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OXF ORD A M E R I CA N CA R D I O L O G Y L I B R A R Y
Dyslipidemia
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OXF ORD A M E R I CA N CA R D I O L O G Y L I B R A R Y
Dyslipidemia
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This material is not intended to be, and should not be considered, a substitute for medical or other professional advice. Treatment for the conditions described in this material is highly dependent on the individual circumstances. While this material is designed to offer accurate information with respect to the subject matter covered and to be current as of the time it was written, research and knowledge about medical and health issues are constantly evolving, and dose schedules for medications are being revised continually, with new side effects recognized and accounted for regularly. Readers must therefore always check the product information and clinical procedures with the most up-to-date published product information and data sheets provided by the manufacturers and the most recent codes of conduct and safety regulation. Oxford University Press and the authors make no representations or warranties to readers, express or implied, as to the accuracy or completeness of this material, including without limitation that they make no representations or warranties as to the accuracy or efficacy of the drug dosages mentioned in the material. The authors and the publishers do not accept, and expressly disclaim, any responsibility for any liability, loss, or risk that may be claimed or incurred as a consequence of the use and/or application of any of the contents of this material. The Publisher is responsible for author selection and the Publisher and the Author(s) make all editorial decisions, including decisions regarding content. The Publisher and the Author(s) are not responsible for any product information added to this publication by companies purchasing copies of it for distribution to clinicians.
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OXFORD AMER I C AN C AR DI O L O G Y L I BR AR Y
Dyslipidemia Ragavendra R. Baliga, MD, MBA, FACP, FRCP (Edin), FACC Vice Chief & Asst Division Director Professor of Internal Medicine The Ohio State University Medical Center Columbus, Ohio
Christopher P. Cannon, MD Associate Professor of Medicine Harvard Medical School Brigham and Women's Hospital Boston, Massachusetts
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Disclosures Dr. Baliga has served on the Speakers Bureau for Boehringer-Ingelheim, GlaxoSmithKline, Pfizer, Reliant Pharmaceuticals, Merck-Schering Plough/ Merck, and AstraZeneca. He has also received consultant fees/honoraria from Mardil.
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Dr. Cannon has received research grants/support from Accumetrics, AstraZeneca, GlaxoSmithKline, Intekrin Therapeutics, Merck, and Takeda. He has served on the advisory boards for Alnylam, Bristol-Myers Squibb/Sanofi Partnership, and Novartis, and has received honoraria from AstraZeneca and Pfizer for independent educational symposia. He has also been a clinical advisor for Automedics Medical Systems.
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Preface Coronary heart disease (CHD) is not only a major clinical problem but also a public health burden. Every year an estimated 700,000 individuals have a coronary event, 500,000 will have a recurrent coronary event, 500,000 will have a new stroke, and 200,000 will have a recurrent stroke in the United States.1 The estimated prevalence of coronary heart disease is 13 million. The prevalence of CHD risk equivalents includes 20 million diabetics and 8 million individuals with peripheral arterial disease. There are several modifiable risk factors to reduce this public health burden, including highdensity lipoprotein cholesterol (HDL-C)2,3 and non HDL-C4,5 (particularly low-density lipoprotein cholesterol [LDL-C]6,7 and serum triglycerides). Despite aggressive goals recommended by National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) 2004 update8 and ACC/ AHA guidelines for secondary prevention 2006 update and the ACC/AHA update statement that “it is generally possible to achieve LDL-C reductions >50% with therapy,” many patients are still not at optimal levels of LDL-C.9,10 In addition to elevated LDL-C, low HDL-C is associated with increased CHD risk at all levels of LDL-C.4 Every 1-mg/dL increase in HDL-C is associated with a 2% decrease in CHD risk, and every change of 10 mg/dL in the HDL-C level is associated with a 50% change in risk.8 Elevated serum triglyceride levels are also an independent risk factor for CHD, irrespective of LDL-C.11,12 Meta-analysis of 17 prospective studies13 suggests that for every increase in the serum triglyceride level of 89 mg/dL, the risk of CHD increases by approximately 30% in men and approximately 75% in women. Other important risk factors are high-sensitivity C-reactive protein (hs-CRP)14 and lipoprotein15 fractions. Therefore, there is a significant opportunity to reduce CHD risk.16 We invited an international group of experts to discuss the role of dyslipidemia in CHD and the opportunities to modify this risk. Drs. Antonio Gotto and Jennifer Moon from Cornell discuss the role of LDL-C, Dr. Philip Barter from the Heart Research Institute, Sydney, Australia, discusses HDL-C, Dr. Vera Bittner from the University of Alabama discusses nonHDL-C, Drs. Roger Blumenthal, Garth Graham, and Catherine Campbell from Johns Hopkins discuss hs-CRP; Drs. Patrick McBride, Edwin Ferguson, and Donald Wiebe from University of Wisconsin discuss the role of advanced lipoprotein testing, Dr. William Kannel from the Framingham Heart Study discusses risk stratification, and Drs. William Virgil Brown and Charles Harper from Emory discuss therapy of dyslipidemia. Several of the chapters have a clinical vignette that readers will be able to compare with their own patients.
