6 arteriography 26 age factors arteriolohyalinosis (Kimmelstiel-Wilson kidney) cataracts 171 26 hypertension and proteinuria 28 AS-3201 124 retinopathy 129, 134 ascorbic acid (vitamin C) 179 age-adjusted death rate 180 ASPECT study 61 ALADIN-II study 87 aspirin 47, 48 albumin-creatinine ratio 25 myocardial infarction 43 albuminuria 22, 24 peripheral vascular disease 62, 68, 70 Albustix 24, 25 stroke 47, 48 alcohol dependency 51, 52 atenolol 63 aldose reductase 76, 85, 86, 124, 171, 187, 188, atherosclerosis 35 189 atorvastatin 67 aldose reductase inhibitors 85, 113–14, 113, autonomic neuropathy 80, 81 124 alkaline phosphatase 32, 110 B allodynia 80, 91, 116 balanitis 52 alpha-lipoic acid 114, 124 BDA Cohort Study 35, 36 alpha-oxoaldehydes 182, 183 beading 144 alprostadil (prostaglandin E1) 56 Becaplermin 108 ALT-462/486 186 Berlin Retinopathy Study 13, 14 alteplase 47, 69 beta-blockers 40, 63 biopsy Amadori rearrangement 179, 182, 183, 185 nerve 101–2 amblyopia 137 skin 102 Page numbers in italic refer to figures; those in bold refer to tables.

INDEX

biothesiometer 99 bisphosphonates 110 blindness 7, 8, 9, 75 neuropathy 129 retinopathy 129, 137 blood-retinal barrier 156 boat shaped haemorrhage 144 body mass index 5 bradykinin 207 brain-derived neurotrophic factor 88, 115 branch retinal vein occlusion 173, 174 British Diabetic Association 149 British Diabetic Association Cohort study 3 Bruch’s membrane 158, 168 Bypass Angioplasty Revascularization Investigation (BARI) trial 44, 66 C C-peptide 89, 124 C-reactive protein 66 calcium 190, 197, 200, 202, 204 caldesmon 200 calphostin 208, 209 capsaicin 118 captopril 29, 63, 73 carbamazepine 117, 125 carbonyl stress 182–3, 184 carboxymethyl-lysine 179 cardiomyopathy 37, 193, 206 carotid stenoses 46 carpal tunnel syndrome 80 cataracts 171–2, 188 treatment 172 central retinal vein occlusion 173 cerebral haemorrhage 43, 45, 48 cerebral infarcts 44 cerebral small-artery disease 46 cerebrovascular disease see stroke Charcot neuroarthropathy 108–10, 108, 109 management 110 X-rays 109 Charcot neuropathy 79 cholesterol and coronary heart disease 18, 19, 20, 36, 37, 38, 40, 43, 67 peripheral neuropathy 93 retinopathy 135 Cholesterol And Recurrent Events study 40 chorioretinal scarring 137 chronic inflammatory demyelinating polyneuropathy 83 chronic sensorimotor neuropathy 79–80 cilostazol 68, 69 circinate of exudates 142, 157 citalopram 116, 125

claudication 67–8, 68, 69 clinically significant macular oedema 142, 158 clomethiazole 49 clopidogrel 48, 62, 66, 71 Clopidogrel in Unstable angina to prevent Recurrent ischaemic Events (CURE) study 62 Clopidogrel vs. Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) study 48 collagen 86, 179, 183, 185, 205 compound muscle action potential 100–1 connexin-43 199 CONSENSUS II trial 41, 63 corneal confocal microscopy 102, 103 coronary heart disease 18, 35–44 aetiology 36–7, 37 anti-platelet therapy 43 environmental factors 36 epidemiology 35–6, 36 and ethnicity 38–9 evidence-based practice 38–44 fetal nutrition 36 glycaemic control 41–3, 42 hazard ratios 16 incidence 35 lipid-lowering therapy 43–4 management 40–1 microalbuminuria 38 mortality 19, 35, 36, 37, 38, 43 obesity 35, 36 prevention 61–7 prognosis 37–8, 38 screening 39 statins 43 vascular risk assessment 38–9 see also myocardial infarction cost of diabetes 7–10, 9, 10 cotton wool spots 139, 141, 142, 143, 173, 174 cranial nerve palsy 174 cranial neuropathy 82 creatinine 26, 27, 31, 32, 73 cross-link formation 185 CT-angiography 26 cyclic GMP 53 cystoid macular oedema 157, 172 D DECODE study 182 delquamine 57 3-deoxyglucosone 179, 182 desipramine 116 Diabetes Control and Complications Trial (DCCT) 3, 14, 28, 93, 132 Diabetes in Early Pregnancy Study 136 diabetic amyotrophy 82, 83

