Dyslipidemia Oxford American Cardiology Library

O A C L 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 00-Baliga-Prelims.indd i 9/20/2011 1:...

Author: Ragavendra R. Baliga | Christopher P. Cannon

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O A C

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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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O A C

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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

xii

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

8

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

9

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 <46 mg/dL 5,804 patients, ages 70–82, with vascular disease or multiple risk factors 10,305 hypertensive patients, with at least 3 other major risk factors, total cholesterol (TC) <251 mg/dL 2,838 patients with type 2 diabetes and at least one other major risk factor, LDL <160 mg/dL 17,802 patients without CHD, LDL-C <130 mg/dL, and hsCRP >2 mg/L

Patients

CHAPTER 1

LDL Cholesterol

(continued)

44% reduction in MI, stroke, revascularization, unstable angina, or CHD mortality; 54% reduction in MI; 20% reduction in all-cause mortality

31% reduction in nonfatal MI or CHD death; 33% reduction in CHD deaths 37% reduction in ﬁrst major coronary event; 40% reduction in MI; 33% reduction in revascularization 15% reduction in CHD death, nonfatal MI, and stroke; 24% reduction in CHD mortality 36% reduction in nonfatal MI and fatal CHD; 27% reduction in stroke; 29% reduction in total coronary events 37% reduction in major cardiovascular events; 27% reduction in total mortality

Outcomes

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1,667 patients with angina or silent ischemia following percutaneous coronary intervention, TC 135–270 mg/dL 4,162 patients recently hospitalized with 16% reduction in cardiovascular events; acute coronary syndromes 14% reduction in revascularization; 29% reduction in recurrent angina

10,001 patients with stable CHD and LDL-C <130 mg/dL

Pravastatin 40 mg/d vs. placebo; 5 years Pravastatin 40 mg/d vs. placebo; 6.1 years

Simvastatin 40 mg/d vs. placebo; 5 years

Fluvastatin 40 mg/d vs. placebo; 3.9 years

Atorvastatin 80 mg/d vs. pravastatin 40 mg/d; 2 years

Atorvastatin 80 mg/d vs. 10 mg/d; 5 years

Heart Protection Study (HPS)23

Lescol Intervention Prevention Study (LIPS)26

Pravastatin or Atorvastatin Evaluation and Infection Therapy—Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22)28 Treating to New Targets (TNT)11

20,536 patients with coronary disease, diabetes, non-coronary occlusive disease, hypertension

9,014 patients with history of MI or unstable angina, TC 155–271 mg/dL

4,159 patients with history of MI

22% reduction in ﬁrst major cardiovascular event

30% reduction in all-cause mortality; 42% reduction in CHD mortality; 34% reduction in major coronary event 24% reduction in nonfatal MI or CHD death; 25% reduction in MI 24% reduction in CHD mortality; 22% reduction in all-cause mortality; 20% reduction in revascularization 17% reduction in vascular deaths; 13% reduction in all-cause mortality; 27% reduction in nonfatal MI and CHD death; 30% reduction in ischemic stroke 22% reduction in major adverse cardiac events

Cholesterol and Recurrent Events (CARE)19 Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID)20

4,444 patients with angina or previous MI, TC 213–309 mg/dL

Simvastatin 20–40 mg/d vs. placebo; 5.4 years

Outcomes

Secondary Prevention Scandinavian Simvastatin Survival Study (4S)22

Patients

LDL Cholesterol

Comparison and Duration

CHAPTER 1

Study

Table 1.2 Continued

10

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Indication Primary prevention of CHD by reducing the risk of clinical events, including MI, stroke, unstable angina, coronary revascularization, and/or cardiovascular mortality in patients with hypercholesterolemia, multiple risk factors, and/or diabetes# Reduce total cholesterol (TC), LDL-C, apo B, and triglycerides in patients with primary hypercholesterolemia and mixed dyslipidemias Reduce TC and LDL-C only in patients with primary hypercholesterolemia Increase HDL-C in patients with primary hypercholesterolemia and mixed dyslipidemias Reduce triglycerides in patients with hypertriglyceridemia and primary dysbetalipoproteinemia Slowing progression of atherosclerosis

X

X

X

X

X

Fluvastatin

Atorvastatin X

X

11

Lovastatin X

X

X

Pitavastatin

Table 1.3 U.S. Food and Drug Administration-Approved Indications for Statins*

X

X

X

Pravastatin X

X

X

X

X

CHAPTER 1

X

X

(continued)

Simvastatin X

LDL Cholesterol

Rosuvastatin X

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#

X

X

X

X

X

Fluvastatin X

Atorvastatin

X

Lovastatin X

Pitavastatin

X

X

Pravastatin X

X

X

X

X

X

Simvastatin

LDL Cholesterol

Rosuvastatin

CHAPTER 1

Speciﬁc indications vary, and each drug is not indicated for all of the above. Physicians should consult the full prescribing information for more detailed indications.

*Data from package inserts.

Indication Slowing progression of atherosclerosis in CHD patients Reduce risks for MI, stroke, revascularization, angina, hospitalization for congestive heart failure, and/or cardiovascular mortality in secondary prevention# Treatment of adolescent patients with heterozygous FH Treatment of homozygous FH

Table 1.3 Continued

12

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LDL Cholesterol CHAPTER 1

13

a 37% reduction in ﬁrst acute major coronary events in patients with “average” cholesterol levels and low HDL-C.9 Angiographic trials with lovastatin have demonstrated slowing in the progression of atherosclerotic plaques. Pravastatin is dosed at 10 to 80 mg/d, with a maximum reduction in LDL-C of 37% at the highest dose. The usual starting dosage is 40 mg/d at any time of day. The West of Scotland Coronary Prevention Study (WOSCOPS), conducted in men with very high LDL-C levels, was the ﬁrst large-scale trial to show clinical event reduction with statins in primary prevention.18 In secondary prevention, pravastatin has shown clinical event reduction in the Cholesterol and Recurrent Events (CARE) and Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) trials.19,20 The Prospective Study of Pravastatin in Elderly at Risk (PROSPER), which demonstrated risk reduction for CHD death, helped establish the efﬁcacy and safety of statin therapy in older individuals.21 Angiographic trials with pravastatin have showed attenuation of atherosclerotic plaque progression. Daily dosages for simvastatin range from 5 to 80 mg/d, with usual starting dosages of 20 or 40 mg taken once a day in the evening. High-risk individuals should begin at a dosage of 40 mg/d. Maximum reductions in LDL-C of 47% can be achieved with dosages of 80 mg/d. Simvastatin can interact with amiodarone and verapamil, in addition to inhibitors of hepatic CYP3A4. Simvastatin was the ﬁrst statin to show clinical beneﬁt in a large randomized trial. In the Scandinavian Simvastatin Survival Study (4S), a mean LDL-C reduction of 36% in the intervention group was associated with a 30% reduction in all-cause mortality compared to placebo.22 The Heart Protection Study extended these ﬁndings of improved survival to a wider population, including women, the elderly, and people with “average” LDL-C levels.23 The recent SEARCH trial compared intensive (80 mg/d) with standard (20 mg/d) simvastatin therapy in 12,000 patients with previous MI over a period of 6.7 years.24 Although intensive therapy reduced mean LDL-C levels by an additional 14 mg/dL compared to standard therapy, the observed 6% relative reduction in clinical events was nonsigniﬁcant, and the intensive arm experienced signiﬁcantly more cases of myopathy (53 vs. 6). Based on these results, it is advisable to avoid prescribing simvastatin at maximal dosages and to instead achieve intensive lipid-lowering by combining simvastatin at standard dosages with another agent such as ezetimibe or by considering more potent statin alternatives. Fluvastatin is dosed at 20 to 80 mg/d, with starting dosages determined by the required degree of LDL-C reductions. For patients needing reductions of at least 25%, the initial dosage should be 40 mg as one capsule in the evening, titrated to 80 mg in either one or two doses at any time of the day. For patients requiring lesser reductions in LDL-C, the starting dosage should be 20 mg/d. At maximum dosages, ﬂuvastatin can reduce LDL-C by 36%. The angiographic Lipoprotein and Coronary Atherosclerosis Study (LCAS) demonstrated slowing in the progression of atherosclerosis.25 Fluvastatin has also shown beneﬁt in the Lescol Intervention Prevention Study (LIPS), which examined early initiation of statin therapy following percutaneous coronary intervention in patients with average cholesterol levels,26 and in the Assessment of Lescol in Renal Transplantation (ALERT) study in renal transplant recipients.27

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LDL Cholesterol CHAPTER 1

14

Atorvastatin is one of the most highly prescribed drugs in the world, and its efﬁcacy and safety have been extensively tested in large trials. Dosages range from 10 to 80 mg/d, with maximal reductions in LDL-C of 60% at the highest dosage. Recommended starting dosages for patients with primary hypercholesterolemia or mixed dyslipidemia are 10 or 20 mg/d. Patients who require LDL-C reductions greater than 45% may be started on a dosage of 40 mg/d. Within secondary prevention, the Pravastatin or Atorvastatin Evaluation and Infection Therapy—Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) study demonstrated beneﬁt with early initiation of intensive statin therapy following acute coronary syndromes,28 and TNT showed clinical event reduction with intensive atorvastatin treatment in patients with stable CHD.11 Within primary prevention, atorvastatin showed clinical beneﬁt compared to placebo in high-risk hypertensive patients in the Anglo-Scandinavian Cardiac Outcomes Trial—Lipid-Lowering Arm (ASCOT-LLA)29 and in high-risk diabetic patients in the Collaborative Atorvastatin Diabetes Study (CARDS).30 In the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial, which measured coronary atheroma burden using intravascular ultrasound, intensive atorvastatin therapy outperformed standard pravastatin therapy, with atorvastatin demonstrating lack of atherosclerotic plaque progression.31 Atorvastatin is also available in a combined formulation with amlodipine (Caduet), which is indicated in patients for whom treatment with both amlodipine (a calcium channel blocker which is indicated for the treatment of hypertension) and atorvastatin is appropriate. The dosing for rosuvastatin ranges from 5 to 40 mg/d, taken with or without food and at any time of the day. The usual starting dosage is 10 mg/d, but 20 mg/d can be considered for high-risk individuals with baseline LDL-C levels above 190 mg/dL. At a dosage of 40 mg/d, rosuvastatin can reduce LDL-C levels by 63%. Recent results from the JUPITER study have established the efﬁcacy of rosuvastatin in primary prevention, particularly for individuals with low LDL-C but elevated levels of hsCRP.17 Stopped early after a median 1.9 years of follow-up due to clear evidence of beneﬁt, JUPITER showed that rosuvastatin at 20 mg/d reduced LDL-C levels by 50% to a median of 55 mg/dL and decreased hsCRP levels by 37%, corresponding to a 44% relative reduction in major cardiovascular events and a 20% reduction in all-cause mortality compared to placebo. Individuals who achieved LDL-C levels of less than 70 mg/dL and hsCRP levels of less than 1 mg/L experienced the greatest beneﬁt, with a 79% relative reduction in cardiovascular events.32 The 5-year number-needed-to-treat to prevent a cardiovascular event for the study overall was 25, considerably lower than that observed for AFCAPS/TexCAPS and WOSCOPS (approximately 50).17 The JUPITER results suggest that for individuals initiating statin therapy at increased risk for cardiovascular events, reductions in both LDL-C and CRP are indicators of the greatest cardiovascular beneﬁt. Based on these ﬁndings, the FDA advisory recently approved an expanded indication for rosuvastatin for primary prevention in men 50 years or older or women 60 years or older, with hsCRP levels above 2 mg/L and at least one additional cardiovascular risk factor.33 Rosuvastatin is the ﬁrst statin with an indication based on measures of hsCRP. In terms of imaging studies, A Study to Evaluate the Effect of

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LDL Cholesterol CHAPTER 1

15

Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden (ASTEROID) was one of the ﬁrst major trials to demonstrate atherosclerotic regression, using three separate measures of atheroma burden.34 Pitavastatin was approved by the FDA in August 2009 and has been available in the U.S. since June of 2010. It has been available in Japan since 2003, as well as in other Asian countries. Dosing for pitavastatin ranges from 1 to 4 mg/d, with a usual starting dose of 2 mg/d. At the maximum dosage of 4 mg/d, pitavastatin reduces LDL-C by approximately 44%. Dose-ranging studies indicate that pitavastatin is non-inferior to atorvastatin and simvastatin in terms of its effects on lipids in patients with primary hyperlipidemia or mixed dyslipidemia, and it effects signiﬁcantly greater reductions in LDL-C in elderly patients compared to pravastatin (per the package insert). The major side effects of statins relate to liver enzymes and skeletal muscle.35 Elevations in serum alanine and aspartate transaminases have been observed with all of the statins and appear to be a class effect. Clinically relevant elevations of hepatic enzymes are deﬁned as a sustained increase in circulating levels exceeding three times the upper limit of normal; at standard statin dosages, these elevations occur in less than 1% of patients. Increases in hepatic enzyme levels are typically observed within the ﬁrst 3 to 4 months of therapy but generally resolve with continuation, reduction, or cessation of statin therapy. It does not appear that these changes result in lasting liver damage. Before initiation of statin therapy, it is recommended that liver function tests be performed; tests should be repeated 12 weeks after statin initiation or dose titration, then semi-annually. Statins are contraindicated in patients with liver disease and should be used with caution in patients who consume large quantities of alcohol. Muscular side effects, which have been observed with all of the statins, range from myalgia to myopathy to life-threatening rhabdomyolysis.35 Myopathy is diagnosed when muscle pain or soreness is accompanied by creatine kinase (CK) levels exceeding 10 times the upper limit of normal; it occurs in approximately 1 in 10,000 patients. Myalgia refers to muscle pain or soreness without the CK increases seen with myopathy. Rhabdomyolysis, which is signaled by CK levels exceeding 40 times the upper limit of normal, can cause myoglobinuria and potential renal failure. The risk of progression from myopathy to rhabdomyolysis is extremely low and is increased by high statin doses and concurrent treatment with interacting drugs, especially ﬁbrates. Risk for statin-mediated myotoxicity in general is increased by combination therapy with ﬁbrates, particularly gemﬁbrozil; by interactions with drugs that are metabolized by the cytochrome P450 system; and in patients with renal impairment, hypothyroidism, and advanced age. A recent study suggests that common variants in the gene encoding OAT polypeptide 1B1 (OATP1B1), which is thought to regulate the hepatic uptake of statins, are strongly associated with an increased risk of statin-induced myopathy.36 Patients should be advised to report any unexplained signs of muscle pain or weakness. After cessation of statin therapy, symptoms should resolve fully within a few weeks. The JUPITER trial reported a small but signiﬁcant increase in physiciandiagnosed diabetes with statin treatment (270 in rosuvastatin group vs. 216 in

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LDL Cholesterol CHAPTER 1

16

placebo group; p = 0.01).17 In contrast, WOSCOPS, the ﬁrst study to report an association between statin therapy and diabetes, observed a protective effect with statins on the risk of incident diabetes.18 A recent meta-analysis of ﬁve large statin trials, including JUPITER but excluding WOSCOPS, found a small increase in incident diabetes (relative risk 1.13 [95% CI, 1.03–1.23]) that does not appear to be drug- or dosage-speciﬁc.37 However, including the WOSCOPS data rendered the results of the meta-analysis nonsigniﬁcant. It appears that statins may slightly increase risk for diabetes, although the magnitude of this increased risk is outweighed by the known cardiovascular beneﬁts of this class of drug. Bile Acid Resins The bile acid resins or sequestrants bind to cholesterol-rich bile acids in the intestines, preventing their normal recirculation back to the liver and increasing their excretion within the feces.2,16 Increased excretion of bile acids leads to increased synthesis of bile acids by the liver, which decreases intrahepatic cholesterol levels and triggers upregulation of the LDL receptor with increased clearance of apoB-containing lipoproteins from the circulation. Therapy with bile acid resins can be expected to reduce LDL-C by 15% to 25%, which is their primary effect. Resins can also minimally increase HDL-C by 3% to 5% and have variable effects on triglycerides, sometimes increasing levels, particularly in patients with preexisting hypertriglyceridemia. Available agents include cholestyramine (LoCholest, Questran, Prevalite), colestipol (Colestid), and colesevelam (Welchol). Colesevelam was developed speciﬁcally to maximize binding with bile acids and may be better tolerated by patients than other formulations. Cholestyramine and colestipol can be administered as a powdered resin that may be mixed with liquids or combined with food, and colestipol and colesevelam are available in tablet form. The primary indication for all three agents is treatment of primary hypercholesterolemia.2,16 Colesevelam received an additional FDA indication in 2008 for improved glycemic control in the treatment of type 2 diabetes, as combination therapy with metformin, sulfonylureas, or insulin. Resins are not absorbed into the systemic circulation and have minimal systemic effects. They may reduce the absorption of digoxin, warfarin, beta-blockers, thyroxine, thiazides, furosemide, statins, ezetimibe, and ﬁbrates by nonspeciﬁc binding; if these drugs are co-administered with resins, they should be taken 1 hour before or 4 hours after the resin dose. Long-term treatment with resins may stimulate a compensatory increase in HMG-CoA reductase activity, which can increase cholesterol synthesis and plasma LDL-C levels. The Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT) with cholestyramine provided early evidence of the beneﬁt of lipid lowering, although the absolute reduction in coronary events was minimal, possibly due to problems with study design.38 Treatment with cholestyramine reduced LDL-C by 20% over a period of 7.4 years, resulting in a 19% relative reduction in CHD death or MI compared to placebo but no signiﬁcant reduction in mortality. Compliance to the study medication was decreased because of gastrointestinal

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LDL Cholesterol CHAPTER 1

Cholesterol Absorption Inhibitors The cholesterol absorption inhibitor ezetimibe, the ﬁrst in its class, reduces LDL-C by selective inhibition of the Niemann-Pick C1 Like 1 Protein (NPC1L1) at the brush border of the small intestine, where dietary cholesterol and other phytosterols are absorbed.39 As a result, the delivery of intestinal cholesterol to the liver is decreased, which reduces intrahepatic cholesterol levels and causes a compensatory increase in cholesterol clearance from the blood. This mechanism of action is complementary to that of the statins, and ezetimibe is often used in combination with statins. As monotherapy, ezetimibe at the recommended dosage of 10 mg/d reduces LDL-C by approximately 17%; when added to any dose of statin, it reduces LDL-C by an additional 25%.40 HDL-C may be increased minimally by 3% and triglycerides decreased by 8%. Available preparations are 10 mg of ezetimibe alone (Zetia) and ezetimibe/simvastatin (Vytorin), which combines 10 mg of ezetimibe with 10, 40, or 80 mg of simvastatin. Ezetimibe is indicated to improve lipid levels in the treatment of primary and mixed hyperlipidemias, either alone or in combination with statins; to treat homozygous FH in combination with atorvastatin or simvastatin; and to reduce sitosterol and campesterol in patients with homozygous sitosterolemia. It is not recommended in patients with moderate or severe hepatic impairment, and it may interact with cyclosporine and fenoﬁbrate. Despite its demonstrated efﬁcacy in lipid lowering, the clinical beneﬁt of ezetimibe has yet to be established in large post-marketing trials. Recent results from three small trials, which have failed to show clinical beneﬁt, have subsequently exposed ezetimibe to considerable controversy. The Effect of Combination Ezetimibe and High-Dose Simvastatin vs. Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia (ENHANCE) trial showed that in patients with FH, treatment with ezetimibe/simvastatin did not have a greater effect on carotid plaque size compared to simvastatin alone, although the combination did achieve a greater degree of LDL-C lowering.41 However, both the placebo and intervention groups had baseline carotid measures that were essentially normal. In the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial, the ezetimibe/simvastatin combination did not reduce the primary composite endpoint of aortic valve and ischemic events in patients with mild to moderate asymptomatic aortic stenosis compared to simvastatin alone, although there was a signiﬁcant reduction in ischemic events.42 The SEAS results also suggested that ezetimibe might be associated with an increased risk of cancer, although this ﬁnding was most likely due to chance.43 Finally, the Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6-HDL and LDL Treatment Strategies (ARBITER 6-HALTS), which compared the effects of increasing HDL-C with niacin versus further decreasing LDL-C with ezetimibe

17

side effects (primarily constipation), which are the primary factor limiting the use of resins in general. Constipation, which can become severe, can be minimized with increased intake of ﬂuid and ﬁber or the use of stool softeners.

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LDL Cholesterol CHAPTER 1

18

in patients already taking statins, found that niacin was superior in reducing carotid plaque progression.44 The results of the large-scale Improved Reduction of Outcomes: Vytorin Efﬁcacy International Trial (IMPROVE-IT) in patients with acute coronary syndromes and the Study of Heart and Renal Protection (SHARP) in patients with chronic kidney disease will provide much-awaited data on the clinical efﬁcacy of this drug. In the meantime, ezetimibe remains a viable option as monotherapy in hyperlipidemic patients who are intolerant of statins or as combination therapy in patients requiring large reductions in LDL-C levels. Niacin Niacin, or nicotinic acid, is an essential B vitamin that is primarily used for the treatment of mixed hyperlipidemias.2,16 Niacin’s primary effect is to decrease the hepatic production and release of VLDL, the ﬁrst step in endogenous lipid metabolism, which results in decreased levels of triglyceride-rich lipoproteins and of LDL. It also reduces the release of free fatty acids from peripheral adipose tissue into the circulation, thus limiting the availability of the substrate needed for hepatic VLDL synthesis. Nicotinic acid is the most effective drug for increasing HDL-C levels, with expected increases of 15% to 35%, and it decreases triglycerides by 20% to 50%. Reductions in LDL-C of between 5% and 25% can also be expected. Immediate- and sustained-release preparations of niacin are available over the counter. Dosing of prescription extended-release niacin (Niaspan) begins at 500 mg/d at bedtime after a low-fat snack, with gradual titration to 1 to 2 g/d to minimize side effects. Prescription niacin is indicated for the treatment of primary hypercholesterolemia and mixed dyslipidemias, either alone or in combination with lovastatin or bile acid resins. It also has an indication to reduce the risk of recurrent nonfatal MI, and it may be used for treatment of patients with severe hypertriglyceridemia (levels above 2,000 mg/dL) who are at risk for pancreatitis. Nicotinic acid should be used with caution in patients with peptic ulcer, diabetes, liver disease, or a history of gout.2,16 Niacin can causes elevations in liver enzymes, and liver function tests should be performed periodically. The risk of myopathy, though rare, is increased with concomitant treatment with statins or ﬁbrates. A common side effect that tends to limit patient compliance is prostaglandinmediated ﬂushing, often accompanied by pruritus. Pretreatment with aspirin, use of the prescription formulation, and gradual dosage titration may lessen the ﬂushing side effect. The major trial demonstrating clinical beneﬁt with niacin was the Coronary Drug Project, which enrolled 8,341 men with previous MI. After a mean 6.2 years, treatment with niacin was associated with a 16% relative reduction in nonfatal MI and CHD death, a 28% reduction in nonfatal MI, and a 21% reduction in stroke and transient ischemic attacks compared to placebo.45 Nicotinic acid has generally been evaluated in combination therapy, as in the ARBITER 6-HALTS study discussed above, which compared HDL-raising versus LDLlowering strategies on a background of statin therapy.44 Angiographic trials evaluating niacin in combination therapy have found reduced progression of coronary atherosclerotic lesions.

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LDL Cholesterol CHAPTER 1

19

Fibrates The ﬁbrates, or ﬁbric acid derivatives, are agonists for the peroxisome proliferator-activated receptor-A (PPAR-A), a nuclear hormone receptor that exerts multiple complex effects on lipoprotein and fatty acid metabolism, as well as possible pleiotropic effects.2,16 Their primary therapeutic effects are to reduce triglycerides by 20% to 50%, to increase HDL-C by 10% to 20%, and to increase the size of small dense LDL particles. They have variable effects on LDL-C levels and are especially used for treatment of the atherogenic lipid triad. Available agents and formulations include gemﬁbrozil (Lopid), fenoﬁbrate (Tricor) and fenoﬁbric acid delayed release (Trilipix). Dosing for gemﬁbrozil is 1,200 mg/d administered in two divided doses taken 30 minutes before the morning and evening meal. Dosing for fenoﬁbrate is 48 to 145 mg/d and for fenoﬁbric acid delayed release is 45 to 135 mg/d. Fenoﬁbrate fenoﬁbric acid and gemﬁbrozil are indicated for the treatment of primary hypercholesterolemia and mixed dyslipidemias. Gemﬁbrozil is also indicated for the treatment of severely hypertriglyceridemic patients (levels above 2,000 mg/dL) at risk for pancreatitis, while fenoﬁbrate and fenoﬁbric acid areapproved for treatment of more moderate hypertriglyceridemia. Contradictions include hepatic or severe renal dysfunction and preexisting gallbladder disease. In addition, ﬁbrates may increase the risk for elevated liver enzymes and cholelithiasis; can interact with oral anticoagulants, necessitating reduced dosages of warfarin; and can increase the risk for myopathy when taken in combination with statins. Regular monitoring of liver function is recommended. The two major trials showing signiﬁcant clinical beneﬁt with ﬁbrates were the primary prevention Helsinki Heart Study (HHS) and the secondary prevention Veterans Affairs HDL Intervention Trial (VA-HIT). In the HHS, treatment with gemﬁbrozil reduced the relative risk of CHD death and MI by 34% compared to placebo in asymptomatic men,46 while in the VA-HIT, gemﬁbrozil, which had no effect on LDL-C levels, was associated with a 22% relative reduction in the risk of MI or CHD death compared to placebo in men with CHD.47 With fenoﬁbrate, the Fenoﬁbrate Intervention and Event Lowering in Diabetes (FIELD) study demonstrated trends in clinical beneﬁt in diabetic subjects, although ﬁndings were inconclusive.48

Areas of Ambiguity Mechanism of LDL Reduction Although epidemiological evidence and clinical trial data with statins indicate that “lower is better” with regards to LDL-C levels, it remains uncertain whether other mechanisms for LDL lowering are clinically efﬁcacious. The lack of outcomes data for ezetimibe, which effectively lowers LDL-C but has not yet demonstrated improvements in cardiovascular morbidity and mortality, has fuelled this debate in recent years, and it is hoped that the conclusion of the AIM-HIGH and SHARP studies should address this gap. However,

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LDL Cholesterol CHAPTER 1

20

the Robinson meta-analysis of various types of lipid-lowering trials, discussed above, provides a strong indication that LDL lowering is clinically beneﬁcial independent of the mechanism employed.6 Of course, speciﬁc agents may have potential off-target effects that need to be considered. The ongoing development of experimental agents to reduce LDL-C levels, including microsomal triglyceride-transfer protein (MTP) inhibitors, antisense oligonucleotides, apoB antibodies, and thyroid hormone analogs, may help to provide additional insight on this issue. Alternative Lipid Parameters The use of emerging risk factors, such as measures of LDL particle size or of levels of apo B, is currently recommended to help guide the intensity of therapy in intermediate-risk patients. However, research suggests that alternative lipid parameters, including measures of apoB and the ratio of apo B to apoA-I, the primary protein component in HDL, may more accurately quantify cardiovascular risk than LDL-C or non-HDL-C, the two therapeutic targets endorsed by ATP III.49 The superior predictive value of apoB and of the apoB-to-apoA-I ratio compared to traditional lipid measures was conﬁrmed by post hoc analysis of the AFCAPS/TexCAPS, TNT, and IDEAL studies, although the clinical utility of these alternative parameters remains to be determined.50,51 In addition, it remains unclear whether residual cardiovascular risk can be best reduced by achieving greater reductions in LDL-C or by employing combination therapy to target other lipids, such as HDL-C and triglycerides. The ARBITER 6-HALTS trial provided suggestive evidence that HDL raising with nicotinic acid was superior to LDL lowering with ezetimibe, in combination with statin therapy,44 but agents that raise HDL-C without the side effects associated with niacin remain in development. Further research is needed to clarify how to most safely and effectively target HDL-C and triglycerides in conjunction with LDL-C. C-Reactive Protein and Inﬂammation Results from the JUPITER trial suggest that measures of hsCRP may help identify at-risk individuals within primary prevention who may not qualify for statin therapy on the basis of LDL-C levels alone. However, it remains unclear whether hsCRP is an inﬂammatory marker that indicates increased cardiovascular risk or whether it plays an independent pathogenic role in atherosclerosis and CHD. While JUPITER found an unexpectedly large magnitude of clinical beneﬁt with simultaneous reductions in LDL-C and hsCRP, it is unknown whether lowering levels of hsCRP and of inﬂammation in general, without also lowering LDL-C, would have a protective effect. A recent Mendelian randomization study, which included more than 28,000 cases and 100,000 controls, found that polymorphisms in ﬁve genetic loci were strongly associated with increased CRP levels, but that these genotypes were not associated with CHD risk.52 This large-scale study argues against a causal association of CRP with CHD, although a large body of basic science research indicates that inﬂammation still plays a pivotal and complicated role in atherosclerosis.4

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LDL Cholesterol

Since its inception in 1985, the NCEP has issued three sets of clinical guidelines on cholesterol testing and management in adults. The latest ATP III guidelines were issued in 2001 and updated in 2004; new ATP IV guidelines are expected in 2010. ATP III considers LDL-C to be the primary target of lipid-lowering therapy.5,13 An LDL-C level less than 100 mg/dL is considered optimal, and a total cholesterol level less than 200 mg/dL is desirable. LDL-C goals are determined based on the presence or absence of CHD, CHD risk equivalents, major risk factors, and Framingham risk scoring. Potential secondary targets are nonHDL-C and the metabolic syndrome. CHD includes history of myocardial infarction, unstable and stable angina, coronary revascularization procedures, or evidence of clinically signiﬁcant myocardial ischemia. CHD risk equivalents are diabetes and clinical forms of non-coronary atherosclerotic disease, including peripheral arterial disease, abdominal aortic aneurysm, and symptomatic carotid artery disease. Other than LDL-C, the major risk factors identiﬁed by ATP III are:

CHAPTER 1

Guidelines

Cigarette smoking • Hypertension (blood pressure 140/90 mm Hg or higher or on antihyperten-

21

sive medication) • Low HDL-C (less than 40 mg/dL)

HDL-C level of 60 mg/dL or higher counts as a “negative” risk factor that removes one risk factor from the total count. • Family history of premature CHD (CHD in male ﬁrst-degree relative before age 55 years; CHD in female ﬁrst-degree relative before age 55 years) • Age (men 45 years and up; women 55 years and up) The presence of at least two major risk factors necessitates a short-term (10-year) risk assessment for CHD using Framingham scoring to determine the appropriate intensity of lipid-lowering therapy. Individuals with less than two major risk factors are considered to have a lower short-term risk for CHD, and Framingham scoring is not necessary. Framingham scoring estimates a patient’s 10-year risk for CHD based on age, gender, total cholesterol, HDL-C, smoking status, and systolic blood pressure. It divides patients into 10-year risk categories of more than 20%, 10% to 20%, and less than 10%. Traditionally, Framingham scores have been calculated by totaling the points associated with each risk factor, but they can now be easily computed online (http://hp2010.nhlbihin.net/atpiii/calculator.asp) or by using software downloaded to a personal digital assistant or smartphone. The 2004 update of the ATP III treatment guidelines describes four categories of risk to guide clinicians in determining the nature and intensity of lipid-lowering therapy (Table 1.4). For all four categories, TLC should be initiated whenever LDL-C levels are above the recommended goal; in high-risk or moderately high-risk individuals, TLC should be considered regardless of LDL-C level if any lifestyle-related risk factors (e.g., obesity, physical inactivity, elevated triglycerides, low HDL-C, or metabolic syndrome) are present. •

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LDL Cholesterol CHAPTER 1

22

Based on trials of intensive statin therapy, the 2004 update recommends more aggressive treatment, including lower LDL-C targets and earlier initiation of drug therapy, for patients deemed to be at high risk and for those with multiple risk factors. Of particular signiﬁcance is a recommended goal of less than 100 mg/dL in high-risk patients, with an optional lower target of less than 70 mg/ dL in very-high-risk patients, deﬁned as those who have established cardiovascular disease in addition to (1) multiple major risk factors (especially diabetes); (2) severe and poorly controlled risk factors (especially cigarette smoking); (3) multiple risk factors for the metabolic syndrome (especially high triglycerides [200 mg/dL or higher], non-HDL-C levels 130 mg/dL or higher, and low HDL-C [less than 40 mg/dL]); or (4) acute coronary syndromes. Physician judgment is crucial to determining the appropriateness of this lower target in very-high-risk patients; similarly, deciding between the recommended target of less than 130 mg/dL and the optional lower goal of less than 100 mg/dL in patients categorized as being at moderately high risk requires careful consideration. A 2006 update of the joint guidelines for secondary prevention from the American Heart Association (AHA) and the American College of Cardiology (ACC) speciﬁcally addresses the treatment of very-high-risk patients to an LDL-C level below 70 mg/dL, endorsing this strategy as reasonable based on existing clinical trial data.53 The AHA/ACC update further suggests increasing statin doses gradually in this population and, if necessary, combining statin therapy with ezetimibe, a bile acid resin, or niacin to achieve greater reductions in LDL-C. A consensus statement from the American Diabetes Association (ADA) and the ACC slightly modiﬁes the deﬁnitions of “very high risk” and “high risk” from ATP III in suggesting appropriate LDL-C treatment goals.54 According to the ADA/ACC statement, individuals with CHD or diabetes, plus one other major risk factor, are considered to be at very high risk, with a recommended LDL-C goal of less than 70 mg/dL. Individuals who have CHD or CHD risk equivalents

Table 1.4 ATP III LDL-C Goals According to Categories of Risk5,13 Risk Category High risk: CHD and CHD risk equivalents (10-yr risk >20%) Very high risk Moderately high risk: ≥2 risk factors (10-yr risk 10%–20%) Moderate risk: ≥2 risk factors (10-yr risk <10%) Low risk: 0 or 1 risk factor

01-Baliga-Chap01.indd 22

LDL-C Goal <100 mg/dL

Consider Drug Therapy ≥100 mg/dL

Optional goal of <70 mg/dL <130 mg/dL (optional goal of <100 mg/dL) <130 mg/dL

Optional if <100 mg/dL

<160 mg/dL

≥190 mg/dL, optional if 160–189 mg/dL

≥130 mg/dL Optional if 100–129 mg/dL ≥160 mg/dL

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Low-density lipoprotein, which is rich in apoB, is believed to play an initiating role in the atherosclerotic process. Results from multiple epidemiologic and clinical trials have veriﬁed that reductions in LDL-C levels are associated with a reduced risk of CHD. No lower threshold beyond which LDL-C reduction ceases to be beneﬁcial has yet been identiﬁed. Primary and secondary prevention aims to reduce the risk of cardiovascular disease through modiﬁcation of risk factors, with LDL-C being the primary target of therapy. Therapeutic lifestyle changes, including diet, smoking cessation, and weight loss, are the initial treatment modality, but optimal management of dyslipidemia may necessitate additional pharmacological measures. Numerous clinical trials have established the efﬁcacy and safety of statins, which are the mainstay of lipid-lowering therapy. Cholesterol absorption inhibitors, bile acid resins, niacin, and ﬁbrates may also be used for the treatment of primary hypercholesterolemia and mixed dyslipidemias. Future research can help clarify how emerging biomarkers and lipid fractions other than LDL-C may enhance cardiovascular prevention, diagnosis, and treatment.

LDL Cholesterol CHAPTER 1

Summary and Recommendations

23

and a 10-year risk of more than 20% (but no other major risk factors) are considered to be at high risk, with a recommended LDL-C goal of less than 100 mg/dL.

Practical Points Prevention of CHD is a vitally important strategy for improving the public health. The goal of primary prevention is to address cardiovascular risk factors before symptoms of CHD develop. Secondary prevention combines comprehensive risk factor modiﬁcation with pharmacological treatment to low LDL-C levels. A target of less than 70 mg/dL is an option in very-high-risk patients. • Patients should be routinely assigned to risk categories based on major cardiovascular risk factors and Framingham scoring, and they should be treated to the appropriate LDL-C target based on their level of risk. • Pharmacologic therapy should aim for LDL-C reductions of 30% to 40%. • Statin therapy has been shown to improve clinical outcomes and reduce mortality in both primary and secondary prevention. The results of the JUPITER study suggest that the population of at-risk patients who may beneﬁt from statin therapy may be expanded to include individuals with elevated levels of hsCRP and additional risk factors, but without elevated levels of LDL-C. • Combination therapy involving statins with ﬁbrates or nicotinic acid increases the risk for myopathy and liver enzyme elevations, although the risk remains low. However, judicious use of combination therapy may be warranted in patients with mixed dyslipidemias.

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LDL Cholesterol CHAPTER 1

24

References 1. Murphy HC, Burns SP, White JJ, et al. Investigation of human low-density lipoprotein by (1)H nuclear magnetic resonance spectroscopy: mobility of phosphatidylcholine and sphingomyelin headgroups characterizes the surface layer. Biochemistry. 2000;39(32):9763–70. 2. Gotto AM. Contemporary Diagnosis and Management of Lipid Disorders, 4th ed. Newtown, PA: Handbooks in Health Care, 2008. 3. Gustafsson M, Borén J. Mechanism of lipoprotein retention by the extracellular matrix. Curr Opin Lipidol. 2004;15:505–14. 4. Libby P, Ridker PM, Hansson GK. Inﬂammation in atherosclerosis: from pathophysiology to practice. J Am Coll Cardiol. 2009;54(23):2129–38. 5. Grundy SM, Cleeman JI, Merz CNB, et al, for the Coordinating Committee of the National Cholesterol Education Program. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110;227–39. 6. Robinson JG, Smith B, Maheshwari N, et al. Pleiotropic effects of statins: beneﬁt beyond cholesterol reduction? A meta-regression analysis. J Am Coll Cardiol. 2005;46:1855–62. 7. Keys A. Seven Countries. Cambridge, MA: Harvard University Press, 1980. 8. Kannel WB, Dawber TR, Kagan A, Revotskie N, Stokes J. Factors of risk in the development of coronary heart disease—six-year follow-up experience. The Framingham Study. Ann Intern Med. 1961;55:33–50. 9. Downs JR, Clearﬁeld M, Weis S, et al, for the AFCAPS/TexCAPS Research Group. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels. Results of AFCAPS/TexCAPS. JAMA. 1998;279:1615–22. 10. Cholesterol Treatment Trialists’ Collaborators. Efﬁcacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005;366:1267–78. 11. LaRosa JC, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352:1425–35. 12. LaRosa JC, Grundy SM, Kastelein JJ, et al. Safety and efﬁcacy of atorvastatininduced very low-density lipoprotein cholesterol levels in patients with coronary heart disease (a post hoc analysis of the Treating to New Targets [TNT] study). Am J Cardiol. 2007;100:747–52. 13. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;285:2486–97. 14. Pletcher MJ, Lazar L, Bibbins-Domingo K, et al. Comparing impact and cost-effectiveness of primary prevention strategies for lipid-lowering. Ann Intern Med. 2009;150(4):243–54. 15. Davidson MH, Robinson JR. Management of elevated low-density lipoprotein cholesterol. In: Gotto AM, Toth PP, eds. Comprehensive Management of High Risk Cardiovascular Patients. New York: Informa Pub., 2007:255–93. 16. Gotto AM, Opie LH. Lipid-modifying and antiatherosclerotic drugs. In: Opie LH, Gersh BJ, eds. Drugs for the Heart, 7th ed. Philadelphia: Saunders, 2009:341–72.

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LDL Cholesterol CHAPTER 1

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17. Ridker PM, Danielson E, Fonseca FA, et al; for the JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359:2195–207. 18. Shepherd J, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med. 1995;333:1301–7. 19. Sacks FM, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med. 1996;335:1001–9. 20. The Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med. 1998;339:1349–57. 21. Shepherd J, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet. 2002;360:1623–30. 22. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994; 344(8934):1383–9. 23. Heart Protection Study Collaborative Group: MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in. 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360:7–22. 24. Results from the world’s largest trial of the beneﬁts of more intensive cholesterol-lowering and of the safety of folic acid supplementation [press release]. Oxford: University of Oxford Clinical Trial Service Unit & Epidemiological Studies Unit, Nov. 9, 2008. 25. Herd JA, Ballantyne CM, Farmer JA, et al. Effects of ﬂuvastatin on coronary atherosclerosis in patients with mild to moderate cholesterol elevations (Lipoprotein and Coronary Atherosclerosis Study [LCAS]). Am J Cardiol. 1997;80:278–86. 26. Serruys PW, de Feyter P, Macaya C, et al. Fluvastatin for prevention of cardiac events following successful ﬁrst percutaneous coronary intervention: a randomized controlled trial. JAMA. 2002;287(4):3215–22. 27. Holdaas H, Fellström B, Jardine AG, et al. Effect of ﬂuvastatin on cardiac outcomes in renal transplant recipients: a multicentre, randomized, placebocontrolled trial. Lancet. 2003;361(9374):2024–31. 28. Cannon CP, Braunwald E, McCabe CH, et al.; PROVE IT-TIMI 22 Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350:1495–504. 29. Sever PS, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet. 2003;361:1149–58. 30. Colhoun HM, Betteridge DJ, Durrington PN, et al; CARDS Investigators. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomized placebo-controlled trial. Lancet. 2004;364(9435):685–96. 31. Nissen SE, Tuzcu EM, Schoenhagen P, et al; for the REVERSAL Investigators. Effect of intensive compared with moderate lipid-lowering therapy on

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LDL Cholesterol CHAPTER 1

32.