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PEREFACE
We hope that this book will serve as useful resource for physicians and physician extenders to provide better care of their patients and reduce the burden of CHD worldwide. Ragavendra R. Baliga, MD Christopher P. Cannon, MD
1. Roger VL, Go AS, Lloyd-Jones DM, et al. Heart disease and stroke statistics— 2011 update: a report from the American Heart Association. Circulation. 2011;123(4):e18–e209. 2. Barter P, Gotto AM, LaRosa JC, et al. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med. 2007;357(13):1301–10. 3. Kannel WB. High-density lipoproteins: epidemiologic profile and risks of coronary artery disease. Am J Cardiol. 1983;52(4):9B–12B. 4. Liu J, Sempos CT, Donahue RP, et al. Non-high-density lipoprotein and verylow-density lipoprotein cholesterol and their risk predictive values in coronary heart disease. Am J Cardiol. 2006;98(10):1363–8. 5. Bittner V, Hardison R, Kelsey SF, et al. Non-high-density lipoprotein cholesterol levels predict five-year outcome in the Bypass Angioplasty Revascularization Investigation (BARI). Circulation. 2002;106(20):2537–42. 6. Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350(15):1495–504. 7. Gotto AM, Jr. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;351(7):714–7. 8. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110(2):227–39. 9. Smith SC, Jr., Allen J, Blair SN, et al. AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update: endorsed by the National Heart, Lung, and Blood Institute. Circulation. 2006;113(19):2363–72. 10. Davidson MH, Maki KC, Pearson TA, et al. Results of the National Cholesterol Education (NCEP) Program Evaluation Project Utilizing Novel E-Technology (NEPTUNE) II survey and implications for treatment under the recent NCEP Writing Group recommendations. Am J Cardiol. 2005;96(4):556–63. 11. Castelli WP. Epidemiology of triglycerides: a view from Framingham. Am J Cardiol. 1992;70(19):3H-9H. 12. Assmann G, Cullen P, Schulte H. The Munster Heart Study (PROCAM). Results of follow-up at 8 years. Eur Heart J. 1998;19(Suppl A):A2–11. 13. Hokanson JE, Austin MA. Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level: a meta-analysis of population-based prospective studies. J Cardiovasc Risk. 1996;3(2):213–9.
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References
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PEREFACE
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14. Ridker P, Rifai N, Koenig W, et al. C-reactive protein and cardiovascular risk in the Framingham Study. Arch Intern Med. 2006;166(12):1327–8. 15. Stein JH, McBride PE. Should advanced lipoprotein testing be used in clinical practice? Nat Clin Pract Cardiovasc Med. 2006;3(12):640–1. 16. Brown WV. Estimating risk and setting targets for treatment in the national effort to reduce cardiovascular diseases. Foreword. J Clin Lipidol.4(3):139–41.