227

228

INDEX

Diabetic Control and Complications Trial (DCCT) 113 diabetic foot 105–10 amputation 105, 106, 107, 125 angioplasty 107 callus formation 105 causes 105–6, 105 education 107 healing 107, 108 hyperbaric oxygen 107 management guidelines 125 PEDIS classification 106 prevention 107 recombinant platelet derived growth factor 108 revascularization 107 risk factors 80, 105 UTDWCS classification 106 Wagner classification 106 diabetic nephropathy see nephropathy diabetic neuropathy see neuropathy Diabetic Retinopathy Study 163 Diabetic Retinopathy Vitrectomy Study 168 diabetic truncal radiculoneuropathy 82–3 diacylglycerol (DAG) 87, 90, 189, 193, 205 DAG-PKC pathway 114, 187, 189 generation of 192 diagnosis 5 dialysis 23, 32 2,3-diaminophenazone 86 diet coronary heart disease 36, 40 nephropathy 30–1 DIGAMI therapy 48, 64 diplopia 82, 174 dipyridamole 48, 70, 71 disc new vessels 145, 164 dot and blot haemorrhages 141 E E-selectin 209 Early Treatment Diabetic Retinopathy Study (ETDRS) 43, 135, 142, 151 EDTA clearance 30 electrophysiology 99–101, 100 enalapril 29, 41, 63, 87 end-stage renal failure 22 endophthalmitis 167, 172, 175 endothelial permeability 197–204, 197, 198, 199, 201 and hyperglycaemia 200 intercellular gaps 198–9 and protein kinase C 200, 203 endothelin 53, 206

entrapment neuropathy 80, 82 environmental factors 4, 35, 136 epalrestat 114, 124 epidemiology 4–6 type 1 diabetes 4 type 2 diabetes 4–6 see also individual conditions Epidemiology of Diabetes Complications (EDC) Study 93 erectile dysfunction 51–7 autonomic neuropathy 52, 55 causes 55 clinical presentation 51–2 diagnostic features 54 drug-related 54 evidence-based practice 54–7, 55, 56 incidence 51 management 54–7 pathophysiology 52–3, 53 erythropoietin 33 essential fatty acids 124 ethnicity 21 coronary heart disease 38–9 epidemiology 5 nephropathy 23 EURODIAB Controlled Trial of Lisinopril in Insulin-Dependent Diabetes Mellitus (EUCLID) 75, 93, 134 EURODIAB IDDM Complications Study 93 European Stroke Prevention Study 48, 70 external ocular muscle palsies 174 extracellular signal-regulated kinases 86 exudates 141, 142 exudative maculopathy 151 F F-actin 199 F-waves 101 ferritin 32 fibrates 43 fibrinogen 37, 62, 209 fidarestat 124 flame-shaped haemorrhages 141 fluorescein angiography 102, 153, 154–5, 154, 155, 156, 173, 174 fluoxetine 116 folic acid 67 foot ulceration see diabetic foot fovea 141 foveola 141 foveolar avascular zone 151 Framingham study 19, 33, 35, 38, 45 free fatty acids 187, 192, 193 fructosamine 13, 182, 183