33. 34.

35. 36. 37. 38.

26

39.

40. 41.

42. 43. 44. 45.

46.

47.

48.

progression of coronary atherosclerosis: a randomized controlled trial. JAMA. 2004;291:1071–80. Ridker PM, Danielson E, Fonseca FAH, et al, on behalf of the JUPITER Trial Study Group. Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial. Lancet. 2009;373:1175–82. US FDA approves new indication for CRESTOR® (rosuvastatin calcium) [press release]. Wilmington, DE: AstraZeneca, Feb. 8, 2010. Nissen SE, Nicholls SJ, Sipahi I, et al; for the ASTEROID Investigators. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA. 2006;295:1556–65. Armitage J. The safety of statins in clinical practice. Lancet. 2007;370(9601): 1781–90. SEARCH Collaborative Group. SLCO1B1 variants and statin-induced myopathy—a genomewide study. N Engl J Med. 2008;359(8):789–99. Rajpathak SN, Kumbhani DJ, Crandall J, et al. Statin therapy and risk of developing type 2 diabetes: a meta-Analysis. Diabetes Care. 2009;32(10):1924–9. The Lipid Research Clinics Coronary Primary Prevention Trial results. I. Reduction in incidence of coronary heart disease. JAMA. 1984;251(3):351–64. Davies JP, Scott C, Oishi K, et al. Inactivation of NPC1L1 causes multiple lipid transport defects and protects against diet-induced hypercholesterolemia. J Biol Chem. 2005;280(13):12710–20. Dembowski E, Davidson MH. Statin and ezetimibe combination therapy in cardiovascular disease. Curr Opin Endocrinol Diabetes Obes. 2009;16:183–8. Kastelein JJ, Akdim F, Stroes ES, et al, and the ENHANCE Investigators. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med. 2008;358:1431–43. Rossebφ AB, et al, for the SEAS Investigators. Intensive lipid lowering with simvastatin and ezetimibe in Aortic Stenosis. N Engl J Med. 2008;359(13):1343–56. Peto R, et al. Analyses of cancer data from three ezetimibe trials. N Engl J Med. 2008;359(13):1357–66. Taylor AJ, Villines TC, Stanek EJ, et al. Extended-release niacin or ezetimibe and carotid intima-media thickness. N Engl J Med. 2008;361(22):2113–22. Brown BG, Canner PL, McGovern M, et al. Nicotinic acid. In: Ballantyne CM, ed. Clinical Lipidology: A Companion to Braunwald’s Heart Disease. Philadelphia: Elsevier, 2009:298–314. Frick MH, Elo O, Haapa K, et al. Helsinki Heart Study: primary-prevention trial with gemﬁbrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med. 1987;317(20):1237–45. Rubins HB, et al. Gemﬁbrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med. 1999;341:410–8. Keech A, et al. Effects of long-term fenoﬁbrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet. 2005;366:1849–61.

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LDL Cholesterol CHAPTER 1

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49. Mudd JO, Borlaug BA, Johnston PV, et al. Beyond low-density lipoprotein cholesterol: deﬁning the role of low-density lipoprotein heterogeneity in coronary artery disease. J Am Coll Cardiol. 2007;50(18):1735–41. 50. Gotto AM, Whitney E, Stein EA, et al. Relation between baseline and on-treatment lipid parameters and ﬁrst acute major coronary events in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS). Circulation. 2000;101:477–84. 51. Kastelein JJ, van der Steeg WA, Holmes I, et al. Lipids, apolipoproteins, and their ratios in relation to cardiovascular events with statin treatment. Circulation. 2008;117:3002–9. 52. Elliott P, Chambers JC, Zhang W, et al. Genetic loci associated with C-reactive protein levels and risk of coronary heart disease. JAMA. 2009;302(1):37–48. 53. Smith SC, Allen J, Blair SN, et al. AHA/ACC Guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update. Circulation. 2006;113:2363–72. 54. Brunzell JD, Davidson M, Furberg CD, et al. Lipoprotein management in patients with cardiometabolic risk: consensus conference report from the American Diabetes Association and the American College of Cardiology Foundation. J Am Coll Cardiol. 2008;51:1512–24.

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Chapter 2

HDL Cholesterol Philip Barter and Kerry-Anne Rye

Peter is a 59-year-old accountant who has presented for a checkup. He has no speciﬁc complaints but is concerned because his brother, aged 63, had recently had a myocardial infarction (MI). He is not aware of any other family history of cardiovascular disease, although he remembers that his mother developed diabetes when she was in her 60s. He smoked 20 cigarettes per day between the ages of 18 and 41 but has not smoked for the past 18 years. His work is sedentary and he does little exercise in his leisure time. He drinks one glass of wine with dinner on most days. He states that he has been slowly gaining weight since he was about 30, when he stopped playing competitive tennis. He takes no medication. On examination, he is 177 cm and weighs 95 kg with a BMI of 30.3. His waist circumference is 109 cm. His blood pressure (sitting) is 145/90. His physical examination is otherwise normal.

29

Clinical Vignette

Laboratory Data His fasting blood sugar is 110 mg/dL. Liver function tests are normal. His total cholesterol is 188 mg/dL, his high-density lipoprotein (HDL) cholesterol is 31 mg/dL, and his non-HDL cholesterol is 157 mg/dL. His plasma triglycerides level is 205 mg/dL and the calculated low-density lipoprotein (LDL) cholesterol is 116 mg/dL. His resting ECG is normal. Case Discussion The combination of abdominal obesity, mild hypertension, and a dyslipidemia characterized by a low level of HDL-C and a mild elevation of plasma triglycerides is typical of someone with the metabolic syndrome. When considered in the light of his brother’s recent MI, this proﬁle identiﬁes Peter as someone at moderate to high cardiovascular risk. The low HDL-C and the elevated nonHDL-C levels are of particular concern. The single most important intervention is lifestyle modiﬁcation. He should be given advice on how to reduce his caloric intake and build a program of 40 to 60 minutes of moderate physical activity (such as brisk walking) into his day. He must understand that this lifestyle modiﬁcation will need to be lifelong. If compliant, he will slowly lose weight, his waist circumference will slowly decrease, his plasma triglyceride and non-HDL-C levels will slowly fall, and his HDL-C level will slowly increase. But he should understand that none of these changes will be rapid and that he will remain at moderate to high cardiovascular risk for a considerable time. In the meantime, there is a strong case for prescribing a statin to reduce his non-HDL-C level to

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HDL Cholesterol

below 130 mg/dL and, if the HDL-C level remains below 40 mg/dL, for adding niacin to increase his HDL-C level.

CHAPTER 2

An inverse relationship between the concentration of cholesterol in highdensity lipoproteins (HDLs) and the risk of having a cardiovascular event has been documented in many large-scale prospective studies.1,2 On the basis of the population studies, it has been concluded that for every 1-mg/dL increase in HDL-C, the cardiovascular disease (CVD) risk is reduced by 2% to 3%.3 A low level of HDL-C remains predictive of future CVD risk even when the concentration of cholesterol in low-density lipoproteins (LDLs) has been taken to low levels by aggressive treatment with statins.4 In support of the human population studies, there are many intervention studies in animals demonstrating that an increase in the HDL concentration, whether achieved by infusing HDLs intravenously or by genetic manipulations that increase the synthesis of apolipoprotein (apo) A-I (the main HDL protein), inhibits the development of atherosclerosis.5–8 In humans, however, evidence that HDL-raising interventions reduce cardiovascular events, while growing stronger, remains circumstantial and still awaits direct conﬁrmation.

30

What Are HDLs? HDLs are the smallest and densest of the plasma lipoproteins. They comprise several discrete subpopulations that contain particles of differing shape, size, density, composition, and surface charge9 (Fig. 2.1). Most HDL particles are spherical and consist of a fatty core (mainly cholesteryl esters with a small amount of triglyceride) surrounded by a surface layer of phospholipids, free (non-esteriﬁed) cholesterol, and apolipoproteins. There is also a minor population of discoidal HDL particles that contain only surface constituents arranged

Background

Lipid-poor apoA-I Single molecule of apoA-I (with or without small amount of phospholipid) Prebeta-migrating

Discoidal HDL Two or three molecules of apoA-I (plus phospholipid with or without unesterified cholesterol) Prebeta-migrating Spherical HDL

Two or more molecules of apoA-I (plus phospholipid, unesterified cholesterol, cholesteryl esters and triglyceride with or without apoA-II) Alpha-migrating Figure 2.1 ApoA-I exists in three forms in plasma.

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HDL Cholesterol CHAPTER 2

31

as a molecular bi-layer consisting of phospholipids and free cholesterol encircled by apolipoproteins. The discoidal particles represent a nascent form of HDLs that generally exist only transiently in the circulation before being rapidly converted into the spherical form.9 The two main apolipoproteins of HDLs are apoA-I (about 70% of the total HDL protein) and apoA-II (about 20% of the total). Some HDL particles also contain other minor apolipoproteins, such as apoA-IV, apoA-V, apoC-I, apoC-II, apoC-III, apoD, apoE, apoJ, and apoL. Furthermore, HDLs transport several additional proteins, including cholesteryl ester transfer protein (CETP), lecithin:cholesterol acyltransferase (LCAT), phospholipid transfer protein (PLTP). and paraoxonase (PON).9 It is interesting to note that the concentration of apoA-I in normal human subjects is approximately 1.0 g/L, making it one of the most abundant proteins in human plasma. HDLs may be separated on the basis of density into HDL2 (1.063 < d < 1.125 g/mL) and HDL3 (1.125 < d < 1.21 g/mL) and on the basis of particle size into at least ﬁve distinct subpopulations. HDLs may also be separated on the basis of their apolipoprotein composition. One subpopulation comprises HDLs containing apoA-I but no apoA-II (A-I HDLs), while the other comprises particles containing both apoA-I and apoA-II (A-I/A-II HDLs). In most people apoA-I is distributed approximately equally between A-I HDLs and A-I/A-II HDLs, while virtually all of the apoA-II resides in A-I/A-II HDLs.10 A small proportion of the apoA-I exists in a lipid-free or lipid-poor form. HDLs also vary in surface charge. When separated by agarose gel electrophoresis, HDLs may have alpha or pre-beta mobility. The alpha-migrating particles tend to be spherical lipoproteins and account for the major proportion of HDLs in human plasma. Alpha-migrating HDLs include the HDL2 and HDL3 subfractions as well as the spherical A-I HDL and A-I/A-II HDL subpopulations. Pre-beta HDLs are either lipid-poor (or lipid-free) apoA-I or discoidal particles consisting of apoA-I complexed with phospholipids and possibly a small amount of unesteriﬁed cholesterol. Studies investigating relationships between CVD risk and concentrations of speciﬁc HDL subpopulations have yielded inconsistent results. Thus, it remains unknown whether the cardioprotective properties of HDLs are inﬂuenced by their apolipoprotein composition, their size, their density, their electrophoretic mobility, or a combination of all of these properties. Origin and Metabolism of HDLs The HDLs in human plasma have their origin in the liver and intestine, beginning as discoidal lipid-poor particles that acquire most of their lipid constituents after entering the plasma. The lipidation is achieved in a series of reactions that culminate in the formation of mature, spherical HDL particles (Fig. 2.2). These reactions, and also the subsequent remodeling (Fig. 2.3) of the mature HDLs, are the result of activity of several factors,9 including the ATP-binding cassette A1 (ABCA1), ATP-binding cassette G1 (ABCG1), scavenger receptor type B1 (SR-B1), LCAT, CETP, PLTP, hepatic lipase, lipoprotein lipase, and endothelial lipase (Table 2.1).

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HDL Cholesterol

Liver and Intestine

Lipid-poor apoA-I

CHAPTER 2

ABCA1

Discoidal AI-HDLs

LCAT CE CE

CE LCAT

Small, spherical AI-HDLs

Large, spherical AI-HDLs

32

Figure 2.2 Formation of apoA-I–containing HDLs. Lipid-poor apoA-I originates in liver and intestine. Lipid-poor apoA-I acquires PL and UC from cells (via ABCA1) to form discoidal HDLs. Discoidal AI-HDLs are acted on by LCAT in plasma to form small, spherical AI-HDLs. Small spherical AI-HDLs are then converted into large spherical AI-HDLs in an LCAT-mediated process that involves either particle fusion or the incorporation of lipid-poor apoA-I into small spherical HDLs.

Large spherical A-I HDL

Excretion through kidney

CE TG

CE

Discoidal A-I HDL ABCA1

CETP HL

Lipid-poor apoA-I

CE LCAT

CE TG

TG CE

CE

CE

Small spherical A-I HDL

UC

UC

CE LCAT

Large spherical A-I HDL

Figure 2.3 Remodeling of apoA-I–containing HDLs. Dissociation of lipid-poor apoA-I from HDL accompanies the remodeling of HDL by triglyceride-rich lipoproteins, CETP, and hepatic lipase. CETP promotes the exchange of HDL cholesteryl esters (CE) for triglyceride (TG) in triglyceride-rich lipoproteins (TGR-LP) to form CE-depleted, TG-enriched HDL particles. Subsequent hydrolysis of HDL TG by hepatic lipase (HL) reduces the size of the HDL core. The consequent redundancy of surface constituents results in a dissociation of a proportion of the apoA-I from the HDL surface and thus the generation of a pool of monomolecular, lipid-free/lipid-poor apoA-I.

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HDL Cholesterol 33

ABCA1 and ABCG1: cell membrane transporters that facilitate the delivery of cholesterol from cells to HDLs in the extracellular space SR-B1: an HDL receptor present mainly in the liver that promotes the selective hepatic uptake of HDL-C LCAT: a plasma protein that acts primarily on the cholesterol in HDLs to form cholesteryl esters. LCAT is responsible for virtually all of the cholesteryl esters in plasma. About 80% of the cholesterol in HDLs (and 70% of that in the total plasma fraction) exists in the esteriﬁed form. CETP: a plasma protein that promotes the redistribution of cholesteryl esters between plasma lipoproteins. Activity of CETP results in a mass transfer of cholesteryl esters from HDLs to LDLs and triglyceride-rich lipoproteins. PLTP: a plasma protein that promotes transfers of phospholipids between HDL and other plasma lipoproteins Hepatic lipase: a triglyceride lipase that resides on the surface of endothelial cells in hepatic sinusoids and the capillary beds of steroid hormone synthesizing tissues. Its preferred substrate is HDL triglyceride. Lipoprotein lipase: an enzyme that resides on the surface of the endothelial cells in most tissues. It hydrolyzes triglyceride in chylomicrons VLDLs in a process accompanied by transfer of phospholipids and apolipoproteins to HDLs. Endothelial lipase: an enzyme present on the surface of endothelial cells. Its preferred substrate is HDL phospholipid. Its function is poorly understood.

CHAPTER 2

Table 2.1 Factors Involved in the Formation and Remodeling of HDLs

Functions of HDLs HDLs have several functions that have the potential to protect against atherothrombotic disease (Fig. 2.4). These functions fall into two categories: those involved in plasma cholesterol transport and those that appear to be unrelated to cholesterol transport. Role of HDLs in Plasma Cholesterol Transport To understand the role of HDLs in plasma cholesterol transport, it is necessary to have some understanding of how other lipoprotein fractions are involved and how they interact with HDLs. Very-low-density lipoproteins (VLDLs) are assembled in the liver and contain a core that is mainly triglyceride plus a small amount of cholesterol. After being secreted into plasma the triglyceride in VLDLs is broken down by the enzyme lipoprotein lipase in a reaction that releases free fatty acids for uptake by tissues for use as energy or (in adipose tissue) for reconversion into triglyceride to be stored at fat. As it loses its triglyceride, the VLDL particle becomes progressively smaller and, in a complex series of reactions, is ultimately converted into a triglyceride-poor, cholesterolrich LDL particle. The cholesterol in an LDL particle is delivered to tissues following binding of the particle to the LDL receptor that is present on the surface of most cells in

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HDL Cholesterol

Anti-oxidant

CE HDL

CHAPTER 2

Anti-thrombotic - antiplatelet - protein C activation

Anti-inflammatory

Pro-fibrinolytic

Enhanced reverse cholesterol transport

34

Anti-atherothrombotic

Figure 2.4 Role of HDLs in delivering cholesterol from peripheral tissues to the liver. The unesteriﬁed cholesterol (UC) in peripheral tissues is incorporated into HDLs and subsequently delivered to the liver by a number of pathways. It may be delivered to the liver as unesteriﬁed cholesterol in a process involving binding of HDLs to hepatic SR-B1 (pathway 1). There is evidence in humans that this pathway accounts for most of the cholesterol transported from the plasma to the liver. Other pathways involve the esteriﬁcation of HDL cholesterol by LCAT with subsequent delivery of the newly formed cholesteryl esters (CE) to the liver by either of two pathways. In most animal species (including rodents) all of the cholesteryl esters in HDLs are delivered directly to the liver after binding of HDLs to hepatic SR-B1 (pathway 2). In humans and selected animal species such as non-human primates and rabbits, a proportion of the HDL cholesteryl esters is delivered to the liver by an indirect pathway involving CETP-mediated transfer to the VLDL-LDL fraction and subsequent delivery of the cholesteryl esters to the liver following the binding of LDLs to hepatic LDL receptors (pathways 3 and 4). There is evidence that these direct and indirect pathways for delivering HDL cholesteryl esters to the liver are approximately equal.

the body. Since the level of expression of the LDL receptor is increased in cells that are depleted of cholesterol and decreased in cells that are overloaded with cholesterol, this process ensures that the cholesterol in LDLs is delivered precisely where it is needed, whether this is a return of the cholesterol to the liver (for elimination from the body in bile or for recycling into new VLDL particles) or a delivery of cholesterol to cells in extrahepatic tissues to be used in the synthesis of cell membranes. The liver and some endocrine glands have the ability to convert the cholesterol into bile acids (liver) or steroid hormones (endocrine glands). Other tissues do not have this capacity, and removal of surplus cholesterol can be achieved only by delivery of cell cholesterol to acceptors in the extracellular space. The predominant extracellular acceptors of tissue cholesterol are HDLs. There are two main processes that promote the efﬂux of cholesterol from cells. One involves activity of the ABCA1 transporter, with lipid-free apoA-I acting as the main extracellular acceptor.11 The second involves the ABCG1

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HDL Cholesterol CHAPTER 2

transporter, with large spherical HDLs acting as the preferred extracellular acceptors.12 Once cholesterol has been transferred from cells to HDLs in the extracellular space, it may be delivered to the liver for elimination from the body by either direct or indirect pathways (Fig. 2.5). It may be delivered directly to the liver in a process involving binding of HDLs to the hepatic SR-B1 receptor. Alternatively, it may be delivered to the liver by an indirect pathway involving the CETP-mediated transfer of HDL cholesteryl esters to the VLDLs and LDLs, with delivery to the liver then being achieved by the receptor-mediated uptake of LDLs. Non-lipid Functions of HDLs In addition to their well-known role in plasma cholesterol transport, HDLs also have a number of other functions, some of which may contribute substantially to their anti-atherogenic properties13 (Table 2.2). For example, HDLs have

Liver LDL-R

(3) CE

CE SR-B1

VLDL/LDL

(3)

UC (2)

35

SR-B1

CETP

(1) CE

Bile

HDL

LCAT UC

Extrahepatic tissues UC

Figure 2.5 HDLs may protect against atherosclerosis by several mechanisms.

Table 2.2 Functions of HDLs with the Potential to Protect Against CVD Cholesterol efﬂux: By promoting the efﬂux of cholesterol from foam cells, HDLs inhibit the progression (and even promote the regression) of atherosclerosis. Antioxidant properties: HDLs inhibit the oxidative modiﬁcation of the LDLs and thus reduce their atherogenicity. Anti-inﬂammatory properties: HDLs inhibit expression of endothelial cell adhesion molecules and MCP-1 and thus inhibit the recruitment of monocytes into the artery wall. Antithrombotic properties: HDLs are antithrombotic. Enhancement of endothelial function: HDLs stimulate the generation of nitric oxide, thus reducing the endothelial dysfunction that may precede the development of atherosclerosis. Endothelial repair: HDLs promote the repair of damaged endothelium.

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HDL Cholesterol CHAPTER 2

antioxidant properties. This may be achieved either by the paraoxonase that is transported by HDLs or by apolipoproteins such as apoA-I, apoA-II, apoA-IV, and apoE, all of which have antioxidant properties. HDLs also inhibit vascular inﬂammation.14 They are antithrombotic,15 they normalize endothelial function in patients with either low HDL levels or high LDL levels,16 and they promote the repair of damaged endothelium.17,18 The extent to which any (or all) of these functions contribute to the cardioprotective properties of HDLs is still not known.

Evidence that Raising HDL Concentrations Protects Against Atherosclerosis

36

Intervention Studies in Animals There have been many studies demonstrating direct anti-atherogenic properties of HDLs in a variety of animal models5–8 (Table 2.3). These include the infusion of HDLs into cholesterol-fed rabbits and the overexpression of apoA-I in transgenic rabbits and mice. It should be emphasized, however, that all animal models have their limitations and that none is a true model for the disease that develops in humans. Intervention Studies in Humans Despite the very large body of epidemiological evidence identifying the concentration of HDL-C as a powerful negative risk factor in humans, there are very few human intervention studies that have put this proposition directly to the test. While there are several human intervention studies in which drug-induced elevations of HDL-C were associated with a reduction in atherosclerosis, most of these trials were not designed speciﬁcally to test the beneﬁts of raising the HDL-C level. A recent post hoc analysis of data from the Framingham Offspring study supported the hypothesis that raising the HDL-C level is associated with a reduction in cardiovascular risk across the spectrum of patients receiving lipid therapy.19 After adjusting for changes in LDL-C, plasma triglycerides, and pretreatment blood lipid levels, as well as potential confounders (such as smoking, weight, and the use of beta-blockers), it was found that a 5-mg/dL increase in HDL-C translated into a 21% decrease in cardiovascular risk (Fig. 2.6). Furthermore,

Table 2.3 HDL-Raising Interventions in Animals that Protect Against Atherosclerosis Overexpression of the apoA-I gene in mice and rabbits Intravenous infusion of native or reconstituted HDLs in rabbits Overexpression of LCAT in rabbits Inhibition of CETP in rabbits

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HDL Cholesterol

HR (95% CI) 0.79 (0.67, 0.93)

0.6

0.8

1.0

1.2

1.4

Hazard ratio per 5 mg/d Lincrease in HDL-C Figure 2.6 Hazard ratio of major cardiovascular events associated with raising HDL-C by 5 mg/dL. These results were from a post hoc analysis of the Framingham Offspring Study.19 Results were adjusted for changes in LDL-C and triglyceride levels, pretreatment plasma lipid levels, and other potential confounders, including smoking, body weight, and the use of non-lipid medications.

the lower the pretreatment level of LDL-C, the greater the beneﬁcial impact of raising HDL-C. There are two direct studies in humans that support the proposition that raising the level of HDLs is anti-atherogenic. One was a small study in which a preparation of reconstituted HDLs (rHDLs) was infused into human subjects with coronary artery disease.20 The rHDLs contained a variant of apoA-I (known as apoA-IMilano) complexed with a phospholipid. After receiving intravenous injections of the rHDL preparation at weekly intervals for 5 weeks, there was a signiﬁcant reduction in the atheroma burden in coronary arteries as assessed by intravascular ultrasound, a result consistent with a protective action of HDLs. A second, larger study also used rHDLs, but in this case the rHDLs were prepared from normal human apoA-I.21 Patients were randomly assigned to receive four weekly infusions of either saline or the rHDLs. In this study, infusion of rHDLs did not have a signiﬁcant effect on the percentage change in coronary atheroma volume (as assessed by intravascular ultrasound) compared with placebo. There was, however, a statistically signiﬁcant improvement in both the plaque characterization index and the coronary score as assessed by quantitative coronary angiography.

CHAPTER 2

Events 79

37

N 454

Deﬁnition of Low HDL-C Population studies indicate that the higher the level of HDL-C, the lower the risk of having a cardiovascular event.2 The association is continuous up to an HDL-C concentration of about 80 mg/dL, above which there appears to be no further protection.2 The choice of any single value to deﬁne a “low” HDL-C concentration is thus rather arbitrary. Many guidelines recommend that concentrations of HDL-C below 40 mg/dL (1.03 mmol/L) in men and below 45 mg/ dL (1.16 mmol/L) in women be regarded as lower than desirable and thus an indication for HDL-raising therapy.

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HDL Cholesterol CHAPTER 2

38

Causes of Low HDL-C Most people with “low” levels of HDL-C have either the metabolic syndrome or type 2 diabetes.22 Both conditions are driven by the presence of abdominal obesity and are now approaching epidemic proportions worldwide. Less commonly, a low level of HDL-C may have a genetic origin, such as in a genetic deﬁciency of apoA-I or ABCA1.23 Genetic conditions causing hypertriglyceridemia (including familial combined hyperlipidemia and familial hypertriglyceridemia) are also associated with a low level of HDL-C. However, it is the presence of type 2 diabetes and the metabolic syndrome that accounts for the overwhelming majority of people with low levels of HDL-C. The metabolic syndrome is a cluster of abnormalities that deﬁnes a condition with high cardiovascular risk. The components of the syndrome include central obesity, insulin resistance, dyslipidemia, mild hypertension, and a proinﬂammatory state.24 The precise relationship of the metabolic syndrome to type 2 diabetes is not known, although the coexistence of the two conditions in some families suggests that there is a link. Some consider the metabolic syndrome to be a prediabetic state. The lipid abnormalities in type 2 diabetes and the metabolic syndrome are remarkably similar. They include an increased concentration of plasma triglycerides; an LDL fraction characterized by small, dense particles; a decreased level of HDL-C; and an HDL fraction characterized by small, dense particles.22 The low level of HDL-C in people with type 2 diabetes or the metabolic syndrome is caused mainly by an increased rate of HDL catabolism, possibly secondary to a CETP-mediated triglyceride enrichment of the particles.

Management of Low HDL States Lifestyle Weight Reduction Many (although not all) overweight people have a low level of HDL-C. Weight reduction is usually accompanied by an increase in the HDL-C level, although to be effective the weight loss needs to be both substantial and sustained. Physical Activity High levels of aerobic activity are generally accompanied by high concentrations of HDL-C. Furthermore, increasing physical activity in people with low levels of HDL-C, especially those who are overweight, is usually accompanied by an increased HDL-C concentration. Indeed, it may be argued that the single most important preventable cause of low HDL-C in the 21st century is a low level of physical activity. While any increase in physical activity is likely to be beneﬁcial, there is growing evidence that there may be additional beneﬁts of exercising for more than the currently recommended 30 minutes per day of moderate-intensity exercise.

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HDL Cholesterol

Alcohol Alcohol consumption increases the level of HDL-C, with most evidence favoring a selective increase in the HDL3 subfraction. The mechanism is uncertain, nor is it known whether the HDL increase associated with alcohol consumption is cardioprotective.

CHAPTER 2

Smoking Cessation Smoking reduces the concentration of HDL-C, and smoking cessation is associated with an HDL-C increase of up to 10%. The mechanism and impact on CHD of smoking-mediated effects on HDLs are not known.

Fibrates Treatment with ﬁbrates increases the concentration of HDL-C by 2% to 20%.25–27 Fibrates belong to a class of drugs that exert their effects by activating the hormone-activated nuclear receptors, peroxisome proliferator-activated receptors (PPARs). PPARs regulate gene expression. One of them, PPARa, is activated by endogenous molecules, such as fatty acids and also by synthetic compounds such as ﬁbrates. Fibrates increase expression of the genes for both apoA-I and apoA-II, although the magnitude of the increases in the plasma concentrations of these proteins tends to be small. Generally, the increase in plasma apoA-II is greater than that of apoA-I.28,29 This results in an increase in the concentration of HDL particles containing both apoA-I and apoA-II but a decrease in those containing apoA-I without apoA-II. Other potential mechanisms by which ﬁbrates increase the level of HDL-C include an enhancement of cell cholesterol efﬂux secondary to an induction of cell ABCA1 expression. The reported magnitude of the HDL-C increase in people treated with ﬁbrates varies greatly, and in some studies the increase has been rather small. In people with diabetes in the very large FIELD study, treatment with fenoﬁbrate increased HDL-C levels by less than 2%.25 While there is convincing clinical trial evidence that treatment with ﬁbrates reduces the risk of having a cardiovascular event, especially when given to people with features of the metabolic syndrome,27 there is little evidence to indicate that this beneﬁt is due to a ﬁbrate-induced increase in the concentration of HDL-C.

39

Pharmacological Management Currently available drugs with the capacity to increase the concentration of HDL-C include ﬁbrates, statins, and niacin.

Statins Statins are used primarily to reduce the concentration of LDL-C. However, they also have an HDL-raising effect, with reported increases in HDL-C in the order of 5% to 15%. The dose–response curve for statin-induced increases in HDL-C concentration differs markedly from that of statin-induced LDL-C lowering. Most of the increase in HDL-C is achieved at relatively low dosages of statins; in some cases, the effect is already maximal at the lowest recommended dosage. In the case of atorvastatin, the increase in HDL-C falls off at higher dosages. The mechanism by which statins increase the concentration of HDL-C is

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HDL Cholesterol CHAPTER 2

40

not known, nor is it known why different statins vary in their effects on HDL-C levels or whether such differences have any clinical relevance. Evidence from statin intervention trials indicates that most of the observed reduction in cardiovascular events can be explained by the reduction in concentration of LDL-C. The relationship between statin-induced increases in HDL-C and cardiovascular events is uncertain, although there is some evidence that HDL-C raising with statins is independently predictive of a slowing of progression or even regression of atheroma as assessed by coronary artery intravascular ultrasound.30 An individual patient meta-analysis of 32,258 patients treated with rosuvastatin, atorvastatin, or simvastatin has provided some insights into the effects of statins on HDL-C levels.31 It was apparent from this analysis that for both rosuvastatin and simvastatin there was a dosage-dependent increase in HDL-C, whereas for atorvastatin, the increase in HDL-C was inversely related to the dosage. Statin-induced changes in HDL-C were totally unrelated to the changes in LDL-C. The strongest predictor of statin-induced increase in HDL-C was the pretreatment HDL-C level: the lower the pretreatment HDL-C level, the greater the increase in HDL-C after statin treatment. In people with type 2 diabetes, however, the statin-induced increase in HDL-C was less than in non-diabetics, despite the fact that the diabetic subjects had lower HDL-C levels.31 Niacin Of currently available agents, niacin (nicotinic acid) is the most effective HDLraising drug.32 Niacin has long been used as a broad-spectrum lipid-modifying agent.33 It lowers plasma triglyceride levels by 30% to 40%. It lowers LDL-C by up to 20% and increases HDL-C by up to 30%. Niacin has also been shown to reduce cardiovascular events and to promote regression of atheroma. However, until recently its widespread therapeutic use has been limited by the unpleasant side effects experienced by most people. As outlined below, more recent formulations of niacin are much better tolerated, and the use of this agent is likely to increase substantially over the next few years. The mechanism by which niacin raises HDL-C levels is not known, although there is evidence that it acts both to increase HDL synthesis and to decrease HDL catabolism. The precise mechanism is the subject of extensive current investigation. Two early clinical trials demonstrated the ability of niacin to reduce the risk of having a cardiovascular event. The Coronary Drug Project34 involved the treatment of patients with MI with a daily dose of 3 g of the immediate-release form of niacin for a total of 6.5 years. Major cardiovascular events were significantly reduced by more than 25%. There was no signiﬁcant reduction in total mortality at the end of the trial, but in an analysis of the 15-year follow-up data there was a statistically signiﬁcant 11% lower mortality in the people who had originally been allocated to the niacin group.35 The extent to which HDL raising contributed to the reduction in cardiovascular events is not known. Another early study was the Stockholm Ischaemic Heart Disease Secondary Prevention Study,36 in which MI survivors were randomized at discharge from

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02-Baliga-Chap02.indd 41

HDL Cholesterol CHAPTER 2

41

the hospital into one of two groups: one was an untreated control group, and the other received 3 g/d of niacin and 2 g/d of cloﬁbrate. The study lasted 5 years. The combined treatment with niacin and cloﬁbrate was accompanied by a statistically signiﬁcant reduction in both total (26% reduction) and cardiovascular (36% reduction) mortality. Whether the beneﬁt was related to the niacin, the ﬁbrate, or the combination could not be determined. Again, the extent to which HDL raising contributed to the reduction in cardiovascular events is not known. In addition to the clinical end-point studies, there have been several studies investigating the effects of niacin on atherosclerosis in both the carotid and coronary arteries. There has been a consistent ﬁnding that treatment with niacin slows the progression of atherosclerosis,32 and in some studies it promoted substantial plaque regression.37 Despite these positive results, until recently niacin has not been widely used in clinical practice. The main reason for its limited use has been the occurrence of unpleasant side effects in many people. The most common side effect is ﬂushing, which in many people is simply not tolerated. This was especially so with earlier immediate-release formulations. To a large extent, the ﬂushing problems associated with the immediate-release forms of niacin have been overcome by the development of extended-release niacin formulations.38 An additional approach to reducing ﬂushing involves the co-administration of an extended-release formulation of niacin with laropiprant, a selective antagonist of the prostaglandin D(2) receptor subtype 1 (DP1) that mediates niacininduced vasodilation.39 By inhibiting the DP1 receptor, laropiprant further suppresses the ﬂushing. Niacin has been shown to reduce insulin sensitivity,40 raising concerns that it may be contraindicated in insulin-resistant states such as type 2 diabetes and the metabolic syndrome. However, such concerns appear not to be a signiﬁcant problem, suggesting that there is no reason in clinical practice to withhold niacin from subjects with diabetes or insulin resistance. Indeed, there is evidence that niacin improves vascular function and decreases atherosclerosis in people with type 2 diabetes with coronary heart disease.41 Two ongoing trials with niacin are testing the hypothesis that adding niacin on top of statin therapy further reduces cardiovascular events. The Atherothrombosis Intervention in Metabolic Syndrome with Low HDL-C/High Triglyceride and Impact on Global Health Outcomes (AIM-HIGH) study is a 6-year study designed to determine whether the combination of an extendedrelease form of niacin plus simvastatin is superior to simvastatin alone in preventing cardiovascular events in people with established vascular disease and dyslipidemia (low HDL-C and high triglyceride levels). The results of this trial should be available in about 2012. HPS2-THRIVE is a very large trial involving 25,000 people who are receiving effective LDL-lowering therapy (either simvastatin 40 mg/d alone or with ezetimibe 10 mg/d). Eligible subjects have been randomized to receive either a placebo or the combination of extended-release niacin plus laropiprant. This trial is planned to be completed in 2013.

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HDL Cholesterol CHAPTER 2

42

New HDL-Raising Strategies Currently Under Investigation CETP Inhibitors Inhibitors of CETP are currently under investigation as HDL-raising agents that have the potential to reduce the risk of having a cardiovascular event. CETP is a plasma protein that promotes the transfer of cholesterol from the protective HDL fraction to potentially pro-atherogenic particles in the VLDL/LDL fractions. Its inhibition results in an increase in the concentration of HDL-C and a decrease in the concentration of cholesterol in the VLDL/LDL fraction. CETP inhibition is markedly anti-atherogenic in rabbits. Drugs that inhibit CETP have been developed and tested in humans. One of these, torcetrapib, increased HDL-C by more than 50% and decreased LDL-C by up to 20%. However, a large trial designed to test the cardioprotective effects of inhibiting CETP with torcetrapib (the ILLUMINATE trial) had to be terminated early because of an excess of deaths in the torcetrapib-treated group.4 Three imaging trials had just been completed at around the time the ILLUMINATE trial was terminated. The results of all three trials were essentially the same, with no evidence that adding torcetrapib to atorvastatin provided any beneﬁts over and above those of atorvastatin alone.43–45 Thus, the excess of both cardiovascular events and total mortality in participants taking torcetrapib in the ILLUMINATE trial did not support the hypothesis that CETP inhibition is cardioprotective. However, torcetrapib increased blood pressure, reduced serum potassium, and increased serum levels of bicarbonate and sodium, effects that were all consistent with an observed torcetrapib-induced increase in serum aldosterone.4 It has since been found in basic studies conducted after termination of the ILLUMINATE trial that torcetrapib induces the synthesis of both aldosterone and cortisol in adrenal cortical cells.46 Furthermore, this effect is shared by analogues of torcetrapib that do not inhibit CETP. The discovery that torcetrapib had off-target adverse effects (unrelated to CETP inhibition) that may have been responsible for the harm caused by this agent has left the door open for retesting the hypothesis with CETP inhibitors that do not share the off-target effects of torcetrapib. Two such agents are dalcetrapib47 and anacetropib,48 both of which are currently under investigation in human clinical trials. Reconstituted HDLs Intravenous infusions of rHDLs comprising complexes of apoA-I and phospholipids have already been shown in human trials to improve endothelial function and to promote regression of coronary artery atheroma as assessed by intravascular ultrasound.20,21 Preparations of rHDLs are currently under further investigation as agents for clinical use. HDL Mimetic Peptides There have been a number of reports of peptides that mimic one or more of the functions of HDLs. Some of these peptides have been shown to be antiatherogenic in animal models,49 but to date their effects on human atherosclerosis and cardiovascular events have not been reported.

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Relationship Between the Concentration and Function of HDL There are circumstances in which HDL function may be impaired. This may occur in people with diabetes, in whom the HDL fraction may contain glycated apoA-I and have impaired functionality.50 There have also been reports of people whose HDL function may be impaired despite the concentration of HDL-C being very high.51 The clinical and practical implications of HDLs with impaired function are currently uncertain, in part because there is no easy way to assess HDL function. In general, however, function does parallel concentration, and until there are valid and easy ways to measure HDL function the concentration of HDL-C should be the therapeutic target.

HDL Cholesterol CHAPTER 2

Possibility that HDLs Are Not Directly Protective Until there is unequivocal direct evidence that HDLs protect against CVD events in humans, it remains possible that HDLs are not directly protective against human CVD, but rather that a low level of HDL-C is a reﬂection of the presence of other factors that cause the disease. For example, a low level of HDL-C is common in people with hypertriglyceridemia, raising the possibility that the observed increase in CVD risk in people with low levels of HDL-C reﬂects no more than the presence of higher levels of potentially atherogenic triglyceride-rich lipoproteins. Furthermore, patients with low levels of HDL-C are often obese or have type 2 diabetes, conditions known in their own right to be associated with an increased risk of CVD. However, there is robust evidence in humans that a low concentration of HDL-C predicts CVD events, independent of the levels of LDL cholesterol, plasma triglyceride, body weight, and the presence of diabetes.2 This, combined with compelling direct evidence from intervention studies in animals and mounting direct evidence in humans, suggests that HDLs are in fact directly protective and that raising their concentration in humans will most likely translate into a reduced risk of having a cardiovascular event.

43

Areas of Ambiguity

HDL Subpopulations The HDL fraction in human plasma is extremely heterogeneous, comprising a number of discrete subpopulations of particles of varying size, shape, and composition. Given that there is no consistent evidence that any one HDL subpopulation is more protective than any other, there is no current indication to measure the HDL subpopulation distribution as part of clinical assessment. Value of Measuring apoA-I It has been suggested that the concentration of apoA-I may be superior to HDL-C as an indicator of the protective effects of HDLs.52 However, given that the concentration of apoA-I tends to parallel that of HDL-C, and given that the predictive power of the two measurements is similar,2 there is no compelling reason at present to go beyond HDL-C as an indication of the degree of cardioprotection.