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Contents Contributors xi 1 2 3 4
LDL Cholesterol HDL Cholesterol Non-HDL Cholesterol Use of High Sensitivity C-Reactive Protein for Risk Assessment 5 Advanced Lipoprotein Testing: Assessment of Cardiovascular Risk and Therapy Beyond Standard Lipid Measurements 6 Stratification of Dyslipidemic Risk 7 Drugs for Treatment of Blood Lipoprotein Abnormalities
1 29 49 67
87 105 117
Index 135
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Contributors Director, Heart Research Institute Professor of Medicine University of Sydney Sydney, Australia
Vera Bittner, MD, MSPH Professor of Medicine Section Head, Preventive Cardiology Division of Cardiovascular Disease University of Alabama at Birmingham Birmingham, AL
Roger S. Blumenthal, MD Professor of Medicine Division of Cardiology Johns Hopkins Ciccarone Center for the Prevention of Heart Disease Baltimore, MD
William Virgil Brown, MD Professor of Medicine Emory University School of Medicine Chief of Medicine Atlanta VA Medical Center Atlanta, GA
Catherine Y. Campbell, MD Postdoctoral Fellow Johns Hopkins Ciccarone Center for the Prevention of Heart Disease Baltimore, MD
Edwin E. Ferguson, MD Professor of Medicine Section of Cardiovascular Medicine
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University of Wisconsin School of Medicine and Public Health Madison, WI
Antonio M. Gotto, Jr., MD, DPhil Stephen and Suzanne Weiss Dean Professor of Medicine Weill Medical College of Cornell University New York, NY
Garth Graham, MD Postdoctoral Fellow Johns Hopkins Ciccarone Center for the Prevention of Heart Disease Baltimore, MD
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Philip Barter, MD, PhD
Charles Harper, MD Associate Professor of Medicine Emory University School of Medicine Atlanta, GA
William B. Kannel, MD, FACC Professor Emeritus Boston University School of Medicine Senior Investigator National Heart Lung and Blood Institute’s Framingham Study Framingham, MA
Kerunne Ketlogetswe, MD Postdoctoral Fellow Johns Hopkins Ciccarone Center for the Prevention of Heart Disease Baltimore, MD
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CONTRIBUTORS
Patrick E. McBride, MD, MPH Professor of Medicine and Family Medicine Section of Cardiovascular Medicine University of Wisconsin School of Medicine and Public Health Madison, WI
Jennifer Moon, PhD Weill Medical College of Cornell University New York, NY
Samia Mora, MD, MHS
Postdoctoral Fellow Johns Hopkins Ciccarone Center for the Prevention of Heart Disease Baltimore, MD
Kerry-Anne Rye, PhD Associate Director, Heart Research Institute Conjoint Professor, Faculty of Medicine University of Sydney Sydney, Australia
Donald A. Wiebe, PhD Associate Professor Department of Pathology and Laboratory Medicine University of Wisconsin School of Medicine and Public Health Madison, WI
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Attending Physician Fish Center for Women’s Health Assistant Professor of Medicine Harvard Medical School Boston, MA
Kiran Musunuru, MD, PhD
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Chapter 1
LDL Cholesterol Antonio M. Gotto, Jr. and Jennifer Moon
The patient is a 53-year-old, nonsmoking, professional male who underwent coronary artery bypass graft surgery 2 years ago following a myocardial infarction (MI). His father had died from MI at age 57. Since his own heart attack, the patient has been exercising regularly, has lost weight, and has become highly committed to his local organic food co-op. He has also been taking aspirin, a beta-blocker, an ACE inhibitor, and atorvastatin 20 mg/d. His fasting lipid profile indicated a low-density lipoprotein cholesterol (LDL-C) level of 125 mg/dL, triglycerides of 118 mg/dL, and a high-density lipoprotein cholesterol (HDL-C) level of 37 mg/dL. His body mass index was 25, his blood pressure was 125/75 mm Hg, his high-sensitivity C-reactive protein (hsCRP) level was 1.9, and he was normoglycemic. At the initial visit after seeing a new physician, the patient was counseled to maintain his program of exercise and healthy eating. The atorvastatin dosage was increased to 40 mg/d, and by the 6-week follow-up visit, the patient’s LDL-C level had decreased to 117 mg/dL and his HDL-C was 38 mg/dL. Since the patient has coronary heart disease (CHD) and three major cardiovascular risk factors (antihypertensive medication, low HDL-C, and age), he is considered to be at very high risk and has an LDL-C target of 100 mg/dL, with an optional lower target of 70 mg/dL. Doubling a statin dosage decreases LDL-C by approximately 6%, so in order to achieve maximal LDL-C reduction, ezetimibe at 10 mg/d was added to atorvastatin 40 mg/d. Addition of ezetimibe would be expected to reduce LDL-C an additional 25% to about 88 mg/dL. To address the low HDL-C, extended-release nicotinic acid was also added, with gradual dosage titration to 1 g/d. Addition of nicotinic acid would be expected to increase HDL-C to at least 45 mg/dL, and depending on the patient’s response, could also lower LDL-C levels, possibly to below 70 mg/dL.