INDEX

G gabapentin 117, 125 gamma-linolenic acid 114, 124 gangrene 24, 35, 47 gastroparesis 33 gemfibrozil 43 gene expression 205 genetics 36 microvascular disease 135 nephropathy 19, 23 retinopathy 135–6 type 1 diabetes 4 type 2 diabetes 4 GF109203X 213 GISSI-3 41, 63 glaucoma 146, 172 ghost-cell 166 haemolytic 166 neovascular 146, 172 glitazones 43 glomerular filtration rate 22, 31 glomerulopathy 209–10 glomerulosclerosis 25, 26, 185 GLUT-1 transporters 187, 189 glycaemic control, and cardiovascular risk 41–2, 42 glycine antagonists 49 glycoprotein IIb/IIIa glycoprotein receptor inhibitors 62–3 glycosylated haemoglobin (HbA1C) 13, 19, 27, 185 and amputation 67 hazard ratios 70 and myocardial infarction 181 retinopathy 14, 15, 16, 136 glyoxal 182, 183 Gothenburg study 45 grid macular treatment 157 growth factors 88–9, 166 gustatory sweating 32, 81 GUSTO-1 study 63

intracranial 47, 69 intraretinal 141 preretinal 145, 147 retinal 140–1, 144, 168 subarachnoid 45 vitreous 139, 147, 166, 167, 169 hallux valgus 97 Heart Outcomes Prevention Evaluation (HOPE) study 29–30, 41, 42, 48, 64, 65, 67, 71 heparin 47 stroke 48, 69 surface modified intraocular lenses 172 high density lipoprotein (HDL) 18, 135 histamine 199, 200 homocysteinaemia 67 HOT study 62 hydronephrosis 26 hydroxymethylglutaryl CoA reductase inhibitors 88 hyperalgaesia 116 hyperbaric oxygen 107 hyperglycaemia 6, 13–19, 14–18 balanitis 52 cataracts 171 diabetic angiopathy 179, 181 endothelial hyperpermeability 200, 201, 202, 206 endothelial permeability 200 macrovascular disease 13, 16 microvascular disease 13, 18, 19, 132 polyol pathway 187 protein kinase C activation 189, 192, 193, 194, 207, 212 retinopathy 132, 133 stroke 46, 47, 48 treatment 64, 115 vascular injury 181 hyperglycaemic neuropathy 80, 85, 89, 93 hyperlipidaemia 5, 19–21, 20 coronary heart disease 36 erectile dysfunction 53 retinopathy 135 H hypertension 19–21, 20 haematuria 26 coronary heart disease 36, 39 haemodialysis 32 hazard ratios 72 haemoglobin peripheral vascular disease 24 advanced glycated (Hb-AGE) 186 and proteinuria 28 glycosylated see glycosylated haemoglobin retinopathy 25–6, 134 haemorrhage treatment 28–9, 29, 32, 49, 54, 73 boat shaped 144 hypertriglyceridaemia 20–1, 67 cerebral 43, 45, 48 hypoaesthetic neuropathy 92–3 dot and blot 141 hypotension, postural 32, 81 flame-shaped 141

229

230

INDEX

I and hyperglycaemia 13, 16 IgA nephropathy 26 and hypertension 30 imipramine 116, 125 see also coronary heart disease; stroke impaired glucose tolerance 85 macular oedema impotence see erectile dysfunction classification 147 insulin neuritis 80 clinically significant 142, 158 insulin-like growth factor 89, 115 cystoid 157, 172 intercellular adhesion molecule-1 (ICAM-1) 209 duration of diabetes 152, 153 International Working Group of the Diabetic and retinopathy 152 Foot 106 maculopathy 139, 141, 151–61 intracavernosal injection therapy 56 diagnosis 153–6 intraocular pressure 137, 169 diffuse oedema 157 intraretinal haemorrhage 141 epidemiology 151 intraretinal microvascular abnormalities 143, fluorescein angiography 153, 154–5, 155, 165, 165 156 iris neovascularization 146, 164, 165, 172 focal oedema 157 ischaemia, lower limb 4 grid macular treatment 157 leg ulcers 105, 106, 107 ischaemic 151, 153, 154 ischaemic maculopathy 151, 153, 154 laser therapy 157–60 isoquinolinesulphonamides 213 micropulsed diode laser 160 isosorbide dinitrate 115 optical coherence tomography 155–6 spray 118 pathogenesis 156 surgery 158 K treatment 157–8 kidneys see also macular oedema asymmetrical 32 magnesium 49 biopsy 26 magnetic field therapy 110 morphological changes 26 magnetic resonance imaging 102 see also renal Maillard reaction 179, 182 Kimmelstiel-Wilson kidney (arteriolohyalinosis) matrix metalloproteinase 86 26 membrane transport 209–10 metabolic syndrome 5, 19, 20, 53 L metformin 11, 32, 42 lactic acidosis 26, 32 methylglyoxal 182 lacunar infarcts 45, 46 metoprolol 63 lamotrigine 117 mexilitine 117 laser therapy 157–60, 167–8 micro-HOPE study 48 complications 168 microalbuminuria 13, 73 left ventricular hypertrophy coronary heart disease 38 coronary heart disease 38 nephropathy 19, 23–9, 24, 27, 32, 71, 135, nephropathy 24 217 lens proteins, glycation 171 retinopathy 14, 134–5 lidorestat 124 microaneurysms 140 LIPID study 49 micropulsed diode laser 160 lipid-lowering therapy 43–4 microvascular disease 4 lisinopril 29, 41, 63 and erectile dysfunction 52 low density lipoproteins (LDL) 18 genetic factors 135 lubeluzole 49 and hyperglycaemia 13, 18, 19, 132 LY333531 see ruboxistaurin and hypertension 20 smoking 21 M mitogen-activated protein (MAP) kinases 205 macrovascular disease MOLD 184 evidence-based interventions 61 monocytes 209