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HDL Cholesterol CHAPTER 2

HDL-C Targets While many population studies provide clear evidence that a low level of HDL-C identiﬁes people with an increased risk of having a cardiovascular event, there is currently no information from intervention trials to indicate what level of HDL-C should be the target of therapy. Thus, the evidence supporting HDL-C targets is much weaker than that for target levels of LDL-C. Guidelines from most countries state that a concentration of HDL-C less than 40 mg/dL in men or below 50 mg/dL in women is indicative of increased risk and supports more aggressive interventions to reduce all risk factors, without necessarily recommending HDL-raising therapy. However, some guidelines go further and even without supporting evidence recommend using HDL-raising therapy in high-risk people to increase the HDL-C to above 40 mg/dL in men and above 50 mg/dL in women.

44

Summary and Recommendations The epidemiological evidence demonstrating an inverse relationship between the risk of having a cardiovascular event and the plasma concentration of HDL-C is overwhelming. The likelihood that the relationship is causal is supported by the observation that HDLs possess a number of properties with antiatherogenic potential. Furthermore, raising the level of HDL reduces or even reverses atherosclerosis in virtually all animal models that have been studied. The challenge ahead is to demonstrate conclusively that raising the plasma concentration of HDL also inhibits the development of atherosclerosis (or even reverses the process) in humans. Several studies addressing this issue are currently under way, and their results are awaited with great interest.

Practical Points A low level of HDL-C is predictive of cardiovascular events even when the level of LDL-C is very low. • There are several actions of HDLs with the potential to protect against cardiovascular disease. • The most common causes of low HDL-C are abdominal obesity and type 2 diabetes. • There is compelling direct evidence in animals and circumstantial evidence in humans that increasing the plasma level of HDLs translates into a reduction in cardiovascular risk. • On the basis of current evidence, it is reasonable to aim for target levels of HDL-C of above 40 mg/dL in men and above 45 mg/dL in women; higher levels may be recommended in future as further evidence becomes available. • Lifestyle measures such as weight reduction, increased physical activity, and stopping smoking all raise HDL levels and should be strongly recommended in all people with low levels of HDL-C.

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of reconstituted HDL, look promising but will have to await the results of trials before their clinical value will be known.

References 1. Gordon T, Castelli WP, Hjortland MC, et al. High-density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am J Med. 1977;62:707–14. 2. Di Angelantonio E, Sarwar N, Perry P, et al. Major lipids, apolipoproteins, and risk of vascular disease. JAMA. 2009;302:1993–2000. 3. Gordon DJ, Probstﬁeld JL, Garrison RJ, et al. High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies. Circulation. 1989;79:8–15. 4. Barter PJ, Caulﬁeld M, Eriksson M, et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med. 2007;357:2109–22. 5. Badimon JJ, Badimon L, Fuster V. Regression of atherosclerotic lesions by high density lipoprotein plasma fraction in the cholesterol-fed rabbit. J Clin Invest. 1990;85:1234–41. 6. Rubin EM, Krauss RM, Spangler EA, et al. Inhibition of early atherogenesis in transgenic mice by human apolipoprotein AI. Nature. 1991;353:265–7. 7. Duverger N, Kruth H, Emmanuel F, et al. Inhibition of atherosclerosis development in cholesterol-fed human apolipoprotein A-I-transgenic rabbits. Circulation. 1996;94:713–7. 8. Nicholls SJ, Cutri B, Worthley SG, et al. Impact of short-term administration of high-density lipoproteins and atorvastatin on atherosclerosis in rabbits. Arterioscler Thromb Vasc Biol. 2005;25:2416–21. 9. Rye KA, Clay MA, Barter PJ. Remodelling of high-density lipoproteins by plasma factors. Atherosclerosis. 1999;145:227–38. 10. Cheung MC, Albers JJ. Distribution of high-density lipoprotein particles with different apoprotein composition: particles with A-I and A-II and particles with A-I but no A-II. J Lipid Res. 1982;23:747–53. 11. Wang N, Tall AR. Regulation and mechanisms of ATP-binding cassette transporter A1-mediated cellular cholesterol efﬂux. Arterioscler Thromb Vasc Biol. 2003;23:1178–84. 12. Wang N, Lan D, Chen W, et al. ATP-binding cassette transporters G1 and G4 mediate cellular cholesterol efﬂux to high-density lipoproteins. Proc Natl Acad Sci U S A. 2004;101:9774–9. 13. Barter PJ, Nicholls S, Rye KA, et al. Antiinﬂammatory properties of HDL. Circ Res. 2004;95:764–72. 14. Nicholls SJ, Dusting GJ, Cutri B, et al. Reconstituted high-density lipoproteins inhibit the acute pro-oxidant and proinﬂammatory vascular changes induced by a periarterial collar in normocholesterolemic rabbits. Circulation. 2005;111:1543–50.

02-Baliga-Chap02.indd 45

HDL Cholesterol

and has been shown to reduce cardiovascular events. • New therapies under development, including CETP inhibitors and infusions

CHAPTER 2

to adopt a healthier lifestyle; in such people, drug therapy is indicated. • Of currently available agents, niacin is the most effective HDL-raising agent

45

• In many high-risk people, the level of HDL-C remains low even after they try

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HDL Cholesterol CHAPTER 2

46

15. Mineo C, Deguchi H, Grifﬁn JH, et al. Endothelial and antithrombotic actions of HDL. Circ Res. 2006;98:1352–64. 16. Bisoendial RJ, Hovingh GK, Levels JH, et al. Restoration of endothelial function by increasing high-density lipoprotein in subjects with isolated low high-density lipoprotein. Circulation. 2003;107:2944–8. 17. Seetharam D, Mineo C, Gormley AK, et al. High-density lipoprotein promotes endothelial cell migration and reendothelialization via scavenger receptor-B type I. Circ Res. 2006;98:63–72. 18. Tso C, Martinic G, Fan WH, et al. High-density lipoproteins enhance progenitor-mediated endothelium repair in mice. Arterioscler Thromb Vasc Biol. 2006;26:1144–9. 19. Grover SA, Kaouache M, Joseph L, et al. Evaluating the incremental beneﬁts of raising high-density lipoprotein cholesterol levels during lipid therapy after adjustment for the reductions in other blood lipid levels. Arch Intern Med. 2009;169:1775–80. 20. Nissen SE, Tsunoda T, Tuzcu EM, et al. Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. JAMA. 2003;290:2292–300. 21. Tardif JC, Gregoire J, L’Allier PL, et al. Effects of reconstituted high-density lipoprotein infusions on coronary atherosclerosis: a randomized controlled trial. JAMA. 2007;297:1675–82. 22. Barter P. Metabolic abnormalities: high-density lipoproteins. Endocrinol Metab Clin North Am. 2004;33:393–403. 23. Brooks-Wilson A, Marcil M, Clee SM, et al. Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deﬁciency. Nat Genet. 1999;22:336–45. 24. Alberti KG, Eckel RH, Grundy SM, et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation. 2009;120:1640–5. 25. Keech A, Simes RJ, Barter P, et al. Effects of long-term fenoﬁbrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet. 2005;366:1849–61. 26. Manttari M, Tenkanen L, Maenpaa H, et al. High-density lipoprotein cholesterol elevation with gemﬁbrozil: effects of baseline level and modifying factors. Clin Pharmacol Ther. 1993;54:437–47. 27. Barter PJ, Rye KA. Cardioprotective properties of ﬁbrates: which ﬁbrate, which patients, what mechanism? Circulation. 2006;113:1553–5. 28. Hiukka A, Leinonen E, Jauhiainen M, et al. Long-term effects of fenoﬁbrate on VLDL and HDL subspecies in participants with type 2 diabetes mellitus. Diabetologia. 2007;50:2067–75. 29. Taskinen MR, Sullivan DR, Ehnholm C, et al. Relationships of HDL cholesterol, ApoA-I, and ApoA-II with homocysteine and creatinine in patients with type 2 diabetes treated with fenoﬁbrate. Arterioscler Thromb Vasc Biol. 2009;29:950–5. 30. Nicholls SJ, Tuzcu EM, Sipahi I, et al. Statins, high-density lipoprotein cholesterol, and regression of coronary atherosclerosis. JAMA. 2007;297:499–508.

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02-Baliga-Chap02.indd 47

HDL Cholesterol CHAPTER 2

47

31. Barter PJ, Brandrup-Wognsen G, Palmer MK, et al. Effect of statins on HDL: a complex process unrelated to changes in LDL: analysis of the VOYAGER database. J Lipid Res. 2010;51(6):1546–53. 32. Bodor ET, Offermanns S. Nicotinic acid: an old drug with a promising future. Br J Pharmacol. 2008;153(Suppl 1):S68–75. 33. Carlson LA. Nicotinic acid: the broad-spectrum lipid drug. A 50th anniversary review. J Intern Med. 2005;258:94–114. 34. Cloﬁbrate and niacin in coronary heart disease. JAMA. 1975;231:360–81. 35. Canner PL, Berge KG, Wenger NK, et al. Fifteen-year mortality in Coronary Drug Project patients: long-term benefit with niacin. J Am Coll Cardiol. 1986;8:1245–55. 36. Carlson LA, Rosenhamer G. Reduction of mortality in the Stockholm Ischaemic Heart Disease Secondary Prevention Study by combined treatment with cloﬁbrate and nicotinic acid. Acta Med Scand. 1988;223:405–18. 37. Taylor AJ, Villines TC, Stanek EJ, et al. Extended-release niacin or ezetimibe and carotid intima-media thickness. N Engl J Med. 2009;361:2113–22. 38. McCormack PL, Keating GM. Prolonged-release nicotinic acid: a review of its use in the treatment of dyslipidaemia. Drugs. 2005;65:2719–40. 39. Paolini JF, Mitchel YB, Reyes R, et al. Effects of laropiprant on nicotinic acidinduced ﬂushing in patients with dyslipidemia. Am J Cardiol. 2008;101:625–30. 40. Garg A, Grundy SM. Nicotinic acid as therapy for dyslipidemia in non-insulindependent diabetes mellitus. JAMA. 1990;264:723–6. 41. Lee JM, Robson MD, Yu LM, et al. Effects of high-dose modiﬁed-release nicotinic acid on atherosclerosis and vascular function: a randomized, placebo-controlled, magnetic resonance imaging study. J Am Coll Cardiol. 2009;54:1787–94. 42. Sorrentino SA, Besler C, Rohrer L, et al. Endothelial-vasoprotective effects of high-density lipoprotein are impaired in patients with type 2 diabetes mellitus but are improved after extended-release niacin therapy. Circulation. 2010;121:110–22. 43. Kastelein JJ, van Leuven SI, Burgess L, et al. Effect of torcetrapib on carotid atherosclerosis in familial hypercholesterolemia. N Engl J Med. 2007;356:1620–30. 44. Nissen SE, Tardif JC, Nicholls SJ, et al. Effect of torcetrapib on the progression of coronary atherosclerosis. N Engl J Med. 2007;356:1304–16. 45. Bots ML, Visseren FL, Evans GW, et al. Torcetrapib and carotid intima-media thickness in mixed dyslipidaemia (RADIANCE 2 study): a randomised, doubleblind trial. Lancet. 2007;370:153–60. 46. Hu X, Dietz JD, Xia C, et al. Torcetrapib induces aldosterone and cortisol production by an intracellular calcium-mediated mechanism independently of cholesteryl ester transfer protein inhibition. Endocrinology. 2009;150:2211–9. 47. Stein EA, Roth EM, Rhyne JM, et al. Safety and tolerability of dalcetrapib (RO4607381/JTT-705): results from a 48-week trial. Eur Heart J. 2010;31:480–8. 48. Bloomﬁeld D, Carlson GL, Sapre A, et al. Efﬁcacy and safety of the cholesteryl ester transfer protein inhibitor anacetrapib as monotherapy and coadministered with atorvastatin in dyslipidemic patients. Am Heart J. 2009;157:352–60. 49. Van Lenten BJ, Wagner AC, Anantharamaiah GM, et al. Apolipoprotein A-I mimetic peptides. Curr Atheroscler Rep. 2009;11:52–7.

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HDL Cholesterol CHAPTER 2

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50. Nobecourt E, Davies MJ, Brown BE, et al. The impact of glycation on apolipoprotein A-I structure and its ability to activate lecithin:cholesterol acyltransferase. Diabetologia. 2007;50:643–53. 51. Olsson AG. Is high HDL cholesterol always good? Ann Med. 2009;41:11–8. 52. Florvall G, Basu S, Larsson A. Apolipoprotein A1 is a stronger prognostic marker than are HDL and LDL cholesterol for cardiovascular disease and mortality in elderly men. J Gerontol A Biol Sci Med Sci. 2006;61:1262–6.

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Chapter 3

Non-HDL Cholesterol Vera Bittner

R.S. is a 59-year-old white female who presents to the ofﬁce concerned about her cardiovascular risk because her 58-year-old sister was just released from the hospital after getting a coronary stent. She has no other ﬁrst-degree relatives with cardiovascular disease. She works part-time in a restaurant as a cashier, does all her housework, and takes care of her two grandchildren after school. R.S. has no cardiovascular symptoms and has not had any decline in her exercise tolerance in recent years. She attends the children’s athletic events but has no time for any structured exercise of her own. She doesn’t have time to cook and tends to eat fast food with the kids or eats at the restaurant. She has gained about 8 lbs over the past year. She has never smoked. She has had hypertension for several years and has been told that she has “borderline diabetes.” She has not seen a physician in about a year and has run out of all her prescriptions. She does not remember her exact cholesterol numbers, but says that her “bad cholesterol” has been checked multiple times and has always been ﬁne. On exam, she is 5-foot-3 and weighs 195 lbs (body mass index [BMI] 34.5). Her waist circumference is 36 inches. Blood pressure is 152/90 mm Hg, heart rate 78/min. She has no stigmata of hyperlipidemia and her examination is otherwise completely benign. Further data are as follows: • Fasting blood sugar: 145 mg/dL, A1C 7.8% • Liver function tests, renal function, and thyroid proﬁle: normal • Lipid proﬁle: total cholesterol (TC) 229 mg/dL, high-density lipoprotein cholesterol (HDL-C) 42 mg/dL, low-density lipoprotein cholesterol (LDL-C) 98 mg/dL, triglycerides (TG) 348 mg/dL, non-HDL-C 187 mg/dL • Resting ECG: normal

49

Clinical Vignette

Case Discussion R.S. is likely to have diabetes based on her fasting blood sugar and A1C measurements (even though this assumption is based on a single measurement) and thus has a “coronary heart disease (CHD) equivalent.” In addition, there is a positive family history in a sibling, she has hypertension, she is sedentary and obese, and she eats a poor diet. Other than her diabetes and lifestyle risk factors, she has no evidence of secondary causes of dyslipidemia such as renal, liver, or thyroid dysfunction, and she is not taking any medications that could

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Non-HDL Cholesterol CHAPTER 3

affect her lipid proﬁle. Based on the patient’s recollection, prior interpretation of her lipid proﬁle has been solely focused on her LDL-C, which is indeed in the “optimal” range, but she has signiﬁcant hypertriglyceridemia and low HDL-C for a woman and a markedly elevated non-HDL-C. Based on her increased waist circumference, hypertension, abnormal glucose, hypertriglyceridemia, and low HDL-C, she meets all ﬁve criteria for metabolic syndrome. Her non-HDL-C goal is <130 mg/dL, and some practitioners would try to achieve an even lower level given her high-risk status. Therapeutic lifestyle changes must be emphasized throughout her therapy. Statin therapy should be started simultaneously with lifestyle therapy, given her high-risk status, and titrated accordingly.

50

Background What is Non-HDL-C? Non-HDL-C is calculated by subtracting HDL-C from TC and thus includes not only LDL-C but also cholesterol contained in all other apoprotein B (apoB)-containing and potentially atherogenic lipoproteins circulating in blood, including cholesterol in lipoprotein (a) (Lp(a)), intermediate-density lipoprotein (IDL), and that in triglyceride-rich lipoproteins including very-low-density lipoprotein (VLDL) particles, and cholesterol-enriched remnant lipoproteins. Measured apoB and calculated non-HDL-C are highly correlated.1,2 Since neither TC nor HDL-C is signiﬁcantly affected by food intake, non-HDL-C can be measured not only in the fasting state but also postprandially. Since the normal VLDL-C should be below 30 mg/dL, therapeutic goals for non-HDL-C were set 30 mg/dL higher than for LDL-C in the Adult Treatment Panel (ATP) III guidelines.3 Epidemiology Non-HDL-C Distribution in the U.S. Population Using the ATP III categorization of LDL-C in adults as a guide, optimal nonHDL-C would be a non-HDL-C below 130 mg/dL, 130 to 159 mg/dL would be considered “near or above optimal,” and 160 mg/dL or above would be considered elevated.3 In the National Health and Nutrition Examination Survey (NHANES) III conducted in 1988–94, which measured cardiovascular risk factors in adults age 25 years and above, the mean non-HDL-C was 154 ± 45 mg/ dL among women and 160 ± 42 mg/dL among men.4 Among adult men, the median was 160 mg/dL, indicating that half the male U.S. population had elevated non-HDL-C concentrations by ATP III criteria. Among women, the proportion was slightly lower, with a median of 149 mg/dL and a 75th percentile of 181 mg/dL. Non-HDL-C levels were highest among Caucasians, slightly lower among Mexican Americans, and lowest among African Americans. Among men, non-HDL-C increased with age until middle age, then decreased at age 65 and beyond. Among women, non-HDL-C levels peaked a decade later. Population data on non-HDL-C in U.S. children are available from the Bogalusa Heart Study.5 Further analyses from this community-based study suggest that elevated

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Non-HDL Cholesterol CHAPTER 3

51

levels of non-HDL-C in childhood not only correlate with non-HDL-C levels in adulthood, but also predict adult dyslipidemia (elevated levels of LDL-C and TG, low levels of HDL-C) as well as adult obesity, hyperglycemia, and hyperinsulinemia.6 As for LDL-C, non-HDL-C values should be interpreted in the context of an individual’s cardiovascular risk. Using serial NHANES surveys, Ghandehari reported that the proportion of individuals at their non-HDL-C goal overall had increased from 67.4% in the 1988–94 survey to 71.9% in the 2003–04 survey.7 However, only 46.5% of patients with underlying cardiovascular disease (CVD), 42.6% of patients with diabetes, and 43.6% of patients with chronic kidney disease were at their non-HDL-C goal in 2003–04, and distance from goal was large, varying between 60 and 85 mg/dL.7 The distance from goal was disproportionately larger for non-HDL-C compared to LDL-C in most comparable risk groups, suggesting under-recognition of non-HDL-C as a treatment target and subsequent undertreatment.7 Such under-recognition and undertreatment are also suggested by the results of the National Cholesterol Education Program Evaluation Project Utilizing Novel E-Technology (NEPTUNE) II Survey, a survey of almost 4,885 patient records from 376 practices published in 2005.8 Among individuals with TG above 200 mg/dL, only 33% of patients with CHD were at their non-HDL-C target, among diabetic patients only 25% were at target, and among individuals with other CHD equivalents only 17% achieved their non-HDL-C goal.8 Correlates of Non-HDL-C Among children in the Bogalusa study, BMI, age, gender (higher levels in girls), waist circumference, and cigarette smoking were independently associated with non-HDL-C levels but accounted for only 7.7% of the variance in non-HDL-C levels.5 There were no ethnic differences among white and African American youths. Among U.S. adults, non-HDL-C levels are highest in Caucasians, intermediate among Mexican Americans, and lowest among African Americans.4 In women, but not men, non-HDL-C levels have been linked to lower levels of education.4 Oversecretion and impaired catabolism of triglyceride-rich lipoproteins are common in individuals with visceral adiposity and states of insulin resistance (e.g., metabolic syndrome, diabetes mellitus),9–13 and such individuals often have elevated non-HDL-C levels. Non-HDL-C levels are correlated with fasting and postprandial glucose concentrations.14 Lower non-HDL-C levels have been demonstrated in individuals who participate in high-intensity physical activity,15 but there is signiﬁcant heterogeneity in studies that have correlated physical activity, physical ﬁtness, and non-HDL-C levels.13,16,17 Variations in nonHDL-C level by apoE genotype have been reported with higher concentrations among probands who are heterozygous or homozygous for the E4 allele, intermediate levels in those with the E3/E3 genotype, and lowest levels among those who are heterozygous or homozygous for the E2 allele.18 Non-HDL-C and Measures of Atherosclerosis Severity Correlations between non-HDL-C levels and atherosclerosis severity have been demonstrated in adolescents and young adults. In the Pathobiological

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Non-HDL Cholesterol CHAPTER 3

52

Determinants of Atherosclerosis in Youth (PDAY) Study,19–21 an autopsy study of 15- to 34-year-old men and women who died of non-cardiovascular causes, postmortem non-HDL-C levels were associated with levels of lipids in the coronary arteries, fatty streaks, raised lesions, and coronary stenoses of 40% or greater.19,21 The importance of abnormal non-HDL-C levels in youth is further highlighted by a recent report from Finland in which non-HDL-C levels measured between the ages of 12 and 18 years strongly predicted carotid intimal medial thickness measured 21 years later.22 A relationship with brachial ﬂowmediated dilation measured in adulthood could not be demonstrated in this study. In cross-sectional analyses among adults, non-HDL-C levels correlate with coronary calciﬁcation in non-diabetic and diabetic cohorts.23,24 In pre-dialysis patients with chronic kidney disease, non-HDL-C levels are correlated with carotid intimal medial thickness.25 In the Cholesterol Lowering Atherosclerosis Study, non-HDL-C levels were the predominant predictor of coronary artery disease progression on serial coronary angiograms.26 Non-HDL-C Levels and Cardiovascular Events and Mortality Over the past decade, the relationship between non-HDL-C and clinical outcomes has been explored in cohorts with and without underlying cardiovascular disease, with and without diabetes, in both genders, and in groups of different ethnic origin.27–41 Table 3.1 is not an exhaustive listing of all published studies but rather a selection of large cohorts that have been reported. While most of the studies show a relationship between non-HDL-C and outcome, there is some heterogeneity in results. Cohorts differ signiﬁcantly in age, clinical characteristics, baseline non-HDL-C levels, and covariate adjustment and other statistical modeling methodology, making it impossible to directly compare risk ratios. Even within the same cohort, results can differ by follow-up time, as seen in the AMORIS study.39 A recent meta-analysis summarizing ﬁndings from 68 studies in 21 countries concluded that the hazard ratio for non-HDL-C in predicting CHD was slightly stronger at younger ages and at lower systolic blood pressure.40 The authors did not ﬁnd important variation by sex, levels of other lipid fractions, diabetes, BMI, or fasting status. The adjusted hazard ratio for prediction of ischemic stroke was weaker than for CHD at 1.12 (95% CI, 1.04–1.20).40 Given the algorithm recommended by the ATP III, it seems most relevant to assess residual risk conferred by elevated non-HDL-C in the setting of “optimal” LDL-C. Such an analysis was done by Arsenault and colleagues in the EPIC-Norfolk Study.41 Among individuals with baseline LDL-C below 100 mg/ dL, a non-HDL-C of at least 130 mg/dL was associated with a hazard ratio of 1.84 (95% CI 1.12–3.04) compared to a non-HDL-C below 130 mg/dL.41 The public health impact of even modest changes in non-HDL-C can be substantial. A recent analysis from the British Regional Heart Study suggested that 10% of the decline in age-adjusted hazard of myocardial infarction among men (–62% over the last 25 years) was related to the observed decline in non-HDL-C levels (non-HDL-C levels fell by 10.8 mg/dL [95% CI, 6.2–15.4], p < 0.001, over this period).42

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CV mortality

10 years 9,132 men and 8,631 women, aged 25–89 years

14 prospective cohorts

Prospective cohort study

4 prospective cohort studies

Rancho Bernardo (US) Von Muehlen

Pooled analysis (US) Liu

12,660 men and 6,721 women

13 years

CHD mortality

3, 5, 10 years CV mortality

CV mortality

19 years

2,406 men and 2,056 women aged 40–64 years

Prospective cohort study

1,386 women and 1,094 men (mean age 69 years)

Total mortality

30,802 men, 60,417 10 years women, age 40–79

53

Outcome Total mortality

Prospective cohort study

Follow-up 19 years

N / gender / age 2,406 men and 2,056 women aged 40–64 years

Design Prospective cohort study

Study/Author Lipid Research Clinics Follow-up Study (US) Cui Ibaraki Prefectural Health Study (Japan) Noda Lipid Research Clinics Follow-up Study (US) Cui Decode Study (Europe) Zhang

Table 3.1 Non-HDL-C and Cardiovascular Risk: Selected Studies

Age-adjusted

1.19 (1.13–1.26) for men; 1.15 (1.06–1.25) for women

CHAPTER 3

Non-HDL Cholesterol

(continued)

Multivariable

Multivariable

Multivariable

Multivariable HR

0.88 (0.85–0.91) for men, 0.91 (0.87–0.94) for women

NFG: 1.01 (0.91–1.11) IFG: 1.20 (1.00–1.50) NGT:1.07 (0.97–1.19) IGT: 0.94 (0.78–1.13) New diabetes: 1.17 (0.93–1.46)

Adjustment Age-adjusted

HR / OR / RR 1.49 (1.18–1.88) for men; 1.61 (1.22–2.12) for women

Men: 1.17 (0.83–1.66), 0.94 (0.71–1.26), 1.17 (0.98–1.39) Women: 0.82 (0.51–1.33), 0.80 (0.60–1.08), 0.91 (0.76–1.09) No diabetes: 0.95 (0.65–1.39) and <130 mg/dL without diabetes is 2.73 (1.27–5.87) referent; 130–159/ Diabetes: 2.73 (1.60–4.66) and mgdL, t160 mg/dL 3.68 (2.51–5.39)

Per SD

1-unit increase in Z-score

Per 30 mg/dL non-HDL-C increase

Per 30 mg/dL non-HDL-C increase

Contrast Non-HDL-C t220 mg/dL vs. <160 mg/dL

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2108 American Indian men and women, age 45–74

Prospective cohort study

Prospective cohort study

Strong Heart Study (US) Lu

Women’s Health Study (US) Mora

27,673 women, 45 years or older

2,693 men, 3,101 women aged >30 years

Prospective cohort study

Framingham Heart Study and Framingham Offspring Study (US) Liu

11 years

Incident fatal and nonfatal CVD Incident CVD

9 years

Quintiles of nonHDL-C (lowest quintile referent)

Tertiles of nonHDL-C, lowest tertile referent

<160 mg/dL as reference; 160–189 mg/dL, >189 mg/dL

Incident CHD

15 years

Contrast Per 30 mg/dL non-HDL-C increase

Per SD

Outcome CHD mortality

3, 5, 10 years CHD mortality

N / gender / age Follow-up 30,802 men, 60,417 10 years women, age 40–79

1,386 women and 1,094 men (mean age 69 years

Design Prospective cohort study

Prospective cohort study

Study/Author Ibaraki Prefectural Health Study (Japan) Noda Rancho Bernardo (US) Von Muehlen

Table 3.1 Continued

54

Multivariable

Multivariable

Women: 1.33 (0.96–1.83), 1.80 (1.32–2.46) Men: 1.02 (0.69–1.52), 2.23 (1.41–3.43) 1.19 (0.89–1.59), 1.87 (1.43–2.43), 1.94 (1.49–2.52), 2.52 (1.95–3.25)

Multivariable

Multivariable

Adjustment Multivariable

Non-HDL Cholesterol

Men: 1.45 (0.94–2.24; 1.33 (0.91–1.94); 1.21 (0.95–1.54) Women: 1.11 (0.64–1.95), 0.98 (0.68–1.42) 0.99 (0.77–1.28) Men: 1.64 (1.13–2.40) and 2.21 (1.57–3.11) Women: 1.72 (0.95–3.11) and 2.34 (1.38–3.95)

HR / OR / RR 1.23 (1.11–1.37) for men, 1.07 (0.95–1.21) for women

CHAPTER 3

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BARI (US) Bittner

Patients with multi- 5 years vessel coronary artery disease

Nonfatal MI

55

MI or CHD Highest vs. lowest death quintile

18,225 men, mean age 66

Nested case control in prospective cohort study Prospective cohort study within RCT

6 years

Acute MI

5,731 cases of AMI, NA 6,459 controls

Per 10 mg/dL increase

Per SD

Per 2 SD difference

Case control

Acute MI

3,510 cases of AMI, N/A 9,805 controls

Highest vs. lowest quintile

Case control

Major CV event

ISIS Study (UK) Parish INTERHEART (international) Karthikeyan Health Professionals Follow-Up Study (US) Pischon

15,632 women, age 10 years 45 or older

Prospective cohort study

Women’s Health Study (US) Ridker

CHAPTER 3

Multivariable

Multivariable

Multivariable

Multivariable

Multivariable

Non-HDL Cholesterol

1.049 (1.006–1.093) for every 0 .26 mmol/L increase

2.76 (1.66–4.58)

Asians 1.14 (1.09–1.20), Non-Asians 1.20 (1.13–1.27)

2.10 (1.89–2.33)

2.51 (1.69–3.72)

Non-HDL Cholesterol CHAPTER 3

56

Strategies/Approach Evaluation The ﬁrst step in the evaluation and treatment of non-HDL-C elevations is the calculation of non-HDL-C and recognition that non-HDL-C is indeed elevated in a speciﬁc patient. While non-HDL-C is easily calculated from routine lipid proﬁles, Blaha and coworkers suggest that lack of explicit reporting of non-HDL-C by many laboratories is a signiﬁcant barrier to the treatment of atherogenic dyslipidemia by busy practitioners.43 Both the National Lipid Association Task Force and the American College of Cardiology/American Diabetes Association Expert Panel have thus recommended routine reporting of non-HDL-C on all laboratory reports.43,44 Recognition of an elevated nonHDL-C should then prompt a detailed review of concomitant cardiovascular risk factors and conditions known to correlate with non-HDL-C elevations (see above). Risk for events should be assessed with the Framingham algorithm or another suitable risk prediction instrument, and concomitant conditions known to have adverse effects on the lipid proﬁle should be treated (e.g., achieving better glycemic control in patients with diabetes, removing medications that could adversely affect the lipid proﬁle). Management with Therapeutic Lifestyle Change Patients who smoke should be counseled to quit and provided with the appropriate support to do so. Weight control and increased physical activity enhance reduction of non-HDL-C in individuals with atherogenic dyslipidemia. A metaanalysis by Dattilo and colleagues reported changes in blood lipids by weight loss.45 Based on the data provided, one can estimate that every kilogram of weight loss would result in an approximately 2.38-mg/dL decrease in non-HDLC.45 Two recent meta-analyses suggest that both aerobic exercise in the form of walking and resistance exercise lower non-HDL-C levels by approximately 4% to 5%.46,47 The impact of changes in dietary composition on lipids and lipoproteins, including non-HDL-C, is quite variable, depending on the baseline diet, whether diet changes are isocaloric or result in weight loss, and whether measurements are made during active weight loss or after attainment of steady state. In patients with diabetes mellitus (and presumably also in patients with metabolic syndrome who have not crossed the threshold to diabetes), a diet rich in monounsaturated fatty acids may be preferable to a low-fat diet with higher carbohydrate intake.48 Plant sterols can help reduce non-HDL-C levels in diabetic and non-diabetic patients.49 Management with Medications (Clinical Trials) LDL-C is the primary treatment target for hypertriglyceridemic individuals with triglyceride levels between 200 and 500 mg/dL. Statin therapy is thus used as the initial treatment in most of these patients. If non-HDL-C levels remain above target after the LDL-C target has been reached, doubling of the statin dose can be expected to decrease non-HDL-C by 3% to 6%.50 Adding nicotinic acid to existing statin therapy has been reported to result in somewhat greater

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Non-HDL Cholesterol CHAPTER 3

incremental non-HDL-C lowering, ranging from 6.5% with 1,000 mg of nicotinic acid to 15.1% with 2,000 mg of nicotinic acid.51 When fenoﬁbrate is added to statin therapy, approximately 9% incremental non-HDL-C lowering can be expected.52 Adding omega-3 fatty acids at a dosage of 4 g/day lowered nonHDL-C by an additional 6% when added to simvastatin compared to simvastatin monotherapy.53 To date, there have not been any pharmacological lipid-lowering outcomes/ event trials that have enrolled patients based on elevated non-HDL-C levels and have speciﬁcally targeted non-HDL-C reduction, nor have there been trials that have compared a strategy of LDL-C lowering with a non-HDL-C-lowering strategy. Using non-HDL-C reductions reported in 30 clinical trials involving a variety of pharmacological and non-pharmacological interventions, Robinson and associates estimated a 1% decrease in CHD risk over 4.5 years for every 1% lowering of non-HDL-C.54

While epidemiological studies have amply documented the relationship between non-HDL-C and CVD risk, there is intense debate whether apoB is superior to non-HDL-C as a risk predictor and should be chosen as the treatment target instead of non-HDL-C. Lau and Smith recently published a detailed review of studies that have attempted to compare the predictive value of LDL-C with other “advanced lipid measures,” including non-HDL-C, and/or also compared the “advanced lipid measures” against each other.55 They concluded that nonHDL-C, apoB, and LDL particle number were generally more predictive than LDL-C, that lipid and apolipoprotein ratios tended to be more predictive than the individual lipid variables, and that adjustment for risk factors associated with the atherogenic proﬁle tended to attenuate associations.55 The Emerging Risk Factor Collaboration pooled data from 68 long-term studies encompassing 2.79 million person-years of follow-up.40 The investigators found virtually identical hazard ratios for non-HDL-C and apoB for a variety of outcomes and suggested that the choice of one or the other should be based on practical considerations such as cost, availability, and standardization of assays rather than differences in strength of the epidemiological associations.40 Concerns about standardization of apoB assays have been largely resolved in recent years. Many laboratories, however, do not offer this testing in house, and timely availability of test results and cost remain important considerations. The more important question is, however, whether a treatment approach based on apoB would yield measurably better clinical outcomes than a strategy based on non-HDL-C, the approach currently recommended by ATP III.3 While the two measures are highly correlated, studies that compare percentiles of the distribution of each measure demonstrate that there is “misclassiﬁcation”— that is, individuals classiﬁed by non-HDL-C into a particular risk category may not always end up in the same risk category when classiﬁed by apoB due to under- and overestimation of risk.1 However, only a minority of individuals are

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Areas of Ambiguity

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misclassiﬁed in such a way that treatment by non-HDL-C classiﬁcation would lead to “undertreatment.” Among those who appear at greater risk by nonHDL-C than the corresponding apoB value, we have no evidence that withholding treatment or treating less aggressively would be justiﬁed. Nevertheless, a recent consensus panel of experts from the American Diabetes Association and American College of Cardiology suggested that apoB should be measured in patients at cardiometabolic risk who are on pharmacological therapy and that these apoB measurements be used to guide adjustments to therapy.44 There is no randomized controlled clinical trial evidence that a therapeutic approach targeting non-HDL-C would be superior to an approach targeting LDL-C. There are multiple reasons for this lack of data: (a) clinical trials of lipid lowering have often excluded hypertriglyceridemic patients; (b) non-HDL-C data are rarely reported; (c) LDL-C is often calculated and thus not available in individuals with hypertriglyceridemia, the subgroup most likely to show incremental beneﬁt from a non-HDL-C targeted approach; and (d) statins, which have most often been used in outcomes trials of lipid-lowering therapy, lower both LDL-C and non-HDL-C, making it very difﬁcult, if not impossible, to attribute cardiovascular outcomes to one or the other. Future trials of combination therapy in individuals with combined hyperlipidemia may provide better insight into the relative value of treatment strategies targeting LDL-C and nonHDL-C.

Guidelines The approach to non-HDL-C as a measure of risk and as a treatment target varies by country and across guidelines within the United States.3,44,56–62 Some guidelines, while acknowledging the relationship between non-HDL-C and cardiovascular risk, choose not to set treatment targets in the absence of randomized trial evidence; others set speciﬁc targets based on patient risk. Treatment goals for LDL-C, non-HDL-C, and apoB for patient populations at varying risk are shown in Table 3.2 based on recommendations from ATP III and the ADA/ ACC Consensus Statement.3,44,56 ATP III is the most widely used lipid treatment guideline in the United States and its recommendations have been adopted by many other organizations. ATP III guidelines will thus be discussed in more detail.3,44 In ATP III, non-HDL-C was chosen as a secondary target of therapy rather than apoB for three reasons: because standardized measures of apoB were not widely available in clinical practice in 2001 when this guideline went to press, because there were no large prospective studies where apoB had been shown to have greater predictive power than non-HDL-C in patients with hypertriglyceridemia, and because of the added expense associated with measurement of apoB. In patients with triglyceride levels 200 to 499 mg/dL (many of whom have metabolic syndrome), LDL-C lowering remains the primary focus of therapy, but non-HDL-C becomes the secondary target of lipid-lowering therapy after achievement of LDL-C goals. Non-HDL-C goals are 30 mg/dL higher than

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<130 mg/dL

<160 mg/dL

<160 mg/dL

<190 mg/dL

<100 mg/dL

<130 mg/dL

<130 mg/dL

<160 mg/dL

High risk (CHD, CHD risk equivalents, >20% 10-year Framingham risk for hard events)

Moderate risk (10-year Framingham risk 10–20%) Moderate risk with multiple risk factors (<10% 10-year Framingham risk) Low risk (0 or 1 risk factor)

* Optional per Grundy et al.56

Non-HDL-C <100 mg/dL*

LDL-C <70 mg/dL*

Risk Highest risk (CHD or CHD risk equivalent with additional risk factors

ATP III Goals

–

–

59

Risk Highest-risk patients: Known CVD Diabetes plus one or more additional major CVD risk factors High-risk patients: No diabetes or known clinical CVD, but t2 additional major CVD risk factors Diabetes but no other major CVD risk factors –

–

–

–

–

–

CHAPTER 3

<130 mg/dL

<100 mg/dL

–

Non-HDL-C <100 mg/dL

LDL-C <70 mg/dL

ADA / ACC Consensus Statement

Table 3.2 Non-HDL-C Targets in ATP III and the ADA/AHA Consensus Statement

Non-HDL Cholesterol

–

–

–

<90 mg/dL

Apo-B Target <80 mg/dL

Non-HDL Cholesterol CHAPTER 3

60

corresponding LDL-C goals. Weight control and increased physical activity enhance reduction of non-HDL-C in these individuals with atherogenic dyslipidemia. Statins remain ﬁrst-line therapy and may be sufﬁcient to achieve nonHDL-C goals in some patients with appropriate dose titration. Alternatively, moderate doses of statins can be combined with a TG-lowering drug such as nicotinic acid or a ﬁbrate. The latter strategy has the additional advantage of raising HDL-C as well. When hypertriglyceridemia is more severe (TG > 500 mg/dL), prevention of pancreatitis is the ﬁrst priority and drugs designed to lower TG such as ﬁbrates and nicotinic acid become ﬁrst-line therapy. In such patients, the non-HDL-C may overestimate atherogenicity of the plasma, since some of the cholesterol is likely transported in larger VLDL particles and chylomicrons felt not to be atherogenic. The ATP III panel thus suggested that achievement of the nonHDL-C goal of 30 mg/dL higher than LDL-C goal may be not only difﬁcult but also unnecessary in these individuals. Weight control and regular physical activity are critical in severely hypertriglyceridemic persons, restriction of alcohol intake and avoidance of high-carbohydrate diets may be very helpful, and patients should be encouraged to quit smoking. As in all patients, medications should be reviewed and agents known to cause hypertriglyceridemia should be discontinued, if possible.

Summary and Recommendations The non-HDL-C level is easily derived from the routine lipid proﬁle. It is correlated with measures of atherosclerosis severity in cross-sectional analyses, predicts progression of angiographic coronary artery disease, and is an important independent predictor of future cardiovascular events and mortality. Non-HDL-C has been designated a secondary target of therapy in individuals with TG between 200 and 500 mg/dL. Such individuals often have a number of lifestyle risk factors that are amenable to nonpharmacological therapy. While there are no clinical trials that have speciﬁcally targeted non-HDL-C lowering, reanalysis of existing data in trials that have targeted LDL-C suggests that treatment beneﬁt correlates with the degree of non-HDL-C lowering. Non-HDL-C as a marker of risk and as a treatment target is underused. Universal reporting of non-HDL-C levels and treatment targets analogous to those currently reported by clinical laboratories for LDL-C may facilitate incorporation of nonHDL-C treatment into clinical practice.

Practical Points Calculate non-HDL-C routinely in all patients with hypertriglyceridemia who have TG between 200 and 500 mg/dL. • Look for conditions commonly associated with non-HDL-C elevations (e.g., metabolic syndrome, components of metabolic syndrome, renal dysfunction, medications) and treat underlying conditions as appropriate.