1
Clinical Vignette
Background Low-density lipoprotein, the primary transporter of cholesterol in the blood, consists of a hydrophobic core composed mainly of cholesteryl esters as well as triglycerides, which is encased by a surface monolayer of phospholipids and free cholesterol. A single molecule of apolipoprotein B-100 (apoB-100) covers
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LDL Cholesterol CHAPTER 1
2
approximately 30% of the surface of LDL and plays crucial roles in both normal lipid metabolism and the pathophysiology of atherosclerosis.1 ApoB-100 is also present in very-low-density lipoprotein (VLDL) and intermediate-density lipoprotein (IDL); a truncated form, apoB-48, is contained in chylomicrons and chylomicron remnants. All of the apoB-containing lipoproteins have atherogenic potential, although LDL is the most highly associated with increased cardiovascular risk. LDL particles, which are produced by the liver, vary by size and density.2 Small dense LDL particles are believed to have enhanced atherogenicity due to an increased susceptibility to oxidative modification and a greater degree of endothelial permeability. In conjunction with high triglycerides and low HDL-C, small dense LDL is a characteristic phenotype, known as the “lipid triad,” in patients with diabetes and metabolic syndrome. LDL can be modified by the covalent binding of its apoB component to apolipoprotein(a) to form lipoprotein(a) [Lp(a)], considered to be an emerging marker of cardiovascular risk. Lp(a) levels are thought to be mostly genetically determined, and the clinical significance of Lp(a) reduction remains uncertain. Plasma cholesterol levels are regulated by LDL receptors located primarily in the liver. These receptors, also called B/E receptors, recognize specific binding regions on apoB-100 as well as on molecules of apoE, which are present in all of the other apoB-containing lipoproteins except LDL. Receptor-mediated clearance of LDL and other lipoproteins from the circulation is followed by excretion of excess cholesterol to the intestines via the biliary system. Within the intestines, some of the cholesterol is absorbed and returned to the liver, while some is excreted as fecal bile acids. Role in Atherosclerosis Subendothelial retention of apoB-100-containing lipoproteins by proteoglycans in the arterial wall is hypothesized to be the initiating step in atherosclerosis.3 Building on the traditional response-to-injury model of atherosclerosis, the response-to-retention hypothesis suggests that the normal flux of lipoproteins through the arterial wall is derailed when glycosaminoglycans on proteoglycans bind to sites on apoB-100, precipitating conformational changes in the molecule and rendering LDL particles more prone to pro-atherogenic modification by oxidation and glycation. Retained LDL particles can damage the endothelial lining of the arterial wall, triggering a complex inflammatory and immune response with increased production of chemoattractant molecules, cytokines, and cell adhesion molecules.4 Circulating monocytes are recruited into the arterial intima and converted into macrophages. Activated macrophages trigger a host of pro-inflammatory mediators and ingest modified LDL through scavenger receptors, eventually becoming lipid-laden foam cells. This process of atherosclerosis can be accelerated by the presence of comorbid conditions and major cardiovascular risk factors, including hypercholesterolemia, hypertension, cigarette smoking, diabetes, obesity, and aging. In time, foam cells mass to form a necrotic lipid core, leading to arterial stenosis and, potentially, plaque rupture and thrombosis.