INDEX

mortality 3, 38, 39 coronary heart disease 19, 35, 36, 37, 38, 43 myocardial infarction 30, 37, 40 stroke 45 Multiple Risk Factor Intervention Trial study 36 myo-inositol 124 myocardial infarction 20 anticoagulation 61 DIGAMI therapy 48, 64 and glycosylated haemoglobin (HbA1C) 181 mortality 30, 37, 40 statins 66–7 thrombolysis 47, 61 myoinositol deficiency 86 myopia 137 myosin light chain kinase 199 N N-[carboxymethyl]-lysine 179, 183, 184 NADH 113, 114 NADPH 113 NADPH oxidase 206 necrobiosis lipoidica 21 nephropathy 21, 23–34 antihypertensive agents 28–9 clinical presentation 23–4, 24, 25, 26 diagnostic features 24–8, 27, 28 diet adjustment 30–1 and ethnicity 23 evidence-based practice 28–31, 29, 30, 71–3, 72, 73 genetics 19, 23 haematuria 26 IgA 26 left ventricular hypertrophy 24 microalbuminuria 19, 23–9, 24, 27, 32, 71, 135, 217 monitoring renal function 31–3, 33 and retinopathy 134–5 ruboxistaurin treatment 216–17, 218–19 nephrotic syndrome 22 nerve biopsy 101–2 nerve conduction velocity 100 nerve growth factor 124 neuropathy 79–84 acute sensory 80 autonomic 80, 81 blindness 129 Charcot’s 79 cholesterol 93 chronic inflammatory demyelinating polyneuropathy 83 chronic sensorimotor 79–80 classification 79, 123 clinical screening 97–8

cranial 82 diabetic amyotrophy 82, 83 diabetic truncal radiculoneuropathy 82–3 entrapment 80, 82 evidence-based interventions 75–6 hyperglycaemic 80, 85, 89, 93 hypoaesthetic 92–3 invasive assessment 101–2 management guidelines 121–5, 122–5 non-invasive assessment 102–3, 103 painful 91–2, 91 pathophysiology 85–90 advanced glycation end-products 86–7 growth factors 88–9 hydroxymethylglutaryl CoA reductase inhibitors 88 immune mechanisms 90 myoinositol deficiency 86 oxidative stress 87 polyol pathway 85–6, 113 protein kinase C-β 87–8 vascular factors 87 peripheral see peripheral neuropathy quantitative sensory testing 98–101, 99, 122 electrophysiology 99–101, 100 thermal thresholds 99 vibration perception threshold 88, 92, 98–9 staging 80, 81 symptoms 97 Neuropathy Disability Score (NDS) 97, 98 Neuropathy Impairment Score (NIS) 97 neuropeptide-Y 53 neurotrophins 88, 115 new vessels elsewhere 145, 146, 163, 164, 165 nisoldipine 87 nitric oxide synthase 207–9 nitroglycerine 57 non-ketotic hyperosmolar states 47 normoglycaemia 113 O obesity 5, 11 childhood diabetes 4, 11 coronary heart disease 35, 36 ocular perfusion pressure 137 oculoischaemic syndrome 173, 174 oculomotor nerve palsy 82 OPB-9195 187 ophthalmoscopy 148 opioids 125 optical coherence tomography 155–6 oral glucose tolerance test 6 oxidative stress 87, 200, 207 oxycodone 125