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Disclosures Current and past research grants: Glaxo Smith Kline, Hoffman La Roche, Pﬁzer, Merck, Atherogenics, NIH-Abbott.

Non-HDL Cholesterol

bination therapy with statins and TG-lowering agents such as niacin, ﬁbrates, or ﬁsh oil.

CHAPTER 3

• Assess global risk and determine LDL-C and non-HDL-C goals. • Emphasize therapeutic lifestyle changes. • Pharmacological therapy may include intensiﬁcation of statin therapy or com-

1. Sniderman AD, St-Pierre AC, Cantin B, et al. Concordance/discordance between plasma apolipoprotein B levels and the cholesterol indexes of atherosclerotic risk. Am J Cardiol. 2003;91:1173–7. 2. Grundy SM, Vega GL, Tomassini JE, et al. Correlation of non–high-density lipoprotein cholesterol and low-density lipoprotein cholesterol with apolipoprotein B during simvastatin–fenoﬁbrate therapy in patients with combined hyperlipidemia (a subanalysis of the SAFARI trial). Am J Cardiol. 2009;104:548–53. 3. National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III): ﬁnal report. Circulation. 2002;106:3143–421. 4. Gardner CD, Winkelby M, Fortman SP. Population frequency distribution of non-high-density lipoprotein cholesterol (Third National Health and Nutrition Examination Survey (NHANES III), 1988–1994). Am J Cardiol. 2000;86:299–304. 5. Srinivasan S, Myers L, Berenson GS. Distribution and correlates of non-high density lipoprotein cholesterol in children. The Bogalusa Heart Study. Pediatrics. 2002;110:e29. 6. Srinivasan SR, Frontini MG, Xu J, et al. Utility of childhood non–high-density lipoprotein cholesterol levels in predicting adult dyslipidemia and other cardiovascular risks: The Bogalusa Heart Study. Pediatrics. 2006;118:201–6. 7. Ghandehari H, Kamal-Bahl S, Wong ND. Prevalence and extent of dyslipidemia and recommended lipid levels in US adults with and without cardiovascular comorbidities: The National Health and Nutrition Examination Survey 2003– 2004. Am Heart J. 2008;156:112–9. 8. Davidson MH, Maki KC, Pearson TA, et al. Results of the National Cholesterol Education Program (NCEP) evaluation project utilizing novel e-technology (NEPTUNE) II survey and implications for treatment under the recent NCEP writing group recommendations. Am J Cardiol. 2005;96:556–63. 9. Denke MA, Sempos CT, Grundy SM. Excess body weight: an underrecognized contributor to dyslipidemia in white American women. Arch Intern Med. 1994;154:401–10. 10. Denke MA, Sempos CT, Grundy SM. Excess body weight: an underrecognized contributor to high blood cholesterol levels in white American men. Arch Intern Med. 1994;153:1093–103.

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27. Cui Y, Blumenthal RS, Flaws JA, et al. Non-high-density lipoprotein cholesterol level as a predictor of cardiovascular disease mortality. Arch Intern Med. 2001;161:1413–9. 28. Noda H, Iso H, Irie F, et al. Association between non-high-density lipoprotein cholesterol concentrations and mortality from coronary heart disease among Japanese men and women. The Ibaraki Prefectural Health Study. J Atheroscl Thromb. 2010;17:30–6. 29. Zhang S, Qiaoa Q, Tuomilehtoa J, et al. for the DECODE Study Group. The impact of dyslipidaemia on cardiovascular mortality in individuals without a prior history of diabetes in the DECODE Study. Atherosclerosis. 2009;206:298–302. 30. Von Muehlen D, Langer RD, Barrett-Connor E. Sex and time differences in the associations of non-high-density lipoprotein cholesterol versus other lipid and lipoprotein factors in the prediction of cardiovascular death (the Rancho Bernardo Study). Am J Cardiol. 2003;91:1311–5. 31. Liu J, Sempos CT, Donahue RP, et al. Non-high-density lipoprotein and very-low density lipoprotein cholesterol and their risk predictive values in coronary heart disease. Am J Cardiol. 2006;98:1363–8. 32. Lu W, Resnick HE, Jablonski KA, et al. Non-HDL cholesterol as a predictor of cardiovascular disease in type 2 diabetes. Diabetes Care. 2003;26:16–23. 33. Mora S, Otvos JD, Rifai N, et al. Lipoprotein particle proﬁles by nuclear magnetic resonance compared with standard lipids and apolipoproteins in predicting incident cardiovascular disease in women. Circulation. 2009;119:931–9. 34. Ridker PM, Rifai N, Cook NR, et al. Non-HDL cholesterol, apolipoproteins A-I and B100, standard lipid measures, lipid ratios, and CRP as risk factors for cardiovascular disease in women. JAMA. 2005;294:326–33. 35. Parish S, Peto R, Palmer A, et al. for the International Studies of Infarct Survival (ISIS) Collaborators. The joint effects of apolipoprotein B, apolipoprotein A1, LDL cholesterol, and HDL cholesterol on risk: 3510 cases of acute myocardial infarction and 9805 controls. Eur Heart J 2009;30:2137–46. 36. Karthikeyan G, Teo KK, Islam S, et al. Lipid proﬁle, plasma apolipoproteins, and risk of a ﬁrst myocardial infarction among Asians. An analysis from the INTERHEART Study. J Am Coll Cardiol. 2009;53:244–53. 37. Pischon T, Girman CJ, Sacks FM, et al. Non-high-density lipoprotein cholesterol and apolipoprotein B in the prediction of coronary heart disease in men. Circulation. 2005;112:3375–83. 38. 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;106:2537–42. 39. Holme I, Aastveit AH, Jungner I, et al. Relationships between lipoprotein components and risk of myocardial infarction: age, gender and short versus longer follow-up periods in the Apolipoprotein MOrtality RISk study (AMORIS). J Intern Med. 2008;264:30–8. 40. The Emerging Risk Factors Collaboration. Major lipids, apolipoproteins, and risk of vascular disease. JAMA. 2009;302:1993–2000. 41. Arsenault BJ, Rana JS, Stroes ESG, et al. Beyond low-density lipoprotein cholesterol. Respective contributions of non–high-density lipoprotein cholesterol levels, triglycerides, and the total cholesterol/high-density lipoprotein cholesterol ratio to coronary heart disease risk in apparently healthy men and women. J Am Coll Cardiol 2010;55:35–41.

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42. Hardoon SL, Whincup PH, Lennon LT, et al. How much of the recent decline in the incidence of myocardial infarction in British men can be explained by changes in cardiovascular risk factors? Evidence from a prospective populationbased study. Circulation. 2008;117:598–604. 43. Blaha MJ, Blumenthal RS, Brinton EA, et al., on behalf of the National Lipid Association Task Force on non-HDL cholesterol. The importance of non–HDL cholesterol reporting in lipid management. J Clin Lipidol. 2008;2:267–73. 44. Brunzell JD, Davidson M, Furberg CD, et al. Lipoprotein management in patients with cardiometabolic risk: consensus statement from the American Diabetes Association and the American College of Cardiology Foundation. Diabetes Care. 2008;31:811–22. 45. Dattilo AM, Kris-Etherton PM. Effects of weight reduction on blood lipids and lipoproteins—a meta-analysis. Am J Clin Nutr. 1992;56:320–8. 46. Kelley GA, Kelley KS, Tran ZV. Walking and non–HDL-C in adults: a metaanalysis of randomized controlled trials. Prev Cardiol. 2005;8:102–7. 47. Kelley GA, Kelley KS. Impact of progressive resistance training on lipids and lipoproteins in adults: a meta-analysis of randomized controlled trials. Prev Med. 2009;48:9–19. 48. Garg A. High-monounsaturated-fat diets for patients with diabetes mellitus: a meta-analysis. Am J Clin Nutr. 1998;67:S577–82. 49. Lau VWY, Journoud M, Jones PJH. Plant sterols are efﬁcacious in lowering plasma LDL and non-HDL cholesterol in hypercholesterolemic type 2 diabetic and nondiabetic persons. Am J Clin Nutr. 2005;81:1351–8. 50. Nicholls SJ, Brandrup-Wognsen G, Palmer M, et al. Meta-analysis of comparative efﬁcacy of increasing dose of atorvastatin versus rosuvastatin versus simvastatin on lowering levels of atherogenic lipids (from VOYAGER). Am J Cardiol. 2010;105:69–76. 51. Ballantyne CM, Davidson MH, McKenney J, et al. Comparison of the safety and efﬁcacy of a combination tablet of niacin extended release and simvastatin vs. simvastatin monotherapy in patients with increased non–HDL cholesterol (from the SEACOAST I Study). Am J Cardiol. 2008;101:1428–36. 52. Grundy SM, Vega GL, Yuan Z, et al. Effectiveness and tolerability of simvastatin plus fenoﬁbrate for combined hyperlipidemia (the SAFARI trial). Am J Cardiol. 2005;95:462–8. 53. Maki KC, McKenney JM, Reeves MS, et al. Effects of adding prescription omega-3 acid ethyl esters to simvastatin (20 mg/day) on lipids and lipoprotein particles in men and women with mixed dyslipidemia. Am J Cardiol. 2008;102:429–33. 54. Robinson JG, Wang S, Smith BJ, et al. Meta-analysis of the relationship between non–high-density lipoprotein cholesterol reduction and coronary heart disease risk. J Am Coll Cardiol. 2009;53:316–22. 55. Lau JF, Smith DA. Advanced lipoprotein testing: recommendations based on current evidence. Endocrinol Metab Clin North Am. 2009;38:1–31. 56. Grundy SM, Cleeman JI, Bairey Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. Circulation. 2004;110:227–39. 57. Smith SC, Allen J, Blair SN, et al. AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 Update. J Am Coll Cardiol. 2006;47;2130–9.

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58. Rosenzweig JL, Ferrannini E, Grundy SM, et al. Primary prevention of cardiovascular disease and type 2 diabetes in patients at metabolic risk: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2008;93:3671–89. 59. British Cardiac Society, British Hypertension Society, Diabetes UK, HEART UK, Primary Care Cardiovascular Society, The Stroke Association. JBS 2: Joint British societies guidelines on prevention of cardiovascular disease in clinical practice. Heart. 2005;91(Suppl V):v1-v52. 60. Graham I, Atar D, Borch-Johnson K, et al. European guidelines on cardiovascular disease prevention in clinical practice: executive summary. Eur J Cardiovasc Prev Rehabil. 2007;14(suppl 2):E1-E40. 61. Ryden L, Standl E, Bartnik M, et al. Guidelines on diabetes, pre-diabetes, and cardiovascular diseases: full text. Eur Heart J. 2007;28(1):88–136. 62. National Heart Foundation of Australia and the Cardiac Society of Australia and New Zealand. Position statement on lipid management. Heart Lung Circulation. 2005;14:275–91.

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Chapter 4

Use of High-Sensitivity C-Reactive Protein for Risk Assessment Garth Graham, Kerunne Ketlogetswe, Catherine Y. Campbell, Kiran Musunuru, Samia Mora, and Roger S. Blumenthal

In the United States over three quarters of a million individuals experience a myocardial infarction (MI) each year, with a similar number suffering from stroke.1 A number of risk classiﬁcation strategies are used in clinical practice to assist in the prediction and management of coronary artery disease (CAD). These include tools such as the National Cholesterol Education Program Adult Treatment Panel (ATP) III global risk score based on the Framingham risk estimate for hard coronary heart disease (CHD) events, which are deﬁned as nonfatal MI and fatal CHD events. These estimates of risk use traditional risk factors such as hyperlipidemia, yet only half of the individuals who suffer from stroke or MI have evidence of clear hyperlipidemia and almost one ﬁfth of these individuals have none of the other major traditional risk fators.2,3 Despite the fact that nearly two out of three men and one out of two women after the age of 40 will develop cardiovascular disease (CVD) within their lifetimes,4 the Framingham risk score identiﬁes as “high risk” or “intermediate risk” only a minority of men and women who will actually suffer from stroke or MI over the next decade. Using the ATP III global risk score, only about 5% of asymptomatic men and less than 1% of asymptomatic women in the United States without CHD are classiﬁed as high risk.5,6 This highlights the need for improved assessment of an individual’s risk for developing CAD, most notably those who are asymptomatic and are classiﬁed as being at “intermediate risk.”7 The impetus for understanding and accurately estimating the risk of individuals within this category rests primarily on the large number of people who are classiﬁed as being at intermediate risk. Using a 10-year absolute risk of a hard event of 6% to 20% as the deﬁnition of intermediate risk places approximately 10% and 40% of asymptomatic women and men, respectively, in the intermediate risk category.5 Thus, using innovative tools and methodologies to accurately gauge their true risk of CAD has important implications for public health.

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Introduction

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68

Biology and Pathogenesis of C-Reactive Protein A number of studies over the past two decades have established a role for inﬂammation in atherogenesis; inﬂammation appears to contribute to all stages of atherosclerosis.8–13 Histological analysis of the development of atherosclerosis has identiﬁed roles for inﬂammation via both the cellular and humoral pathways. Oxidized low-density lipoprotein (LDL) interacts with macrophages to release a number of cytokines, including interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor alpha.13–15 These cytokines are produced at a number of sites, including macrophages, adipose tissue, and vessel walls. They subsequently act on the liver to produce a number of markers of inﬂammation, including ﬁbrinogen and C-reactive protein (CRP). Thus, it is not surprising that elevation of inﬂammatory markers such as CRP is associated with a higher risk of heart disease. CRP is a liver-derived, nonglycosylated, circulating pentraxin composed of ﬁve identical subunits arranged with pentameric symmetry.16 The plasma halflife is about 19 hours under both basal and stress conditions, and as such the plasma levels are more related to synthetic rate. Whether the relevance of CRP is solely as a marker for inﬂammation or whether it has a direct role in the process of atherogenesis is still being studied and debated.13 What is known is that CRP binds to LDL and, when it does, allows LDL to be taken up by macrophages without any further modiﬁcation.17 CRP is found in atherosclerotic lesions, and when CRP is infused into normal individuals it is associated with marked elevations in not only inﬂammatory markers but markers of coagulation as well.18 CRP has been shown to inhibit ﬁbrinolysis through its effects on tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) and also induces endothelial cell apoptosis. In animal models, treatment with CRP was noted to increase the overall area and size of atherosclerotic plaques.18 Thin-capped ﬁbroatheromas are a common precursor lesion for acute coronary syndrome (ACS); CRP has recently been found to be associated with coronary arterial remodeling and ﬁbrous cap thickness in patients with ACS, suggesting that inﬂammation simultaneously contributes to both plaque growth and plaque instability.19 Microvascular angina is a condition characterized by angina-like chest pain and normal coronary angiography. Endothelial dysfunction and systemic inﬂammation with elevated CRP levels are thought to play a role in its pathogenesis.20

Genetics of CRP CRP expression is a complex trait that is inﬂuenced by both environmental and genetic factors. CRP levels are a continuous trait, with a log-normal distribution, a mean of about 1.6 mg/L, and wide variation.21 Variations in baseline CRP levels have been associated with environmental factors and toxins, such as cigarette smoking, infection, age, gender, lipid proﬁle, blood pressure, and obesity.22

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Observational evidence suggests a genetic component to CRP levels. In the National Heart Lung and Blood Institute (NHLBI) Family Heart Study (FHS), a cohort study examining the genetic and nongenetic determinants of CHD, baseline CRP levels displayed a high degree of heritability among ﬁrst-degree relatives, even after excluding participants with a personal history of smoking, known CHD, or other indices of atherosclerosis.23 Interindividual variation in blood CRP level was estimated to be between 35% and 40%. Monozygotic twin studies conﬁrmed that CRP levels exhibit a moderate but signiﬁcant degree of heritability.24 MacGregor and coworkers compared monozygotic versus dizygotic twin pairs and found a greater correlation of CRP level among monozygotic than dizygotic twins, with an estimated heritability of 52%.25 There are also ethnic- and race-speciﬁc differences in the distribution of CRP gene polymorphisms, with the greatest nucleotide diversity seen in African Americans.26 The CRP gene is located on the proximal long arm of chromosome 1 in the 1q23.2 region, and the CRP gene sequence consists of two exons and one intervening intron.27 The ﬁrst exon encodes a signal peptide and the ﬁrst two amino acids of the mature protein, followed by a 278-nucleotide-long intron that includes a polymorphic (GT)n repeat sequence that is 30 nucleotides long.28 The second exon encodes the remaining 204 amino acids, followed by a stop codon. Regulation of CRP expression involves IL-6 as a major inducer of transcription, with IL-1 acting synergistically to enhance the effect; thus, IL-1 and IL-6 gene polymorphisms are associated with differences in blood CRP levels.29 The polymorphism of the length of the GT repeat in the CRP intron contributes to variation in the blood level of CRP. A single nucleotide polymorphism (SNP) or coding region variant occurs when one nucleotide is substituted for another. In some cases the substitution does not cause a change in the amino acid produced (e.g., CTG l CTC will still result in formation of leucine); in others the substitution will result in either an altered amino acid or a premature truncation of the protein. To identify rare and common variants that may be associated with CRP levels among individuals with extreme phenotypes, Miller and colleagues resequenced the CRP gene in 192 subjects with no known CVD in the Women’s Health Study (WHS; n = 717) who had extremely high or low baseline CRP levels. Seven common CRP SNPs (minor allele frequency greater than 0.05) and nine rare CRP SNPs (minor allele frequency less than 0.05) were identiﬁed. The seven common CRP SNPs were then genotyped among subjects in the WHS (n = 717), Pravastatin Inﬂammation/CRP Evaluation trial (PRINCE; n = 1,110), and Physicians’ Health Study (PHS; n = 509).29 All of the subjects in this study had no known CVD at baseline and had not been exposed to hormone replacement therapy. In the WHS, CRP SNP genotyping was performed using extremes of phenotype, among 359 Caucasian women with very low CRP levels (CRP 0.03 to 0.20 mg/L) and 358 Caucasian women with high CRP levels (CRP greater than 5.0 mg/L). In the PRINCE cohort, CRP SNP genotyping was performed in 1,110 Caucasians without known CAD, and in the PHS cohort genotyping was performed among 610 participants who subsequently developed either MI

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(n = 346) or thromboembolic stroke (n = 264) during the follow-up period, as well as 696 control study participants who remained free of cardiovascular disease. After adjusting for the effects of age, smoking, and BMI, highly signiﬁcant and consistent associations were seen between the minor allele of SNPs -757T>C, -286C>T>A, IVS1+29A>T, and 1444C>T and high CRP levels across populations. Linkage disequilibrium (LD; the non-random association of alleles at two or more loci) and haplotype analyses suggest that -286C>T>A is the functional SNP, and the associations seen with the other SNPs are due to strong LD between their minor alleles and one or the other minor allele of -286C>T>A. Signiﬁcant associations were seen between the minor allele of 1059G>C and 1846G>A and low CRP levels in all populations in the unadjusted and adjusted analyses. These ﬁndings were consistent with those reported in smaller series by several different groups.30–32 However, although there was an association between CRP variants and baseline CRP, this association did not correlate with clinical cardiovascular events. Indeed, when studying the PHS participants with atherothrombotic events (MI, ischemic stroke), none of the minor alleles of CRP SNPs were associated with risk of atherothrombotic events in the direction predicted by the association of SNP genotype with CRP level. Only the minor allele -717A>G (which was not associated with CRP level) was associated with a reduced risk of atherothrombotic events in this analysis. Arguing for the relatively small contribution of polymorphisms to variance in CRP was that the proportion of variance in CRP level due to age, BMI, and smoking (21% and 20% in the PRINCE and PHS cohort, respectively) was signiﬁcantly higher than that attributable to variation in the CRP gene (2% and 5% in PRINCE and PHS, respectively). This ﬁnding suggests that environmental exposures and lifestyle factors play a much larger role in inﬂuencing CRP and hence CVD risk, or that there are as-yet-undiscovered genetic loci that affect CRP levels. The concept of Mendelian randomization has been used to investigate the causal relationship of CRP level on CHD. If CRP is to be assumed to be causally linked to CHD, then genetic variants inﬂuencing the trait should also inﬂuence the disease risk. Because Mendelian randomization is based on the premise of the random assignment of genotype at meiosis, it should be relatively unaffected by confounding from environmental factors. Elliott and colleagues used a multistaged design to identify common genetic variants associated with CRP levels, and then used Mendelian randomization to investigate the causal relationship of CRP levels with CHD.33 Using a genome-wide association study (GWAS) to identify genetic variants associated with CRP levels in several combined populations, they identiﬁed a SNP strongly associated with CRP levels (SNP rs7553007), yet found that this SNP was not signiﬁcantly associated with CHD. In a three-way comparison of CRP genetic variants, CRP levels, and CHD risk, there was signiﬁcant association of CRP variants with CRP levels, and CRP levels with CHD, but not CRP variants with CHD. Elliott and coworkers suggested that the observational data linking CRP levels and CHD may be confounded by association with other CHD risk factors

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C-Reactive Protein and Primary Prevention Atherosclerosis and thrombosis of the coronary vessels is inﬂuenced by a combination of lipid accumulation and inﬂammation. A number of established factors, such as diabetes, hypertension, smoking, and hyperlipidemia, are known to accelerate these processes. Since its discovery over 80 years ago, CRP has emerged as a tool in the primary prevention of CVD. A number of prospective cohort studies have demonstrated that high-sensitivity CRP (hsCRP) predicts future CVD risk independent of other risk factors (Table 4.1).34–50 hsCRP provides independent prognostic information for CVD risk after controlling for Framingham risk factors and/or diabetes and obesity.43–50 In apparently healthy individuals with no history of a prior atherosclerotic disease event, at least 12 major studies have shown a beneﬁt to measuring hsCRP (Fig. 4.1). Indeed, it appears to have a predictive value similar to that of cigarette smoking or systolic blood pressure. In a meta-analysis of 22 prospective studies, the overall odds ratio for CHD in the highest versus the lowest tertiles of hsCRP levels was 1.6 (95% CI, 1.5–1.7) after adjusting for traditional risk factors.51 hsCRP can be added to standard risk assessment models for more accurate CVD risk assessment. In WHS, adding hsCRP to the ATP III global risk score resulted in reclassiﬁcation of about 40% of intermediate-risk women into a lower or higher risk category (if one uses less than 5% as a fourth category of denoting very low risk and if one looks at an expanded CVD endpoint).52 Measurement of hsCRP levels also results in improved prediction using the Framingham risk score in elderly women at high risk and elderly men at intermediate risk.53 The Reynolds Risk Score is a recent risk prediction algorithm that adds two new variables—hsCRP and parental family history of premature CHD—to the existing variables in the ATP III global risk score.54 The Reynolds model predicts CVD risk in women more accurately than the existing ATP III global risk score. In fact, there have been large and clinically important differences between

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or may reﬂect a reverse causation (i.e., a secondary inﬂammatory response being caused by atherosclerosis). Regardless of whether CRP is causal in CHD, proponents of its selective use argue that it remains a useful clinical biomarker for inﬂammation and high vascular risk. It could be argued that the importance of understanding CRP genetic sequence variations and their phenotypic expression is that they may one day present targets for drugs to alter gene expression of those polymorphisms most related to a greater risk of CVD. However, it is unlikely that the genotypic expression of CRP polymorphisms will lend itself as a viable target for drug therapy. Given the combined association of elevated CRP with acquired exposures and the relatively small contribution of polymorphic variance to CRP level, modifying gene expression alone for durable clinical beneﬁt, even if it could be proven, would be a far more costly strategy than lifestyle modiﬁcation and use of lipid-lowering and blood pressure-lowering therapy.

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Population Iowa 65+ Rural Heart Study Hoorn Study

Women’s Health Study

Caerphilly Prospective Heart Disease Study

Helsinki Ageing Study Physician’s Health Study Study of Osteoporotic Fractures EPIC-Norfolk Kuopio Heart Study

Study Harris et al. (1999) (13) Jager et al. (1999) (14)

Ridker et al. (2000) (15)

Mendall et al. (2000) (16)

Strandberg and Tilvis (2000) (17) Albert et al. (2002) (18) Tice et al. (2003) (19) Boekholdt et al. (2006) (20) Laaksonen et al. (2005) (21)

455 299 9,704 987 1,476

2,512

27,939

N 1,293 610

>75 >40 >65 >45 >50

>45

>44

Age (years) >65 >50

Endpoint Total mortality CV mortality Total mortality CV mortality Total mortality CV mortality Total mortality Total mortality Sudden death CV mortality CV mortality CV mortality Total mortality

Sex M, W M, W M, W W W M M M, W M W M, W M M

HR (95% CI) 1.6 (1.0–2.6)1 2.2 (1.0–5.2)1 1.9 (1.1–3.2)1 2.0 (1.4–3.0)1 1.5 (1.2–1.8)1 2.4 (1.3–4.4)4 2.3 (1.5–3.7)4 1.2 (1.1–1.4)2 2.7 (0.9–8.8)3 8.0 (2.2–29.0)1 2.9 (1.8–4.7)3 2.9 (1.5–5.9)1 2.0 (1.4–3.1)1

Table 4.1 hsCRP in the Prediction of Total and Cardiovascular Mortality in Prospective Cohorts of Apparently Healthy Men and Women

72

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FINRISK Study Cardiovascular Health Study

MONICA-Augsburg Cohort Study

Tuomisto et al. (2006) (23) Jenny et al. (2007) (24)

Koenig et al. (2008) (12)

per 10-mg/L change

those in the top vs. bottom quartile, or

top vs. bottom quintile. All HRs, except those from Mendall et al. (16), are adjusted for available traditional risk factors.

3

4

M, W M, W M, W M M W W M M

2.1 (1.3–3.3)3 1.7 (1.3–2.2)3 2.4 (1.4–4.1)3 4.3 (2.2–8.4)3 4.1 (2.7–6.4)3 2.3 (1.0–4.9)3 2.3 (1.4–3.9)3 2.2 (1.4–3.3)1 1.9 (1.4–2.5)1

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(From Ridker PM. High-sensitivity C-reactive protein as a predictor of all-cause mortality: implications for research and patient care. Clin Chem 2008;54:234–7. Copyright 2008 Reproduced with permission of American Association for Clinical Chemistry, Inc.)

>3 mg/L vs. <1 mg/L

CV mortality Total mortality Total mortality CV mortality Total mortality CV mortality Total mortality CV mortality Total mortality

2

>45

>65

3,348

3,620

>25 >65

>50

6,051 2,480

2,155

1

HR calculated as a comparison of those with hsCRP

Strong Heart Study

Okin et al. (2005) (22)

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0.0

1.0

2.0

3.0

1.0

1.0

2.0

3.0

HPFUS 2004

PHS 1997

hsCRP <1 mg/L

EPIC 2005

WHS 2000

Strong 2005

UK 2000

hsCRP 1 to 3 mg/L

Kuopio 2005

MONICA 2004

74

CHS 2005

ARIC 2004

hsCRP >3 mg/L

PIMA 2005

FHS 2006

NHS 2004

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Iceland 2004

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Figure 4.1 Independent impact of hsCRP on cardiovascular risk. Multivariate adjusted relative risks of future cardiovascular events according to baseline levels of high-sensitivity C-reactive protein (hsCRP) less than 1 mg/L, 1 to 3 mg/L, and more than 3 mg/L in 14 major prospective cohort studies. (Reprinted from Ridker PM. C-reactive protein and the prediction of cardiovascular events among those at intermediate risk: moving an inﬂammatory hypothesis toward consensus. J Am Coll Cardiol. 2007;49:2129–38, with permission from Elsevier.) ARIC = Atherosclerosis Risk in Communities study; CHS = Cardiovascular Health Study; EPIC = Evaluation for Prevention of Ischemic Complications-Norfolk study; FHS = Framingham Heart Study; HPFUS = Health Professionals Follow-Up Study; Iceland = Reykjavik Heart Study data; Kuopio = Kuopio Heart Study; MONICA = Monitoring Trends and Development in Cardiovascular Disease study; NHS = Nurses Health Study; PHS = Physicians Health Study; PIMA = Pima Indian study; Strong = Strong Heart Study; UK = British general practice cohort; WHS = Women’s Health Study.

Fully adjusted relative risk

Estimated 10-year CVD risk using Age, BP, smoking, TC, and HDLC (ATP-III)

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Estimated 10-year CVD risk using Age, BP, smoking, TC, HDLC, hsCRP, and parental history (Reynolds risk score) <5%

13,500

N = 80,000 5 to <10%

5 to <10%

48,500

Low to moderate risk

N = 20,000 10 to <20%

10 to <20%

32,500

Moderate to high risk

20%

5,400

N = 100,000

75

prediction models with and without hsCRP. This is especially signiﬁcant for reclassifying people who according to ATP-III criteria would be classiﬁed as being at intermediate global risk. For a representative population of 100,000 U.S. women without diabetes (80,000 at 5% to less than 10% 10-year risk and 20,000 at 10% to less than 20% 10-year risk by ATP III), additional knowledge of hsCRP and family history would place 13,500 of these women at low risk, 48,500 at low to moderate risk, 32,500 at moderate to high risk, and 5,400 at high risk (Fig. 4.2).55 In comparing estimated to actual event rates, this reclassiﬁcation of risk has been shown to be correct for well over 95% of those reclassiﬁed. Thus, hsCRP levels would be most useful for risk assessment in intermediate-risk adults and in a small proportion of selected low-risk adults.49,50 hsCRP testing is not recommended for very-low-risk patients, as even a doubling or tripling of risk in this group is not likely to inﬂuence patient or physician behavior. Similarly, hsCRP testing is not recommended for risk prediction in high-risk patients, as these patients should receive aspirin and lipid-lowering therapy and undertake therapeutic lifestyle changes regardless of their hsCRP levels, although some have proposed that hsCRP may be used for targeting the intensity of lipid-lowering therapy. hsCRP screening is most appropriate for intermediate-risk patients (ATP III score 5% to 20%). In these patients, reclassiﬁcation to a higher or lower cardiovascular risk status could inﬂuence preventive strategies (i.e., the addition or withholding of aspirin and lipid-lowering

Low risk

High risk

100,000

Figure 4.2 Risk reclassiﬁcation using hsCRP and parental history. Impact of highsensitivity C-reactive protein (hsCRP) (representing inﬂammation) and family history (representing genetics) on estimates of global cardiovascular risk for a representative population of 100,000 U.S. women at 5% to 10% and 10% to 20% 10-year risk according to the Adult Treatment Panel III (ATP III). (Data adapted from references 34 and 35.) BP = blood pressure; CVD = cardiovascular disease; HDLC = high-density lipoprotein cholesterol; TC = total cholesterol.

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therapy). In women at intermediate risk by ATP III, the Reynolds Risk Score can be used to more accurately assess the need for preventive strategies.56 A suggested algorithm for hsCRP screening is outlined in Figure 4.3. Measurement of hsCRP appears to be reasonably cost-effective for selective screening in the primary prevention setting.39 Measurement of hsCRP at the time of lipid evaluation may be reasonable in intermediate-risk patients, if these patients do not already qualify for lipid-lowering and aspirin therapies. As hsCRP testing is relatively inexpensive, this approach may be more efﬁcient than arranging phlebotomy and a second physician visit after lipid results are obtained. Furthermore, isolated hsCRP elevation may reﬂect some increased cardiovascular risk even in a patient with normal lipid values.57 Elevated CRP is signiﬁcantly associated with age, smoking, hypertension, body mass index, the metabolic syndrome, and elevated homocysteine and lipoprotein(a) levels.58 High levels of hsCRP are also associated with an increased risk for developing type 2 diabetes.59–68 Furthermore, among individuals with diabetes or the metabolic syndrome, hsCRP levels further stratify cardiovascular risk.69 Elevated hsCRP levels in patients with the metabolic syndrome should prompt more vigorous efforts to implement lifestyle modiﬁcations such as diet and exercise. hsCRP levels also correlate with risk of stroke,70,71 with the relative risk associated with hsCRP ranging from 1.5 to 2.0, which is comparable to that for LDL-C in some studies. Thus, hsCRP measurement can be considered to help reﬁne risk assessment tools in the primary prevention of CVD. The JUPITER Trial The Justiﬁcation for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) was conducted to investigate whether

Low risk ATP risk score <5%

hsCRP testing not recommended, as even a doubling or tripling of risk in this group is not likely to influence patient or physician behavior Reevaluate risk based on hsCRP cutpoints of <1, 1–3, and >3mg/dL

Intermediate risk ATP risk score 5–20%

Incorporate hsCRP into Reynolds risk score

High risk ATP risk score >20%

Adjust lipid goals and need for aspirin therapy according to new risk classification

hsCRP testing recommended

About 13% of intermediate risk women will be reclassified as low risk and 5% will be reclassified as high risk

hsCRP testing not recommended, as these patients should receive aspirin and statin therapy regardless of their hsCRP levels

Figure 4.3 Suggested algorithm for hsCRP screening.

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treatment with rosuvastatin, compared with placebo, would decrease the rate of ﬁrst major cardiovascular events, deﬁned as the combined end point of cardiovascular death, stroke, MI, hospitalization for unstable angina, or arterial revascularization among individuals with low LDL-C and elevated hsCRP levels. 72,73 The study was a randomized, double-blind, placebocontrolled, multicenter trial conducted at 1,315 sites in 26 countries A total of 17,802 persons with LDL-C of less than 130 mg/dL and hsCRP of at least 2 mg/L were randomized to rosuvastatin (20 mg/d) or placebo.72–75 JUPITER was unique in its use of hsCRP to stratify individuals. The patient population enrolled in the JUPITER study was quite different from the patient populations enrolled in previous primary prevention and secondary prevention statin trials in that the median LDL-C was 108 mg/dL and the mean LDL-C was 104 mg/dL. These values were much lower than in the prior primary prevention statin trials. The trial was stopped after a median follow-up of 1.9 years (maximum, 5.0 years). Rosuvastatin reduced LDL-C levels by 50% and hsCRP levels by 37%.72,73 Also, rosuvastatin signiﬁcantly decreased the incidence of death from any cause as well as the occurrence of major cardiovascular events. Within the rosuvastatin group there was 20% lower all-cause mortality, a 54% lower incidence of MI, and a 48% lower incidence of stroke. This was particularly notable as almost all the individuals in this study had lipid levels at baseline that were well below the threshold for treatment according to current prevention guidelines. The JUPITER study showed the beneﬁt of statin therapy in individuals with low to normal LDL-C but with a marker of elevated inﬂammation. For the end point of MI, stroke, revascularization, or death the extrapolated 5-year number needed to treat (NNT), the number of individuals needed to be treated in a 5-year time period to prevent one clinical event, was 25 (95% CI, 14–34).76 In comparison, in other statin primary prevention trials, such as the Air Force/ Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS)77 and West of Scotland Coronary Prevention Study (WOSCOPS),78 the calculated 5-year NNT values were approximately 50. It is estimated that there are an additional 3.9 million men over 50 years and 2.6 million women over 60 years who could now be potential candidates for statin therapy based on the JUPITER entry criteria.79 In fact, there are an estimated 37 million adults over the age of 20 without known CAD or CAD equivalent who have a low to normal LDL-C and elevated hsCRP who may beneﬁt from at least more intensiﬁed lifestyle changes.

Secondary Prevention In patients who already have underlying CAD, elevated CRP is associated with an elevated risk of a future cardiovascular event, though it is weakly associated with the amount of disease that is present.60–62 In the Prevention of Events With Angiotensin-Converting Enzyme Inhibition (PEACE) trial, 3,771 patients with

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stable CAD were analyzed using the Centers for Disease Control/American Heart Association (CDC/AHA) hsCRP cutpoints (<1, 1 to 3, and >3 mg/L, respectively); higher hsCRP levels, even above 1 mg/L, were associated with a signiﬁcantly greater risk of cardiovascular death, MI, or stroke.80 hsCRP levels also predicted coronary artery bypass graft failure and in-stent restenosis.81 For such patients, the best long-term clinical outcomes were observed among those with low levels of LDL-C (less than 70 mg/dL) and low levels of hsCRP (less than 2 mg/L). High hsCRP levels before coronary stent implantation were also associated with an increased risk of death or MI, but were not related to target vessel revascularization or stent thrombosis. This suggests that preprocedural hsCRP is more a predictor of global cardiovascular risk than a predictor of stent-related complications.82 Similarly, in patients with CHD on statin therapy, low levels of both LDL-C and hsCRP predicted the best outcomes.83–85 Individuals with elevated hsCRP levels received the greatest beneﬁt from statin therapy.84,85 In the Pravastatin or Atorvastatin Evaluation and Infection Therapy—Thrombolysis in Myocardial Infarction 22 (PROVE IT–TIMI 22) and Aggrastat to Zocor (A to Z) trials, an achieved hsCRP level of below 2 mg/L appeared about as important as an LDL-C level below 70 mg/dL for improving survival and reducing the risk of future coronary events (see Fig. 4.3).86,87 In patients with coronary disease, lower achieved hsCRP levels were also associated with a lower risk of stroke.88 Thus, more intensive lifestyle changes to lower hsCRP values should be encouraged in individuals with an hsCRP level of 2 mg/L or higher.

Measuring CRP Levels Methods for measuring CRP were initially developed to evaluate infection and inﬂammation that resulted in levels between 3 and 5 mg/L. These levels were higher than the levels found in most individuals. hsCRP testing is able to detect levels as low as 0.3 mg/L, which are more applicable for risk factor analysis and modiﬁcation in healthy individuals. A consensus statement from the CDC/ AHA established the following recommendation for testing: an average of two assays, fasting or nonfasting, and optimally obtained 2 weeks apart provide a more stable estimate than a single measurement.89 For the determination of cardiovascular risk, low, average, and high risk values were deﬁned as less than 1, 1 to 3, and more than 3 mg/L. Obtaining a value above 10 mg/L should initiate a search for a source of infection or inﬂammation. Persistently elevated hsCRP levels greater than 10 mg/L suggest even higher CVD risk,80,89 even in the presence of collagen vascular disease or other underlying chronic systemic inﬂammatory diseases. Fasting is not required for hsCRP testing. Intraindividual variation of hsCRP levels is similar to that of cholesterol levels. Thus, measuring hsCRP values twice (if the initial value is elevated) may improve the predictive value of hsCRP levels. CVD risk increases in a linear fashion across the full range of hsCRP levels. Even mild elevations in hsCRP (above 1 mg/L) suggest elevated CVD

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risk.90 The cutpoints of less than 1, 1 to 3, and above 3 mg/L are recommended, though using ﬁve categories of hsCRP levels (less than 0.5, 0.5 to 1.0, 1.0 to 3.0, 3.0 to 5.0, and above 5.0 mg/L) may improve risk discrimination.80 As hsCRP levels may be falsely elevated during an acute phase response, patients should be metabolically stable at the time of hsCRP. Initial evaluation with hsCRP in individuals greater than 40 years may be appropriate. Although elevated hsCRP levels in teenagers predict increased CVD risk,57 it is not recommended to measure this biomarker in those at very low absolute risk of an MI over the next decade. Median hsCRP levels vary by gender and across different ethnic populations. For example, African Americans appear to have higher hsCRP levels on average than Caucasian and Asian Americans.91,92 In the Reasons for Geographic And Racial Differences in Stroke (REGARDS) study, 40% of participants had hsCRP levels above 3 mg/L. African Americans, women, and obese people were at highest risk for increased hsCRP. Among nondiabetic women at 5% to 20% Framingham vascular predicted risk, hsCRP data led to reclassiﬁcation of 48% to a higher risk group and 19% to a lower risk group.93 For men, these percentages were 24% and 40%. Blacks were more often reclassiﬁed to a higher risk group than whites. In this national study, a majority of participants, especially blacks and women, were reclassiﬁed to a different 10-year vascular risk category on the basis of hsCRP testing after risk assessment.

Future Directions Although the correlation between hsCRP levels and CVD risk is well established, it is unclear whether CRP itself directly contributes to the pathophysiology of CVD. The question over whether CRP is a causal agent versus simply a marker is still being debated. Supporting data for a role for CRP in atherothrombosis remains limited to in vitro studies and experiments in animal models.94 Nonetheless, a recent meta-analysis looking at over 160,000 people without a history of vascular disease from 54 long-term prospective studies showed that CRP concentration had a continuous association with not only the risk of CHD and stroke, but also the risk of vascular mortality and death from several cancers and lung disease, suggesting that CRP is relevant to a broad range of disorders.95

Conclusions hsCRP is an inexpensive and validated test that improves model calibration and helps to provide a more accurate prediction of CVD risk than standard risk prediction models alone. Its predictive value has been conﬁrmed in both the primary prevention and secondary prevention settings. In the primary prevention setting, it is most useful for intermediate-risk patients, for reclassifying patients into a higher or lower risk category and appropriately targeting preventive therapies.