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Relative risk for coronary heart disease (log scale)
LDL Cholesterol CHAPTER 1
3
Relationship Between LDL-C Levels and CHD Risk Elevated plasma LDL-C levels are incontrovertibly linked to increased cardiovascular risk. In general, epidemiological and clinical trial data demonstrate a log-linear relationship between LDL-C levels and the relative risk for CHD, so that each 30-mg/dL decrease in LDL-C translates into a relative reduction in risk of approximately 30% (Fig. 1.1).5 Stated differently, each 1% reduction in LDL-C decreases CHD risk by approximately 1% over a period of 5 years.6 Population studies beginning in the 1950s, including the Seven Countries Study and the Framingham Heart Study, posited a correlation between elevated cholesterol levels and cardiovascular risk,7,8 but it was not until the development of the lipid-lowering class of drugs known as 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, that this relationship was firmly established. Beginning in the 1990s, a series of randomized controlled trials with statins in primary and secondary prevention demonstrated that reductions in LDL-C led to corresponding reductions in cardiovascular morbidity and mortality across a range of patient subgroups. For example, the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS), which enrolled 6,605 individuals with average LDL-C levels and low HDL-C, showed that treatment with lovastatin over approximately 5 years led to a mean reduction in LDL-C of 25% from baseline and a mean increase in HDL-C of 6%.9 These alterations in lipids were associated with a highly significant 37% reduction in first acute major coronary events compared to placebo. The Cholesterol Treatment Trialists’ meta-analysis of 14 randomized trials, which included more than 90,000 participants, found that each 1-mmol/L (approximately 39-mg/dL) reduction in LDL-C translated into relative reductions of 12% for all-cause mortality, 26%
3.7 2.9 2.2 1.7 1.3 1.0 40
70
100
130
160
190
LDL-Cholesterol (mg/dL)
Figure 1.1 Log-linear relationship between LDL-C levels and relative risk for CHD. This relationship is consistent with a large body of epidemiological data and with data available from clinical trials of LDL-lowering therapy. These data suggest that for every 30-mg/dL change in LDL-C, the relative risk for CHD is changed in proportion by about 30%. The relative risk is set at 1.0 for LDL-C = 40 mg/dL. (Reprinted from Grundy SM, Cleeman JI, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. J Am Coll Cardiol 2004;44(3): 720–32, with permission from Elsevier.)
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LDL Cholesterol CHAPTER 1
4
for nonfatal MI, 23% for major coronary events, 24% for revascularization, and 17% for stroke.10 Clinical benefit was determined to be proportional to the absolute reduction in LDL-C, regardless of baseline levels. This meta-analysis also confirmed the safety of statin therapy and showed that reductions in cholesterol levels were not associated with increased risk for cancer and that the 5-year excess risk for rhabdomyolsis, the primary serious adverse reaction with statins, was extremely low and nonsignificant (absolute excess 0.01% [SE 0.01]; p = 0.4). Beginning at the turn of the millennium, studies comparing intensive versus standard-dosage statin therapy in secondary prevention provided support for the hypothesis that “lower is better.” Major trials with aggressive statin therapy in high-risk patients with CHD or multiple major risk factors demonstrated clinical benefit when LDL-C levels were reduced to below 100 mg/ dL, or even lower. For example, the Treating to New Targets (TNT) study examined the safety and efficacy of lowering LDL-C to well below 100 mg/dL in 10,000 patients with stable CHD and baseline LDL-C of less than 130 mg/dL.11 Following 5 years of therapy, the arm treated with standard (10 mg/d) atorvastatin therapy reached a mean LDL-C of 101 mg/dL, while the intensive (80 mg/d) arm achieved a mean LDL-C of 77 mg/dL, which was associated with a 22% relative reduction in the risk of a first major cardiovascular event and no increase in adverse events. Post hoc analysis of the TNT study showed greater benefit as on-treatment LDL-C levels declined, and patients who achieved LDL-C levels below 64 mg/dL experienced the greatest cardiovascular benefit.12 Based on current evidence, there is no lower threshold beyond which LDL-C reduction ceases to be beneficial. Clinical benefit also appears independent of the lipid-lowering mechanism employed. A meta-analysis of 19 trials by Robinson and coworkers, which included 5 dietary trials, 3 trials with bile acid sequestrants, 1 ileal bypass study, and 10 statin trials, found that the linear relationship between percentage reductions in LDL-C and relative risk reductions for nonfatal MI and CHD death was maintained across a variety of lipidlowering modalities (Fig. 1.2).6
