1. TC LDL- C HDL- C Nonfatal MI/CHD death CHD death All- cause mortality *As compared to placebo. † P=0.003. CARE: Effect of Lipid Lowering on Lipid Values and Coronary Events in CHD Patients With Average Cholesterol %+ * * * †

2. 0 5 10 15 12345 Pravastatin Placebo Yr n=269 n=206 CARE: Fatal CHD or Nonfatal MI (Primary End Point) % with events Sacks FM et al. N Engl J Med. 1996;335:1001-1009. -24% reduction P=0.002

3. CARE: Secondary End Points Reductions observed in:% P Confirmed nonfatal MI230.02 MI, fatal and nonfatal250.006 CABG260.005 PTCA230.01 Sacks FM et al. N Engl J Med. 1996;335:1001-1009.

4. CARE: Impact of Drug Therapy on Lipids and Lipoproteins in Older Patients With MI Data from Lewis SJ et al. Ann Intern Med. 1998;129:681-689. TCLDL-CTG HDL-C P<0.001 for all comparisons with placebo %  

5. CARE: Reduction in Coronary Events, Revascularizations, and Stroke in Older Adults With MI and Average Cholesterol Levels Major coronary events CHD death Revascular- izations Stroke *P=0.005; † P=0.001; ‡ P>0.2; § P=0.004; || P=0.01; ¶ P=0.03. All P values represent within-group differences (treatment vs placebo). * † ‡ † || ¶ ‡ § RR (%) <65 yr (n=2,876) 65-75 yr (n=1,283)

6. CARE: Incidence of Coronary Events in Younger Versus Older Patients 5 10 15 20 30 25 0 5 10 15 20 30 25 0 102345102345 Yr Patients at risk, n Placebo1,435 1,341 1,273 1,194 1,119 265 Pravastatin1,441 1,357 1,285 1,228 1,177 294 <65 yr  65 yr Placebo Pravastatin Placebo Pravastatin -19% P=0.005 -32% P=0.001 % patients 643 595 559 515 477 119 640 590 563 534 505 125

7. AFCAPS/TexCAPS: Effects of LDL- C Lowering in Patients With Average Cholesterol Levels %  TC LDL- C HDL- C MI C UARV P<0.001 P=0.002 P=0.02P=0.001

8. Statin Trials: Therapy Reduces Major Coronary Events in Women 4S (n=827) CARE (n=576) AFCAPS/TexCAPS (n=997) 2  Prevention1  Prevention -50 -45 -40 -35 -30 -25 -20 -15 -10 -5 0 5 10 Major coronary events* -34 -46 %  P=0.012 P=0.001

9. Overall Risk Reduction for Major Coronary Events by Age: A Meta-analysis No. of EventsRRR, %ARR/1000NNT P  65 y74053932 (23 to 39)44 (30 to 58)<0.001 4S16812238 (19 to 53) 98 (43 to 154)23<0.001 CARE1116942 (20 to 57)65 (27 to 103)(17- 33)<0.001 LIPID34927025 (11 to 37)42 (17 to 67)0.001 AFCAPS1127832 (8 to 49)21 (5 to 38)0.01 PIStatin(95% CI)(95% CI) (95% CI) Value

10. Overall Risk Reduction for Major Coronary Events by Age: A Meta-analysis (Cont.) No. of EventsRRR, %ARR/1000NNT P <65 y 1302 951 31 (24 to 36) 32 (24 to 40) <0.001 4S45430938 (27 to 47)83 (55 to 110)<0.001 CARE16314314 (-9 to 32)14 (-8 to 37)310.21 LIPID36628725 (12 to 37) 31 (13 to 48)(25- 41)<0.001 WOSCOPS24817431 (16 to 44)23 (11 to 34)<0.001 AFCAPS713847 (22 to 63)19 (8 to 31)0.001 PIStatin(95% CI)(95% CI) (95% CI) Value