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References 1. Ridker PM, Cook NR. Clinical utility of very high and very low levels of C-reactive protein across the full range of Framingham risk scores. Circulation. 2004;109:1955–9. 2. Khot UN, Khot MB, Bajzer CT, et al. Prevalence of conventional risk factors in patients with coronary heart disease. JAMA. 2003;290:898–904. 3. Greenland P, Knoll MD, Stamler J, et al. Major risk factors as antecedents of fatal and nonfatal coronary heart disease events. JAMA. 2003;290:891–7. 4. Rosamond W, Flegal K, Friday G, et al. Heart disease and stroke statistics–2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2007;115:e69–171. 5. Ajani UA, Ford ES. Has the risk for coronary heart disease changed among U.S. adults? J Am Coll Cardiol. 2006; 48:1177–82. 6. Ford ES, Giles WH, Mokdad AH. The distribution of 10-year risk for coronary heart disease among US adults: ﬁndings from the National Health and Nutrition Examination Survey III. J Am Coll Cardiol. 2004;43:1791–6. 7. Pasternak RC, Abrams J, Greenland P, et al. 34th Bethesda Conference: Task force #1—Identiﬁcation of coronary heart disease risk: is there a detection gap? J Am Coll Cardiol. 2003;41:1863–74. 8. Pradhan AD, Manson JE, Rifai N, et al. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA. 2001;286:327–34. 9. Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med. 1999; 340:115–26. 10. Pearson TA, Mensah GA, Alexander RW, et al. Markers of inﬂammation and cardiovascular disease: application to clinical and public health practice: A statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation. 2003;107:499. 11. Kushner, I. The phenomenon of the acute phase response. Ann N Y Acad Sci 1982;389:39. 12. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005;352:1685–95. 13. Libby P, Ridker PM. Inﬂammation and atherothrombosis from population biology and bench research to clinical practice. J Am Coll Cardiol. 2006;48:A33A46. 14. Tintut Y, Patel J. Tumor necrosis factor-alpha promotes in vitro calciﬁcation of vascular cells via the cAMP pathway. Circulation. 2000;102:2636–42. 15. Kartinen A. Mast cells in rupture prone areas of human coronary atheromas produce and store TNF-alpha. Circulation. 1996;94:2787–92. 16. Ridker PM. C-reactive protein: eighty years from discovery to emergence as a major risk marker for cardiovascular disease. Clin Chemistry. 2009;55(2):209–15. 17. Zwaka TP, Hombach V, Torzewski J, et al. C-reactive protein-mediated low density lipoprotein uptake by macrophages: implications for atherosclerosis. Circulation. 2001;103:1194–7. 18. Schwedler, SB, Amann, K, Wernicke, K, et al. Native C-reactive protein increases whereas modiﬁed C-reactive protein reduces atherosclerosis in apolipoprotein E-knockout mice. Circulation. 2005;31:1460–5.

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19. Kashiwagi M, Tanaka A, Kitabata H, et al. Relationship between coronary arterial remodeling, ﬁbrous cap thickness and high-sensitivity C-reactive protein levels in patients with acute coronary syndrome. Circulation. 2009;73(7):1291–5. 20. Sakr SA, Abbas TM, Amer MZ, et al. Microvascular angina. The possible role of inﬂammation, uric acid, and endothelial dysfunction. Intl Heart J. 2009;50(4):407–19. 21. Koenig W, Sund M, Frohlich M, et al. C-reactive protein, a sensitive marker of inﬂammation, predicts future risk of coronary heart disease in initially healthy middle-aged men: results from the MONICA (Monitoring Trends and Determinants in Cardiovascular Disease) Augsburg Cohort Study, 1984 to 1992. Circulation. 1999;99:237–42. 22. Ledue TB, Rifai N. Preanalytic and analytic sources of variations in C-reactive protein measurement: implications for cardiovascular disease risk assessment. Clin Chem. 2003;49:1258–71. 23. Pankow JS, Folsom AR, Cushman M, et al. Familial and genetic determinants of systemic markers of inﬂammation: the NHLBI Family Heart Study. Atherosclerosis. 2001;154:681–9. 24. Retterstol L, Eikvar L, Berg K. A twin study of C-reactive protein compared to other risk factors for coronary heart disease. Atherosclerosis. 2003;169:279–82. 25. MacGregor AJ, Gallimore JR, Spector TD, et al. Genetic effects on baseline values of C-reactive protein and serum amyloid a protein: a comparison of monozygotic and dizygotic twins. Clin Chem. 2004;50:130–4. 26. Crawford DC, Yi Q, Smith JD, et al. Allelic spectrum of the natural variation in CRP. Hum Genet. 2006;119:496–504. 27. Walsh MT, Divane A, Whitehead AS. Fine mapping of the human pentraxin gene region on chromosome 1q23. Immunogenetics. 1996;44:62–9. 28. Lei KJ, Liu T, Zon G, et al. Genomic DNA sequence for human C-reactive protein. J Bio Chem. 1985;260:13377–83. 29. Miller DT, Zee RYL, Danik JS, et al. Association of common CRP gene variants with CRP levels and cardiovascular events. Ann Hum Genet. 2005;69:623–38. 30. Brull DJ, Serrano N, Zito F, et al. Human CRP gene polymorphism inﬂuences CRP levels: implications for the prediction and pathogenesis of coronary heart disease. Arterioscler Thromb Vasc Biol. 2003;23:2063–9. 31. Chen J, Zhao J, Huang J, et al. -717A>G polymorphism of human C-reactive protein gene associated with coronary heart disease in ethnic Han Chinese: the Beijing atherosclerosis study. J Mol Med. 2005;83:72–8. 32. Kovacs A, Green F, Hansson LO, et al. A novel common single nucleotide polymorphism in the promoter region of the C-reactive protein gene associated with the plasma concentration of C-reactive protein. Atherosclerosis. 2005;178:193–8. 33. Elliott P, Chambers JC, Zhang W, et al. Genetic loci associated with C-reactive protein levels and risk of coronary heart disease. JAMA. 2009;302:37–48. 34. Ridker PM. Clinical application of C-reactive protein for cardiovascular disease detection and prevention. Circulation. 2003;107:363–9. 35. Ballantyne CM, Hoogeveen RC, Bang H, et al. Lipoprotein-associated phospholipase A2, high-sensitivity C-reactive protein, and risk for incident coronary heart disease in middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) study. Circulation. 2004;109:837–42.

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36. Kuller LH, Tracy RP, Shaten J, et al. Relation of C-reactive protein and coronary heart disease in the MRFIT nested case-control study. Am J Epidemiol. 1996;144:537–47. 37. Pradhan AD, Manson JE, Rossouw JE, et al. Inﬂammatory biomarkers, hormone replacement therapy, and incident coronary heart disease: prospective analysis from the Women’s Health Initiative Observational Study. JAMA. 2002;288:980–7. 38. Danesh J, Whincup P, Walker M, et al. Low grade inﬂammation and coronary heart disease: prospective study and updated meta-analyses. Br Med J. 2000;321:199–204. 39. Roivainen M, Viik-Kajander M, Palosuo T, et al. Infections, inﬂammation, and the risk of coronary heart disease. Circulation. 2000;101:252–7. 40. Rutter MK, Meigs JB, Sullivan LM, et al. C-reactive protein, the metabolic syndrome, and prediction of cardiovascular events in the Framingham Offspring Study. Circulation. 2004;110:380–5. 41. Sakkinen P, Abbott RD, Curb JD, et al. C-reactive protein and myocardial infarction. J Clin Epidemiol. 2002;55:445–51. 42. Ridker PM, Cushman M, Stampfer MJ, et al. Inﬂammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med. 1997;336:973–9. 43. Tsimikas S, Willerson JT, Ridker PM. C-reactive protein and other emerging blood biomarkers to optimize risk stratiﬁcation of vulnerable patients. J Am Coll Cardiol. 2006;47:C19–31. 44. Curb JD, Abbott RD, Rodriguez BL, et al. C-reactive protein and the future risk of thromboembolic stroke in healthy men. Circulation. 2003;107:2016–20. 45. Laaksonen DE, Niskanen L, Nyyssonen K, et al. C-reactive protein in the prediction of cardiovascular and overall mortality in middle-aged men: a populationbased cohort study. Eur Heart J. 2005;26:1783–9. 46. Wakugawa Y, Kiyohara Y, Tanizaki Y, et al. C-reactive protein and risk of ﬁrstever ischemic and hemorrhagic stroke in a general Japanese population: the Hisayama Study. Stroke. 2006;37:27–32. 47. Boekholdt SM, Hack CE, Sandhu MS, et al. C-reactive protein levels and coronary artery disease incidence and mortality in apparently healthy men and women: the EPIC-Norfolk prospective population study 1993–2003. Atherosclerosis. 2006;187:415–22. 48. Wilson PW, Nam BH, Pencina M, et al. C-reactive protein and risk of cardiovascular disease in men and women from the Framingham Heart Study. Arch Intern Med. 2005;165:2473–8. 49. Ridker PM, Rifai N, Rose L, et al. Comparison of C-reactive protein and lowdensity lipoprotein cholesterol levels in the prediction of ﬁrst cardiovascular events. N Engl J Med. 2002;347:1557–65. 50. Koenig W, Lowel H, Baumert J, et al. C-reactive protein modulates risk prediction based on the Framingham Score: implications for future risk assessment: results from a large cohort study in southern Germany. Circulation. 2004;109:1349–53. 51. Scirica BM, Morrow DA, Verma S, et al. Is C-reactive protein an innocent bystander or proatherogenic culprit? Circulation. 2006; 113:2128–51. 52. Cook NR, Buring JE, Ridker PM. The effect of including C-reactive protein in cardiovascular risk prediction models for women. Ann Intern Med. 2006;145:21–9.

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53. Cushman M, Arnold AM, Psaty BM, et al. C-reactive protein and the 10-year incidence of coronary heart disease in older men and women: the Cardiovascular Health Study. Circulation. 2005;112:25–31. 54. Ridker PM, Buring JE, Rifai N, et al. Development and validation of improved algorithms for the assessment of global cardiovascular risk in women: the Reynolds risk score. JAMA. 2007;297:611–9. 55. Ridker PM. C-reactive protein and the prediction of cardiovascular events among those at intermediate risk: moving an inﬂammatory hypothesis toward consensus. J Am Coll Cardiol. 2007;49(21):2129–38. 56. Cook NR, Buring JE, Ridker PM. The effect of including C-reactive protein in cardiovascular risk prediction models for women. Ann Intern Med. 2006;145:21–9. 57. van der Meer IM, de Maat MP, Killiaan AJ, et al. The value of C-reactive protein in cardiovascular risk prediction: the Rotterdam Study. Arch Intern Med. 2003;163:1323–8. 58. Ridker PM. C-reactive protein and the prediction of cardiovascular events among those at intermediate risk: moving an inﬂammatory hypothesis toward consensus. J Am Coll Cardiol. 2007;49(21):2129–38. 59. Cushman M, Arnold AM, Psaty BM, et al. C-reactive protein and the 10-year incidence of coronary heart disease in older men and women: the Cardiovascular Health Study. Circulation. 2005;112:25–31. 60. Ridker PM, Buring JE, Rifai N, et al. Development and validation of improved algorithms for the assessment of global cardiovascular risk in women: the Reynolds risk score. JAMA. 2007;297:611–9. 61. Blake GJ, Ridker PM, Kuntz KM. Potential cost-effectiveness of C-reactive protein screening followed by targeted statin therapy for the primary prevention of cardiovascular disease among patients without overt hyperlipidemia. Am J Med. 2003;114:485–94. 62. Zieske AW, Tracy RP, McMahan CA, et al. Elevated serum C-reactive protein levels and advanced atherosclerosis in youth. Arterioscler Thromb Vasc Biol. 2005;25:1237–43. 63. Festa A, D’Agostino R Jr, Tracy RP, et al. Elevated levels of acute-phase proteins and plasminogen activator inhibitor-1 predict the development of type 2 diabetes: the Insulin Resistance Atherosclerosis Study. Diabetes. 2002;51:1131–7. 64. Barzilay JI, Abraham L, Heckbert SR, et al. The relation of markers of inﬂammation to the development of glucose disorders in the elderly: the Cardiovascular Health Study. Diabetes. 2001;50:2384–9. 65. Freeman DJ, Norrie J, Caslake MJ, et al. C-reactive protein is an independent predictor of risk for the development of diabetes in the West of Scotland Coronary Prevention Study. Diabetes. 2002;51:1596–600. 66. Thorand B, Lowel H, Schneider A, et al. C-reactive protein as a predictor for incident diabetes mellitus among middle-aged men: results from the MONICA Augsburg cohort study, 1984–1998. Arch Intern Med. 2003;163:93–9. 67. Spranger J, Kroke A, Mohlig M, et al. Inﬂammatory cytokines and the risk to develop type 2 diabetes: results of the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study. Diabetes. 2003;52:812–7. 68. Duncan BB, Schmidt MI, Pankow JS, et al. Low-grade systemic inﬂammation and the development of type 2 diabetes: the Atherosclerosis Risk in Communities Study. Diabetes. 2003;52:1799–805.

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69. Laaksonen DE, Niskanen L, Nyyssonen K, et al. C-reactive protein and the development of the metabolic syndrome and diabetes in middle-aged men. Diabetologia. 2004;47:1403–10. 70. Rost NS, Wolf PA, Kase CS, et al. Plasma concentration of C-reactive protein and risk of ischemic stroke and transient ischemic attack: the Framingham Study. Stroke. 2001;32:2575–9. 71. Cao JJ, Thach C, Manolio TA, et al. C-reactive protein, carotid intima-media thickness, and incidence of ischemic stroke in the elderly: the Cardiovascular Health Study. Circulation. 2003;108:166–70. 72. Ridker PM, Danielson E, Fonseca FAH, et al., for the JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359:2195–207. 73. Ridker PM, Danielson E, Fonseca FAH, et al., on behalf of the JUPITER Trial Study Group. Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial. Lancet. 2009;373:175–82. 74. Ridker PM, on behalf of the JUPITER Study Group. Rosuvastatin in the primary prevention of cardiovascular disease among patients with low levels of lowdensity lipoprotein cholesterol and elevated high-sensitivity C-reactive protein: rationale and design of the JUPITER trial. Circulation. 2003;108:2292–7. 75. Ridker PM, Fonseca F, Genest J, et al. Baseline characteristics of participants in the JUPITER trial, a randomized placebo-controlled primary prevention trial of statin therapy among individuals with low low-density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein. Am J Cardiol. 2007;100:1659–64. 76. Ridker PM, MacFadyen JG, Fonseca FAH, et al., for the JUPITER Study Group. Number needed to treat with rosuvastatin to prevent ﬁrst cardiovascular events and death among men and women with low low-density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein: justiﬁcation for the use of statins in prevention: an intervention trial evaluating rosuvastatin (JUPITER). Circ Cardiovasc Qual Outcomes. 2009;2(6):616–23. 77. Downs R, Clearﬁeld M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. JAMA. 1998;279:1615–22. 78. Shepherd J, Cobbe SM, Ford I, et al. West of Scotland Coronary Prevention Study Group. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med. 1999;333:1301–7. 79. Ridker PM, on behalf of the JUPITER Study Group. Rosuvastatin in the primary prevention of cardiovascular disease among patients with low levels of lowdensity lipoprotein cholesterol and elevated high-sensitivity C-reactive protein: rationale and design of the JUPITER trial. Circulation. 2003;108:2292–7. 80. Sabatine MS, Morrow DA, Jablonski KA, et al. Prognostic signiﬁcance of the Centers for Disease Control/American Heart Association high-sensitivity C-reactive protein cut points for cardiovascular and other outcomes in patients with stable coronary artery disease. Circulation. 2007;115:1528–36. 81. Kangasniemi OP, Biancari F, Luukkonen J, et al. Preoperative C-reactive protein is predictive of long-term outcome after coronary artery bypass surgery. Eur J Cardiothorac Surg. 2006;29:983–5.

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82. Hong YJ, Jeong MH, Lim SY, et al. Relation of soft plaque and elevated preprocedural high-sensitivity C-reactive protein levels to incidence of in-stent restenosis after successful coronary artery stenting. Am J Cardiol. 2006;98:341–5. 83. Danesh J, Wheeler JG, Hirschﬁeld GM, et al. C-reactive protein and other circulating markers of inﬂammation in the prediction of coronary heart disease. N Engl J Med. 2004;350:1387–97. 84. Liuzzo G, Biasucci LM, Gallimore JR, et al. The prognostic value of C-reactive protein and serum amyloid A protein in severe unstable angina. N Engl J Med. 1994;331:417–24. 85. Lindahl B, Toss H, Siegbahn A, et al. Markers of myocardial damage and inﬂammation in relation to long-term mortality in unstable coronary artery disease. FRISC Study Group. Fragmin during Instability in Coronary Artery Disease. N Engl J Med. 2000;343:1139–47. 86. Morrow DA, de Lemos JA, Sabatine MS, et al. Clinical relevance of C-reactive protein during follow-up of patients with acute coronary syndromes in the Aggrastat-to-Zocor Trial. Circulation. 2006;114:281–8. 87. Morrow DA, Rifai N, Antman EM, et al. C-reactive protein is a potent predictor of mortality independently of and in combination with troponin T in acute coronary syndromes: a TIMI 11A substudy. Thrombolysis in Myocardial Infarction. J Am Coll Cardiol. 1998;31:1460–5. 88. Mega JL, Morrow DA, Cannon CP, et al. Cholesterol, C-reactive protein, and cerebrovascular events following intensive and moderate statin therapy. J Thromb Thrombolysis. 2006;22:71–6. 89. Pearson TA, Mensah GA, Alexander RW, et al. Markers of inﬂammation and cardiovascular disease: application to clinical and public health practice: A statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation. 2003;107:499–511. 90. Tracy RP, Psaty BM, Macy E, et al. Lifetime smoking exposure affects the association of C-reactive protein with cardiovascular disease risk factors and subclinical disease in healthy elderly subjects. Arterioscler Thromb Vasc Biol. 1997;17:2167–76. 91. Albert MA, Glynn RJ, Buring J, et al. C-reactive protein levels among women of various ethnic groups living in the United States (from the Women’s Health Study). Am J Cardiol. 2004;93:1238–42. 92. Albert MA, Ridker PM. C-reactive protein as a risk predictor: do race/ethnicity and gender make a difference? Circulation. 2006;114:e67–74. 93. Cushman M, McClure LA, Howard VJ, et al. Implications of increased C-reactive protein for cardiovascular risk stratiﬁcation in black and white men and women in the US. Clin Chem. 2009;55:1627–36. 94. Libby P, Ridker PM. Inﬂammation and atherothrombosis from population biology and bench research to clinical practice. J Am Coll Cardiol. 2006;48: A33-A46. 95. C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. Lancet. 2010;375(9709):132–40.

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Chapter 5

Advanced Lipoprotein Testing: Assessment of Cardiovascular Risk and Therapy Beyond Standard Lipid Measurements Edwin E. Ferguson, Donald A. Wiebe, Patrick E. McBride

Evidence-based clinical trials have ﬁrmly established that reduction of lowdensity lipoprotein cholesterol (LDL-C) signiﬁcantly reduces the risk of cardiovascular disease (CVD). Standard lipid measurements determine the concentration of cholesterol carried by lipoprotein particles in plasma. The LDL-C reported by most laboratories is often an indirect calculation based on the Friedewald equation, and can vary substantially with increasing triglyceride (TG) levels. A signiﬁcant number of patients treated to, or below, clinical practice guideline-recommended levels of LDL-C continue to have CVD events. It has become apparent that standard laboratory measurements of LDL-C and other lipid concentrations do not fully predict the risk of CVD or response to treatment. LDL particles play a primary role in the initiation and progression of atherosclerosis. The number and distribution of circulating lipoprotein particles is a signiﬁcant predictor of atherosclerosis, and recent evidence suggests that their measurement may be more predictive than serum LDL-C levels. The majority of high-risk patients have an atherogenic dyslipidemia characterized by elevations of LDL-C and TG levels, and low levels of high-density lipoprotein cholesterol (HDL-C). Patients with higher TG and lower HDL-C levels often have an excess of small, dense LDL particles, and standard laboratory LDL-C measurements may underestimate atherosclerotic risk. Advanced lipoprotein testing using newer methodology and technology has been proposed to improve risk prediction and to establish therapeutic goals. Determination of apolipoprotein B-100 (apoB) levels and the determination of the distribution and number of LDL particles by advanced lipoprotein testing better predict the onset or recurrence of CVD. This review discusses the theoretical and clinical foundation for going beyond LDL-C measurements with advanced lipoprotein testing.

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Background

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Clinical Vignette A 56-year-old man, despite “optimal” conventionally measured lipid values, has acute coronary syndrome (ACS). The patient has no history of diabetes mellitus or renal, hepatic, or thyroid disease. The patient has normal blood pressure. His body mass index (BMI) was 27 and his waist circumference was 39 inches. The patient’s fasting total cholesterol was 190 mg/dL, triglycerides 140 mg/dL, HDL-C 42 mg/dL, and LDL-C 120 mg/dL. The patient’s LDL-C concentration was 76 mg/dL after initiating statin treatment. Advanced lipoprotein testing found that the LDL particle number was 1,650 nmol/L and the apoB level 135 mg/dL. The LDL particle number was in the high-risk range and demonstrated elevated numbers of small, dense LDL particles. Aggressive treatment with higher-dose statin and extended-release niacin was started. Following treatment changes, the LDL particle number was 1,072 nmol/L, apoB 85 mg/dL, and LDL-C 58 mg/dL. LDL-C is below the 5th percentile, while the LDL particle number and apoB are now near the 20th percentile based on Framingham offspring population data.1,2 While clinical trial data are needed to establish the utility of further lowering LDL particle number or apoB to 5th percentile levels (less than 700 nmol/L and less than 65 mg/dL, respectively), this approach reﬂects aggressive treatment in a high-risk patient.

Background Risk Beyond LDL-C Large clinical trials have established the beneﬁts of lowering the LDL-C concentration in both the primary and secondary prevention of CVD.3 More recent trials indicate that the lower the LDL-C achieved with statin therapy, the greater the beneﬁt, in both very-high-risk and moderately high-risk patients.3 An optional treatment target goal for LDL-C of less than 70 mg/dL has been suggested for very-high-risk patients (ACS), and for high-risk patients with CVD or coronary risk equivalent with multiple risk factors or baseline LDL-C below 100 mg/dL.4 Despite aggressive lowering of LDL-C and the use of high-dose statin therapy in more recent trials, a signiﬁcant number of patients have recurrent CVD events or revascularization. Recent analysis further illustrates that there is a diminishing return in event reduction as LDL-C is progressively lowered below 100 mg/dL, and a high 10-year residual risk of CVD events remains despite aggressive lowering of LDL-C with statin therapy. In addition to the presence of other risk factors, further evaluation of dyslipidemias may be considered. Table 5.1 gives information on risk reduction from statins in clinical trials. The Framingham Heart Study found that LDL-C has limitations in distinguishing patients with and without coronary artery disease (CAD). Twenty-six-year follow-up data from Framingham showed signiﬁcant overlap of LDL-C between populations with and without coronary disease; 80% of patients with a history of myocardial infarction (MI) had similar LDL-C values as those who did not

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# Events Statin 1490

% Risk Reduction

30,817

# Events Control 2042

4S/CARE/ WOSCOPS/LIPID/ AFTEXCAPS HPS ASCOT-LLA PROVE-IT* CARDS TNT**

20,536 10,305 4,162* 2,838 10,001

1212 154 542 127 548**

898 100 470 83 434**

26 36 16 37 22

26

*PROVE-IT compared pravastatin 40 mg (results listed under control group) versus atorvastatin 80 mg (results listed under statin group). **TNT compared 10 mg atorvastatin (results listed under control group) versus 80 mg atorvastatin (results listed under statin group).

have an MI.5 Furthermore, elevated LDL-C is frequently not the primary lipid abnormality associated with coronary disease, and an LDL-C above 130 mg/dL is present in as few as 25% of cases of premature CVD.6 Meta-analysis has shown that a high percentage of patients with CVD have hypertriglyceridemia with serum triglyceride (TG) levels above 150 to 200 mg/ dL,6 although whether elevated TGs are an independent risk factor for CVD remains controversial.6 The presence of hypertriglyceridemia is associated with multiple metabolic abnormalities that accelerate atherosclerosis (Table 5.2).6,7 Elevated serum TG levels are associated with postprandial hyperlipidemia, atherogenic remnant particles, and the production of very atherogenic small, dense LDL particles; low levels of HDL-C whose carrier lipoproteins are also small and do not function well to reduce development of atherosclerosis; and a procoagulant and inﬂammatory state.6 The combination of elevated LDL-C and TG, smaller LDL particles, and low levels of HDL-C has been called atherogenic dyslipidemia or the atherogenic lipoprotein phenotype.6 These metabolic abnormalities are associated with a greater number of LDL particles than would be suspected by standard measurements of LDL-C concentration. Evidence suggests that the number of LDL particles, and not the cholesterol that these particles carry, best predicts CVD risk.6,8 The cluster of metabolic abnormalities and excessive numbers of LDL particles is common for patients with CVD, the metabolic syndrome, insulin resistance, and diabetes mellitus.8,9 This atherogenic state is often genetically predetermined and compounded by adverse lifestyle habits. LDL-C measurements are usually derived clinically by an indirect calculation using the Friedewald equation: LDL-C = TC – (HDL-C + TG/5), where VLDL-C = TG/5. The Friedewald equation assumes that VLDL-TG/cholesterol content is constant over a wide range of TG values (below 400 mg/dL), which is often not correct. The Friedewald calculated LDL-C may become inaccurate even at fairly low TG levels, as compared to directly measured LDL-C (by ultracentrifugation).6

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CHAPTER 5

Statin Trial

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Table 5.1 Risk Reduction from Statins in Clinical Trials3

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Table 5.2 Beyond LDL-C: Atherogenic Dyslipidemia Atherogenic dyslipidemia is a metabolic milieu often associated with overweight and modestly elevated LDL-C (above 100 to 130 mg/dL). It is often also associated with many or all of the following additional atherogenic risk factors: • • • • • • • • •

Elevated triglyceride levels (above 100 to 150 mg/dL) Low HDL-C (below 40 to 50 mg/dL) Postprandial hyperlipidemia Triglyceride-rich remnant lipoproteins (such as IDL) Increased number of small, dense LDL particles* Changes in lipoprotein particle size (LDL, VLDL, HDL) Insulin resistance Procoagulant state Proinﬂammatory state

The impaired metabolism is associated with an increased number of small LDL particles and increased cardiovascular risk.6 *Small, dense LDL particles appear to be particularly atherogenic

90

Advanced Lipoprotein Testing Advanced lipoprotein testing has shown that the number and size of lipoprotein particles, and not the lipids that are measured chemically, provide a higher positive predictive value than LDL-C. The basic lipid values used clinically are surrogate markers for lipoproteins. Fredrickson stated that “all abnormalities in plasma lipid concentrations, or dyslipidemias, can be translated into dyslipoproteinemias . . . the shift of emphasis to lipoproteins offers distinct advantages in the recognition and management of such disorders.”10 Cholesterol and TGs are insoluble in the aqueous phase and must be transported by lipoprotein particles. The nonpolar lipid core of these particles is surrounded by a polar surface coat that contains phospholipids, some free cholesterol, and apoproteins that act as ligands for receptors that determine how the lipoproteins are utilized or metabolized. Atherosclerosis is initiated by oxidized LDL particles being recognized by a scavenger receptor on macrophages in the arterial intima, and once bound and activated the inﬂammatory atherosclerotic cascade commences.11 It is now clear that the lipoprotein particles promote atherosclerosis and not the lipids that the particles carry. The atherogenic lipoprotein phenotype is caused by overproduction of lipoprotein particles, changes in particle core lipid composition, and impaired clearance of lipoprotein particles. Conventional lipid testing does not reveal the variability in the number of lipoprotein particles and lipid composition and size of lipoprotein particles that determine atherogenicity.6,8,12,13 Apolipoprotein B The single apolipoprotein B-100 (apoB) produced by the liver and incorporated into each VLDL particle stays with VLDL as it is converted to intermediate-

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density lipoprotein (IDL) and then LDL by the sequential activity of lipoprotein lipase and hepatic lipase. ApoB is a surrogate measure of all non-HDL lipoproteins (VLDL, IDL, LDL, Lp(a)). The one-to-one ratio of apoB to LDL particles is constant, even if the cholesterol content of LDL varies. On average, more than 90% of apoB is found associated with LDL particles.14 Thus, apoB should provide a reliable indicator of the number of LDL particles. Small, dense LDL particles are relatively low in cholesterol and thus appear relatively enriched in apoB, although there is only one apoB molecule per particle. Thus, individuals with a preponderance of small, dense LDL particles usually have an LDL-C level that may be deceptively normal, but with an elevated apoB level that reﬂects the increased number of small, dense LDL particles.12–14 Some, but not all, epidemiological and clinical trial studies have shown that apoB concentration is a stronger predictor of CVD risk than LDL-C concentration,13 particularly the on-treatment LDL-C level.14–18 An elevated apoB level greater than 125 mg/dL may help identify patients at risk who have a relatively normal LDL-C concentration.19 The risk of CVD developing in men with small, dense LDL particles was dramatically increased when apoB concentration was also elevated in the Quebec Cardiovascular Study.20,21 Although apoB is more concordant with non-HDL-C than with LDL-C, the correlation is lower for obese patients with metabolic syndrome and diabetes mellitus.13,22 In individuals with the metabolic syndrome, the discrepancies between apoB, LDL-C, and non-HDL cholesterol are greater, suggesting that apoB may be a more useful risk predictor in this population.13,16,22 The Air Force/ Texas Coronary Atherosclerosis Prevention Study included 6,505 patients without known CVD, with below the mean HDL-C levels, and compared treatment with lovastatin to placebo.3,23 ApoB, apoA1 (a major apolipoprotein of HDL), and apoB/apoA-1 levels at baseline and at 1 year predicted coronary events at 5.2 years. Neither LDL-C nor non-HDL-C was a signiﬁcant predictor at either time point. In other clinical trials of cholesterol treatment of patients with CVD, LDL-C lost its predictive value, when compared with the apoB level or with the non-HDL-C level, and LDL-C lost signiﬁcance as a risk predictor in subjects whose LDL-C was below 100 mg/dL, while non-HDL-C level, apoB level, and the ratio of apoB to apoA-1 remained signiﬁcant risk predictors.24–26 Although measurement of apoB appears to offer a signiﬁcant advantage for assessing CVD risk, difﬁculties with apoB measurement standardization have reduced this test’s clinical application.27,28 Certiﬁed laboratories have an international reference standard that reduces the coefﬁcient of variability, imprecision, and bias; it was developed by several organizations in 1994.29 Population percentile levels for apoB goals derived from the National Health and Nutrition Examination Survey III (NHANES III) study30 that correspond to revised ATP III LDL-C goals of below 70 mg/dL, below 100 mg/dL, below 130 mg/dL, and below 160 mg/dL would be an apoB of below 65 mg/dL, below 85 mg/dL, below 105 mg/dL, and below 125 mg/dL (5th, 20th, 50th, and 80th percentile, respectively). ApoA-I and apoA-II are the major apolipoproteins of HDL. Differences in HDL-C concentration between individuals may be due to differences in the

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Advanced Lipoprotein Testing: Determination of Lipoprotein Size and Particle Number A close association has been shown between apoB measured by immunoassay and LDL particle number measured by nuclear magnetic resonance spectroscopy (NMR), which would lead to the expectation that the two measures would show similar relationships with CVD outcomes.33 However, four studies found that apoB was less predictive for CVD than LDL particle number. In VA-HIT, on-trial levels of LDL-particle number predicted recurrent CVD events, but apoB did not.34 In the Women’s Health Study,35 LDL particle number was the best lipid or lipoprotein predictor of incident CVD events and stroke, and was much more strongly related to these outcomes than apoB. Atherosclerosis and CVD risk is highly correlated with the number of atherogenic LDL particles in the circulation. The size of LDL particles, and the core lipid composition of these particles, both affect the number of LDL particles at any given LDL-C concentration. Size analysis of a patient’s LDL has received increased interest for categorizing a patient’s CVD risk. Popular clinical approaches most commonly applied to analyze patient specimens and assign LDL sizing include non-denaturing gradient gel electrophoresis, VAP ultracentrifugation, and NMR. A fourth approach, ion mobility, has been in development and has only recently become available clinically for LDL sizing. Each of these techniques is brieﬂy discussed with respect to the technology employed with the different approaches.

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production or catabolic rates of apoA-I. However, previous epidemiological studies have not supported total apoA-I concentration as a signiﬁcantly better inverse predictor of CVD risk than HDL-C concentration.27 Furthermore, assays for these apolipoproteins are not readily available for widespread clinical use. A comparison of the utility of apoA-I, apoB, LDL-C, and HDL-C for predicting CVD events found that adding apo B, apo A-I, and the apo B/apo A-I ratio predicted CVD events better than LDL-C.31 There was a 41% increase in risk of nonfatal MI using the apoB/apoA-1 ratio, greater than the 34% observed with apoB alone.32

Gradient Gel Electrophoresis Non-denaturing gradient polyacrylamide gel electrophoresis (GGE) (Berkeley HeartLab, Inc., Burlingame, CA) can separate LDL and HDL particles by size. The LDL particle diameter is assigned for the average LDL peak that is distributed across multiple LDL subclasses. If a majority of LDL migrates in the ﬁrst three classes the patient is noted to have large buoyant particles, and if the LDL is predominantly in the latter four bands then the patient is assigned to the small dense classiﬁcation. The percentage goals given for small LDL particles (III a + b less than 15% and IV b less than 5%) are based on values for the lowest coronary plaque progression rates measured by quantitative coronary angiography in the Stanford Coronary Risk Intervention Project.37 Below-median versus above-median apoB levels of 116 mg/dL added to the predictive power of GGE-measured LDL particle size in predicted risk for angina, MI, and sudden

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Vertical-Spin Density-Gradient Ultracentrifugation Vertical-spin density-gradient ultracentrifugation, now offered as VAP-II (Vertical Auto Proﬁle-II) (Atherotech, Birmingham, AL) sorts the major lipoproteins by density using a deﬁned salt gradient.39 The resolution of lipoprotein subfractions depends upon the density range of the salt solution. The vertical placement of the tubes during centrifugation allows for much shorter centrifugation times as opposed to ﬁxed-angle or horizontal rotors to separate the lipoproteins. Following the ultracentrifugation, the contents of the centrifuge tube are eluted and continuously monitored by enzymatic methods to determine the cholesterol content of lipoprotein particles, including Lp(a) and IDL. VAP provides a direct and accurate measurement of LDL-C, and LDL particle size, even in a non-fasting state or in the presence of hypertriglyceridemia. VAP-II assigns LDL size to pattern A (large), B (small), or AB (intermediate). However, because the amount of cholesterol or TGs carried inside lipoprotein particles varies between individuals, ultracentrifugation is not capable of measuring the absolute number of lipoprotein particles present.40 VAP does report a calculated apoB level that correlates with an immunochemical apoB assay calibrated to the international apoB standard; the mean bias of the calculated value is 3.8% higher than the measured value.39 The VAP-II advanced lipoprotein testing did not improve identiﬁcation of subclinical atherosclerosis using carotid artery intima-media thickness in young adults when compared to traditional lipoprotein determination using enzymatic methods, or Friedewald formula estimation of LDL-C.40

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death in the Quebec Cardiovascular Study.20,21 Smaller LDL particle size has been correlated to higher risk using this technology.38

Ion Mobility Ion mobility requires the use of an albumin-depleted serum. The modiﬁed serum sample is introduced into an evacuated chamber, where the lipoproteins became charged and then the charged species are attracted to an oppositely charged target. The smaller the charged species the faster they arrive at the target, and thus the lipoproteins can be isolated and measured by their size. Resolution of ion mobility is capable of detecting four different sizes of LDL. LDL particle sizes often overlap in several size categories, and the patient’s LDL size is assigned on the basis of where the majority of the LDL resides. The approach for assignment of LDL size is comparable to the methods used for GGE and VAP. Proton (1H) NMR Analysis 1 H NMR is applied to a fasting serum sample to obtain the methyl group chemical shift. Cholesterol has ﬁve methyl groups per molecule; this represents the majority of the 1H NMR methyl chemical shift and represents the nature of cholesterol associated with the lipoproteins. In contrast, TG and phospholipids have three and two methyl groups, respectively. The 1H NMR chemical shift pattern represents the environment of these methyl groups, which are primarily lipid compounds, and how they exist in serum. Thus, although the chemical shift pattern is extremely complex, a computer algorithm is applied to derive the various lipid and lipoprotein NMR proﬁles for the patient specimen.

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LDL Particle Number and Size While LDL particle number has been associated with CVD incidence, measures of LDL or other lipoprotein particle sizes have not been shown to add incremental beneﬁt to traditional risk factor assessment.41 Several technologies have been introduced that measure LDL particle number, but they have yet to be validated against apoB or LDL particle number as determined by more established technology. Spectracell Laboratories (Houston, TX) separates lipoproteins by density using ultracentrifugation and then measures lipoprotein particles photometrically. Berkeley HeartLab offers an ion mobility transfer analysis that can determine LDL particle number (available from Quest Diagnostics, Madison, NJ). LipoScience, Inc. (Raleigh, NC) offers a validated NMR lipoprotein analysis (NMR Lipoproﬁle) that determines the number of LDL particles in the circulation, as well as LDL, HDL, and VLDL particle sizes.8 NMR-derived LDL particle number appears to be equally predictive as apoB, although few studies have compared the predictive risk of LDL particle number as measured by NMR with standard lipid proﬁle variables that have been performed using apoB. Both large and small LDL particles have been associated with increased atherosclerotic risk. Multivariate analysis has shown that LDL particle size does not add predictive value consistently: both large and small LDL particles can be equally atherogenic.8,9,33,41,42 Lipoprotein subclasses of different size broadcast a spectrum of signals when subjected to a microsecond radiofrequency NMR pulse, whose amplitude correlates with the size of the lipoprotein particles. NMR provides reproducible information on LDL, HDL, and VLDL particle size, and, most importantly, LDL particle number. NMR lipoprotein proﬁles give three size measurements for VLDL and HDL (large, intermediate, and small), two for LDL (large and small), and one for IDL. The clinical report contains the number of LDL particles and levels of risk based on percentiles in the Multi-Ethnic Study of Atherosclerosis (MESA) population.33,43 The optimal risk category (below 1,000 nmol/L) corresponds to an LDL-C level lower than 100 mg/dL, which deﬁnes the lowest 20% of the population. Respective 5th, 20th, 50th, and 80th population percentiles correspond to an LDL particle number of less than 700 nmol/L, less than 1,000 nmol/L, less than 1,300 nmol/L, and less than 1,600 nmol/L. At a constant LDL-C, small increases in particle diameter correspond to large increases in LDL volume and thus a decreased number of LDL particles, since larger particles can carry a much larger amount of cholesterol per particle. The converse is also true. NMR has shown that among individuals for any given LDL-C level, for a patient with predominantly small, dense LDL particles, there will be more LDL particles (up to 70% more) in the circulation than for a patient with large LDL particles, and thus the patient is at higher risk.8 Because the NMR LipoProﬁle assay can analyze plasma stored for long periods at –70°C, archived baseline samples from numerous completed observational and intervention studies have been analyzed to establish relationships between the various NMR lipoprotein measures, particularly LDL particle number and size; “hard” clinical and “soft” subclinical CVD outcomes; and endpoints such as insulin resistance, diabetes, and metabolic syndrome.

