1. Lipids and Cardiovascular Disease Prevention Epidemiology Clinical Trials Evidence Dietary and Pharmacologic Management Nathan Wong

2. 0 5 10 15 20 25 30 (2.60)(3.25)(3.90)(4.50)(5.15)(5.80)(6.45)(7.10)(7.75)(8.40)(9.05) Cholesterol and CHD: Seven Countries Study TC mg/dL (mmol/L) CHD mortali ty rates (%) Verschuren WMM et al. JAMA. 1995;274:131-136. 100125150175200225250275300325350 Northern Europe United States Southern Europe, Inland Southern Europe, Mediterranean Siberia Japan

3. Effects of Increasing TC Levels on the Risk for CHD in the Presence of Other Risk Factors Low HDL Smoking Hyperglycemia Hypertension No Other Risk Factors Schaefer EJ, adapted from the Framingham Heart Study CHD Risk Per 1000 (in 6 years) Serum Cholesterol (mg/dL)

4. Total Cholesterol Distribution: CHD vs Non-CHD Population Adapted from Castelli WP. Atherosclerosis. 1996;124(suppl):S1-S9. 35% of CHD Occurs in People with TC<200 mg/dL 150 200 Total Cholesterol (mg/dL) 250 300 No CHD CHD Framingham Heart Study—26-Year Follow-up

5. HDL-C Distribution in US Adults RF = risk factors Data from NHANES III, 1988–1994 HDL-C (mg/dL) < 35 35–< 45 45–< 60  60 CHD 0 2 4 6 8 10 12 14 16  2 RF, no CHD No. of US adults (millions)

6. CHD Risk According to HDL-C Levels Framingham Study 4.0 3.0 2.0 1.0 25 45 65 HDL-C (mg/dL) CHD risk ratio Kannel WB. Am J Cardiol 1983;52:9B–12B 2.0 1.0 0 4.0

7. Wine Consumption and CHD CHD = -4.99W + 652.4 r = -0.580 020406080100 Finland U.S. Australia New Zealand Ireland U.K. Canada Denmark Norway Sweden Netherlands W. Germany Belgium Austria Japan Switzerland Italy France Wine, liter/capita-year Mortality rate 1000 800 600 400 200

8. CHD Risk According to HDL-C Levels Prospective Cardiovascular Münster Study 110 30 21 0 20 40 60 80 100 120 < 3535–55> 55 Incidence per 1,000 (in 6 years) HDL-C (mg/dL) Assmann G, ed. Lipid Metabolism Disorders and Coronary Heart Disease. Munich: MMV Medizin Verlag, 1993 186 events in 4,407 men (aged 40–65 y)

9. Low HDL-C Levels Increase CHD Risk Even When Total-C Is Normal Risk of CHD by HDL-C and Total-C levels; aged 48–83 y Castelli WP et al. JAMA 1986;256:2835–2838 0 2 4 6 8 10 12 14 < 4040–4950–59  60 < 200 230–259 200–229  260 HDL-C (mg/dL) Total-C (mg/dL) 14-y incidence rates (%) for CHD 11.24 11.91 12.50 11.91 6.56 4.67 9.05 5.53 4.85 4.15 3.77 2.78 2.06 3.83 10.7 6.6

10. Hypertriglyceridemia Increases CHD Risk in Patients with Low HDL-C Levels Prospective Cardiovascular Munster Study * Bar represents 5% of subjects in which 25% of CHD events occurred. 24 31 116 245 0 50 100 150 200 250  5.0 > 5.0 * LDL-C/HDL-C ratio Incidence per 1,000 (in 6 years) TG < 200 mg/dL TG  200 mg/dL

11. Distribution of HDL-C Levels in Men With CHD VA-HIT Study Group HDL-C level Whites BlacksAll subjects (mg/dL) (n = 2,891)(n = 572) (n = 8,578) < 35 42%20% 38% 35–40 25%23% 25% > 40 32%57% 36% Rubins HB et al. Am J Cardiol 1995;75:1196–1201 } 63%

12. CHD Incidence Related to HDL-C Levels in Various Trials % change in risk per 1 mg/dL increment in HDL-C 0 -2 -4 -6 -8 -10 FHS LRCF CPPT MRFIT FHS LRCF CHD incidence Men Women

13. Population, Gender, and Ethnic Variability in HDL-C Levels Mean HDL-C level (mg/dL) Population MenWomen United States (NHANES III) 1 Whites 4454 African-Americans 5155 Turkey (Turkish Heart Study) 2 3742 1. NHANES III, 1988–1994 (unpublished data) 2. Mahley RW et al. J Lipid Res 1995;36:839–859

14. Ethnic Variations in Lipid Parameters Insulin Resistance Atherosclerosis Study African-Non-Hispanic Americans Hispanics Whites P value n462 (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 TG (mg/dL)102.1147.7134.0< 0.001 Haffner SM et al. Arterioscler Thromb Vasc Biol 1999;19:2234–2240.