231

232

INDEX

P painful neuropathy 91–2, 91 pamidronate 110 pancreatic/islet cell transplantation 113 papaverine 56 paroxetine 116, 125 pars plana vitrectomy 168–9 PEDIS classification 106 pentosidine 183, 184 pericytes 140 peripheral neuropathy 91–5 combined assessments 93 negative sensory symptoms 92–3 positive sensory symptoms 91–2, 91 risk factors 94 ruboxistaurin 224 stages of 122 treatment 113–19 peripheral vascular disease diabetic foot 105–10 evidence-based interventions 67–8, 67 smoking 19–21, 20, 67 peritoneal dialysis 32 Peyronie’s disease 52 phentolamine 56, 57 phimosis 52 phosphodiesterase inhibitors 54 pimagedine 186 plasminogen activatory inhibitor-1 37 platelet derived growth factor, recombinant 108 platelet-mediated vasodilation 209 polycystic kidneys 26 polyol pathway 85–6, 113, 183, 187–8, 187 cataracts 171 ponalrestat 124 population screening 11 pravastatin 67 pregabalin 117, 125 pregnancy, retinopathy in 136 prevalence of diabetes 6 proliferative retinopathy 144–6, 163–70 definitions 163–4, 164, 165 diagnosis/natural history 164–6, 165 disc new vessels 145, 164 epidemiology 163 iris neovascularization 164, 165 laser therapy 167–8 new vessels elsewhere 145, 146, 163, 164, 165 pathogenesis 166 retinal detachment 145–6 treatment 166–7, 167 vascular permeability factor 166 vitrectomy 168–9 vitreous detachment 166

protein kinase C 189–95, 189 and endothelial permeability 200, 203 endothelial and vascular smooth muscle function 206–10, 207 and gene expression 205 isoforms 191 vascular permeability 197–204 protein kinase C inhibitors 213–20 protein kinase c-β 87–8 activation of 194 inhibitors of 114–15, 119 proteinuria 13, 17, 19, 29 public health impact 3–11 pyridoxamine 86, 187 pyrraline 87 R ramipril 29–30, 42 myocardial infarction 65 stroke 48, 65 reactive oxygen species 207 Reduction of Cholesterol in Ischaemia and Function of the Endothelium (RECIFE) trial 67 RENAAL study 30, 72 retinal detachment 145–6 retinal haemorrhage 144 retinal hypoxia 166 retinal ischaemia 142 retinal mean circulation time 216 retinal neovascularization 146 retinal photography 148 retinal pigment epithelium 156 retinal vascular abnormalities 173–4, 173 retinopathy 14–16, 14, 15, 139–50 ACE inhibitors 134 background 139–42 blindness 129, 137 circinate exudate rings 142 classification 146–7, 147 clinically significant macular oedema 142 cotton wool spots 139, 141, 142, 143, 173, 174 deep retinal haemorrhages 144 diagnosis 147 direct ophthalmoscopy 148 disc new vessels 145, 164 epidemiology 129–37 evidence-based interventions 74–5, 74, 75 exudates 141, 142 familial clustering 135 growth factors 166 haemorrhages 140–1, 140 incidence 132 intraretinal microvascular abnormalities 143, 165, 165