11. Overall Risk Reduction for Major Coronary Events by Sex: A Meta-analysis No. of EventsRRR, %ARR/1000NNTP Women24718029 (13 to 42) 33 (13 to 52) <0.001 4S916037 (10 to 56)69 (17 to 122) 310.01 CARE392343 (3 to 66)54 (4 to 104) (19- 75)0.04 LIPID1049015 (-15 to 37)18 (-16 to 51)0.30 AFCAPS13746 (-31 to 78)12 (-5 to 29)0.17 PIStatin(95% CI) (95% CI) (95% CI) Value

12. Overall Risk Reduction for Major Coronary Events by Sex: A Meta-analysis (Cont) No. of EventsRRR, %ARR/1000NNTP PIStatin(95% CI) (95% CI) (95% CI) Value Men1795131031 (26 to 35)37 (29 to 44) <0.001 4S53137138 (28 to 47)90 (62 to 118) <0.001 CARE23518922 (5 to 36)26 (5 to 47) 270.02 LIPID61146727 (17 to 36)39 (23 to 55) (23-34) <0.001 WOSCOPS24817431 (16 to 44)23 (11 to 34) <0.001 AFCAPS <0.001( 710 )10937 (20 to 50)22 (10 to 33)

13. FATS FATS STARS HARP LCAS (nicotinic acid (lovastatin (diet + resin) (diet + + colestipol) + colestipol) fluvastatin) Event Reduction in Angiographic Plaque Regression Trials +% stenosis* Event reduction (%)%

14. Post-CABG: Impact of Aggressive vs Moderate Lowering of LDL-C on Atherosclerosis Study group characteristics Sample size: 1,351 (M/F) 1 to 11 yr post-CABG 2 patent SVGs (1 in females) LDL-C 130-174 mg/dL after diet Treatment Randomized, blinded to –lovastatin 40-80 mg/day + cholestyramine 8 g/day (if needed) –lovastatin 2.5-5 mg/day + cholestyramine 8 g/day (if needed) –aggressive LDL-C target:  85 mg/dL –moderate LDL-C target: 130-140 mg/dL Monitoring Quantitative coronary angiography

15. 80 90 100 110 120 130 140 150 160 012243648 Follow-up (mo) Aggressive Tx (93-96)* Moderate Tx (134-136)* Post-CABG Study: Aggressive vs Moderate Treatment 6 Post-CABG Trial Investigators. N Engl J Med. 1997;336:153-162. LDL-C (mg/dL) * Mean achieved.

16. Post-CABG: End Points, Results, Conclusions Primary end point: Mean per-patient percentage of grafts with significant progression in SVG (  0.6 mm change) Secondary end point: New occlusions, new lesions, lumen narrowing Results: –aggressive treatment group: significantly less (P<0.001) progression, fewer new occlusions and lesions, and  mean lumen diameter –revascularization rate  29% (P=0.03) Conclusions: Mean LDL-C levels of 95 mg/dL associated with greater benefit than mean LDL-C of 135 mg/dL Post-CABG Trial Investigators. N Engl J Med. 1997;336:153-162.

17. P value Post-CABG Angiographic Outcomes MREDifference ModerateAggressive% Progression3928 <0.001 New occlusions161040<0.001 New lesions211052<0.001 Mean lumen change in mm Minimum diameter-0.38-0.2048<0.001 Mean diameter-0.34-0.1652<0.001 MRE=Mean per-patient percentage of grafts. Post-CABG Trial Investigators. N Engl J Med. 1997;336:153-162.

18. 0 5 10 15 % Yr after enrollment Aggressive Moderate Event=PTCA or bypass surgery P=0.03. Post-CABG: Event Rates by Cholesterol Group 0.51.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5

19. *P=0.001. † 95% confidence interval of percentage of relative reduction. Effects of Statins on Stroke Events: A Meta-analysis of Primary- and Secondary-Prevention Trials Relat ive redu ction in rates (%) 1° Prevention (- 42 to -27) † 2° Prevention (13-45) † Combined (11- 40) †

20. % * * † ‡ § * Confidence interval (CI) not reported. † 95% CI, 14%-41%. ‡ 95% CI, 16%-37%. § 95% CI, 12%-31%. Hebert PR et al. JAMA. 1997;278:313-321. Impact of Lowering LDL-C on CVD Events and Total Mortality Nonfatal/ fatal CHD CVD mortality

