Slide Source: Lipids Online Slide Library High-Density Lipoprotein and the Epidemiology of Coronary Heart Disease Michael Miller, MD, FACC, FAHA

Slide Source: Lipids Online Slide Library Distribution and Prevalence of Low Levels of High-Density Lipoprotein Cholesterol

Slide Source: Lipids Online Slide Library Normal Values for Plasma Concentrations of High-Density Lipoprotein Cholesterol* NORMAL VALUES (mg/d) MALES (percentages)FEMALES (percentages) AGE (yrs) –95– – – – – – – – – – – – – NHLBI. In: The Lipid Research Clinics Population Studies Data Book. Vol NIH publication *Values are based on population-based studies conducted the United States and Canada. Data on 3,524 white males and 2,545 white females (nonusers of sex hormones) are derived from NIH publication All subjects were sampled in the fasting state.

Slide Source: Lipids Online Slide Library Ethnic Variations in Lipid Parameters: Insulin Resistance Atherosclerosis Study African- AmericansHispanics Non- Hispanic WhitesP Value n (%)462 (27)546 (34)612 (38)< Total-C (mg/dL) LDL-C (mg/dL) HDL-C (mg/dL) < TGs (mg/dL) < LDL size ( Å ) < Haffner SM, et al. Arterioscler Thromb Vasc Biol. 1999;19: C = cholesterol; LDL = low-density lipoprotein; HDL = high-density lipoprotein; TGs = triglycerides

Slide Source: Lipids Online Slide Library HDL-C Distribution in U.S. Adults NCHS. NHANES III data files, documentation, and SAS code. No. of U.S. Adults (millions) CHD ≥2 RFs; ≥2 RFs; no CHD no CHD RFs = risk factors; CHD = coronary heart disease; HDL-C = high-density lipoprotein cholesterol <35 HDL-C (mg/dL) 35 to <45 45 to <60 ≥60

Slide Source: Lipids Online Slide Library Distribution of Low HDL-C Levels in NHANES III Population (%) Men Women 5-9 Miller M, et al. Curr Opin Cardiol. 2004;19:380 – HDL-C (mg/dL) HDL-C = high-density lipoprotein cholesterol NHANES = National Health and Nutrition Examination Survey

Slide Source: Lipids Online Slide Library NHANES III: Prevalence of Low Levels of HDL-C and Low or High Levels of Triglycerides Low HDL-C* and Low TGs † Low HDL-C* and High TGs ‡ Age (yr)nMen (%)Women (%)Men (%)Women (%) 20 – 343, § § 4.7§ 35+6, *Level <40 mg/dL in men and <50 mg/dL in women † Level <100 mg/dL ‡ Level ≥200 mg/dL § p < , as derived from a chi square analysis of the two age groups Reprinted from Miller M, et al. Atherosclerosis. 2003;169:347 – 348, with permission from Wolters Kluwer Health. HDL-C = high-density lipoprotein cholesterol NHANES = National Health and Nutrition Examination Survey TGs = triglycerides

Slide Source: Lipids Online Slide Library NHANES III: Prevalence of Isolated Low HDL-C* AgenMenWomen 20 – 343,0472.5%8.8% 35 – 441,7212.2%5.5% 45 – 541,0761.6% 55 – 641,1331.3%2.1% 65 – 741,1431.7%1.1% 75+1,1612.4%1.0% Modified from Miller M. In: Clinical Lipidology: A Companion to Braunwald's Heart Disease. 2009; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; NHANES = National Health and Nutrition Examination Survey *Cut points: HDL-C <40 mg/dL in men and <50 mg/dL in women; triglycerides <150 mg/dL; and LDL-C < 100 mg/dL.

Slide Source: Lipids Online Slide Library Low High-Density Lipoprotein Cholesterol and Coronary Heart Disease Risk

Slide Source: Lipids Online Slide Library Coronary Heart Disease Risk According to HDL-C Levels: The Framingham Heart Study Kannel WB. Am J Cardiol. 1983;52:9B – 12B. CHD Risk Ratio HDL-C (mg/dL) CHD = coronary heart disease; HDL-C = high-density lipoprotein cholesterol

Slide Source: Lipids Online Slide Library Coronary Heart Disease Risk According to HDL-C Levels: The PROCAM Study 186 CHD Events* in 4,407 Men Aged 40 – 65 Years HDL-C Tertile (mg/dL) Observed CHD Events (per 100) Incidence of CHD Events at 6 Years (per 1,000) < † 3 – > *134 definite nonfatal myocardial infarctions and 52 definite atherosclerotic CHD-related deaths † Approximately a 4-fold increased risk of CHD at 6 years for this tertile CHD = coronary heart disease; HDL-C = high-density lipoprotein cholesterol; PROCAM = Prospective Cardiovascular M ü nster Study Assmann G, Schulte H. In: Lipid Metabolism Disorders and Coronary Heart Disease. 1993;19-68.