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NMR analysis has best illustrated what may be termed a disconnect8,42 between LDL-C concentration and the number of circulating LDL particles, which is correlated to differences in particle size and lipid core composition. This disconnect explains the excess risk seen in many patients with atherogenic dyslipidemia, for example, when standard lipid measurements are at ATP III goals. This excessive risk is highly correlated to increased numbers of circulating LDL particles, often of small size, which are not accounted for by traditional LDL-C measurements. These patients usually have elevated TG levels (large VLDL particles), which drive the metabolic reactions that yield small, dense LDL particles, as well as low HDL-C levels (which are often small and less effective for reverse cholesterol transport). Conversely, in some patients there may be a reverse disconnect, where despite an elevated LDL-C concentration, there may be low numbers of circulating LDL particles and thus lower cardiovascular risk. Most, but not all, of these patients have low levels of TGs and optimal levels of HDL-C. In both situations described above, therapy would be different because of the different risk levels determined not by LDL-C but by LDL particle number. NMR lipoprotein analysis has examined the association between NMR particle concentrations and CVD risk and atherosclerotic endpoints in several prospective clinical and angiographic trials.8,34,35 LDL particle number appears to be a stronger predictor of future cardiovascular events or angiographic progression of atherosclerosis than traditional standard lipid measurements, including LDL-C, HDL-C, non-HDL-cholesterol, and TG levels. Other studies support data from these prospective trials. A summary of 17 cross-sectional epidemiological, eight prospective epidemiological, and six clinical intervention trials that have examined the relationship between LDL particle size, LDL particle number, and CVD risk has been presented.8 The data indicate that the relation of small LDL particle size with CVD is intertwined with a metabolic milieu that includes elevated TGs, low HDL-C, and increased numbers of LDL particles (measured indirectly by apoB or directly by NMR). After multivariate adjustment for these confounding risk factors, LDL particle number, but not LDL particle size per se, appears to be a signiﬁcant, independent predictor of CVD risk.34,41 These observations indicate that LDL particle number is a better predictor of risk,8 signiﬁcantly more so than LDL-C and other standard lipid measurements. When does LDL-C begin to fail to reﬂect the number of circulating LDL particles (the disconnect) and thus the best assessment of atherosclerotic risk? In a post hoc analysis of the Framingham Offspring Study (Fig. 5.1 and Table 5.3),2 the disconnect between conventionally measured “optimal” LDL-C and increased numbers of LDL particles was characterized.44 Increased TGs and decreased HDL-C levels were signiﬁcantly associated with this disconnect.8,44 The disconnect between measured LDL-C and NMR-derived LDL particle number began to occur at a TG concentration of more than 70 mg/dL, and at an HDL-C concentration of below 60 mg/dL.42 Data from NMR analysis of LDL particle number in patients with ATP III deﬁned metabolic syndrome45 from the Framingham Offspring Study also reveal an often profound disconnect between LDL-C and LDL particle number.

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Figure 5.1 Relations in the Framingham Offspring Study (n = 3,437) of NMR-measured LDL particles and Friedewald-calculated LDL-C to HDL-C and TGs. (Used by permission of Walter de Gruyter Publishers and J. D. Otvos, from Otvos JD. Why cholesterol measurements may be misleading about lipoprotein levels and CVD disease risk-clinical implications of lipoprotein quantiﬁcation using NMR spectroscopy. Reprinted from Cromwell WC, Otvos JD. Heterogeneity of low-density lipoprotein particle number in patients with type 2 diabetes mellitus and low-density lipoprotein cholesterol <100 mg/dL. Am J Cardiol. 2006;98:1599–602, with permission from Elsevier.)

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Table 5.3 Suggested LDL-C, Non-HDL-C*, ApoB, and LDL Particle Number Goals LDL-C (mg/dL) 70 100 130 160

Non-HDL-C* (mg/dL) 100 130 160 190

ApoB (mg/dL) 65 85 105 125

LDL Particle # (nmol/L) 700 1000 1300 1600

Population Percentile** 5th percentile 20th percentile 50th percentile 80th percentile

* Non-HDL-C is derived by: Total Cholesterol – HDL-C (in mg/dL) **5th percentile risk category: high risk of CVD; 20th percentile risk category: CVD risk equivalent, diabetes mellitus; 50th percentile risk category: more than two major CV risk factors; 80th percentile risk category: zero or one CV risk factors. Based upon Framingham Offspring Study,1,2 National Health and Nutrition Examination Survey III (NHANES III),30 and the Multi-Ethnic Study of Atherosclerosis.33,43 See also ADA/ACC consensus statement.22

LDL-C values often show little or no change as a function of the number of components of the metabolic syndrome that are present. Conversely, patients with metabolic syndrome show much higher numbers of LDL particles overall, and LDL particle size is a function of the number of components of the metabolic syndrome that are present.8 The disconnect between LDL-C and LDL particle number was explained by a three-fold increase in the number of small LDL particles and a corresponding decrease in the number of large LDL particles. Only 23% of patients with “optimal” LDL-C levels of less than 100 mg/dL (below the 20th percentile) had correspondingly low LDL particle numbers (below the 20th percentile). This disparity is further reﬂected in the ﬁnding that 34% of the patients with LDL-C below the 20th percentile had an LDL particle number above the 50th percentile. (Percentiles are derived from subjects enrolled in the Multi-Ethnic Atherosclerosis Study reference population [MESA]).33

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5th 1% (n = 19)

25% (n = 366)

50th 42% (n = 631)

80th 21% (n = 305)

Advanced Lipoprotein Testing

Percentile

11% (n = 163)

15 LDL-C 70–99 mg/dL (n = 1,484)

10

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Percent of subjects

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Patients with type 2 diabetes mellitus have an increased risk of CVD events even when treated to LDL-C goals.3 A recent study46 determined how many diabetic patients with low LDL-C have correspondingly low numbers of LDL particles and the extent to which those achieving target levels of LDL-C and non-HDL-C might still harbor residual risk associated with increased LDL particle number. Split-sample measurements of LDL-C, non-HDL-C, and NMRmeasured LDL particle number were performed on plasma samples from 2,355 patients with type 2 diabetes seen in clinical practice who had LDL-C levels below 100 mg/dL. Substantial heterogeneity of LDL particle number values was noted among patients with low or very low levels of LDL-C (Fig. 5.2). Of 1,484 patients with low LDL-C levels (70 to 99 mg/dL), only 385 (25.9%) had low levels of LDL particle number (less than 1,000 nmol/L; below the 20th percentile of an ethnically diverse contemporary reference population), whereas 468 (31.6%) had LDL

5 0 <600

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Figure 5.2 Distribution of LDL particle number among patients with type 2 diabetes mellitus and LDL-C levels of (top) 70 to 99 mg/dL or (bottom) less than 70 mg/dL. LDL particle number concentrations of 700, 1,000, 1,300, and 1,600 nmol/L correspond closely to the 5th, 20th, 50th, and 80th percentiles of subjects enrolled in the MultiEthnic Atherosclerosis Study (MESA) reference population. (Reprinted from Cromwell WC, Otvos JD. Heterogeneity of low-density lipoprotein particle number in patients with type 2 diabetes mellitus and low-density lipoprotein cholesterol <100 mg/dL. Am J Cardiol. 2006;98:1599–602, with permission from Elsevier.

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particle number values above the 50th percentile (more than 1,300 nmol/L). Among the 871 patients with very low LDL-C (i.e., less than 70 mg/dL), 349 (40.1%) had LDL particle number levels above 1,000 nmol/L (above the 20th percentile) and 91 (10.4%) had LDL particle number levels above the 50th percentile. For patients with high TG values (200 to 400 mg/dL), there was less discordance between LDL particle number and non-HDL-C than between LDL particle number and LDL-C. However, for those with TG levels below 200 mg/ dL, LDL particle number distributions were similarly wide for patients having achieved low or very low targets of LDL-C or non-HDL-C. These data demonstrate that patients with type 2 diabetes mellitus and LDL-C levels below 100 mg/dL are extremely heterogeneous with regard to LDL particle number and, by inference, LDL-based CVD risk.46 The results of this study suggest that determining levels of LDL particle number provides more clinically signiﬁcant information than LDL-C to assess the adequacy of LDL-lowering therapy. Thus, even achieving the most aggressive LDL-C target did not guarantee having low LDL particle number levels. Therapeutic Implications A number of studies have investigated the effects of statins on LDL particle size and LDL particle number. Statins appear to have little or no effect on increasing the size of LDL particles unless a concomitant decrease in VLDL and TG levels occurs as well.6 The number of LDL particles is reduced signiﬁcantly by statin therapy, and thus the number of small, dense atherogenic LDL particles is reduced as well. While statins lower LDL particle number, use of statins does not ensure normal LDL particle number, and additional risk is present if the LDL particle number remains elevated.8,41 Nicotinic acid and ﬁbrates are more effective than statins to increase the size of LDL and HDL particles, especially in patients with small, dense LDL particles.6,34,47 These drugs effectively lower TGs and raise levels of HDL-C. Thus, combination therapy with a statin and nicotinic acid or a ﬁbrate should yield a signiﬁcant reduction in CVD risk by lowering the number of LDL particles directly and by increasing LDL particle size. The increase in HDL particle size with ﬁbrate or nicotinic acid therapy does not necessarily establish increased function of HDL in reverse cholesterol transport.48 Also, there may be a threshold below which TGs must be lowered to produce shifts in LDL particle size.49 When to Consider Advanced Lipoprotein Testing Consider advanced lipoprotein testing when residual CVD risk may be present despite “optimal” LDL-C, TG, and HDL-C goals as recommended by ATP III.45 Patient Selection Patients are likely to have elevated apoB or LDL particle number if they are: • High-risk (diabetic, CVD, or CVD risk equivalent) patients at or near NCEP goal • Metabolic syndrome patients at or near LDL-C level of less than 130 mg/dL

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Routine screening • Patients lacking a family history of premature CVD disease with TGs less than 100 mg/dL and HDL-C above 60 mg/dL • Patients needing treatment with genetic or severe dyslipidemias: • LDL-C above 190 mg/dL • HDL-C below 30 mg/dL • TGs above 500 mg/dL • Patients needing treatment whose lipid levels do not approximate ATP III goals for level of risk (e.g., high-risk patients with LDL-C above 160 mg/dL, TGs above 150 mg/dL, HDL-C below 40 mg/dL)

Advanced Lipoprotein Testing

Primary Prevention Family history of premature CVD, especially if no other risk factors • Metabolic syndrome • Moderately high-risk patients (e.g., patients with hypertension and multiple cardiovascular risk factors) if TG levels exceed 100 mg/dL • CVD events despite “lipids at goal” • Recurrent CVD events despite “lipids at goal” Advanced lipoprotein testing is not indicated for:

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When to Order Advanced Lipoprotein Testing

Summary: Clinical Use of ApoB and Advanced Lipoprotein Testing Measurements of apoB or LDL particle number (by NMR) quantitate the number of atherogenic lipoprotein particles, whereas LDL-C and non-HDL-C are surrogates of the number of atherogenic LDL particles in the circulation. Research suggests that both apoB and LDL particle number may be better measures of CVD risk than LDL-C or non-HDL-C, and they are more reliable indices of on-treatment residual risk.8,13,14,18 ApoB and LDL particle number also appear to provide a better assessment of the adequacy of LDL-C–lowering therapy than LDL-C or non-HDL-C.8,13,24–26,32 Statins lower non-HDL-C levels more than they lower apoB, and reaching the apoB target usually requires more intensive therapy than achieving the equivalent non-HDL-C goal.13,14,18 ApoB and LDL particle number also appear to be more closely associated with obesity, diabetes mellitus, insulin resistance, and other markers of cardiometabolic risk than are LDL-C or non-HDL-C.13,22 When both non-HDL-C and apoB are measured, the two are highly correlated but only moderately concordant.14,22 At any given level of non-HDL-C, there can be considerable variation in apoB levels and vice versa, with this lack of concordance especially marked in patients with elevated TG levels and cardiometabolic risk features.22 The recent consensus conference report from the American Diabetes Association and the American College of Cardiology (ADA/ACC) Foundation on Lipoprotein Management in Cardiometabolic Risk22 concluded that LDL-C

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should remain as the initial measurement to guide therapy. However, a calculation of non-HDL-C should be provided on all laboratory reports and should also be used to ascertain risk in patients with low to moderate LDL-C levels (below 130 mg/dL). Because apoB appears to be a more sensitive index of residual CVD risk when LDL-C is below 130 mg/dL and non-HDL-C is below 160 mg/dL, measurement of apoB, using a standardized assay, is warranted in patients at cardiometabolic risk receiving pharmacologic treatment for dyslipidemia, and apoB levels should be used to guide adjustment of therapy. LDL particle number as measured by NMR appears equally informative as apoB, and while the ADA/ACC consensus statement has expressed concerns with regard to the availability of NMR assays and methodology, for those clinicians familiar with using this advanced lipoprotein technology, NMR-derived LDL particle number is an acceptable measurement, with a solid database supporting consideration of its use. After looking at results from many different studies, study methodologies, populations, and different biostatistical analyses with differing adjustments for different risk factors, non-HDL-C, apoB level, and LDL particle number derived by NMR are better in risk prediction than LDL-C alone. While we await the results of clinical trials that may help determine speciﬁc target levels of apoB or LDL particle number, for patients in different CVD risk categories, use of apoB or LDL particle number goals that mirror current revised ATP III targets at a population equivalent has been suggested, as has been discussed in this review. Further research is required to see if the ratio of apoB to apoA-1 may predict risk better than non-HDL-C, apoB, or LDL particle number, whether in diabetic or nondiabetic populations. Reaching apoB and LDL particle number goals may require combination lipid-altering therapy. Combination therapy may raise HDL-C, and this may confound the issue of whether it is also valuable to further lower apoB or LDL particle number. However, in a patient with new-onset or progressive CVD and the cardiometabolic syndrome with mixed dyslipidemia, it seems reasonable if not mandatory to apply such goals, and one major consensus document22 supports this. In general, risk assessment and therapeutic goals based on advanced lipoprotein testing do not yet have sufﬁcient clinical trial support to establish population or individual guidelines. Although apoB and LDL particle number goals may reduce clinical events, the magnitude of such reduction is unclear, and the cost of such an approach is not fully known. Medical care providers must fully understand the purpose and implications of advanced lipid testing and how to interpret the results before implementing these tests in their practice.50

Acknowledgment We deeply appreciate the secretarial support and expertise of Ms. Rachel Mikkelson.

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1. Contois JH, McNamara JR, Lammi-Keefe CJ. Reference intervals for plasma apolipoprotein B determined with a standardized commercial turbidimetric assay: results from the Framingham Offspring Study. Clin Chem. 1996;42:515–23. 2. Siegel RD, Cupples A, Schaefer EJ, et al. Lipoproteins, apolipoproteins, and low-density lipoprotein size among diabetics in the Framingham offspring study. Metabolism. 1996;45:1267–72. 3. Davidson MH. Pharmacological therapy for cardiovascular disease. In: Davidson MH, Toth PP, Maki KC, eds. Therapeutic Lipidology. Totowa, NJ: Humana Press; 2007:121–48. 4. Grundy SM, Cleeman JI, Merz CNB, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. J Am Coll Cardiol. 2004;44:720–32. 5. Castelli W. Lipids, risk factors and ischaemic heart disease. Atherosclerosis. 1996;124:S1–S9. 6. Ferguson EE Jr. Preventing, stopping, or reversing coronary artery diseasetriglyceride-rich lipoproteins and associated lipoprotein and metabolic abnormalities: the need for recognition and treatment. Dis Mon. 2000;46:421–504. 7. Brewer HB Jr. Hypertriglyceridemia: changes in the plasma lipoproteins associated with an increased risk of cardiovascular disease. Am J Cardiol. 1999;83: 3F–12F. 8. Cromwell WCC, Otvos JD. Utilization of lipoprotein subfractions. In: Davidson MH, Toth PP, Maki KC, eds. Therapeutic Lipidology. Totowa, NJ: Humana Press; 2007:321–47. 9. Kathiresan S, Otvos JD, Sullivan LM, et al. Increased small low-density lipoprotein particle number: a prominent feature of the metabolic syndrome in the Framingham Heart Study. Circulation. 2006;113:20–9. 10. Fredrickson DS, Levy RI, Lees RS. Fat transport in lipoproteins—an integrated approach to mechanisms and disorders. N Engl J Med. 1967;276:148–56. 11. Ross R. Atherosclerosis—an inﬂammatory disease. N Engl J Med. 1999;340: 115–26. 12. Abate N, Vega GL, Grundy SM. Variability in cholesterol content and physical properties of lipoproteins containing apolipoprotein B-100. Atherosclerosis. 1993;104:159–71. 13. Sniderman AS. Targets for LDL-lowering therapy. Curr Opin Lipidol. 2009;20:282–7. 14. Barter PJ, Ballantyne CM, Carmena R, et al. Apo B versus cholesterol in estimating cardiovascular risk and in guiding therapy: report of the thirty-nine person/ ten-country panel. J Intern Med. 2006;259:247–58. 15. Contois JH, McConnell JP, Sethi AA, et al. Apolipoprotein B and cardiovascular disease risk: position statement from the AACC Lipoproteins and Vascular Diseases Division Working Group on Best Practices. Clin Chem. 2009;55:407–19. 16. van der Steeg WA, Boekholdt SM, Stein EA. Role of the apolipoprotein B-apolipoprotein A-1 ratio in cardiovascular risk assessment: a case-control analysis in EPIC-Norfolk. Ann Intern Med. 2007;146:640–8.

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References

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17. Pyorala K, Pedersen TR, Kjekshus J, et al. Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease: a subgroup analysis of the Scandinavian Simvastatin Survival Study (4S). Diabetes Care. 1997;20:614–20. 18. The Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med. 1998;339:1349–57. 19. Brown G, Albers JJ, Fisher LD, et al. Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B. N Engl J Med. 1990;323:1289–98. 20. Lamarche B, Tchernof A, Moorjani S, et al. Small, dense low-density lipoprotein particles as a predictor of risk of ischemic heart disease in men: prospective results from the Quebec Cardiovascular Study. Circulation. 1997;95:69–75. 21. Lamarche B, Despres J-P, Moorjani S, et al. Prevalence of dyslipidemic phenotypes in ischemic heart disease (prospective results from the Quebec Cardiovascular Study). Am J Cardiol. 1995;75:1189–95. 22. Brunzell JD, Davidson M, Furberg CD, et al. Lipoprotein management in patients with cardiometabolic risk. Consensus Conference Report from the American Diabetes Association and the American College of Cardiology Foundation. J Am Coll Cardiol. 2008;51:1512–24. 23. Gotto AM Jr, Whitney E, Stein EA. Relation between baseline and on-treatment lipid parameters and ﬁrst acute major coronary events in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS). Circulation. 2000;101:477–84. 24. LaRosa JC, Grundy SM, Waters DD, et al., for the Treating to New Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352:1–11. 25. Pedersen TR, Faergeman O, Kastelein JJP, et al., for the Incremental Decrease in End Points through Aggressive Lipid Lowering (IDEAL) Study Group. Highdose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction. The IDEAL Study: a randomized controlled trial. JAMA. 2005;294:2437–45. 26. Kastelein JJ, van der Steeg WA, Holme I. Lipids, apolipoproteins, and their ratios in relation to cardiovascular events with statin treatment. Circulation. 2008;117:3002–9. 27. Stampfer MJ, Sacks FM, Saalvini S, et al. A prospective study of cholesterol, apolipoproteins, and the risk of myocardial infarction. N Engl J Med. 1991;325:373–81. 28. Sniderman AD. To (measure apoB) or not (to measure apoB): a critique of modern medical decision making. Clin Chem. 1997;43:1310–4. 29. Marconia SM, Albers JJ, Kennedy H, et al. International Federation of Clinical Chemistry standardization project for measurement of apolipoproteins A-1 and B. IV. Comparability of apolipoprotein B values by use of international reference material. Clin Chem. 1994;40:586–92. 30. Bachorik PS, Lovejoy KL, Carroll MD. Apolipoprotein B and A-1 distributions in the United States, 1998–1991: results of the National Health and Nutrition Examination Survey III (NHANES III). Clin Chem. 1997;43:2364–78.

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31. Keavney B, Palmer A, Parish S, for the International Studies of Infarct Survival (ISIS) Collaborators. Lipid-related genes and myocardial infarction in 4685 cases and 3460 controls: discrepancies between genotype, blood lipid concentrations, and coronary disease risk. Int J Epidemiol. 2004;33:1002–13. 32. Waldius G, Jungner I, Holme I, et al. High apolipoprotein B, low apolipoproteinA-1, and improvement in the prediction of fatal myocardial infarction (AMORIS study): a prospective study. Lancet. 2001;358:2026–33. 33. Jeyarajah EJ, Cromwell WC, Otvos JD. Lipoprotein particle analysis by nuclear magnetic resonance spectroscopy. Clin Lab Med. 2005;26:847–70. 34. Otvos JD, Collins D, Freedman DS, et al. LDL and HDL particle subclasses predict coronary events and are changed favorably by gemﬁbrozil therapy in the Veterans Affairs Intervention Trial (VA-HIT). Circulation. 2006;113: 1556–63. 35. Blake GJ, Otvos JD, Rifai N, et al. LDL particle concentration and size as determined by NMR spectroscopy as predictors of cardiovascular disease in women. Circulation. 2002;106:1930–7. 36. Nichols AV, Krauss RM, Musliner TA. Nondenaturing polyacrylamide gradient gel electrophoresis. Methods Enzymol. 1986;128:417–31. 37. Williams PT, Superko HR, Haskell WL. Smallest LDL particles are most strongly related to coronary disease progression in men. Arterioscler Thromb Vasc Biol. 2003;23:314–21. 38. Superko HR. Small dense LDL: the new coronary artery disease risk factor and how it is changing the treatment of CVD. Prev Cardiol. 1998;1:16–24. 39. Kulkarni KR, French KW. Determination of apolipoprotein B 100 by the vertical auto proﬁle method. Clin Chem. 2007;53(S6):A41. 40. Tzou WES, Douglas PS, Srinivasan SR, et al. Advanced lipoprotein testing does not improve identiﬁcation of subclinical atherosclerosis in young adults: the Bogalusa Heart Study. Ann Intern Med. 2005;142:742–50. 41. Ip S, Lichtenstein AH, Chung M, et al. Systematic review: association of lowdensity lipoprotein subfractions with cardiovascular disease. Ann Intern Med 2009;150:474–84. 42. Otvos JD. Why cholesterol measurements may be misleading about lipoprotein levels and cardiovascular disease risk-clinical implications of lipoprotein quantiﬁcation using NMR spectroscopy. J Lab Med. 2002;26:544–50. 43. Mora S, Szklo M, Otvos JD, et al. LDL particle subclasses, LDL particle size, and carotid atherosclerosis in the Multi-Ethnic Study of Atherosclerosis (MESA). Atherosclerosis. 2007;192:211–7. 44. Otvos JD, Jeyarajah EJ, Cromwell WC. Measurement issues related to lipoprotein heterogeneity. Am J Cardiol. 2002;90(Suppl):22i-29i. 45. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) ﬁnal report. Circulation. 2002;106:3143–421. 46. Cromwell WC, Otvos JD. Heterogeneity of low-density lipoprotein particle number in patients with type 2 diabetes mellitus and low-density lipoprotein cholesterol < 100 mg/dL. Am J Cardiol. 2006;98:1599–602.

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47. Morgan JM, Capuzzi DM, Baksh RI, et al. Effects of extended-release niacin on lipoprotein subclass distribution. Am J Cardiol. 2003;91:1432–6. 48. Duffy D, Rader DJ. Emerging therapies targeting high-density lipoprotein metabolism and reverse cholesterol transport. Circulation. 2006;113:1140–50. 49. Davidson MH, Bays HE, Stein E, et al., for the TRIMS investigators. Effects of fenoﬁbrate on atherogenic dyslipidemia in hypertriglyceridemic subjects. Clin Cardiol. 2006;29:268–73. 50. Lau JF, Smith DA. Advanced lipoprotein testing: recommendations based on current evidence. Endocrinol Metab Clin North Am. 2009;38:1–31.

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Chapter 6

Stratiﬁcation of Dyslipidemic Risk William B. Kannel

Two 56-year-old men with a serum total cholesterol of 250 mg/dL present for cardiovascular disease (CVD) risk assessment. Case #1 has an high-density lipoprotein cholesterol (HDL-C) of 34 mg/dL and a blood pressure of 164/98 mm Hg. He is a smoker and has a history of diabetes. His 10-year global CVD risk by the Framingham multivariable risk score is 45%. Case #2, with the same total cholesterol, has an HDL-C of 50 mg/dL and a blood pressure of 130/85 mm Hg. He is a nonsmoker and has no history of diabetes. His 10-year global CVD risk score is only 10%.

105

Clinical Vignette

Background Risk assessment of dyslipidemia and its treatment should be guided by global risk evaluation, preferably reﬂecting long-term risk. Epidemiological research indicates that CVD is provoked by several biologically plausible and modiﬁable risk factors. The search for these predisposing CVD risk factors was motivated by the magnitude and gravity of the CVD crisis, which is presently responsible for 1 in 3 U.S. deaths. American Heart Association statistics indicate that nearly 2,400 Americans succumb to fatal CVD events each day, with one death occurring every 37 seconds. Estimates of the direct and indirect cost of CVD for 2009 were $475.3 billion. About 60% of cardiac deaths occur before its victims reach a hospital, and often the ﬁrst manifestation is a sudden unexpected death, stressing the need for a preventive approach. In 2005 one third of CVD deaths in the United States occurred prior to age 75 years, which was below the average life expectancy of almost 78 years.1 The average lifetime risk of coronary heart disease (CHD) for 40-year-old participants in the Framingham study was 49% in men and 32% in women, and this lifetime risk was found to increase stepwise with each increment in the serum cholesterol level.2 Comprehensive evidence from epidemiological, clinical, angiographic, postmortem, and clinical trial investigations impugn a causal connection between dyslipidemia and atherosclerotic vascular disease and show that treating dyslipidemia lowers CHD incidence even when the blood

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lipids appear to be within the alleged “normal” range.3,4 Because there are no critical deﬁning CVD risk values for any of the lipids and a substantial overlap of the lipid distributions of cases and non-cases, it is difﬁcult to assign lipid values that deﬁnitively separate potential CVD candidates from the rest of the population.5 Epidemiological data and dyslipidemia trials estimate that each 1% change in total cholesterol or low-density lipoprotein cholesterol (LDL-C) throughout its range imposes a 2% change in the rate of initial or recurrent CHD events.6–8 The average cholesterol level that was formerly considered acceptable was revised downward when epidemiological data showed that in populations with a low CVD incidence, cholesterol values were well below that of the United States. An acceptable lipid value is now designated as that which is optimal for avoiding CVD rather than the average value in the population. Furthermore, risk of CVD at any level of the various blood lipids varies widely depending on the number and level of other risk factors that often come with them. It is interesting to note that most of the currently relevant information about lipids was reported by the Framingham study in 1979.9 It asserted that within the alleged “normal limits” of blood lipids CHD incidence mounts incrementally over a 5-fold range, and that the total cholesterol contribution to risk is determined by its partition in lipoprotein fractions. It also asserted that a large amount of cholesterol in LDL is atherogenic whereas that in HDL is protective, and that the lipid impact is enhanced by other CVD risk factors. Current reﬁnements now include more comprehensive lipid proﬁles and their assessment as a component of a multivariable CVD risk proﬁle.

Evaluation of Dyslipidemic Risk The focus on LDL-C as the principal atherogenic lipid culprit has tended inadvertently to divert awareness away from more effective lipid proﬁles comprising the total cholesterol/HDL-C, LDL-C/HDL-C, and triglyceride/HDL-C ratios. Comparison of the quintile array of each of the standard lipids with the array of lipid ratio quintiles in the Framingham study showed that the standard lipid ratios are more robust CHD predictors than the particular lipids themselves.10 The utility of LDL-C and total cholesterol for CVD risk appraisal is enhanced when it is used as an element of an LDL/HDL or total/HDL cholesterol ratio. In men the total/HDL-C and LDL-C/HDL-C ratios are equal CHD predictors, whereas for women the total/HDL-C ratio is more robust. The Framingham study also found that the triglyceride/HDL-C ratio is almost as robust a predictor of CHD as the total/HDL-C ratio, particularly in women.11 This triglyceride/HDL ratio is also a particularly helpful lipid ratio for assessing lipid atherogenic potential that derives from insulin resistance and/or the metabolic syndrome, which may require another choice of therapy. It also serves as a hallmark of elevated intensely atherogenic small-dense LDL. The clinical utility of a more extensive set of suggested lipid ratios for prediction of initial CHD events in comparison to the lipids per se was recently assessed in great detail by the Framingham study. Lipids and lipid ratios evaluated

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included serum total cholesterol, HDL-C, LDL-C, non-HDL-C, apolipoprotein A-I and apolipoprotein B, and total cholesterol/HDL-C, LDL-C/HDL-C, and apoB/apoA-I ratios.12 In multivariate analysis adjusting for non-lipid risk factors, the apoB/apoA-I ratio was a robust CHD predictor, with a hazard ratio of 1.4 per standard deviation increment, in both men and women. However, in both sexes, models using the apoB/apoA-I ratio performed comparably with, but no better than, those for other lipid ratios. Furthermore, the apoB/apoA-I ratio failed to predict CHD in a model encompassing all components of the Framingham risk score along with the total cholesterol/HDL-C ratio. These Framingham study data do not indicate much advantage for measurement of apoB or apoA-I in clinical practice when total cholesterol and HDL-C are readily accessible. As noted, it is established that the risk of developing CHD is strongly and independently related to the total, LDL-C, and HDL-C levels.13,14 Elevated triglycerides are also a recognized risk for CHD, but it is less clear that triglycerides per se independently contribute to the hazard. Some recent studies have stressed non-fasting triglyceride levels as a CHD risk. Also, triglyceride-rich lipoproteins and very-low-density lipoproteins (VLDLs) in particular are independently associated with atherosclerotic vascular disease.14–17 Hypertriglyceridemia is a dominant attribute of diabetic dyslipidemia and an important forecaster of CHD mortality in persons with impaired glucose tolerance.18 The dyslipidemia of diabetes is characterized by increased triglycerides accompanied by reduced HDL-C, a preponderance of small-dense LDL, and cholesterol-enriched VLDL. Multivariable Risk Assessment Multivariable CVD risk factor analysis was initially used to gain insights about atherogenesis. However, this analysis also enabled generation of a set of risk factors useful for crafting multivariable risk formulations for prediction of CVD. It was soon appreciated that virtually all risk factors are related to the occurrence of CVD in a continuous graded fashion, with no indication of a critical threshold. This lack of a clear demarcation of high-risk CVD candidates based solely on their lipid values indicates the need to consider dyslipidemia in the context of a multivariable CVD risk proﬁle. The dyslipidemic predisposition to CHD is greatly inﬂuenced by the accompanying load of other risk factors often present.19,20 About 65% to 90% of the CVD events that occur in dyslipidemic persons derive from those with two or more accompanying risk factors. It is postulated that there is a metabolic basis for other CVD risk factors to aggregate with dyslipidemia that involves insulin resistance induced by visceral adiposity and autonomic imbalance.6,21 The Framingham study found an upward trend in the sum of other CVD risk factors with increments in body mass index in both sexes for each of the blood lipids, including total cholesterol, LDL-C, HDL-C, and triglycerides.22 As pointed out by Lloyd-Jones and coworkers, calculating a patient’s multivariable 10-year CHD risk provides valuable information, but adding a lifetime risk estimate delivers a more impressive message about CVD risk to both the patient and physician. According to Framingham study data, a 50-year-old man

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with a total cholesterol level of 250 mg/dL, an HDL-C level of 60 mg/dL, and an untreated systolic blood pressure of 160 mm Hg, who is a nonsmoker and a non-diabetic, has an estimated 10-year risk of 7%. Many patients and some physicians might consider this trivial until it is pointed out that this amounts to a lifetime risk of 70% and a median survival shortened by more than 11 years.23 Rationale Underlying Preventive Treatment Guideline Guidelines for the treatment of dyslipidemia have evolved to encompass lipids other than LDL-C, more aggressive correction of elevated lipids, and “global” risk assessment.7,13 The NCEP ATP III guidelines emphasize optimization of LDL-C levels, stress absolute CHD risk assessment, and designate patients with a 10-year risk of CHD exceeding 20% as candidates for aggressive lipid correction (Table 6.1).24 For patients with an absolute 10-year estimated CHD risk of 10% to 20% less aggressive therapy is recommended, but medication is advised if required to maintain an LDL-C less than 130 mg/dL.15 In the NCEP ATP III guidelines, a modiﬁed Framingham risk prediction score was used to calculate absolute CHD risk that differs from prior versions because it does not include diabetes, now considered a “CHD equivalent” rather than a risk factor. Another innovation of the ATP III guidelines was the inclusion of reduced HDL-C and elevated triglycerides as CVD risks. The importance of the metabolic syndrome signifying insulin resistance is also acknowledged in these guidelines. The cluster of risk factors that usually accompany elevated LDL-C represent most of the ingredients of this “metabolic syndrome,” including hypertension, abdominal obesity, hyperglycemia, elevated triglycerides, and low levels of HDL-C. The high CHD risk of persons with criteria for the “metabolic syndrome” (three or more of these risk factors) also serves to emphasize the importance of global risk assessment of dyslipidemia for pre-diabetics. Thus, the magnitude of the CHD risk of dyslipidemia varies considerably relative to the load of accompanying risk factors.25 The high degree of clustering of CVD risk factors that characteristically accompany elevated blood lipids reinforces the concept of dyslipidemia as a component of a cardiovascular multivariable risk proﬁle and/or a feature of an insulin resistance metabolic

Table 6.1 CVD Prevention Using Risk Assessment by Framingham Risk Score CVD Risk Levels. ATP III Guidelines Risk Category Very High Risk

Framingham 10-Year Risk <20%

High Risk Moderate Risk

10%–20% <10%

Low Risk

<10%

Risk Factor Level Established CHD, CHD equivalent, or diabetes >2 risk factors

<2 risk factors 0 or 1 risk factors & healthy lifestyle

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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syndrome. Global risk assessment is required to provide optimal cost-effective preventive therapy. Such risk assessment can be readily accomplished with the aid of multivariable risk formulations like those from the Framingham study.23 These multivariable CVD risk assessment tools are available for patients with or without existing CVD.26,27 The concept of risk-based preventive management of CVD is not new.28 However, it is difﬁcult for physicians to quantify risk when, as is usually the case, the patient has several risk factors. One example for targeting persons with moderately abnormal lipid values in whom drug treatment would be costeffective is that of the European Society of Cardiology, which advocates therapy for elevated LDL-C associated with a CHD risk of 2% per year or greater based on a multivariable CHD risk score.25 This has become necessary because trials have demonstrated beneﬁts of treating what has been considered “normal” lipid values. For example, the AFCAPS/TexCAPS trial demonstrated a beneﬁt of treating persons with average cholesterol levels, making it advisable to consider other criteria for cost-effective preventive interventions.29 The more extensive Heart Protection Study showed that high-risk patients beneﬁt from statin therapy even when those with LDL-C levels less than 100 mg/dL are included.30 This suggests that an optimal LDL-C level for high multivariable-risk persons is well below currently recommended goals. Since low HDL-C levels are often accompanied by elevated triglycerides, and the combination is a common feature of the dyslipidemia of type 2 diabetes, there is good reason to measure these lipids together routinely. This combination is often encountered in hospitalized CVD patients, arguing for targeting HDL-C along with LDL-C in preventive management of dyslipidemia. The VA-HIT trial examined the effects of lipid-altering therapy directed at HDL-C in patients who had low LDL-C levels.31 It found that 50% of patients with low HDL-C levels had evidence of the metabolic syndrome, and also that gemﬁbrozil increased HDL-C and reduced CHD and stroke occurrence in these overweight persons with diabetes and insulin resistance. The true prevalence of insulin resistance in the general population has not been consistently estimated because of the technical difﬁculty of directly measuring it in population studies. Estimates are based on a variety of surrogate measures in population samples of differing age and sex composition, thereby yielding widely varying insulin resistance prevalence estimates.25,29 Best estimates suggest that 76 million Americans age 20 years and older have the metabolic syndrome, representing about 35% of men and women. The estimated hazard for the surrogate insulin resistance is a 3-fold increased risk of CHD and a 5-fold increased CVD mortality.32,33 Likewise, the precise prevalence of insulin resistance in the subgroup of the general population with dyslipidemia is unknown. This makes it difﬁcult to estimate the extent to which insulin resistance is responsible for the cluster of risk factors commonly seen in dyslipidemia and also to estimate the risk of coronary events attributable to insulin resistance. Nevertheless, considering the nature and amount of risk factor clustering noted with dyslipidemia, insulin resistance could account for a large fraction of the high risk of coronary disease found in dyslipidemic persons. BMI and

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waist girth are highly correlated, so that each of them is similarly related to the risk factors of insulin resistance.34,35 Although ATP III has designated LDL-C as the major focus of therapy for dyslipidemia, it nevertheless acknowledges HDL-C and triglycerides as important for management of dyslipidemic risk.11 Lipid targets designated for therapy of LDL-C vary from less than 100 mg/dL to more than 160 mg/dL depending on the load of associated risk factors.10 Acceptable HDL-C values have been raised to more than 40 mg/dL for men and more than 50 mg/dL for women. It recommends that LDL-C be reduced to below 160 mg/dL if only one other risk factor is present; to below 130 mg/dL if two or more risk factors are present and 10-year CHD risk is below 20%; and to below 100 mg/dL if more than two risk factors are present and 10-year CHD risk is at least 20% or there is diabetes. Control of non-HDL-C is also recommended if LDL-C is at goal and triglycerides are elevated. Suggested non-HDL-C goals are below 190 mg/dL for zero or one risk factor; below 160 mg/dL for two or more risk factors or 10-year CHD risk below 20%; and below 130 mg/dL for diabetes or two or more risk factors or 10-year risk more than 20%. Because a high triglyceride level accompanied by reduced HDL-C concentration presumes that a small-dense LDL problem is present, the ATP III guidelines stipulate a potential beneﬁt of treating this high-risk type of dyslipidemia.13 Multivariable Risk Management Thus, effective strategies have been developed for primary and secondary prevention of atherosclerotic CVD during the past three decades that involve, in addition to treatment of dyslipidemia per se, treatment of associated high blood pressure, control of diabetes, and lifestyle changes promoting a healthy diet, weight control, exercise, and smoking cessation. Clinical trials have consistently demonstrated the beneﬁt of LDL-C reduction for both CHD and total mortality, both for patients with and without overt CHD and with either mild or severe dyslipidemia.29,35–37 It is evident, however, that to provide optimal treatment, correction of other major risk factors that usually accompany the dyslipidemia should be considered necessary because this greatly enhances the beneﬁt of dyslipidemia treatment.37–39 Global risk assessment should dictate how aggressive the multivariable therapy should be. Comprehensive treatment of diabetes, the designated “CHD equivalent,” by correcting its accompanying CVD risk factors has been shown to be much more efﬁcacious than rigid control of the blood sugar.40 Estimates of beneﬁts for CHD prevention by optimal control of blood pressure and lipids in patients with the metabolic syndrome, based on NHANES III data, suggest that there is much to be gained.41 Normalization of HDL-C, LDL-C, plus blood pressure was estimated to confer a 51.3% protection for men and 42.6% for women. Dyslipidemia Assessment in Women A review of cardiovascular disease in women by Meagher correctly notes that data about the CVD multivariable impact of dyslipidemia and the efﬁcacy of correcting it are much less extensive for women than men.42 CVD prevention trial data on dyslipidemia that exist for women indicate that lipid-correcting

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medications provide comparable beneﬁts to those observed for men. However, HDL-C and triglyceride levels in women appear to forecast CHD better than total cholesterol or LDL. Hence, improving all CVD-promoting lipid elements deserves greater consideration in women than men.42 Women’s HDL-C levels are about 10 mg/dL higher than those of men, possibly accounting for some of the discrepancy in CVD occurrence between the sexes.43 LDL-C levels are lower in women than men until the menopause, when levels rise and the particles take on a smaller, denser, more atherogenic conﬁguration.44 The Lipid Research Clinics’ Follow-Up Study for CHD and CVD mortality in women has conﬁrmed that HDL-C and triglycerides are more potent atherogenic lipids than total cholesterol or LDL-C for women.41 In both ATP III and the recent AHA guidelines for women, reduction of non-HDL-C is a suggested secondary objective of therapy.45,46 The Heart and Estrogen/Progestin Replacement Study data indicate that lipoprotein(a) is an independent predictor of CHD recurrences in postmenopausal women.47 This is problematic for lipoprotein(a) management of women because it appears resistant to correction by diet, exercise, and most medications used to manage dyslipidemia. Niacin and hormone replacement therapy decrease it, but there are limited CVD outcome data pertaining to women to certify a beneﬁt from such therapy. In contrast to men, women’s CHD mortality rates have continued to rise over the past 20 years despite the availability of statin therapy for dyslipidemia. This paradoxical secular trend may be a consequence of the widespread use of hormone replacement therapy despite scant evidence of any CVD beneﬁts.42

Practical points Whatever the cause, it is prudent to routinely screen the dyslipidemic patient for the presence of the other major risk factors that often accompany it. Target levels for LDL-C correction should be set based on the global risk imposed by these coexistent CVD risk factors.13 Optimal dyslipidemia care requires assessment of the full lipid proﬁle and the multivariable risk. Aggressiveness of dyslipidemic treatment should be dictated by the global CVD risk. For high-risk persons with CHD, stroke, peripheral artery disease, diabetes, or two or more risk factors (which confers a greater than 20% risk of CHD), treating to an LDL-C of less than 70 mg/dL is now suggested.24 When the dyslipidemia is characterized by a high triglyceride level and a low HDL level and this is accompanied by hypertension, abdominal obesity, or glucose intolerance, the insulin-resistant metabolic syndrome should be invoked and treatment chosen with this in mind. LDL-C remains the primary target of dyslipidemia therapy recommended by the ATP III guidelines. However, these guidelines also call for greater attention to triglycerides, considering values above 200 mg/dL as indication for treatment or values above 150 mg/dL as a possible indicator of the metabolic syndrome, particularly if accompanied by an HDL-C level below 40 mg/dL. This atherogenic dyslipidemia is now considered an indication for more intensive and comprehensive therapy of dyslipidemia.

