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

2. Slide Source: Lipids Online Slide Library www.lipidsonline.org Distribution and Prevalence of Low Levels of High-Density Lipoprotein Cholesterol

3. Slide Source: Lipids Online Slide Library www.lipidsonline.org Normal Values for Plasma Concentrations of High-Density Lipoprotein Cholesterol* NORMAL VALUES (mg/d) MALES (percentages)FEMALES (percentages) AGE (yrs)102550102550 5–95–9424954104750 10 – 14404655404552 15 – 19343946384351 20 – 24323845374350 25 – 29323744404755 30 – 34323845404655 35 – 39313643384452 40 – 44313643394855 45 – 49333845394656 50 – 54313644404959 55 – 59313846394758 60 – 64344149384660 65 – 69333949384660 70+334048374860 NHLBI. In: The Lipid Research Clinics Population Studies Data Book. Vol 1. 1980. NIH publication 80-1527. *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 80-1527. All subjects were sampled in the fasting state.

4. Slide Source: Lipids Online Slide Library www.lipidsonline.org Ethnic Variations in Lipid Parameters: Insulin Resistance Atherosclerosis Study African- AmericansHispanics Non- Hispanic WhitesP Value n (%)462 (27)546 (34)612 (38)< 0.001 Total-C (mg/dL) 212.5211.1213.20.782 LDL-C (mg/dL) 143.8139.4140.70.410 HDL-C (mg/dL) 47.042.344.0< 0.001 TGs (mg/dL) 102.1147.7134.0< 0.001 LDL size ( Å ) 262.1257.6259.2< 0.001 Haffner SM, et al. Arterioscler Thromb Vasc Biol. 1999;19:2234 - 2240. C = cholesterol; LDL = low-density lipoprotein; HDL = high-density lipoprotein; TGs = triglycerides

5. Slide Source: Lipids Online Slide Library www.lipidsonline.org HDL-C Distribution in U.S. Adults NCHS. NHANES III data files, documentation, and SAS code. http://www.cdc.gov/nchs/about/major/nhanes/nh3data.htm. 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

6. Slide Source: Lipids Online Slide Library www.lipidsonline.org Distribution of Low HDL-C Levels in NHANES III Population (%) Men Women 5-9 Miller M, et al. Curr Opin Cardiol. 2004;19:380 – 384. 30-34 HDL-C (mg/dL) 10-1415-1920-2425-2935-39 HDL-C = high-density lipoprotein cholesterol NHANES = National Health and Nutrition Examination Survey

7. Slide Source: Lipids Online Slide Library www.lipidsonline.org 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 – 343,047 7.4§ 20.0 6.9§ 4.7§ 35+6,234 4.8 8.7 12.7 12.6 *Level <40 mg/dL in men and <50 mg/dL in women † Level <100 mg/dL ‡ Level ≥200 mg/dL § p < 0.0005, 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

8. Slide Source: Lipids Online Slide Library www.lipidsonline.org 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;119-129. 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.

9. Slide Source: Lipids Online Slide Library www.lipidsonline.org Low High-Density Lipoprotein Cholesterol and Coronary Heart Disease Risk

10. Slide Source: Lipids Online Slide Library www.lipidsonline.org 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) 254565 2.0 1.0 4.0 CHD = coronary heart disease; HDL-C = high-density lipoprotein cholesterol

11. Slide Source: Lipids Online Slide Library www.lipidsonline.org 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) < 3577110 † 3 – 552730 > 552621 *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.

12. Slide Source: Lipids Online Slide Library www.lipidsonline.org 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% 35-4025%23%25% >4032%57%36% Rubins HB, et al. Am J Cardiol. 1995;75:1196 – 1201. 63% HDL-C = high-density lipoprotein cholesterol; VA-HIT = Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial

13. Slide Source: Lipids Online Slide Library www.lipidsonline.org 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)

14. Slide Source: Lipids Online Slide Library www.lipidsonline.org 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) 160220 85 65 45 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

15. Slide Source: Lipids Online Slide Library www.lipidsonline.org 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 245 31 116 24 * *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

16. Slide Source: Lipids Online Slide Library www.lipidsonline.org 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.

17. Slide Source: Lipids Online Slide Library www.lipidsonline.org Statin Treatment and Low High- Density Lipoprotein Cholesterol

18. Slide Source: Lipids Online Slide Library www.lipidsonline.org 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 0.065 0.274 0.036 0.083

19. Slide Source: Lipids Online Slide Library www.lipidsonline.org 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

20. Slide Source: Lipids Online Slide Library www.lipidsonline.org 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;26:890-896. 0.62 38 – 4445 – 52>53 0.82 0.90 1.00 HDL-C = high-density lipoprotein cholesterol; MIRACL = Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering

21. Slide Source: Lipids Online Slide Library www.lipidsonline.org 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<37 0.850.570.550.61Hazard Ratio vs. Q1 ‡ Barter P, et al. N Engl J Med. 2007;357:1301-1310.

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

23. Slide Source: Lipids Online Slide Library www.lipidsonline.org Relation of Coronary Heart Disease to On-Trial HDL-C Level: VA-HIT Robins SJ, et al. JAMA 2001;285:1585 – 1591. Copyright © 2001, American Medical Association. All rights reserved. CHD Risk Rate (%) HDL-C (mg/dL) 25 29 413733 Placebo Gemfibrozil CHD = coronary heart disease; HDL-C = high-density lipoprotein cholesterol; VA-HIT = Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial

24. Slide Source: Lipids Online Slide Library www.lipidsonline.org 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