21. Clinical Trial Findings: The Statins Statins  LDL-C by 25%-35% (achieved in clinical event trials and regression studies) Benefits at various LDL-C levels; evident soon after therapy in some studies  in LDL-C required for  in CHD morbidity/mortality  in all-cause mortality in 2° prevention and in cardiovascular mortality in 1° prevention Studies support treatment in various patient groups –women –elderly –diabetics

22. Recent Landmark Coronary Prevention Studies angina

23. VA-HIT Results *p  0.05 **p=0.07 † Investigator designated † % Change * * *** *

24. LDL Particle Size Subclass IDLL3L2L1 large, buoyant small, dense ABAB

25. Significance of Small, Dense LDL Low cholesterol content of LDL particles –  particle number for given LDL-C level Associated with  levels of TG and LDL-C, and  levels of HDL 2 Marker for common genetic trait associated with  risk of coronary disease (LDL subclass pattern B) Possible mechanisms of  atherogenicity –greater arterial uptake –  uptake by macrophages –  oxidation susceptibility

26. HDL Atherosclerosis Treatment Study (HATS) NIH-funded, the HDL Atherosclerosis Treatment Study is a double-blind, placebo controlled, factorial design, 3-year angiographic trial. Patients (n=160) 15% had diabetes, 10% had impaired glucose tolerance. Patients randomized into four (4) treatment goups: 1. Niacin (2-4 grams/day) + Simvastatin (10-20 mg/day) plus Antioxidant Vitamins 2. Placebo (Niacin+Simvastatin) plus Antioxidant Vitamins 3. Niacin (2-4 grams/day) + Simvastatin (10-20 mg/day) plus Placebo (Vitamins) 4. Placebo (Niacin + Simvastatin) plus Placebo (Vitamins)

27. HDL Atherosclerosis Treatment Study (HATS) Mean Baseline Lipid Levels: LDL-C126 mg/dl HDL-C 31 mg/dl Triglycerides217 mg/dl after Niacin + Simvastatin therapy (average dose: 3.2 gms niacin, 12 mg simvastatin) LDL-C82 mg/dl reduced 35% HDL-C40 mg/dlincreased 30% Triglycerides 144 mg/dlreduced 34% Niacin+SimvastatinHDL increased 30% LP A-1 increased 75% Niacin+Simvastatin+Vitamins HDL increased 20% LP A-1 increased 17% Antioxidant Vitamins blunted the effect of Niacin+Simvastatin on HDL, specifically HDL 2

28. HDL Atherosclerosis Treatment Study (HATS) Primary quantitative angiographic patient endpoint was the average change in percent stenosis of the 9 worst lesions in 9 standard coronary segments: Placebo + 34% Antioxidant Vitamins + 15% Niacin + Simvastatin + Antioxidants + 7% Niacin + Simvastatin - 4%

29. HDL Atherosclerosis Treatment Study (HATS) Primary clinical endpoint was the Kaplan-Meier intention-to-treat time to first event: CAD death, MI, Stroke, Hospital-confirmed unstable ischemia + revascularization. 15% of the patients were diabetic while 10% of the patients had impaired glucose tolerance. Patients on Niacin + Simvastatin had clinical events reduced by 70%. The addition of Antioxidant Vitamins to Niacin + Simvastatin resulted in only a 15% reduction in clinical events.

30. Gould AL et al. Circulation. 1998;97:946-952. Clinical Benefits of Cholesterol Reduction A recent meta-analysis of 38 trials demonstrated that for every 10% reduction in TC –CHD mortality decreased by 15% (P<0.001) –total mortality decreased by 11% (P<0.001) Decreases were similar for all treatment modalities Cholesterol reduction did not increase non-CHD mortality

31. US Adults Who May Require Drug Therapy for Elevated LDL-C Jacobson TA, et al. Arch Intern Med. 2000;160:1361-1369. <2 RF and no CHD  2 RF and no CHD With CHDTotal Millions