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Unresolved Issues Despite convincing evidence of its efﬁcacy, surveys have suggested that there is suboptimal treatment and screening for dyslipidemia in persons meeting recommended criteria for evaluation and treatment. The Lipid Treatment Assessment Project reported that most persons at risk or already afﬂicted with CHD were not reaching the less stringent 1993 NCEP LDL-C goals, with only 38.4% of those treated achieving recommended goals.48 However, some of these surveys preceded publication of the convincing trial data on the efﬁcacy of correcting milder dyslipidemias. Consequently, the interval between knowledge about the value of managing milder dyslipidemia aggressively and implementation of treatment may be shortening. Because the bulk of coronary events occur in persons with moderate dyslipidemia, physicians need to be aware that among such persons those at high risk can be detected and targeted for appropriate treatment by routine assessment for the presence of other risk factors. However, there is currently underuse of available multivariable risk assessment tools. While it is clear that weight reduction in the obese can improve dyslipidemia, its multivariable risk, insulin resistance, and elements of the metabolic syndrome, there are no trials documenting that weight reduction reduces subsequent CVD events. Acquiring such evidence will be difﬁcult because of the current inability of trial subjects to achieve sustained weight reduction. It is also not clear whether treatment of insulin resistance per se in dyslipidemic persons confers a beneﬁt against CVD. It is recommended that all patients with symptomatic atherosclerotic disease have LDL-C target values set below 100 mg/ dL—less than 70 mg/dL if they are at very high risk. However, it is not clear at present whether the more radical lowering of LDL-C yields further clinically relevant beneﬁt. These uncertainties may be delaying adoption of multivariable risk assessment by many physicians.

Summary and Recommendations Dyslipidemia, fundamental to atherogenesis, is a readily correctable risk factor with established efﬁcacy of treatment for reducing risk of CVD. The current concentration on LDL-C for assessment of dyslipidemic CVD risk needs to be modiﬁed to more strongly emphasize the value of the ratios of total cholesterol/HDL and triglycerides/HDL. Lipid therapy should also be individualized to take into account the multivariable risk, non-HDL-C levels, the presence of the metabolic syndrome, and insulin resistance. The intensity and goals of therapy should be linked to multivariable risk, particularly in those with moderate dyslipidemia. Substantial CVD risk factor clustering accompanies all lipid abnormalities, is promoted by adiposity and insulin resistance, and greatly inﬂuences the dyslipidemic CVD hazard. Global risk assessment taking into account the amount and type of clustering is essential for efﬁcient preventive management of lipids.

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In the National Cholesterol Adult Treatment Panel guidelines for dyslipidemia treatment, goals are linked to global coronary disease risk. Those with a 10-year CHD risk of 20% or greater are advised to treat LDL-C to a goal of less than 100 mg/dL, whereas those whose global risk is less than 10% (most people with zero or one risk factors) are set a goal of below 160 mg/dL. The beneﬁts of reducing LDL-C are well established for primary and secondary CHD prevention. For treatment of dyslipidemia and its multivariable risk, it is important to consider the number needed to treat to prevent one case; this increases the lower the risk of the person treated. Effective global CVD risk assessment entails use of a readily attainable and reliably measured set of major independent predisposing risk factors, deﬁnition of clinically relevant categories of risk, and implementation of beneﬁcial preventive approaches.

Acknowledgment I wish to acknowledge the assistance of Ramachandran Vasan, MD, who helped compile relevant recent data, references, and reports for the chapter.

1. American Heart Association. Heart disease and stroke statistics: 2009 update. Dallas: American Heart Association, 2009. 2. Lloyd-Jones DM, Wilson PW, et al. Lifetime risk of coronary heart disease by cholesterol levels at selected ages. Arch Intern Med. 2003;163(16):1966–72. 3. Knopp RH. Drug therapy: drug treatment of lipid disorders. N Engl J Med. 1999;341:498–511. 4. Levine GN, Keaney JF Jr., Vita JA. Cholesterol reduction in cardiovascular disease. N Engl J Med. 1995;332:512–521. 5. Stamler J, Wentworth D, Neaton JD. Is the relationship between serum cholesterol and risk of premature death from coronary heart disease continuous and graded? Findings in 356,222 primary screenees of the Multiple Risk Factor Intervention Trial (MRFIT). JAMA. 1986;256:2823–8. 6. Kwiterovitch PO Jr. State-of-the-art update and review: clinical trials of lipidlowering agents. Am J Cardiol. 1998;82:3U-17U. 7. Grundy SM. Approach to lipoprotein management in 2001 national cholesterol guidelines. Am J Cardiol. 2002;90(suppl):11i-21i. 8. Gotto AM Jr, Farmer JA. Lipid-lowering trials. In: Braunwald E, Zipes DP, Libby P, eds. Heart Disease (6th ed.). New York: WB Saunders, 2001:1006–86. 9. Kannel WB, Castelli WP, Gordon T. Cholesterol in the prediction of atherosclerotic disease. New perspectives based on the Framingham Study. Ann Intern Med. 1979;90:85–91. 10. Kannel WB, Wilson PWF. Efﬁcacy of lipid proﬁles in predicting coronary disease. Am Heart J. 1992;124:768–74. 11. Kannel WB, Vasan RS, Keyes MJ, et al. Usefulness of the triglyceride-high-density lipoprotein versus the cholesterol-high-density lipoprotein ratio for predicting insulin resistance and cardiometabolic risk (from the Framingham Offspring Cohort. Am J Cardiol. 2008;101:497–501.

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References

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12. Ingelsson E, Schaefer EJ, Contois JH, et al. Clinical utility of different lipid measures for prediction of coronary heart disease in men and women. JAMA. 2007;298:776–85. 13. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486–97. 14. Hokanson JE, Austin M. 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;3:213–9. 15. Austin MA, Hokanson JE, Edwards KL. Hypertriglyceridemia as a cardiovascular risk factor. Am J Cardiol. 1998;81:7–12B. 16. Assmann G, Schulte H, Funke H, et al. The emergence of triglycerides as a signiﬁcant independent risk factor in coronary artery disease. Eur Heart J. 1998;19:M8–14. 17. Fontbonne A, Eschwege E, Cambien F, et al. Hypertriglyceridemia as a risk factor of coronary heart disease mortality in subjects with impaired glucose tolerance or diabetes: results of the Paris Prospective Study. Diabetologia. 1989;32:300–4. 18. DeFronzo RA, Ferrannini E. Insulin resistance: a multifaceted syndrome responsible for NIDDM, obesity, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care. 1991;14:173–94. 19. Kannel WB. Prospects for prevention of cardiovascular disease in the elderly. Preventive Cardiol. 1998;1:32–9. 20. Wilson PWF, D’Agostino RB, Levy D, et al. Prediction of coronary heart disease using risk factor categories. Circulation. 1998;97:1837–47. 21. Wilson PWF, Kannel WB, Silberschatz H, et al. Clustering of metabolic factors and coronary heart disease. Arch Intern Med. 1999;159:1104–9. 22. Wilson PWF, Kannel WB. Clustering of metabolic factors and coronary heart disease. Nutr Clin Care. 1999;1:44–50. 23. Lloyd-Jones D, Leip EP, Larson MG, et al. Prediction of lifetime risk for cardiovascular disease by risk factor burden at 50 years of age. Circulation. 2006;113:791–8. 24. Grundy SM, Cleeman JI, Merz NB, et al. Implications of recent trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. Circulation. 2004;110:227–39. 25. Pyorala K, DeBaker G, Graham I, et al. Prevention of coronary heart disease in clinical practice. Eur Heart J. 1994;15:1300–31. 26. Califf RM, Armstrong PW, Carver JR, et al. Stratiﬁcation of patients into high, medium and low risk subgroups for purposes of risk factor management. J Am Coll Cardiol. 1996;27:1007–19. 27. Anderson KM, Wilson PWF, Odell PM, et al. An updated coronary risk proﬁle; a statement for health professionals. Circulation. 1991;83:356–62. 28. Pearson TA, Fuster V. Matching the intensity of risk factor management with the hazard for coronary disease events. J Am Coll Cardiol. 1996;27:961–3. 29. Downs JR, Clearﬁeld M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of the AFCAPS/TexCAPS. JAMA. 1998;279:1615–22.

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30. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomized placebo-controlled trial. Lancet. 2002;360:7–22. 31. Rubins HB, Robins SJ, Collins D, et al. For the Veterans Affairs High-density Lipoprotein Cholesterol Intervention Trial Study Group. Gemﬁbrozil for the secondary prevention of coronary heart disease in men with low levels of highdensity lipoprotein cholesterol. N Engl J Med. 1999;341:410–8. 32. Reaven GM, Chen Y-DI, Jeppesen J, et al. Insulin resistance and hyperinsulinemia in individuals with small-dense low density lipoprotein particles. J Clin Invest. 1993;92:141–6. 33. Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: ﬁndings from the third National Health and Nutrition Examination Survey. JAMA. 2002;28:356–9. 34. Wilson PWF, D’Agostino R, Parise H, et al. Metabolic syndrome as a precursor of cardiovascular disease and type 2 diabetes mellitus. Circulation. 2005;112:3066–72. 35. Dasgupta S, Hazra SC. The utility of waist circumference in assessment of obesity. Indian J Public Health. 1999;43:132–5. 36. Brown B, Albers J, Fisher L, et al. Regression of coronary artery disease as a result of intensive lipid lowering therapy in patients with high levels of apolipoprotein B. N Engl J Med. 1990;323:1289–98. 37. Scandinavian Simvastatin Survival Study Group. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383–9. 38. Sacks F, Pfeffer M, Moye L, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med. 1996;335:1001–9. 39. Haskell W, Alderman E, Farin J, et al. Effects of intensive multiple risk factor reduction on coronary atherosclerosis and clinical cardiac events in men and women with coronary artery disease. The Stanford Coronary Risk Intervention Program (SCRIP). Circulation. 1994;89:975–90. 40. Gaede P, Vedel P, Larsen N, et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med. 2003;348:383–93. 41. Wong ND, Pio JR, Franklin SS, et al. Preventing coronary events by optimal control of blood lipids in patients with the metabolic syndrome. Am J Cardiol. 2003;91:1421–6. 42. Meagher EA. Addressing cardiovascular disease in women: focus on dyslipidemia. J Am Board Family Practice. 2004;17:424–37. 43. Castelli WP. Epidemiology of triglycerides: a view from Framingham. Am J Cardiol. 1992;70:3H-9H. 44. Carr MC, Kim KH, Zambon A, et al. Changes in LDL density across the menopausal transition. J Investig Med. 2000;48:245–50. 45. Bass KM, Newschaffer CJ, Klag MJ, et al. Plasma lipoprotein levels as predictors of cardiovascular death in women. Arch Intern Med. 1993;153:2209–16. 46. Mosca L, Appel LJ, Benjamin EJ, et al. Evidence-based guidelines for cardiovascular disease prevention in women. Circulation. 2004;109:672–93.

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47. Shlipak MG, Simon JA, Vittinghoff E, et al. Estrogen and progestin, lipoprotein(a), and the risk of recurrent coronary heart disease events after menopause. JAMA. 2000;283:1845–52. 48. Pearson TA, Laurora I, Chu H, et al. The Lipid Treatment Assessment Project 9 L-TAP): a multicenter survey to evaluate the percentages of dyslipidemic patients receiving lipid-lowering therapy and achieving low-density lipoprotein cholesterol goals. Arch Intern Med 2000;160:459–67.

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Chapter 7

Drugs for Treatment of Blood Lipoprotein Abnormalities William Virgil Brown and Charles Harper

More than 50 years ago, it was recognized that the blood plasma concentrations of cholesterol associated with low-density lipoproteins (LDL-C) have a strong predictive relationship with the incidence of clinical events attributable to arteriosclerotic cardiovascular disease.1–4 This led to recognition that dietary change could produce effective reductions in this group of lipoproteins, but often this has not lead to optimal concentrations of LDL-C. This is particularly true of patients with genetically determined elevations in LDL such as those with familial hypercholesterolemia. The observation that estrogen, thyroid hormone, niacin, and ﬁbrates reduced blood cholesterol led to initial studies designed to prevent recurrence of myocardial infarction, and the niacin and ﬁbrate treatments gave evidence of success.5 With the introduction of bile acid sequestrants, trials in persons with high LDL-C demonstrated that the incidence of the ﬁrst clinical evidence of coronary artery disease (CAD) could be reduced. Community studies in the 1970s demonstrated that there was a strong correlation of reduced concentrations of high-density lipoprotein cholesterol (HDL-C) and higher prevalence and incidence of CAD.1,2 Subsequently, the combination of low HDL-C and higher triglyceride concentrations was recognized to confer increased risk even when the LDL-C was within a desirable range. These studies led to the development of guidelines for medical intervention on the blood lipoprotein concentrations, with a particular emphasis on initially evaluating total CVD risk based on all risk factors and then targeting a lower concentration of LDL-C appropriate to this total risk.6 More recently, the existence of higher triglyceride levels produced by persistent remnants of very-low-density lipoproteins (VLDLs) and chylomicrons has led to new targets based on the cholesterol in the combination of all lipoproteins other than HDL.7 This so-called non-HDL-C is particularly applicable when triglyceride levels are above approximately 200 mg/dL. Drugs that lower LDL-C are most commonly used by clinicians and include statins, ezetimibe, and niacin, and to a lesser degree the bile acid sequestrants and ﬁbrates are used for this purpose. When triglycerides are elevated, ﬁbrates, niacin, and preparations of fats containing omega-3 fatty acids are useful. Often combining these latter agents with statins provides a very powerful regimen for both plasma triglyceride and LDL-C modiﬁcation.

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Inhibitors of Cholesterol Synthesis Statins Background Mevinolin, the ﬁrst statin, was discovered during the search for a small molecule that would inhibit 3-hydroxyl-3-methyl glutaryl–coenzyme-A (HMG Co-A) reductase, the rate-limiting enzyme in the complex pathway of cholesterol synthesis.8 This compound was the product of a fungal culture, as were three subsequent compounds: lovastatin, pravastatin, and simvastatin. The latter three were developed as drugs that markedly reduce the blood plasma concentrations of LDL-C. Subsequently, synthesis of compounds modeled on the structure of these naturally occurring statins resulted in ﬁve additional drugs in this class. Mechanism of Action All current statins appear to reduce plasma lipoproteins containing apolipoprotein B (apoB) by directly binding to and inhibiting the action of HMG-CoA reductase. This reduces the synthesis of cholesterol and thereby changes the biochemistry of cholesterol balance in the cell. The major effect is to cause the increased synthesis of speciﬁc cell surface receptors for apoB, a key protein component of both LDL and VLDL.9,10 Since the concentration of these receptors on hepatocytes is the major determinant of the rate of removal of apoB-containing lipoproteins from the blood plasma, the action of statins is to markedly reduce LDL and VLDL remnants. The residence time for these particles may be reduced by more than 50% in patients treated with higher doses of the more efﬁcacious statin drugs. The binding site for the LDL receptors is on a region of apoB near the carboxyl-terminal end of the molecule. Chylomicrons contain a truncated version of apoB representing translation of only about 48% of the apoB gene due to mRNA editing in the intestinal cells. As a result, “apoB-48” does not bind to the LDL receptor. However, another protein that is a component of both VLDL and chylomicrons, apolipoprotein E (apoE), also has a high afﬁnity for this receptor, and so increasing LDL receptors can enhance the clearance of chylomicrons. Some studies have shown that statin therapy can also lead to a reduced production of VLDL particles, particularly in hypertriglyceridemic patients.11,12 Preparations Currently Available Seven drugs are currently available in some but not all countries: lovastatin, pravastatin, simvastatin, ﬂuvastatin, atorvastatin, rosuvastatin, and pitavastatin. These are all taken by the oral route as a single tablet daily. The approved dosage range in the United States is up to 80 mg/d for all but rosuvastatin (5 to 40 mg/d) and pitavastatin (1 to 4 mg/d). The average efﬁcacy in reducing LDL-C for several dosages of atorvastatin, pravastatin, simvastatin, and rosuvastatin is shown in Figure 7.1,13 and the effect on triglycerides is shown in Figure 7.2. In general, doubling the dosage produces only a 5% to 7% additional reduction.14 Since approved dosages in most countries are over a 4- to 8-fold range

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Simvastatin (mg) 10 20 40 80

Pravastatin (mg) 10 20 40

–10 –20 –30

–20.1 –24.4 –29.7

–28.3

–40 –50 –45.8 –52.4 –55.0 –60 †

–36.8 –42.6 –47.8 –51.1

–35.0 –38.8 –45.8

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Figure 7.1 LDL-C reduction with various doses of statins. Comparison of LDL-C reduction with commonly used statins in a study of patients (158 to 164 with mean LDL values of 188 to 194 mg/dL in each group). Each group was treated with the dose indicated in a double-blind parallel protocol for 6 weeks. Pravastatin subsequently received approval for an 80-mg dose, but this was not tested in this study. (Reprinted from Jones PH, Davidson MH, Stein EA, et al. Comparison of the efﬁcacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR Trial). Am J Cardiol. 2003;92(2):152–60, with permission from Elsevier.)

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Atorvastatin (mg) 10 20 40 80

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LDL-C (± SE) Reduction (%)

0

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Rosuvastatin (mg) 0

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TG Reduction (%)

–5 –7.7 –8.2

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–19.8 * –23.7 ** –26.1 †

–20 –22.6

–14.8 –17.6 –18.2

–13.2

–26.8 –28.2

Figure 7.2 The efﬁcacy in reducing triglycerides in the same groups of patients from the study in Figure 7.1. The mean baseline concentration of triglycerides in each group varied from 172 to 187 mg/dL and no individual had baseline triglycerides greater than 400 mg/dL. Rosuvastatin and atorvastatin reduced triglycerides to a similar extent with any given dose, even though the reduction of LDL cholesterol was greater with rosuvastatin in this study (see Fig. 7.1). (Reprinted from Jones PH, Davidson MH, Stein EA, et al. Comparison of the efﬁcacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR Trial). Am J Cardiol. 2003;92(2):152–60, with permission from Elsevier.)

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with all of these agents, the starting dosage usually provides at least 50% of the maximum reduction achievable with the highest available strength. Pharmacology Statins are only partially absorbed by the intestine, with approximately 30% to 80% entering the blood. Glucuronidation by the microsomal enzymes uridine diphospho-glucuronosyl transferase (UGT) 1A1 and UGT 1A3 in the intestine and liver produces metabolic products that increase transport across cell membranes, including both that of the basal intestinal cell and the hepatocytes.15 Most of the absorbed statin dose is cleared from the portal blood on the ﬁrst pass through the liver, but the fractional clearance ranges from more than 90% with simvastatin to 60% with pitavastatin. The uptake by the liver is dependent on organic anion transport protein I (OATP I). Genetic variants of this transport system exist in a signiﬁcant portion of the population, and individuals with defective OATP I appear to be more susceptible to the very uncommon but serious adverse effect of rhabdomyolysis.16 Drugs that inhibit the oxidation of the statin by cytochrome p450–3A4 can increase the potential toxicity of statins. This is particularly true of lovastatin, simvastatin, and atorvastatin. Pravastatin and rosuvastatin are not subject to metabolism by the p450–3A4 system.17 Gemﬁbrozil inhibits the glucuronidation of most statins by competing with statin drugs for the glucuronidation process, while fenoﬁbrate has a minimal effect on statin metabolism. As a result, gemﬁbrozil can signiﬁcantly increase the peripheral blood concentration of most statins. Fluvastatin is an exception and can be a useful drug in combination with gemﬁbrozil since it does not compete with gemﬁbrozil for glucuronidation.15 Efﬁcacy The early statins (lovastatin and pravastatin) could achieve an average reduction of LDL-C of approximately 30% to 35% with the highest dosage levels (80 mg/d). Simvastatin provided a signiﬁcant increase in efﬁcacy, reaching average reductions in LDL-C of approximately 40%.14 All three are more effective if taken in the evening. With atorvastatin at 80 mg/d and rosuvastatin at 40 mg/d, mean LDL reductions of 50% to 55% were achieved in groups of hypercholesterolemic patients. The latter two drugs are also more effective in reducing triglycerides, and rosuvastatin is more consistent in raising HDL cholesterol concentrations.13 None of the drugs in this class reduce Lp(a). Adverse Effects The one serious adverse effect of statin therapy relates to myopathy. Rhabdomyolysis occurs in approximately one patient per 100,000 personyears of exposure in large-scale clinical trials with placebo controls.18 This syndrome usually appears with rapid onset of weakness as a major symptom. This is a medical emergency, and the patient needs immediate hospitalization with appropriate therapy to prevent renal failure and severe muscle degradation. Myalgias and other muscle complaints have been attributed to statins, but when the incidence is systematically recorded in long-term double-blind placebocontrolled trials, the incidence of subacute or chronic musculoskeletal pain

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Inhibitors of Sterol Absorption

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has been identical in both treated and control groups.18 Chronic and recurrent myalgias should be evaluated by the physician and not simply attributed to statin therapy. This includes patients with reproducible elevations of creatinine phosphokinase in the range of 2 to 10 times the upper limit of normal, since many muscle disorders can produce these ﬁndings. Elevations of the hepatic enzymes alanine amino-transferase (ALT) and aspartate amino-transferase (AST) occur in 0.5% to 4% of patients treated with statins. This response is dose-related, but to date it has not been associated with signiﬁcant hepatic damage. The prevalence of serious liver disease in statin-treated patients is not distinguishable from that in the general population.19 A transient peripheral neuropathic syndrome has been reported but appears to be extremely rare and of questionable relationship to the statin, since many neuropathies occur spontaneously and are described with similar properties that have other etiologies.20 Age, low body mass index, and chronic renal or hepatic disease are considered risk factors for statin myopathy. The use of other drugs should be considered as providing a potential for interaction. The clinician should always evaluate the potential for drug inhibition of CYP 3A4 or the speciﬁc glucuronosyl transferase enzymes.

Bile Acid Sequestrants Background The fact that a signiﬁcant portion of cholesterol in the liver is converted to bile acids and excreted in the stool led to the idea of attempting to enhance this pathway to potentially reduce blood cholesterol.21,22 Cholestyramine, colestipol, and more recently colesevelam are examples of resins that bind bile acids. These have been prepared in a pharmacologically acceptable format and have shown efﬁcacy in reducing LDL-C. Cholestyramine, in large placebo-controlled trials, was associated with reduced vascular disease events in hypercholesterolemic men.4 Colestipol, when combined with other lipid-modifying drugs, has also reduced vascular lesions.23,24 Mechanism of Action Bile acids solubilize cholesterol and other lipophilic compounds in the bile and allow their transport into the intestinal lumen for potential excretion. The bile acids also interact with dietary fats, converting them into particles known as micelles that provide for lipase action and absorption of cholesterol and other digested fats by the enterocyte. In the distal ileum, organic anion transporters facilitate reabsorption of most bile acids for return to the liver in the portal blood and then resecretion in bile. The loss of bile acids in the stool provides a major route of sterol excretion from the body. The introduction of several grams of the bile acid binding resins (BAS) each day can double or triple the normal loss of the various bile acids. The reduced return of these compounds

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to the hepatocyte activates the oxidative system that converts cholesterol to bile acids, thereby reducing hepatocyte cholesterol content. This in turn stimulates LDL receptors and hence the enhanced clearance of LDL from blood.21,22 Preparations Currently Available Cholestyramine, colestipol, and colesevelam have similar properties and provide equivalent LDL reduction when used in maximum dosages. All are available in a dry powder form that requires suspension in aqueous media for oral administration. These may contain various ﬂavoring additives, and some contain sucrose or other sweeteners to make the granular texture more palatable. Colestipol and colesevelam are also available in encapsulated formulations for more convenient administration. All require dosages of several grams per day. Colesevelam has more potent binding characteristics and the dose is approximately one-tenth the mass of the other two agents. Dosage Range Cholestyramine is available in doses of 4 g of active agent but may contain up to 5 g of sucrose. For colestipol the recommended dose is 5 g. Six doses of either is the recommended maximum total daily dosage. One-gram capsules are also available. Colesevelam is supplied as 625-mg capsules or in the powder form. As with the other agents in this class, six doses is the maximum recommended. Efﬁcacy Taken with meals at least twice daily, the full dosage of these BAS agents can produce a reduction of LDL-C of approximately 30% (Figure 7.3).25 A 10% reduction may be achieved with a single dose given with the largest meal of the day. It is probably used most often to enhance LDL-C reduction in combination

The STELLAR Trial Change in LDL-C From Baseline (%) 0

–5

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–25

–30

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–45

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–50 20 mg **

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–55

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10 mg 10 mg

20 mg 20 mg

40 mg

40 mg

80 mg

Simvastatin Pravastatin

STELLAR = Statin Therapies for Elevated Lipid Levels Compared Across Doses to Rosuvastatin.

*P<.002 vs atorvastatin 10 mg; simvastatin 10, 20, 40 mg; pravastatin 10, 20, 40 mg. **P<.002 vs atorvastatin 20, 40 mg; simvastatin 20, 40, 80 mg; pravastatin 20, 40 mg. †P<.002 vs atorvastatin 40 mg; simvastatin 40, 80 mg; pravastatin 40 mg.

Figure 7.3 Percentage change in LDL-C: pairwise comparison with rosuvastatin 10 mg. Source: Adapted from Jones PH, Davidson MH, Stein EA, et al. STELLAR Study Group. Comparison of the efﬁcacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR trial). Am J Cardiol 2003;92(2):152–60.

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Ezetimibe Background Ezetimibe is an inhibitor of cholesterol absorption at the luminal surface of the intestinal cell. The discovery of ezetimibe greatly facilitated the initial description of the Niemann Pick type C-1 like protein-1 (NPC-1 L-1),29 which is the major pathway of intestinal cholesterol absorption.

Treatment of Blood Lipoprotein Abnormalities CHAPTER 7

Adverse Effects BAS are not absorbed, although some adverse effects can occur. Bile acids in the colon have a natural laxative effect and therefore their removal may lead to constipation.26 Adding ﬁber to the diet usually eliminates this problem. BAS can also adsorb other negatively charged compounds such as thyroid hormone, digitalis, and other drugs. Such drugs should be taken at least 1 hour before or 4 hours after the BAS dose. In the liver, the reduced bile acid concentration can activate triglyceride synthesis, with a signiﬁcant elevation in plasma triglyceride concentrations for those with elevated triglycerides.27 A very high triglyceride concentration (over 400 mg/dL) is thus a relative contraindication.28 This is of no consequence in patients with normal baseline triglycerides. The “mouth feel” of the powdered formulations is similar to sand, and this can cause a compliance problem. Mixing the dose with a soluble ﬁber and with fruit juice reduces this problem.

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with a statin. Some physicians prefer this for children since there is implied safety with a drug that is not absorbed systemically.

Mechanism of Action Ezetimibe, given in doses of 10 mg in humans, causes a reduction in absorption of cholesterol of approximately 50%. As little as 0.25 mg can produce a 25% reduction in cholesterol absorption. This drug has been found to bind speciﬁcally to the NPC-1 L-1, which is localized in the luminal membrane of the enterocyte.29 The inhibition of cholesterol absorption reduces dietary cholesterol transport into the blood plasma by reducing its incorporation into chylomicrons. Since most of the cholesterol in the chylomicron remnant produced by lipoprotein lipase action remains with the residual particle until clearance by the liver, most of the absorbed cholesterol is delivered to the hepatocytes. By reducing cholesterol delivery to the liver, the response is similar to that achieved with hepatic cholesterol reduction by statins, namely to induce the synthesis of LDL receptors and the enhanced clearance of LDL from the plasma. The NPC-1 L-1 protein transports phytosterols as well as cholesterol. The normal enterocyte rejects these phytosterols through reverse transport into the intestinal lumen through the action of the ABC-G5 and ABC-G8 complex. However, some absorption of these sterols does occur even in the normal intestine, resulting in extremely low plasma concentrations, which appear to do no harm. However, genetic defects in the ABC-G5/ABC-G8 proteins can lead to a relatively large absorption with consequent arteriosclerosis and xanthomas in skin and tendons in a disorder known as phytosteroemia. Ezetimibe is a speciﬁc treatment for this disorder since it inhibits both plant sterol and cholesterol absorption.

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Pharmacology Ezetimibe is readily absorbed, with glucuronidation occurring in the intestinal cell and in the liver. The glucuronide is readily transported across cell membranes and is excreted rapidly in the bile.30 This creates a very active entero-hepatic cycle that returns the drug repeatedly to its site of action in the enterocyte membrane. The half-life of ezetimibe is approximately 18 hours, and therefore a single daily dose is adequate for full effect. In animal models, most of the agent is found in the intestinal lumen awaiting binding to the NPCL-1 protein or for excretion in the stool. Dosage Range It is provided as a single 10-mg tablet for oral use once daily.31 Efﬁcacy Ezetimibe reduces LDL-C by approximately 16% to 20% in studies of patient groups. In some the effect is much less, but other patients are more responsive, with an occasional patient showing up to 50% reduction in LDL-C. The reason for this variability is not established. The efﬁcacy on LDL reduction is additive to that with statins.32 In patients with phytosterolemia due to genetic defects in the ABC-G8/ ABC-G8 transporter, the high plasma concentrations of the phytosterols have been shown to fall continuously over several months. This appears to be the only effective treatment for this very rare disorder. Adverse Effects There have been no speciﬁc adverse effects demonstrated with this drug.33,34 Phytosterols Background The sterols that are part of plant cell membranes differ only slightly in structure from cholesterol, and these phytosterols can interfere with cholesterol absorption when given orally in gram amounts. These are more effective when esteriﬁed with long-chain fatty acids. The plant sterols are present in two major classes, phytosterols and phytostanols. The sterols have a double bond in the ﬁrst ring of the sterol structure, whereas this is reduced in the stanols. The major components of phytosterol extracts are beta-sitosterol, campesterol, and ergosterol. Although both classes of compounds occur naturally, the stanols appear to have greater efﬁcacy in reducing the intestinal absorption of cholesterol than the phytosterols.35 Furthermore, a lower percentage of stanols are absorbed with chylomicrons. Recently, the generation of stanols by chemical reduction of the phytosterol ring has generated a preparation that has been made available for use as a food additive. Mechanism of Action Both phytosterols and phystanols form micelles with bile acids, cholesterol, and phospholipids in the intestine. The absorption of cholesterol from these mixed micelles is reduced when they contain plant sterols and stanols. The exact mechanism of this action is not understood.

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Adverse Effects No speciﬁc adverse effects have been described in patients with normal plant sterol absorption and excretion.

Treatment of Blood Lipoprotein Abnormalities

Efﬁcacy Two to three grams per day of plant sterols produce a 5% to 10% reduction in LDL if taken in conjunction with a diet low in cholesterol and saturated fat. Studies without dietary modiﬁcation have reported greater responses in LDL reduction.

CHAPTER 7

Dosage Range The effective dosage of phytosterols and phytostanols is 2 to 6 g/d. Most of the effect is evident at 2 to 3 g/d as a food additive, and this has been the recommended dose.37

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Preparations Currently Available Vegetable oils and a variety of vegetable products such as bran can be rich sources of phytosterols.36 Rice bran and corn oil contain approximately 1 g per 100 g of oil; peanut and olive oils contain about 200 mg and coconut and palm oils only 50 mg per 100 g. Nuts and some legumes, such as beans and peas, are also rich sources, containing approximately 100 mg per 100 g. Isolated phytosterols have been prepared as food additives and are available from many suppliers as oils or capsules or incorporated into products such as fat spreads, mayonnaise, and salad dressing. Phytostanols, prepared by hydrogenation, are also available in similar preparations.

Contraindications Patients with genetic defects in the ABC-G5/ABC-G8 transporter are likely to have an accelerated absorption of the phytosterols, and acceleration of the vascular and other consequences would be expected.

Triglyceride-Reducing Drugs Fibrates Background Cloﬁbrate was the ﬁrst compound in this class. However, cloﬁbrate is not available in most of the world due to the negative ﬁndings of the World Health Organization Study.38 Greater efﬁcacy and possibly safety was demonstrated with other similar derivatives of cloﬁbrate, and several of these latter compounds are used clinically for treatment of hypertriglyceridemia. Two large clinical trials have demonstrated reduction in the incidence of myocardial infarction (MI) or death from coronary heart disease (CHD). The ﬁrst of these, the Helsinki Heart Study, involved the treatment of middle-aged men who had no evidence of vascular disease but whose cholesterol in LDL and VLDL (non-HDL-C) was over 200 mg/dL.39 This study demonstrated a 34% reduction in these events in approximately 5 years of follow-up. The second positive trial was performed in men with known heart disease whose LDL-C

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was less than 130 mg/dL and HDL-C was less than 40 mg/dL. A 22% reduction in MI and CHD death was observed after 5 years.40 Other major studies, such as the WHO study, the Field study, and ACCORD, failed to demonstrate beneﬁt.41,42 However, these trials did not select patients with lipid disorders that involve signiﬁcant hypertriglyceridemia and low HDL. It is subgroups with the latter lipoprotein disorders that have consistently shown evidence for reduction in vascular events. Mechanism of Action Fibrates activate and inhibit a series of genes through binding to a nuclear receptor, peroxisomal proliferator activated receptor alpha (PPAR-A).43 The major effects include inhibiting hepatic synthesis of triglyceride and altering the protein composition of VLDL and chylomicrons by reducing the synthesis of apoCIII and by inducing the synthesis of lipoprotein lipase.44 There is also increased synthesis of the major structural proteins of HDL, apoAI, and apoAII. The net effect is an increase in clearance of triglyceride-rich lipoproteins and a rise in HDL particles.45 Preparations Currently Available Gemﬁbrozil, fenoﬁbrate, and fenoﬁbric acid are available in the United States and much of Europe and Asia. Bezaﬁbrate, ciproﬁbrate, and etoﬁbrate are other available drugs in this class. Dosage Range Gemﬁbrozil is usually given twice daily as a 600-mg tablet. Fenoﬁbrate is administered at 135 to 200 mg as a single dose depending on the formulation. Some contain various additives that affect the intestinal absorption, which determines the dose per tablet. Lower doses are available (45 to 54 mg) for use primarily in patients with liver or renal disorders. Efﬁcacy The recommended doses of the ﬁbrates produce similar effects on fasting concentrations of plasma lipoproteins. The triglyceride concentrations are reduced from 20% to 70%, with greater efﬁcacy observed in patients with higher triglycerides. HDL-C may show no change, but in patients with triglyceride concentrations in the range of 300 mg/dL or higher, a 20% increase is not unusual.46 LDL cholesterol may be reduced by 20% or more when triglyceride concentrations are less than 150 mg/dL but may not change or even rise in hypertriglyceridemic individuals. It is interesting that there is often a decline in the number of LDL particles and a signiﬁcant increase in the cholesterol content per particle with ﬁbrate treatment. Adverse Effects Fibrates have generally been very safe. They are associated with an increase in the activity of ALT and AST in plasma and rarely rhabdomyolysis. The latter is usually in a setting with other drugs associated with myopathy such as statins. All ﬁbrates increase cholesterol excretion in bile that may exceed the amounts of bile acid required to keep this cholesterol in micellar solution. This can in theory lead to increased biliary stone formation.47 Creatinine levels may rise by

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Background Niacin was demonstrated to reduce total plasma cholesterol levels over 50 years ago. This was found to be due to reduction in LDL and VLDL cholesterol accompanied by a signiﬁcant increase in HDL-C. The initial preparations were simply tablets of crystalline niacin, and they were tested in the Coronary Drug Project published in 1975.49 This study compared men with previous MI assigned randomly to placebo (n = 2,789) or niacin (n = 1,119) at a dosage of approximately 3 g/d. The latter had a 48% reduction in coronary artery bypass procedures during a 5-year period and a 22% reduction in recurrent MI. Since that time, multiple studies have demonstrated that niacin in combination with BAS or statins can reduce both the incidence of clinical events and the rate of progression of arterial lesions. Mechanism of Action There is evidence in animals and humans that niacin is active in the liver to reduce VLDL secretion, but its major effect on blood triglyceride concentrations seems to be an enhancement in clearance. Less LDL may be generated due to the lower conversion of VLDL to LDL, but there is also increased clearance of LDL particles.50 The cholesterol content of each LDL particle may actually increase. HDL elevation is also produced by complex mechanisms. The uptake and degradation of HDL particles is retarded but the transfer of HDL-C to the liver is not reduced.51 There is also recent evidence that the ABC-A1 transporter that loads cholesterol into HDL from cell surfaces is increased. In theory, this could improve the transport of cholesterol from peripheral tissues to the liver.

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Niacin

CHAPTER 7

Contraindications Fibrates are contraindicated in patients with signiﬁcant liver disease or renal disease. Lower doses should be considered in patients with moderately severe disease.

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10% to 20%, but this appears to be without structural damage to the kidney, since creatinine levels return to normal when the drugs are discontinued, even after years of therapy.48

Preparations Currently Available There are multiple suppliers of niacin tablets in doses ranging from 50 to 500 mg. These need to be taken in multiple doses totaling 1,000 to 3,000 mg/d to achieve maximal effect without intolerable ﬂushing due to vasodilatation in the skin. Delayed-release formulations in the 250- and 500-mg doses are also available. These markedly slow absorption, reduce ﬂushing, and can be taken once or twice daily. A newer preparation referred to as “extended-release” niacin (Niaspan) uses porous capsules with the niacin in a gel formulation that allows release over several hours. This is available in 500-mg, 750-mg, and 1-g capsules. These preparations can be taken as a single dose or twice daily and have markedly reduced the incidence and severity of the ﬂushing reaction.52

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Dosage Range The most tested and most commonly used dose is 2 g of extended-release niacin. Very little effect is observed with any niacin preparation at a dosage of below 1 g/d in most patients. There is beneﬁt in increasing the dosage to 3 g/d in some patients with severe triglyceride elevations. Efﬁcacy In patients with triglyceride concentrations between 150 and 500 mg/dL, the average reduction of this lipid will be 30% to 50%. LDL-C usually falls by 15% to 25% and HDL increases 25% to 30%.53 Niacin is unique among available lipidlowering drugs in reducing lipoprotein(a) by 25% to 30% as well.54 This effect is thought to be beneﬁcial since lipoprotein(a) is associated with increased risk when elevated above approximately 30 mg/dL. However, no study has tested this hypothesis directly. Adverse Effects The majority of patients given oral niacin will experience cutaneous ﬂushing reactions. In general these are described as an unpleasant feeling of warmth occasionally accompanied by pruritus. They usually last 15 to 60 minutes. In patients taking antihypertensive drugs, the cutaneous vasodilatation can cause a signiﬁcant drop in blood pressure. Flushing usually occurs within 1 to 6 hours of the dose.55 The newer, extended-release forms have reduced the severity of this reaction as well as the incidence. Approximately half of patients experience occasional ﬂushing, but with these preparations they usually disappear within the ﬁrst few weeks. We now understand the mechanism of this reaction and can use that understanding in its management. Niacin directly binds to a receptor on the membrane of Langerhans cells in the skin. These cells are particularly adapted to release prostaglandin D2, and when activated, the niacin receptor causes a release of this hormone. In the immediate environment of the dermis are smooth muscle cells that provide regulation of skin blood ﬂow by maintaining tone in resistance arterioles.56 The prostaglandin causes an immediate relaxation of these cells, allowing a marked increase in blood ﬂow within the skin. The prostaglandin is synthesized by cyclo-oxygenase enzymes in the Langerhans cells, and the amount of this hormone can be reduced by cyclo-oxygenase inhibitors such as aspirin. Most patients who follow a few basic procedures will ﬁnd that ﬂushing is a manageable problem. We suggest educating patients to: (1) Expect a few ﬂushing reactions; (2) Begin with a dose of no more than 500 mg and take it with food twice daily (e.g., breakfast and dinner); (3) Increase the dose to 1 g twice daily after one month; (4) Take 325-mg aspirin tablets twice daily for the ﬁrst 2 months;57 (5) Avoid hot liquids and strong alcoholic beverages immediately after taking the tablets; and (6) Maintain very regular adherence to the regimen; skipping doses is associated with return of the ﬂushing reactions. A new drug that blocks the receptor for prostaglandin D2 is in clinical trials and may provide an additional tool for further reducing this problem. Liver enzyme elevations (ALT and AST) have been reported with niacin, but these appear to be much more common with over-the-counter formulations,

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Omega-3 Fatty Acid Esters Background For more than 30 years, the oil from fatty ﬁsh has been known to reduce plasma triglycerides. This is particularly evident in patients with very high triglycerides (over 500 mg/dL).61 This effect was attributed to the long-chain polyunsaturated fatty acids with double bonds beginning at the third carbon atom from the terminal methyl group—so-called omega-3 fatty acids. From ﬁsh oil, these are eicosapentaenoic acid (20:5, omega-3) and docosahexaenoic acid (22:6, omega-3). Many studies have demonstrated that a rather speciﬁc effect on the reduction of VLDL and chylomicron triglyceride concentrations occurs without signiﬁcantly changing LDL or HDL particle numbers. Two major trials have demonstrated that small dosages of 0.85 to 1.8 g/d of omega-3 fats can reduce the incidence of total mortality and sudden cardiac death. This effect may be conﬁned to patients who already have clinically evident CHD, however.62,63 This beneﬁt does not appear to be related to lipid or lipoprotein modiﬁcation and remains unexplained.