Slide Source: Lipids Online Slide Library Distribution of HDL-C Levels in Men With Coronary Heart Disease: VA-HIT Study Group HDL-C Level (mg/dL) Whites (n = 2,891) Blacks (n = 572) All subjects (N = 8,578) <3542%20%38% %23%25% >4032%57%36% Rubins HB, et al. Am J Cardiol. 1995;75:1196 – % HDL-C = high-density lipoprotein cholesterol; VA-HIT = Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial

Slide Source: Lipids Online Slide Library Frequency of Low HDL-C When Compared With Other Risk Factors in Men With Premature Coronary Heart Disease Cases (n = 321) Risk Factor Controls (n = 601)Not AdjustedAdjusted Cigarette smoking29% 67%* — HDL-C <35 mg/dL19% 63%*57%* Hypertension (BP >150/90)21% 41%* — LDL-C >160 mg/dL26% 34%* Diabetes mellitus 1% 12%* — Reprinted form Genest JJ, et al. Am J Cardiol. 1991;67:1185 – 1189, with permission from Elsevier. BP = blood pressure; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol *Significantly different from controls (P <0.001)

Slide Source: Lipids Online Slide Library Low HDL-C Predicts Coronary Heart Disease Risk Independent of LDL-C: The Framingham Heart Study 100 Relative Risk of Coronary Heart Disease After 4 Years 25 LDL-C (mg/dL) HDL-C (mg/dL) Data for men aged 50 – 70 years Reproduced with permission from Castelli WP. Can J Cardiol. 1988;4(Suppl A):5A-10A. Copyright © 1988 Pulsus Group Inc. HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol

Slide Source: Lipids Online Slide Library Hypertriglyceridemia Increases CHD Risk in Patients With Low HDL-C Levels: The PROCAM Study Assmann G, Schulte H. Am J Cardiol. 1992;70:733 – 737. Incidence per 1,000 (in 6 years) ≤ 5.0 LDL-C / HDL-C Ratio > 5.0 TG < 200 mg/dL TG ≥ 200 mg/dL * *Bar represents 5% of subjects in which 25% of CHD events occurred CHD = coronary heart disease; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; PROCAM = Prospective Cardiovascular M ü nster (PROCAM) Study; TG = triglycerides

Slide Source: Lipids Online Slide Library Coronary Heart Disease Incidence Is Related to HDL-C Levels in Various Clinical Trials *95% confidence intervals for adjusted proportional hazards regression coefficients. % Change in Risk per Increments (1 mg/dL) in HDL-C* FHSLRCFCPPTMRFITFHSLRCF CHD Incidence MenWomen CHD = coronary heart disease; HDL-C = high-density lipoprotein cholesterol Gordon DJ, et al. Circulation. 1989;79:8-15.

Slide Source: Lipids Online Slide Library Statin Treatment and Low High- Density Lipoprotein Cholesterol

Slide Source: Lipids Online Slide Library Effect of Fluvastatin on Coronary Angiographic Progression in Patients With Low HDL-C: The LCAS Reprinted from Ballantyne CM, et al. Circulation 1999;99: 736 – 743, with permission from Wolters Kluwer Health. Progression (MLD Decrease in mm) n=43 Fluvastatin Placebo n=25 n=128n=143 p=0.01 HDL-C <35 mg/dL (p=0.0004) HDL-C ≥35 mg/dL (p=0.09) HDL-C = high-density lipoprotein cholesterol; LCAS = Lipoprotein and Coronary Atherosclerosis Study; MLD = minimum lumen diameter

Slide Source: Lipids Online Slide Library Reduced Coronary Heart Disease Risk Is Associated With Low HDL-C: Statin Trials Ballantyne CM. et al. Prev Cardiol. 2001;4:65 – 72. Copyright © 2002 by Le Jacq Communications Inc. Reproduced with permission of Blackwell Publishing Ltd. Coronary Events (%) HDL-C (mg/dL) ≥43≥52 Statin Placebo ≤38≥39<39>44<33<43≥40≤34 WOSCOPS4SLIPIDCAREAFCAPS/ TexCAPS HDL-C = high-density lipoprotein cholesterol

Slide Source: Lipids Online Slide Library Baseline HDL-C Quartiles and Relative Risk for Coronary Heart Disease: The MIRACL Trial Relative Risk <38 Quartile of Baseline HDL-C (mg/dL) Olsson AG, et al. Eur Heart J. 2005;26: – 4445 – 52> HDL-C = high-density lipoprotein cholesterol; MIRACL = Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering

Slide Source: Lipids Online Slide Library Low HDL-C Increases Cardiovascular Disease Risk Even If LDL-C Levels Are Well-controlled: The Treating to New Targets Study 5-Year Risk of Major Cardiovascular Disease Events (%) HDL-C quintiles* (mg/dL) *On-treatment level (3 months statin therapy) † Mean low-density lipoprotein cholesterol (LDL-C) level = 58 mg/dL; mean triglyceride (TG) level = 126 mg/dL ‡ P=.03 for differences among quintiles of HDL-C Patients (n = 2661) with LDL-C <70 mg/dL on a Statin* † 37 to <4242 to <4742 to <55>55< Hazard Ratio vs. Q1 ‡ Barter P, et al. N Engl J Med. 2007;357:

Slide Source: Lipids Online Slide Library On-Treatment Level of High-Density Lipoprotein Cholesterol in the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT)

Slide Source: Lipids Online Slide Library Relation of Coronary Heart Disease to On-Trial HDL-C Level: VA-HIT Robins SJ, et al. JAMA 2001;285:1585 – Copyright © 2001, American Medical Association. All rights reserved. CHD Risk Rate (%) HDL-C (mg/dL) Placebo Gemfibrozil CHD = coronary heart disease; HDL-C = high-density lipoprotein cholesterol; VA-HIT = Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial

Slide Source: Lipids Online Slide Library Low HDL-C is a risk factor for coronary heart disease, irrespective of LDL-C. Elevated LDL-C and triglyceride levels greatly enhance coronary heart disease risk in patients with low HDL-C. Observational studies suggest that each 1-mg/dL incremental increase in HDL-C is associated with a 2–3% reduction in coronary heart disease risk. Statin therapy attenuates the excess coronary heart disease risk that is associated with low HDL-C, but there is a caveat. Event rates remain higher in patients who have low levels of HDL-C at baseline when compared to those who have higher levels of HDL-C — even when patients are treated with statins. HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol HDL-C and the Epidemiology of Coronary Heart Disease: Summary