15. Lp(a) in Atherogenesis: Another Culprit? Identical to LDL particle except for addition of apo(a) Plasma concentration predictive of atherosclerotic disease in many epidemiologic studies, although not all Accumulates in atherosclerotic plaque Binds apo B-containing lipoproteins and proteoglycans Taken up by foam cell precursors May interfere with thrombolysis

16. Lp(a): An Independent CHD Risk Factor in Men of the Framingham Offspring Cohort RR=relative risk; HT=hypertension; GI=glucose intolerance. Bostom AG et al. JAMA. 1996;276:544-548. 1.9 1.8 1.2 2.7 3.6 RR 0.1 1 10 2 5 0.2 0.5Lp(a)TCHDL- CHTGISmoking

17. Lipid Management: Clinical Trial Data

18. Effect of Lifestyle Changes on Angiographic CAD StudyNPatient typeTherapy Duration (yr) % (Control-Treatment) Progression Regression Lifestyle28CADDiet, exercise, meditation 135-40 STARS90CAD, high TCDiet (including  fiber) 3.235-38 Heidelberg113CADDiet + exercise125-15 Superko HR,Krauss RM. Circulation. 1994;90:1056-1069.

19. -9 -47 -9 -20 -14 -23 -8.5 -19 -11 -34 -50 -45 -40 -35 -30 -25 -20 -15 -10 -5 0 %+%+ * Net difference between treatment and control groups (P values are for events). TC *CHD events * N=number enrolled. Early Primary-Prevention Trials: Overview WHO: Clofibrate N=15,745, P<0.05 Oslo: Diet/smoking cessation N=1,232, P=0.02 Upjohn: Colestipol N=2,278, P  0.02 LRC-CPPT: Cholestyramine N=3,806, P<0.05 HHS: Gemfibrozil N=4,081, P<0.02

20. Early Secondary-Prevention Trials: Overview * Net difference between treatment and control groups (P values are for events). N=number enrolled; ns=not significant. TC *CHD events * CDP: Niacin (n=1,119) N=8,341, P=ns CDP: Clofibrate (n=1,103) N=8,341, P=ns Stockholm: Clofibrate + niacin N=555, P=ns POSCH: Partial ileal bypass N=838, P<0.001 %+%+

21. -20 -26 5 -31 -33 -22 -25 -35 8 -34 -42 -30 -20 -28 5 -24 -20 -9 -45 -40 -35 -30 -25 -20 -15 -10 -5 0 5 10 WOSCOPS (N=6,595)4S (N=4,444)CARE (N=4,159) N=number enrolled. TC LDL-C HDL-C 1 o prevention 2 o prevention Summary of Effects of Lipid Lowering on Lipids and Clinical Events in Recent Statin Trials Nonfatal MI/CHD death CHD death All-cause mortality %+%+

22. -20 -26 5 -33 -22 -31* -35 -30 -25 -20 -15 -10 -5 0 5 10 Shepherd J et al. N Engl J Med. 1995;333:1301-1307. * P<0.0005. † P=0.042. ‡ P=0.051. † TC LDL-C HDL-C Nonfatal MI/CHD death CHD death All-cause mortality WOSCOPS: Effects of Lipid Lowering on Coronary Events in Primary Prevention Trial in Men ‡ %+%+

23. 5-year event rate (per 100) WOSCOPS Group. Circulation. 1998;97:1440-1445. WOSCOPS: Relation of Baseline LDL-C to Event Rate

24. 4S Group. Lancet. 1994;344:1383-1389. *P<0.00001. † 95% CI: -27 to -54. ‡ P=0.003. 4S: Effect of LDL-C Lowering on Coronary Events in Secondary Prevention Trial -25 -35 8 -42 † -30 ‡ -34 -45 -40 -35 -30 -25 -20 -15 -10 -5 0 5 10 TC LDL-C HDL-C Nonfatal MI/CHD death CHD death All-cause mortality %+%+ *

25. 4S: Effects of Cholesterol Lowering on Noncoronary Ischemic Symptoms and Angina Fraction of patients Months Simvastatin Placebo Intermittent ClaudicationCarotid Bruit AnginaCerebrovascular Events

26. Total mortality Coronary mortality Revascularization Percent of patients P=0.009P=0.003 4S: Lipid Lowering Reduces CHD Event Rates in  65-Year-Old Subjects

27. -35 -34 -31 -88 -100 -80 -60 -40 -20 0 Cost of simvastatin therapy LDL-C Hospital days Major CHD events Hospital costs *P<0.0001. † Translates to savings of $3,872/patient. ‡ Translates to cost of $0.28/day. * † LDL-CCHD eventsAdmissionsNet cost of therapy ‡ 4S: Clinical and Economic Benefits of Treatment Over 5-Yr Period %+%+

28. LIPID: Effect of Lipid Lowering on Lipid Values and Coronary Events in CHD Patients With Average Cholesterol LIPID Study Group. N Engl J Med. 1998;339:1349-1357. TCLDL-C Nonfatal MI/CHD death CHD death All-cause mortality HDL-C -18 -25 -24* -22* 5 *P<0.001

29. LIPID: Reduction in Nonfatal MI and CHD Death Risk Stratified by Age at Baseline -32 -20 -28 -15 40 30 20 10 0 Age <5555-6465-69  70 LIPID Study Group. N Engl J Med. 1998;339:1349-1357. %