INDEX

iris neovascularization 146, 164, 165 and microalbuminuria 134–5 microaneurysms 140 neovascular glaucoma 146, 172 new vessels elsewhere 145, 146, 163, 164, 165 preproliferative 142–4, 142 prevalence 129–31, 130, 131 proliferative see proliferative retinopathy retinal detachment 145–6 risk factors 132–7, 133 age 129, 134 blood pressure 25–6, 134 cholesterol 135 duration of diabetes 132 genetics 135–6 glycosylated haemoglobin 15, 16, 136 hyperglycaemia 132, 133 hyperlipidaemia 135 nephropathy 134–5 ocular 137 pregnancy 136 ruboxistaurin 213–17, 215–17, 221–4, 222, 223 screening 148–9 slit-lamp biomicroscopy 148 stages of 139 type 1 diabetes 131 type 2 diabetes 131 UK national screening scheme 149 vascular permeability factor 166 venous abnormalities 144 see also macular oedema; maculopathy revascularization angina 66 diabetic foot 107 risk assessment 38–9 risk factors 13–22 rosiglitazone 43 ruboxistaurin 124, 213 clinical trials 221–4 endothelial dysfunction 221, 222 IC50 values 214 nephropathy 216–17, 218–19 peripheral neuropathy 224 retinopathy 213–17, 215–17, 221–4, 222, 223 structure 214 Rydel-Seiffer tuning fork 97 S San Luis Valley Diabetes Study 93 Scandinavian Simvastin Survival Study 67 selective serotonin-reuptake inhibitors 116, 125

Semmes-Weinstein monofilament 97 serine/threonine kinases 190 sildenafil 51, 54, 56 simvastatin 41, 68 slit-lamp biomicroscopy 148 smoking 19–21, 20, 67 sorbinil 124 Sorbinil Retinopathy Trial 135 sorbitol 187, 188 spinal cord stimulation 119 Starling forces 198 statins 43–4 coronary heart disease 43 myocardial infarction 40, 66–7 nephropathy 33 Steno-2 study 85 Stockholm Diabetes Intervention Study 113 string-of-sausages appearance 144 stroke 45–50 aetiology 46 clinical presentation 46–7 epidemiology 45 evidence-based practice 47–9, 68–71, 69, 70 hyperglycaemia 46, 47, 48 mortality 45 secondary prevention 48 thrombolysis 47, 61 treatment aspirin 47, 48 DIGAMI therapy 48 heparin 48, 69 ramipril 48, 65 substance P 118, 206 sugar cataracts 171 superoxide dismutases 87 sweating, gustatory 32, 81 SYDNEY study 87 T tadalafil 54 talin 199 tenilsetam 86 therapeutic intervention targets 179–95 thermal thresholds 99 thienopyridines 62 thrifty gene hypothesis 5 thrombolysis 47, 61 thrombotic thrombocytopenic purpura 48 ticlopidine 62 timolol 63 tissue plasminogen activator 61 tolrestat 124 tramadol 118, 125 trandalopril 87

233

234

INDEX

transforming growth factor-β 217 transient ischaemic attacks 47 triamcinolone 160 tricyclic antidepressants 116, 125 type 1 diabetes epidemiology 4 natural history 3–4 retinopathy 131 type 2 diabetes epidemiology 4–6 natural history 4 retinopathy 131 tyrosine kinases 190 U UK Prospective Diabetes Study (UKPDS) 4, 30, 42, 54, 59, 132, 181 University Group Diabetes Program 42 urinary albumin excretion rate 197 US Diabetes Control and Complications Trial (DCCT) 132 UTDWCS classification 106 uveitis 172, 174 V VA Cooperative Study on type 2 Diabetes Mellitus (VACSDM) 85 vardenafil 54 vascular adhesion molecule-1 209 vascular endothelial growth factor 89, 115 vascular permeability see endothelial permeability vascular permeability factor 166, 200, 202, 213

vascular risk assessment 38–9 vasodilators 124 Viagra (sildenafil) 51, 54, 56 vibration perception threshold 88, 92, 98–9 vimentin 200 vinculin 199 vitamin E 194–5 vitrectomy see pars plana vitrectomy vitreous detachment 166 Volk Quadraspheric lens 166 Volk Transequator 158 von Willebrand factor 37 W Wagner classification 106 warfarin 48, 61 WARIS study 61 WHO Multinational Study of Vascular Disease 298 Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) 15–16, 67, 129, 151, 163 X xanthine oxidase 206 Y yohimbe 57 Z zenarestat 124 zopolrestat 124