Strategies/Approach The National Cholesterol Education Program, which issues the Adult Treatment Panel III (ATP III) guidelines for cholesterol testing and management, advocates primary prevention of CHD through improved control of cardiovascular risk factors and implementation of therapeutic lifestyle changes (TLC).13 The major aims of primary prevention are to reduce long-term (more than 10 years) risk within the population through education and lifestyle modification and to reduce short-term (10 years or less) risk in specific at-risk individuals through screening and intensive control of risk factors. A recent study estimated that full adherence to existing ATP III primary prevention guidelines in the United States could prevent approximately 20,000 MIs and 10,000 CHD deaths annually.14 Secondary prevention focuses on aggressive treatment to low LDL-C
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60
LDL Cholesterol
Nonfatal MI and CHD death relative risk reduction, %
80
WOSCOPS CARE LIPID AF/TexCAPS HPS ALERT PROSPER ASCOT-LLA CARDS
CHAPTER 1
London Oslo MRC Los Angeles Upjohn LRC NHLBI POSCH 4S
100
40 20 0 –20 20
25 30 LDL-C reduction, %
35
40
Figure 1.2 Estimated change in the 5-year relative risk of nonfatal MI or CHD death associated with mean LDL-C reduction for the diet, bile-acid sequestrant, surgery, and statin trials (dashed line) along with the 95% probability interval (dotted line). The solid line has a slope = 1. The crude risk estimates from the individual studies are plotted along with their associated 95% confidence intervals. Statin trials are designated by the boldface symbols. (Reprinted from Robinson JG, et al. Pleiotropic effects of statins: benefit beyond cholesterol reduction? A meta-regression analysis. J Am Coll Cardiol 2005;46(10):1855–62, with permission from Elsevier.) MRC = Medical Research Council; LRC = Lipid Research Clinics; NHLBI = National Heart, Lung, and Blood Institute; POSCH = Program on the Surgical Control of the Hyperlipidemias; 4S = Scandinavian Simvastatin Survival Study; WOSCOPS = West of Scotland Coronary Prevention Study; CARE = Cholesterol and Recurrent Events study; LIPID = Long-Term Intervention with Pravastatin in Ischemic Disease; AF/TexCAPS = Air Force/Texas Coronary Atherosclerosis Prevention Study; HPS = Heart Protection Study; ALERT = Assessment of Lescol in Renal Transplantation; PROSPER = Prospective Study of Pravastatin in the Elderly at Risk; ASCOT-LLA = Anglo-Scandinavian Cardiac Outcomes Trial–LipidLowering Arm; CARDS = Collaborative Atorvastatin Diabetes Study
5
15
targets, coupled with comprehensive management of lifestyle-related risk factors, for patients at the highest risk of future coronary events. Evaluation To identify individuals at risk for CHD, ATP III recommends that a fasting lipid profile, including measures of total cholesterol, LDL-C, HDL-C, and triglycerides, be obtained every 5 years in all adults aged 20 years and older. In addition to a lipid profile, screening for dyslipidemia should include a physical examination and thorough medical history to identify the presence of CHD, CHD risk equivalents, or major cardiovascular risk factors. A summary of ATP III guidelines for risk stratification and assignment of LDL-C targets is discussed in the Guidelines section below. If a patient has abnormal lipid levels, it is necessary to exclude potential primary (genetic) and secondary causes of dyslipidemia. Very elevated LDL-C levels
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LDL Cholesterol CHAPTER 1
6