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Contraindications Niacin is contraindicated in patients with severe liver disease, renal failure, and inﬂammatory skin conditions.

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particularly those with various additives to slow adsorption.58 A rare case of severe liver damage has been reported with such preparations, but the tested formulations approved by the FDA for prescription use rarely if ever have been associated with signiﬁcant liver disease. Uric acid elevations can be a problem in patients who have elevated levels at baseline, and induction of gout has been documented in clinical trials.59 Chronic pruritus can be a difﬁcult problem in some people. Other preexisting inﬂammatory disorders can be made worse, including gastritis or peptic ulcer disease. Niacin is rarely associated with hypophosphatemia since it is known to reduce absorption of phosphate by the intestine. Other rare adverse effects include retinal edema and reduced platelets. The former can produce blurring of vision, but this clears with discontinuation of the drug. The reduction in platelets is usually mild and to our knowledge has not produced a bleeding diathesis.60

Mechanism of Action Animal and human experiments indicate that the major effect of administering polyunsaturated fatty acids (omega-3 and omega-6) is that they provide substrates for the synthesis of a large series of chemical compounds that have both anti-inﬂammatory and pro-inﬂammatory effects.64 These include eicosanoids (thromboxanes, prostacyclins, and leukotrienes). Those generated from the omega-6 arachidonic acid are particularly inﬂammatory and those from omega-3 fats are less so. The competition may be important in certain reactions. However, the more recent discovery of anti-inﬂammatory products of omega-3 fatty acids such as the resolvins and the omega-3-oxylipins has added another layer of complexity in attempting to understand the regulation of inﬂammation and its modiﬁcation by these dietary compounds.

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The reduction of plasma triglycerides is in great part due to reduced triglyceride synthesis in the liver. This is thought to be attributable to the inhibition of a rate-limiting enzyme, 1,2-diacyglycerol acyltransferase, in triglyceride synthesis.65 Some evidence indicates that an increase in lipoprotein lipase may also contribute to reduction of triglyceride-rich lipoproteins. Preparations Currently Available There are many suppliers of over-the-counter ﬁsh oil preparations containing from approximately 30% to more than 60% omega-3 fat by weight. One prescription formulation is available as omega-3-acid ethyl esters. This is prepared by hydrolyzing the various glycerol esters in ﬁsh oil, concentrating the EPA and DHA, and then re-esterifying these to ethanol. This medication is supplied in capsules containing 1-g doses of the ethyl esters, which are approximately 90% omega-3 fatty acid esters by weight. A signiﬁcant amount of fat containing long-chain omega-3 fatty acids can be obtained from consuming certain ﬁsh. The quantities of these, in grams per 3-oz serving of popular ﬁsh, are published and can amount to 1 to 2 g.66 Dosage Range The dosages used in large clinical trials and studies of effects on various physiological systems such as platelet aggregation have led the American Heart Association to recommend consumption of at least 12 ounces of fatty ﬁsh per week, and for patients with known CHD, supplements containing 1 g/day of omega-3 fatty acids as part of a healthy diet.67 Studies demonstrating signiﬁcant reductions in the blood triglyceride concentrations in patients with very high levels have used ﬁsh oil at 6 to 12 grams or more daily, or sufﬁcient oily ﬁsh such as salmon to provide this dose. The recommended dose of omega-3-acid ethyl ester for treating high plasma triglycerides is four (1-g) capsules daily.68 Efﬁcacy Studies in patients with triglyceride levels over 500 mg/dL, using approximately 4 g/day of EPA and DHA, have demonstrated a 40% to 50% reduction in fasting triglyceride and VLDL cholesterol concentrations. LDL-C will frequently increase by 5% to 15% but the apoB concentration usually does not change, suggesting that the cholesterol per LDL particle has increased without an increase in particle number. Similarly, HDL-C may increase by 5% to 15% but there is usually no signiﬁcant increase in apoAI.68 Adverse Effects Some patients note increased eructation, an annoying ﬁshy taste, and a ﬁshy odor to their breath after taking preparations of ﬁsh oil. These effects can be a problem for adherence but offer no health risks. The eicosanoids and prostanoids produced by omega-3 fatty acids inhibit platelet activation and aggregation and prolong bleeding time. Therefore, caution must be used in patients taking anticoagulants such as warfarin or antiplatelet drugs such as aspirin or clopidogrel. There are no known signiﬁcant interactions with lipid-lowering drugs. High doses of omega-3 fats have not been studied in pregnant women or young children.69

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1. Wilson PWF, D’Agostino RB, Levy D, et al. Prediction of coronary heart disease using risk factor categories. Circulation. 1998;97:1837–47. 2. Stamler J, Wentworth D, Neaton JD, for the MRFIT Research Group. Is relationship between serum cholesterol and risk of premature death from coronary heart disease continuous and graded? Findings in 356222 primary screenees of the Multiple Risk Factor Intervention Trial (MRFIT). JAMA. 1986; 256:2823–8. 3. Lipid Research Clinics Program. The Lipid Research Clinics Coronary Primary Prevention Trial results. II: The relationship of reduction in incidence of coronary heart disease to cholesterol lowering. JAMA. 1984;251:365–74. 4. Stamler J. The Coronary Drug Project: ﬁndings with regard to estrogen, dethyroxine, cloﬁbrate, and niacin. Adv Exp Med Boil. 1977;82:52–75. 5. Lipid Research Clinics Program. The Lipid Research Clinics Coronary Primary Prevention Trial results: reduction in the incidence of coronary heart disease. JAMA. 1984;251:351–64. 6. National Cholesterol Education Program. Second report of the expert panel on detection, evaluation, and treatment of high blood cholesterol in adults. NIH Pub. No. 93–3095. Bethesda, MD: National Heart, Lung, and Blood Institute, 1993; 180 pages. 7. Grundy SM, Cleeman JI, Merz CN. National Heart, Lung, and Blood Institute; American College of Cardiology Foundation; American Heart Association. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110:227–39. 8. Endo A, Kuroda M, Tsujita Y. ML-236A,ML-236B, and ML-236C, new inhibitors of cholesterogenesis produced by Penicillium citrinum. J Antibiot (Tokyo). 1976;29:1346–8. 9. Tobert JA, Bell GD, Birtwell J, et al. Cholesterol-lowering effect of mevinolin, an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, in healthy volunteers. J Clin Invest. 1982;69:913–9. 10. Bilheimer DW, Grundy SM, Brown MS, Goldstein JL. Mevinolin and Colestipol stimulate receptor-mediated clearance of low density lipoprotein from plasma in familial hypercholesterolemia heterozygotes. Proc Natl Acad Sci USA. 1983;80:4124–8. 11. Vega GL, Grundy SM. Management of primary mixed hyperlipidemia with lovastatin. Arch Intern Med. 1990;150:1313–9. 12. Broyles FE, Walden CE, Hunninghake DB, et al. Effect of ﬂuvastatin on intermediate density lipoprotein (remnants) and other lipoprotein levels in hypercholesterolemia. Am J Cardiol. 1995;76:129A-35A. 13. Brewer HB. Beneﬁt-risk assessment of rosuvastatin 10 to 40 mg. Am J Cardiol. 2003;92:23K–9K. 14. Jones P, Kafonek S, Laurora I, Hunninghake D. Comparative dose efﬁcacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and ﬂuvastatin in patients with hypercholesterolemia. Am J Cardiol. 1998;81:582–7.

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Contraindications Allergic reactions to ﬁsh products or signiﬁcant disorders of platelet function or other bleeding disorders should be considered contraindications.69

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15. Prueksaritanont T, Zhao JJ, Ma B, et al. Mechanistic studies on metabolic interactions between gemﬁbrozil and statins. J Pharmacol Exp Ther. 2002;301:1042–51. 16. Group SC, Link E, Parish S, et al. SLCO1B1 variants and statin-induced myopathy—a genomewide study. N Engl J Med. 2008:359:789–99. 17. Harper CR, Jacobson TA. The broad spectrum of statin myopathy: from myalgia to rhabdomyolysis. Curr Opin Lipidol. 2007;18:401–08. 18. Law M, Rudnicka AR. Statin safety: a systematic review. Am J Cardiol. 2006:97:52C-60C. 19. Hsu I, Spinler SA, Johnson NE. Comparative evaluation of the safety and efﬁcacy of HMG-CoA reductase inhibitor monotherapy in the treatment of primary hypercholesterolemia. Ann Pharmacother. 1995;29:743–59. 20. McKenney JM, Davidson MH, Jacobson TA, Guyton JR, National Lipid Association Statin Safety Assessment Task Force. Final conclusions and recommendations of the National Lipid Association Statin Safety Assessment Task Force. Am J Cardiol. 2006;97:89C-94C. 21. Rudling MJ, Reihner E, Einarsson K, et al. Low density lipoprotein receptorbinding activity inhuman tissues: quantitative importance of hepatic receptors and evidence for regulation of their expression in vivo. Proc Natl Acad USA. 1990;87:3469–73. 22. Beil U, Crouse JR, Einarsson K, Grundy SM. Effects of interruption of the enterohepatic circulation of bileacids on the transport of very low density lipoprotein triglycerides. Metabolism. 1982;31:438–44. 23. Blankenhorn DH, Nessim SA, Johnson RL, et al. Beneﬁcial effects of combined colestipol-niacin therapy on coronary atherosclerosis and coronary venous bypass grafts. JAMA. 1987;257:3233–40. 24. Brown G, Albers JJ, Fisher LD, et al. Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B. N Engl J Med. 1990;323:1289–98. 25 Bays HE, Goldberg RB. The ‘forgotten’ bile acid sequestrants: is now a good time to remember? Am J Ther. 2007;14(6):567–80. 26. Davidson MH, Dillon MA, Gordon B. Colesevelam hydrochloride: a new, potent bile acid sequestrants associated with a low incidence of gastrointestinal side effects. Arch Intern Med. 1999;159:1893–1900. 27. Knopp RH. Drug treatment of lipid disorders. N Engl J Med. 1999;341:498–511. 28. Crouse JR III. Hypertriglyceridemia: a contraindication to the use of bile acid binding resins. Am J Med. 1987;83:243–8. 29. Gsrcia-Calvo, Lisnock J, Bull HG. The target of ezetimibe is Niemann-Pick C1-Like 1 (NPC1L1). Proc Natl Acad Sci USA. 2005;102:8132–37. 30. van Heek M, France DF, Compton DS. In vivo metabolism-based discovery of a potent cholesterol absorption inhibitor. SCH58235, in the rat and rhesus monkey through the identiﬁcation of active metabolites of SCH48461. J Pharmacol Exp Ther. 1997;283:157–63. 31. Merck-Schering Plough Pharmaceuticals. Package insert for ZetiaTM (Ezetimibe) tablets. October 2002. 32. Dujovne CA, Ettinger MP, McNeer JF. Efﬁcacy and safety of a new potent selective cholesterol absorption inhibitor, ezetimibe, in patients with primary hypercholesterolemia. Am J Cardiol. 2002;90:1092–97.

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33. Rossebø AB, Pedersen TR, Boman K, et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med. 2008;359:1343–56. 34. Peto R, Emberson J, Landray M, et al. Analyses of cancer data from three ezetimibe trials. N Engl J Med. 2008;359:1357–66. 35. Katan MB. Efﬁcacy and safety of plant stanols and sterols in the management of blood cholesterol levels. Mayo Clin Proc. 2003;78:965–78. 36. Kritchevsky D. Phytosterols: In: Kristchevsky and Bonﬁeld, eds. Dietary Fiber in Health and Disease. New York: Plenum Press, 1997;427:235–42. 37. Hallikainen MA, Uusitupa MI. Effects of 2 low-fat stanol ester-containing margarines on serum cholesterol concentrations as part of a low-fat diet in hypercholesterolemic subjects. Am J Clin Nutr. 1999;69:403–10. 38. Report of the Committee of Principal Investigators. WHO cooperative trial on primary prevention of ischaemic heart disease with cloﬁbrate to lower serum cholesterol: ﬁnal mortality follow-up. Lancet. 1984;8403:600–04. 39. Frick MH, Elo MO, Haapa K, et al. Helsinki Heart Study: primary prevention trial with gemﬁbrozil in middle-aged men with dyslipidemia: safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med. 1987;317:1237–45. 40. Rubins HB, Robins SJ, Collins D, et al., for the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. Gemﬁbrozil for the secondary prevention of coronary heart disease in men with low levels of highdensity lipoprotein cholesterol. N Engl J Med. 1999;341:410–8. 41. Keech A, Simes RJ, Barter P. Effects of long-term fenoﬁbrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised control trial. Lancet. 2005;366:1849–61. 42. The ACCORD Study Group. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med. 2010;362:1563–74. 43. Schoonjans K, Staels B, Auwerx J. Role of the peroxisome proliferator-activated receptor (PPAR) in mediating the effects of ﬁbrates and fatty acids on gene expression. J Lipid Res. 1996;37:907–25. 44. Fruchart JC, Brewer HB Jr, Leitersdorf E. Consensus for the use of ﬁbrates in the treatment of dyslipoproteinemia and coronary heart disease. Am J Cardiol. 1998;81:912–7. 45. Vu-Dac N, Schoonjans K, Kosykh V, et al. Fibrates increase human apolipoprotein A-11 expression through activation of the peroxisome proliferatoractivated receptor. J Clin Invest. 1995;96:741–50. 46. Leaf DA, Connor WE, Illingworth DR, et al. The hypolipidemic effects of gemﬁbrozil in type V hyperlipidemia: a double-blind, crossover study. JAMA. 1989;262:3154–60. 47. Palmer RH. Effects of ﬁbric acid derivatives on biliary lipid composition. Am J Med. 1987;83(suppl 5B):37–43. 48. Hottelart C. El Esper N, Rose F. Fenoﬁbrate increases creatinemia by increasing metabolic production of creatinine. Nephron. 2002;92:536–4. 49. Coronary Drug Project Research Group. Cloﬁbrate and niacin in coronary heart disease. JAMA. 1975;231:360–81. 50. Grundy SM, Mok HYI, Zech L, Berman M. Inﬂuence of nicotinic acid on metabolism of cholesterol and triglycerides in man. J Lipid Res. 1981;22:24–36.

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51. Langer T, Levi RI. The effect of nicotinic acid on the turnover of low density lipoproteins in type II hyperlipoproteinemia. In: Gey KF, Carlson RA, eds. Metabolic Effects of Nicotinic Acid and its Derivatives. Bern, Germany: Hans Huber Publishers, 1971:641–7. 52. Kos Pharmaceuticals Inc. Niaspan (niacin extended-release) tablets prescribing information. Cranbury, NJ: 2005 Oct. 53. Mostaza JM, Schulz I, Vega GL, Grundy SM. Comparison of pravastatin with crystalline nicotinic acid monotherapy in treatment of combined hyperlipidemia. Am J Cardiol. 1997;79:1298–301. 54. Carlson LA. Hamsten A. Asplund A. Pronounced lowering of serum levels of lipoprotein Lp(a) in hyperlipidaemic subjects treated with nicotinic acid. J Intern Med. 1989;226:271–6, 198. 55. Stern RH, Spence JD, Freeman DJ, Parbtani A. Tolerance to nicotinic acid and ﬂushing. Clin Pharm Ther. 1991;50:66–70. 56. Morrow JD, Awad JA, Oates JA, Roberts LJ. Identiﬁcation of skin as a major site of prostaglandin D2 release following oral administration of niacin in humans. J Invest Dermatol. 1992;98:812–15. 57. Oberwwittler H, Baccara-Dinet M. Clinical evidence for the use of acetyl salicylic acid in control of ﬂushing related to nicotinic acid treatment. Int J Clin Pract. 2006;60:707–15. 58. Henkin Y, Oberman A, Hurst DC, Segrest JP. Rechallenge with crystalline niacin after drug induced hepatitis from sustained-release niacin. JAMA. 1990;24:241–43. 59. Gershon Sl, Fox IH. Pharmacological effects of niacin on human purine metabolism. J Lab Clin Med. 1974;84:179–86. 60. Guyton JR, Bays HE. Safety considerations with Niacin therapy. Am J Cardiol. 2007;99:22c–31c. 61. Harris WS. Fish oils and plasma lipid and lipoprotein metabolism in humans: a critical review. J Lipid Res. 1989;30:785–807. 62. Burr ML, Fehily AM, Gilbert JF, et al. Effects of changes in fat, ﬁsh and ﬁbre intakes on death and myocardial reinfarction: Diet and Reinfarction Trial (DART). Lancet. 1989;2:757–61. 63. GISSI-Prevenzione Investigators. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSIPrevenzione Trial. Lancet. 1999;354:447–55. 64. Simopoulos AP. Omega 3 fatty acids in the prevention of coronary heart disease. Am J Clin Nutr. 1999;70:560s–69s. 65. Roche HM, Gibney MJ. Effects of long-chain n-3 polyunsaturated fatty acids on fasting and postprandial triacylglycerol metabolism. Am J Clin Nutr. 2000;71(suppl):232S–7S. 66. Simopoulos AP, Robinson J. The Omega Diet. New York, NY: HarperCollins Publications Inc., 1998. 67. Kris-etherton PM, Harris WS, Appel LJ. Fish consumption, ﬁsh oil, omega-3 fatty acids, and cardiovascular disease. Circulation. 2002;106:2747–57. 68. Davidson MH. Mechanisms for the hypotriglyceridemic effect of marine omega-3 fatty acids. Am J Cardiol. 2006;98:27i–33i. 69. Bays HE. Safety considerations with omega-3 fatty acid therapy. Am J Cardiol. 2007;99:35c–44c.

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A ABCA1 (ATP-binding cassette A1), 31, 32, 33t, 34, 38, 39 ABCG1 (ATP-binding cassette G1), 31, 33t, 34–35 ABCG1 transporter, 34–35 ACE inhibitors, 1 Acute coronary syndrome (ACS), 68, 88 Adult Treatment Panel III (ATP III), 3, 4, 5, 50, 67, 75, 108, 113 Adverse effects bile acid sequestrants, 123 ﬁbrates, 126–127 ﬁsh oils, 130 oral niacin, 128 statins, 42, 120–121 torcetrapib, 42 African Americans CPR gene polymorphisms, 69 hsCRP levels, 79 non-HDL-C levels, 50, 51 AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL-C/High Triglyceride and Impact on Global Health Outcomes) study, 41 Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS), 3, 8, 9t, 13, 14, 77, 91 ALERT (Assessment of Lescol in Renal Transplantation) study, 13 Ambiguous areas alternative lipid parameters, 20 HDL-C targets, 44 HDL concentrationfunction relationship, 43 HDL subpopulations, 43 mechanisms of LDL reduction, 19–20 non-HDL-C, 57–58 protective effects of HDLs, 43

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value of apoA-I measurement, 43 American Diabetes Association/American College of Cardiology (ADA/ACC), 22, 56, 58 Amlodipine (Caduet), 14 Anacetropib, 42 Angina LDL and, 92 microvascular angina, 68 stable angina, 21 unstable angina, 9t, 10t, 21, 77 ApoA-I (apolipoprotein A), 20 ABCA1 transporter and, 34 diabetics and, 43 ﬁbrate use/increased expression of, 39 formation of, 32, 33t Framingham study recommendations, 106–107 HDL composition percentage, 31, 91–92 lipid-poor apoA-I, 30, 32 low HDL-C and, 38 overexpression in animal studies, 36, 36t plasma forms of, 30 remodeling of, 32, 33t values of measuring, 43 variant in rHDLs (in human studies), 37, 42 ApoA-II (apolipoprotein A II), 31, 39 ApoA-IMilano (apoA-I variant), 37 Apolipoprotein B-100 (apoB-100), 1–2, 57, 87, 90–92 Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6-HDL and LDL Treatment Strategies (ARBITER 6-HALTS), 17, 18, 20 ASCOT-LLA (AngloScandinavian Cardiac Outcomes Trial—LipidLowering Arm), 9t, 14, 89t Asian Americans, hsCRP levels, 79

ASTEROID (A Study to Evaluate the Effect of Rosuvastatin on Intravascular UltrasoundDerived Coronary Atheroma Burden) study, 14–15 Atherogenic dyslipidemia, 56, 60, 87, 89, 90t, 95, 111 Atherosclerosis accelerating conditions, 89 AFCAPS/TexCAPS study, 3, 8, 13, 14, 77, 91 apoA-I inhibition of, 30 apoB-100 role, 2 Cholesterol Lowering Atherosclerosis Study, 52 comorbid conditions, 2 CRP and, 20, 69 familial hypercholesterolemia and, 6 HDL protection evidence, 35, 36–37, 36t LCAS study, 13 Lipoprotein and Coronary Atherosclerosis Study, 13 Multi-Ethnic Atherosclerosis Study, 96 non-HDL and, 51–52, 60 REVERSAL trial, 14 role of LDL-C, 2 testing, 87 treatment strategies, 8, 41–42 Atherothrombosis Intervention in Metabolic Syndrome with Low HDL-C/High Triglyceride and Impact on Global Health Outcomes (AIMHIGH) study, 41 Atorvastatin (Lipitor), 1, 4, 8, 9t, 10t–12t, 14–15, 17, 40, 42, 78, 118, 119, 120, 122

135

Index

B Bezaﬁbrate, 126 Bile acid sequestrants (BAS), 16–17, 121–123. See also cholestyramine; colesevelam; colestipol adverse effects, 123 background, 121 for CAD, 117

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INDEX

combinations, 22 dosage range, 122 efﬁcacy, 122–123 mechanism of action, 121–122 BMI (body mass index), 29, 49, 51–52, 70, 88, 109–110 Bogalusa Heart Study, 50, 51 British Regional Heart Study, 52

136

C C-reactive protein, highly sensitive (hsCRP), 1, 67–79 biology/pathogenesis of, 68 conditions involved in, 71 future directions, 79 genetics of, 20, 68–71 JUPITER trial data, 14, 76–77 measurements of, 76, 78–79 monozygotic twin studies, 69 PEACE trial data, 77–78 Pravastatin Inﬂammation/ CRP Evaluation trial, 69 and primary prevention, 71, 75–76 REGARDS study data, 79 screening algorithm, 77 secondary prevention, 77–78 total/cardiovascular mortality predictions, 72t–73t CAD (coronary artery disease) bile acid sequestrant treatment, 117 Framingham Heart Study ﬁndings, 88 hsCRP/LDL-C levels and, 77–78, 88 non-HDL-C levels and, 52, 60 prediction/management strategies, 67 Prince cohort/CRP and, 69–70 reconstituted HDLs and, 37 Caerphilly Prospective Heart Disease Study, 72t CARDS (Collaborative Atorvastatin Diabetes Study), 9t, 89t CARE (Cholesterol and Recurrent Events) study, 10t, 13 Caucasians, hsCRP levels, 79 CETP inhibitors, 42. See also anacetropib; dalcetrapib; torcetrapib

08-Baliga-Index.indd 136

Cholesterol absorption inhibitors, 17–18 Cholesterol Lowering Atherosclerosis Study, 52 Cholesterol synthesis inhibitors. See statins Cholesterol Treatment Trial, 3–4 Cholestyramine (LoCholest, Questran, Prevalite), 16–17, 121–122 Cigarette smoking, 2, 6, 21–23, 36, 37t, 39, 44, 51, 60, 68–71, 75, 76, 110 Ciproﬁbrate, 126 Clinical vignettes dyslipidemic risk stratiﬁcation, 105 HDL cholesterol, 29–30 LDL cholesterol, 1 lipoprotein testing, 88 non-HDL cholesterol, 49–50 Cloﬁbrate, 41, 125 Colesevelam (Welchol), 16, 121–122 Colestipol (Colestid), 16, 121–122 Corneal arcus, 6 Coronary artery atheroma, 14–15, 37, 40, 42 Coronary Drug Project, niacin trial, 18 Coronary heart disease (CHD). See also individual medications average lifetime risk, 105–106 clinical vignette, 1 evaluation, 5–6 Framingham risk assessment, 67 guidelines, 21–22 LDL-C relationship to, 3, 3–4 risk factors, 21–23 statin use (vignette), 1 therapeutic lifestyle changes (TLC), 6–7 Crestor (rosuvastatin), 8 CVD (cardiovascular disease) CRP and, 69, 71, 75, 76 environmental exposures/ lifestyle factors, 70 epidemiology of, 105 HDL-C relationship to, 30, 31, 35t, 43 men-women development ratio, 67 multivariate risk factor analysis, 107–108 NHANES surveys/nonHDL-C goals, 51, 54t non-HDL-C and risk of, 51, 57, 59t

prevention using Framingham Risk Score, 108t risk factors, 59t Women’s Health Study, 69

D Dalcetrapib, 42 Decode Study (Europe), 53t Diabetes. See type 2 diabetes Diabetic dyslipidemia, 107 Discoidal HDL, 30, 30–31, 32 Dyslipidemic risk stratiﬁcation, 105–113 apoB/apoA-I ratio, 107 assessment in women, 111 background information, 105–106 evaluation, 106–107 multivariable risk management, 110 multivariate assessment, 107–108 practical points, 111 preventive treatment guideline rationale, 108–110 recommendations, 112–113 triglyceride/HDL-C ratio, 106 unresolved issues, 112

E Emerging Risk Factor Collaboration study, 57 ENHANCE (Effect of Combination Ezetimibe and HighDose Simvastatin vs. Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia) trial, 617 Etoﬁbrate, 126 Ezetimibe background, 123 combinations, 22 dosage range, 124 efﬁcacy/adverse effects, 124 in HPS2-THRIVE therapy, 41 mechanism of action, 123 pharmacology, 124 Ezetimibe/simvastatin (Vytorin), 17

F Familial combined hyperlipidemia (FCH), 6

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G Gemﬁbrozil (Lopid), 15, 19, 120, 126 Genetic disorders related to LDL-C levels, 5–6

H HDL-C (high-density lipoprotein cholesterol), 29–45. See also low HDL-C ambiguous areas, 43–44 apoA-I/apoA-II components, 31, 91–92 clinical vignette, 29–30 deﬁned/described, 30–31 discoidal HDL, 30, 30–31, 32 functions, 33–37, 34

08-Baliga-Index.indd 137

I Ibaraki Prefectural Health Study (Japan), 53t, 54t IMPROVE IT (Improved Reduction of Outcomes: Vytorin Efﬁcacy International Trial), 18

Inhibitors of cholesterol synthesis, 118 INTERHEART Study, 55t Ion mobility testing method, 92, 93, 94 Iowa 65+ Rural Heart Study, 72t ISIS Study (UK), 55t

INDEX

inverse relationship with cardiovascular events, 30 management, 29, 38–42 origin and metabolism of, 31 practical points, 44–45 raising levels, evidence in favor of, 36–37 recommendations, 44 reconstituted HDLs (rHDLs), 37, 42 remodeling of, 32, 33t spherical HDL, 30, 31, 32, 35 testing efﬁcacy, 87 HDL mimetic peptides, 42 Health Professionals FollowUp Study (US), 55t Heart and Estrogen/ Progestin Replacement Study, 111 Heart Protection Study (HPS), 10t, 13, 89t, 109 Helsinki Ageing Study, 72t, 125 Helsinki Heart Study (HHS), 19 Highly-sensitive C-reactive protein (hsCRP). See C-reactive protein, highly sensitive (hsCRP) Hoorn Study, 72t HPS2-THRIVE LDL-lowering therapy, 41 hsCRP. See C-reactive protein, highly sensitive (hsCRP) Hyperlipidemias genetic causes (possible), 5–6 secondary causes, 6 statin treatments, 15 Hypertriglyceridemia bile acid resin use, 16 case discussion, 50 cloﬁbrate treatment, 125 CVD and, 89 diabetic dyslipidemia and, 107 fenoﬁbrate/fenoﬁbric acid use, 19 genetic causes, 38 low HDL-C levels in, 43 niacin use, 18 non-HDL-C levels and, 58, 60 omega-3 fatty acid treatment, 7 statin use, 11t

J JUPITER (Justiﬁcation for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin) study, 8, 9t, 14, 15–16, 20, 76–77

K Kuopio Heart Study, 72t

L LDL-C (low-density lipoprotein cholesterol), increased levels, 1–23. See also individual medications ADA/ACC testing recommendations, 99–100 areas of ambiguity, 19–20 atherosclerosis, role in, 2 background information, 1–2 causes, 6 CHD, relation to, 3, 3–4, 106 clinical vignettes, 1, 29 CRP and, 68 evaluation, 5–6 genetic disorders related to, 5–6 guidelines, 21–22 lowering of, and continued CVD events, 88–89 measurements of, 87–100 particle number and size testing, 94–98 recommendations, 23 relationship with HDL, 30 testing efﬁcacy, 87 therapeutic lifestyle changes (TLC), 6–7 Lescol (ﬂuvastatin), 5, 8, 10t, 13 Lescor Intervention Prevention Study (LIPS), 10t Lipid-poor apoA-I, 30, 32 Lipid Research Clinics Follow-Up Study, 53t, 111 Lipid Research Clinics Follow-Up Study (US), 53t

137

Familial defective apoB-100 (FDB), 6 Familial hypercholesterolemia (FH), 6, 17 Familial hypertriglyceridemia, 38 Family Heart Study (FHS), 69 Fenoﬁbrate, 17, 19, 39, 57, 120, 126 Fenoﬁbrate Intervention and Event Lowering in Diabetes (FIELD) study, 19, 39 Fenoﬁbric acid, 126 Fenoﬁbric acid delayed release (Trilpix), 19 Fibrates, 19. See also bezaﬁbrate; ciproﬁbrate; cloﬁbrate; etoﬁbrate; fenoﬁbrate; fenoﬁbric acid delayed release; gemﬁbrozil adverse effects, 126–127 available preparations, 126 background, 125–126 contraindications, 127 dosage, efﬁcacy, 126 for increase of HDL-C, 39 mechanism of action, 126 Fluvastatin (Lescol), 8, 10t–12t, 13 Foundation on Lipoprotein Management in Cardiometabolic Risk (ADA/ACC), 99–100 Framingham Heart Study, 54t, 56, 67, 88–89, 105–106, 107–108 Framingham Offspring Study, 54t, 95, 96t Friedewald equation (for lipoprotein measurement), 87, 89, 93, 96

9/19/2011 1:11:38 PM

INDEX

138

LIPID (Long-Term Intervention with Pravastatin in Ischemic Disease) study, 10t Lipitor (atorvastatin), 8 Lipoprotein and Coronary Atherosclerosis Study (LCAS), 13 Lipoprotein size/particle number determination gradient gel electrophoresis, 92–93 ion mobility, 93 proton (1H) NMR analysis, 93 vertical-spin density-gradient ultracentrifugation, 93 Lipoprotein testing, 87–100 advanced testing, 90–98 AFCAPS/TexCAPS data, 91 apolipoprotein B-100, 1–2, 57, 87, 99 clinical uses, 99–100 clinical vignette, 88 Friedewald equation, 87, 89, 93, 96 LDL-C, non-HDL-C, apoB, LDL particle number goals, 96t nuclear magnetic resonance spectroscopy, 92–100 patient selection, 98 reasons for ordering, 99 risks beyond LDL-C, 88–89 therapeutic implications, 98 timing/patient selection, 98 Livalo (pitavastatin), 8 LoCholest (cholestyramine), 16 Lopid (gemﬁbrozil), 19 Lovastatin (Mevacor), 3, 8, 9t, 11t–12t, 13, 18, 91, 118, 120 Low HDL-C causes, 38 deﬁned, 37 management, investigative strategies, 42 management, lifestyle, 29, 38 management, pharmacological, 29–30, 39–40, 40–41

M Mechanism of action cholesterol absorption inhibitors, 17 cholesterol synthesis inhibitors, 118 ezetimibe, 123 ﬁbrates, 126

08-Baliga-Index.indd 138

niacin, 127 omega-3 fatty acid esters, 129 phytosterols, 124 sterol absorption inhibitors, 121–122 Metabolic syndrome. See also AIM-HIGH study cholesterol management and, 21 components of, 108 ﬁbrate treatment, 39 LDL-C particle presence, 89 low HDL-C levels and, 38 risk factors, 22, 29 type 2 diabetes and, 2, 38, 41 Mevacor (lovastatin), 8 Mevinolin, 118 Mexican Americans, nonHDL-C levels, 50–51 Microvascular angina, 68 Multi-Ethnic Atherosclerosis Study, 96 Myocardial infarction (MI) clinical vignettes, 1, 29–30 LDL-C values and, 88–89 niacin trials/results, 18 treatment measurement study, 5 U.S. incidence data, 67

mechanism of action, 127 for non-HDL-C, 56–57 Non-HDL cholesterol, 49–61 African American levels, 50 areas of ambiguity, 57–58 atherosclerotic severity measures, 51–52 cardiovascular riskselected studies, 53t–55t Caucasian levels, 50 correlates of non-HDL-C, 51 deﬁned/described, 50 evaluation, 56 guidelines, 58, 60 Mexican American levels, 50 mortality/cardiovascular events, 52 pharmacologic management, 56–57 practical points, 60–61 recommendations, 60 therapeutic lifestyle changes, 56 U.S. population distribution, 50–51 Nuclear magnetic resonance spectroscopy (NMR), 92–100

N

Omega-3 fatty acid esters, 7, 7t, 57 available preparations, 130 background, 129 contraindications, 131 dosage, efﬁcacy, adverse effects, 130 mechanism of action, 129–130

National Cholesterol Adult Treatment Panel, 113 National Cholesterol Education Program (NCEP), 4, 21 National Health and Nutrition Examination Survey, 50–51 National Health and Nutrition Examination Survey (NHANES), 50–51, 91 National Heart, Lung, and Blood Institute (NHLBI), 69 National Lipid Association Task Force, 56 NEPTUNE II (National Cholesterol Education Program Evaluation Project Utilizing Novel E-Technology) survey, 51 Niacin (nicotinic acid) ARBITER 6-HALTS study, 17–18 available preparations, 127 background, 127 combinations, 22 contraindications, 129 description, 18 dosage, efﬁcacy, adverse effects, 128–129

O

P PDAY (Pathobiological Determinants of Atherosclerosis in Youth) Study, 51–52 PEACE (Prevention of Events With AngiotensinConverting Enzyme Inhibition) trial, 77–78 Pharmacologic agents. See also individual drugs cholesterol synthesis inhibitors, 118–120 sterol absorption inhibitors, 121–125 triglyceride-reducing drugs, 125–131 Physician’s Health Study, 72t Phytostanols, 124, 125 Phytosterols background, 124 current available preparations, 125

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Q Quebec Cardiovascular Study, 91 Quest Diagnostics (Madison, NJ), 94 Questran (cholestyramine), 16

R Rancho Bernardo prospective cohort study (US), 53t, 54t Reconstituted HDLs (rHDLs), 37, 42 REGARDS (Reasons for Geographic and Racial Differences in Stroke) study, 79 REVERSAL (Reversal of Atherosclerosis with Aggressive Lipid Lowering) trial, 14 Reynolds Risk Score risk prediction algorithm, 71–72 Rosuvastatin (Crestor), 8, 9t, 11t–12t, 14–15, 40, 77, 118, 119, 120, 122. See also JUPITER study

S Scandinavian Simvastatin Survival Study, 10t, 13 SEARCH trial (of simvastatin therapy), 13

08-Baliga-Index.indd 139

T Testing lipoproteins. See lipoprotein testing Torcetrapib, 42 Treating to New Targets (TNT) study, 4, 10t Tricor (fenoﬁbrate), 19 Triglycerides case vignettes, 1, 29, 49, 88 CHD and, 107–108 elevated levels, 29–30 in evaluation proﬁle, 5–6 Framingham Offspring Study data, 96 HDL-C levels and, 109–112 LDL-C component, 1–2 metabolic syndrome component, 22 reducing drugs, 125–131

treatment strategies, 7, 7t, 16–19, 21, 36, 117, 118, 119, 120, 123, 126, 129–130 Trilpix (fenoﬁbric acid delayed release), 19 Type 2 diabetes, 9t, 38 colesevelam beneﬁts, 16 CVD event risks, 97 HDL-C levels and, 38, 43, 109 hsCRP levels and, 76 LDL-C levels and, 98 niacin use and, 41 statin use and, 40

INDEX

SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) trial, 17 Side effects. See adverse effects Simvastatin (Zocor), 5, 8, 10t–12t, 13, 15, 17, 40–41, 57, 118, 119, 120, 122 Spectracell Laboratories (Houston, TX), 94 Spherical HDL, 30, 31, 32, 35 Statins. See also atorvastatin; ﬂuvastatin; lovastatin; mevinolin; pitavastatin; pravastatin; rosuvastatin; simvastatin adverse effects, 120–121 for atherosclerosis, 8 background, 118 CHD vignette, 1 contraindications, 8 current preparations, 118, 120 efﬁcacy, 120 in hyperlipidemias, 15 LDL-C reduction, 119 major clinical trials, 9t–10t mechanism of action, 118 with niacin, 18 for non-HDL-C, 56–57, 99 pharmacology, 120 primary effects, 7–8 risk reductions in clinical trials, 89t side effects, 15–16 TNT study, 4 Sterol absorption inhibitors. See bile acid sequestrants; ezetimibe; phytosterols Strong Heart Study (US), 54t

V Vertical-spin density-gradient ultracentrifugation, 93 Veterans Affairs HDL Intervention Trial (VA-HIT), 19 VLDL (very-low density lipoprotein) apoB-100 presence in, 2, 6, 90–91, 118 atherogenic dyslipidemia and, 90 atherosclerotic vascular disease and, 107 CETP inhibitors and, 42 ﬁbrates and, 125–126 Friedewald calculation and, 89 hypertriglyceridemia and, 60 niacin and release of, 18, 127 NMR lipoprotein analysis of, 94–95 non-HDL-C and, 50, 60 omega-3 fatty esters and, 129–130 role in plasma cholesterol transport, 33–35, 35 statins and, 98 triglyceride levels and, 117

139

dosage range, 125 efﬁcacy, adverse effects, contraindications, 123, 125 mechanism of action, 124 Pitavastatin (Livalo), 8, 11t–12t, 15, 118, 120 Postprandial hyperlipidemia, 89, 90t Pravachol (pravastatin), 8 Pravastatin, 8, 9t, 10t, 12t, 13–15, 69, 78, 89, 118, 119t, 120, 122 Pravastatin Inﬂammation/ CRP Evaluation trial, 69 Prevalite (cholestyramine), 16 PROSPER (Prospective Study of Pravastatin in the Elderly at Risk), 9t, 13 PROVE IT—TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy— Thrombolysis in Myocardial Infarction 22) study, 10t, 14, 89t

W West of Scotland Coronary Prevention Study (WOSCOPS), 9t, 13, 16, 77 Women’s Health Study (US), 54t, 55t, 69, 72t

X Xanthelasma, 6

Z Zetia (ezetimibe), 17

9/19/2011 1:11:39 PM