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Lipids and Cardiovascular Disease Prevention

Lipids and Cardiovascular Disease Prevention. Epidemiology Clinical Trials Evidence Dietary and Pharmacologic Management. Nathan Wong. Cholesterol and CHD: Seven Countries Study. Northern Europe United States Southern Europe, Inland Southern Europe, Mediterranean Siberia Japan. 30. 25.

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Lipids and Cardiovascular Disease Prevention

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

  2. Cholesterol and CHD: Seven Countries Study Northern Europe United States Southern Europe, Inland Southern Europe, Mediterranean Siberia Japan 30 25 20 CHDmortality rates(%) 15 10 5 0 100 125 150 175 200 225 250 275 300 325 350 (2.60) (3.25) (3.90) (4.50) (5.15) (5.80) (6.45) (7.10) (7.75) (8.40) (9.05) TC mg/dL (mmol/L) Verschuren WMM et al. JAMA. 1995;274:131-136.

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

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

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

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

  7. 1000 Finland 800 U.S. Australia New Zealand Ireland U.K. Canada 600 Norway Denmark Sweden Mortality rate Netherlands W. Germany Belgium 400 Austria Italy Switzerland 200 France Japan 0 20 40 60 80 100 Wine, liter/capita-year Wine Consumption and CHD CHD = -4.99W + 652.4 r = -0.580

  8. CHD Risk According to HDL-C LevelsProspective Cardiovascular Münster Study 110 120 186 events in 4,407 men (aged 40–65 y) 100 80 Incidence per 1,000 (in 6 years) 60 30 40 21 20 0 < 35 35–55 > 55 HDL-C (mg/dL) Assmann G, ed. Lipid Metabolism Disorders and Coronary Heart Disease. Munich: MMV Medizin Verlag, 1993

  9. Low HDL-C Levels Increase CHD Risk Even When Total-C Is Normal 12.50 11.91 11.91 14 9.05 10.7 11.24 12 6.6 10 5.53 3.83 6.56 8 14-y incidence rates (%) for CHD 4.85 6 4.67  260 2.06 4.15 3.77 4 2.78 230–259 2 200–229 Total-C (mg/dL) 0 < 200 < 40 40–49 50–59  60 HDL-C (mg/dL) Risk of CHD by HDL-C and Total-C levels; aged 48–83 y Castelli WP et al. JAMA 1986;256:2835–2838

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

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

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

  13. Population, Gender, and Ethnic Variability in HDL-C Levels Mean HDL-C level (mg/dL) Population Men Women United States (NHANES III)1 Whites 44 54 African-Americans 51 55 Turkey (Turkish Heart Study)2 37 42 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 n 462 (27%) 546 (34%) 612 (38%) < 0.001 Total-C (mg/dL) 212.5 211.1 213.2 0.782 LDL-C (mg/dL) 143.8 139.4 140.7 0.410 HDL-C (mg/dL) 47.0 42.3 44.0 < 0.001 TG (mg/dL) 102.1 147.7 134.0 < 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 10 5 3.6 2.7 2 1.9 1.8 1.8 1.2 1 RR 0.5 Lp(a) TC HDL-C HT GI Smoking 0.2 0.1 RR=relative risk; HT=hypertension; GI=glucose intolerance. Bostom AG et al. JAMA. 1996;276:544-548.

  17. Lipid Management:Clinical Trial Data

  18. Superko HR, Krauss RM. Circulation . 1994;90:1056-1069. Effect of Lifestyle Changeson Angiographic CAD Duration % (Control-Treatment) Study N Patient type Therapy (yr) Progression Regression Lifestyle 28 CAD Diet, exercise, 1 35 -40 meditation STARS 90 CAD, high TC Diet (including 3.2 35 -38 ­ fiber) Heidelberg 113 CAD Diet + exercise 1 25 -15

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

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

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

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

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

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

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

  26. 4S: Lipid Lowering Reduces CHD Event Rates in ³65-Year-Old Subjects P=0.009 P=0.003 P=0.003 Percent of patients Total mortality Coronary mortality Revascularization

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

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

  29. LIPID: Reduction in Nonfatal MI and CHD Death Risk Stratified by Age at Baseline <55 55-64 65-69 70 0 10 % -15 20 -20 30 -28 -32 40 Age LIPID Study Group. N Engl J Med. 1998;339:1349-1357.

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