are suggestive of a genetic disorder, such as familial hypercholesterolemia (FH), familial combined hyperlipidemia (FCH), or familial defective apoB-100 (FDB).15 The presence of tendinous xanthomas on the Achilles tendon or the extensor tendons of the hands and feet strongly points towards a diagnosis of FH or FDB. Corneal arcus and xanthelasma frequently arise in patients with genetic causes of hypercholesterolemia, but are also commonly found in patients with normal lipid profiles. FH is most often caused by mutations in the LDL receptor gene, and FH homozygotes lack LDL receptors entirely. Homozygous FH, which occurs in approximately 1 in 1 million patients, can cause LDL-C levels in excess of 1,000 mg/dL at birth, with affected children developing severe premature atherosclerosis. Heterozygous FH, which is characterized by half the number of normal LDL receptors and LDL-C levels between 200 and 400 mg/ dL, can be observed in approximately 1 in 500 individuals. FCH, an autosomal dominant disorder, is the most common genetic cause of elevated LDL-C. With this condition, apoB is overproduced, resulting in increased levels of VLDL particles, delayed clearance of postprandial triglycerides, and increased flux of free fatty acids. High levels of VLDL and triglycerides lead, via a series of metabolic steps, to the atherogenic lipid triad of low HDL-C, elevated triglycerides, and increased levels of small dense LDL. FDB is caused by a genetic mutation in apoB that prevents LDL receptor-mediated clearance, and it often resembles FH, though patients may exhibit lesser degrees of LDL-C elevation. If an underlying genetic disorder is suspected, genetic counseling with screening of family members is recommended. Major secondary causes of hyperlipidemia include diabetes, hypothyroidism, chronic renal failure, nephrotic syndrome, chronic liver disease, and drugs including thiazide diuretics, non-cardioselective beta-blockers, antiretroviral therapy, anabolic steroids, corticosteroids, cyclosporine, and progestins.15,16 Tests of liver, kidney, and thyroid function are necessary to rule out potential secondary causes of dyslipidemia. Anorexia nervosa, Cushing syndrome, and porphyrias may additionally cause elevated LDL-C levels. Management Therapeutic Lifestyle Changes Therapeutic lifestyle changes, including dietary modification, aerobic exercise, weight loss, and smoking cessation, are the first line of therapy for patients with hypercholesterolemia.13 All individuals whose LDL-C levels exceed their recommended target should begin and maintain a program of TLC. In Western societies, overconsumption of saturated fat is the primary driver of hypercholesterolemia in the population, with dietary studies demonstrating that for each 1% increase in calories derived from saturated fatty acids, serum LDL-C increases by approximately 2 to 3 mg/dL.7 In contrast, the relationship between dietary cholesterol and plasma cholesterol levels is highly variable between individuals. ATP III guidelines specify that saturated fat consumption should be less than 7% of total caloric intake, and dietary cholesterol intake should not exceed 200 mg/d.13 Total fat should be restricted to 25% to 35% of total calories, with
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LDL Cholesterol CHAPTER 1
Medications For some patients who remain hypercholesterolemic after a trial of TLC or who are deemed to be at high cardiovascular risk, pharmacological therapy to reduce levels of LDL-C is warranted. When drug therapy is initiated, dosages strong enough to achieve reductions in LDL-C of 30% to 40% are recommended.5 Drug classes that primarily lower LDL-C include the statins, bile acid sequestrants, and cholesterol absorption inhibitors. The statins are generally considered the initial drug of choice for reducing LDL-C because of their proven efficacy and few side effects. Nicotinic acid and the fibrates act primarily to increase HDL-C and reduce triglycerides; they produce more modest reductions in LDL-C and are often used in combination with statins for the treatment of mixed dyslipidemias. Prescription-strength omega-3 fatty acids are used to reduce triglycerides in patients with severe hypertriglyceridemia and are discussed further in Chapter 3. Table 1.1 gives information on the effects of the different drug classes on serum lipid levels
7
trans fatty acid consumption kept low. Increased physical activity and weight reduction, which can positively affect risk factors including dyslipidemia, hypertension, and insulin resistance, are also recommended. A 6-week trial of dietary modification and exercise can be followed by specific therapeutic measures that decrease LDL-C levels by inhibiting cholesterol absorption within the intestines, including increased ingestion of plant stanols/sterols (2 g/d) and viscous (soluble) fiber (10 to 25 g/d).
Statins Statins share a common mechanism and act by partially and reversibly reducing the activity of HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis, resulting in decreased intrahepatic cholesterol levels and subsequent upregulation of the LDL receptor.2,16 The primary effect of statin therapy is LDL-C reduction, with expected decreases of 20% to 63% depending on the dosage and specific agent. Individual responses to statin therapy are variable and are thought to have a genetic basis. The statins may effect modest increases in HDL-C, typically ranging from 5% to 15%, and reductions in triglycerides of
Table 1.1 Effects of Drug Classes on Serum Lipids2 Drug Class
Total Cholesterol
LDL-C
HDL-C
Triglycerides
Statins
d 15%–60%
d 20%–63%
i 5%–15%
Bile acid resins
d 20%
d 15%–25%
i 3%–5%
d 10%–37% Variable
d 17–25%
i 3%
d 8%
d 5%–25% Variable
i 15%–35%
d 20%–50%
i 10%–20%
d 20%–50%
N/A
N/A
d 35%–50%
Cholesterol d 13% absorption inhibitors Nicotinic acid d 25% Fibric acid d 15% derivatives Omega-3 fatty acids N/A
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LDL Cholesterol CHAPTER 1
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10% to 37%. Available agents include atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin (Mevacor), pitavastatin (Livalo), pravastatin (Pravachol), rosuvastatin (Crestor), and simvastatin (Zocor). Lovastatin, pravastatin, and simvastatin were the first agents to be released and are fungal derivatives. Atorvastatin, fluvastatin, rosuvastatin, and pitavastatin are synthetic compounds that vary considerably in terms of chemical structure. Recommended daily therapeutic dosages, which typically reduce LDL-C by 30% to 45%, are atorvastatin 10 to 20 mg, fluvastatin 40 to 80 mg, lovastatin 40 mg, pitavastatin 2 to 4 mg, pravastatin 40 mg, rosuvastatin 10 mg, and simvastatin 20 to 40 mg. Clinical trials with statins have demonstrated that reductions in LDL-C translate into reduced risk for all-cause and CHD mortality, MI, coronary revascularization, and ischemic stroke (Table 1.2). Angiographic and other imaging trials with statins have shown regression of atherosclerosis and reduced progression of coronary occlusion, although the clinical significance of these changes remains uncertain. In addition, researchers have proposed that statins might exert beneficial effects, termed pleiotropic effects, that are unrelated to LDL-C reduction. Some of these putative pleiotropic effects include improvement of endothelial function and myocardial ischemia, stabilization of atherosclerotic plaques, antioxidant effects, and reductions in macrophage activity, thrombosis, and inflammation.6 None of these pleiotropic effects have demonstrated clinical benefit except for inflammation. Results from the Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) study, discussed below, suggest that simultaneous reductions in the inflammatory marker hsCRP and LDL-C with statins may confer the greatest benefit in at-risk individuals within primary prevention.17 In general, all of the statins are indicated to improve a patient’s lipid profile and reduce cardiovascular risk as an adjunct to dietary therapy, but their specific U.S. Food and Drug Administration (FDA)-approved indications vary (Table 1.3). Statins are contraindicated in women who are pregnant or planning to become pregnant since cholesterol is essential to fetal development. Women should not breastfeed while taking statins, which are excreted in breast milk. Lovastatin, simvastatin, and atorvastatin are metabolized via the cytochrome P450 (CYP) 3A4 pathway, which increases the potential for interactions with drugs that inhibit the CYP34A pathway, such as ketoconazole, erythromycin, or protease inhibitors. Fluvastatin and rosuvastatin are metabolized by the CYP2C9 pathway, which can increase the risk for interactions with phenytoin and warfarin. Pitavastatin is marginally metabolized by the CYP2C9 pathway, and pravastatin is not significantly metabolized by the CYP pathway.2,16 Lovastatin was the first statin introduced in the United States and the first to become generically available. Dosing is at 10 to 80 mg/d in a single dose or two divided doses. The usual starting dosage is 20 mg/d at the evening meal. At the maximum dose, reductions in LDL-C of 40% can be expected. Lovastatin is also available in an extended release formulation (Altocor). The recommended dosing range is 10 to 60 mg/day, in single doses. Clinical benefit with lovastatin in primary prevention was demonstrated in AFCAPS/TexCAPS, which showed
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Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER)17
Primary Prevention West of Scotland Coronary Prevention Study (WOSCOPS)18 Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS)9 Prospective Study of Pravastatin in the Elderly at Risk (PROSPER)21 Anglo-Scandinavian Cardiac Outcomes Trial—Lipid-Lowering Arm (ASCOTLLA)29 Collaborative Atorvastatin Diabetes Study (CARDS)30
Study
Rosuvastatin 20 mg/d vs. placebo; 1.9 years
Atorvastatin 10 mg/d vs. placebo; 3.9 years
Pravastatin 40 mg/d vs. placebo; 3.2 years Atorvastatin 10 mg/d vs. placebo; 3.3 years
Pravastatin 40 mg/d vs. placebo; 4.9 years Lovastatin 20–40 mg/d vs. placebo; 5.2 years
Comparison and Duration
Table 1.2 Major Clinical Trials with Statin Therapy
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6,595 men, ages 45–64, with no history of MI, LDL-C >155 mg/dL 6,605 men (ages 45–73) and women (ages 55–73), with LDL-C 130–190 mg/dL and HDL-C