Department of Cardiology Government Medical college Statins for primary prevention of coronary heart disease- Review of evidence Dr Ranjith MP Senior Resident Department of Cardiology Government Medical college Kozhikode

INTRODUCTION Primary prevention is treating hypercholesterolemia in patients who do not have clinical evidence of CAD What is the rationale for this approach ? Grundy et al. Recent Clinical Trials and NCEP ATP III , JACC Vol. 44, No. 3, 2004 August 4, 2004:720–32

STATINS Inhibit HMG-CoA reductase Statin Pleiotropy

Earlier Clinical Trials WHO Cooperative Trial (clofibrate ) - 10,577 patients Lipid Research Clinics Coronary Primary Prevention Trial (cholestyramine) - 3806 patients Helsinki Heart Study (gemfibrozil ) - 4081 patients These trials demonstrated Significant reductions in coronary events (25, 19 & 34 % respectively) No reduction in coronary mortality Increase in mortality from noncardiovascular causes 

West of Scotland Coronary Prevention Study (WOSCOPS) Designed to determine whether the administration of pravastatin to men with hypercholesterolemia and no history of myocardial infarction reduced the combined incidence of nonfatal myocardial infarction and death from coronary heart disease James Shepherd, et al, N Engl J Med 1995;333:1301-7

West of Scotland Coronary Prevention Study Group (WOS) Randomized, double-blind, placebo controlled 6595 men, 45 to 64 years of age Average follow-up of 4.9 years (seen at 3 month intervals) Pravastatin (40 mg each evening) vs. placebo James Shepherd, et al, N Engl J Med 1995;333:1301-7

Baseline Characteristics (WOS)

WOSCOPS Endpoints Primary Secondary Other Endpoints Non-fatal MI or coronary heart disease death as a first event Secondary Non-fatal MI Coronary heart disease death Other Endpoints Cardiovascular mortality Total mortality Coronary revascularization procedures

WOSCOPS Reduction in Lipids placebo (intention -to-treat) placebo (actual treatment) pravastatin (intention-to-treat) pravastatin (actual treatment) 20% reduction in TC 26% reduction in LDL 12% reduction in Trigs 5% increase in HDL James Shepherd, et al, N Engl J Med 1995;333:1301-7

Nonfatal MI or CHD Death (Primary Endpoint) 31% Risk Reduction P=0.0001 James Shepherd, et al, N Engl J Med 1995;333:1301-7

Non-Fatal MI (Secondary Endpoint) 31% Risk Reduction P=0.0005 James Shepherd, et al, N Engl J Med 1995;333:1301-7

CHD Death (Secondary Endpoint) 28% Risk Reduction P=0.13 James Shepherd, et al, N Engl J Med 1995;333:1301-7

Cardiovascular Death P=0.033 32% Risk Reduction James Shepherd, et al, N Engl J Med 1995;333:1301-7

Total Mortality 22% Risk Reduction P=0.051 James Shepherd, et al, N Engl J Med 1995;333:1301-7

Coronary Interventions Intervention Placebo Pravastatin Risk (n= 3293) (n=3302) Reductions p-value Coronary Angiography 128 90 31% 0.007 PTCA / CABG 80 51 37% 0.009 James Shepherd, et al, N Engl J Med 1995;333:1301-7

WOSCOPS Results/Clinical Events James Shepherd, et al, N Engl J Med 1995;333:1301-7

WOSCOPS Conclusions Treatment with pravastatin significantly reduced the incidence of myocardial infarction and death from cardiovascular causes without adversely affecting the risk of death from noncardiovascular causes in men with moderate hypercholesterolemia and no history of myocardial infarction Pravastatin had no effect on noncardiovascular-related hospital admissions Pravastatin therapy also resulted in a 30 percent reduction in the risk of developing diabetes James Shepherd, et al, N Engl J Med 1995;333:1301-7

WOS Projected Benefits Treatment of 1000 hypercholesterolemic middle aged men with pravastatin for five years will avoid: 14 coronary angiograms 8 revascularization procedures 20 nonfatal MIs 7 CHD deaths 2 additional deaths James Shepherd, et al, N Engl J Med 1995;333:1301-7

Diet Modification + Pravastatin Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) Trial 7,832 ,men age 40-70 years and postmenopausal women up to age 70 with total cholesterol 220-270 mg/dL Mean BMI 23.8 kg/m2, 21% Diabetics, 20% Current Smokers, baseline total cholesterol 242.6 mg/dL, LDL 157 mg/dL, HDL 57.5 mg/dL, triglycerides 127 mg/dL 32% Female, Mean Age 58 years, Mean Follow-Up 5.3 years Prospective. Randomized. Open-label. Diet Modification n=3,966 Diet Modification + Pravastatin 10-20 mg/day n=3,866 Primary Endpoints: Composite of coronary heart disease events, defined as cardiac and sudden death, fatal and nonfatal myocardial infarction (MI), angina and cardiac or vascular intervention. Secondary Endpoints: Stroke, CHD composite or cerebral infarction, any cardiovascular event, total mortality. Eishu Nango et al, lancet 2006;368:11555-63

MEGA Trial: Cholesterol and Triglyceride Levels Total Cholesterol LDL HDL Triglycerides Total cholesterol, LDL, Triglyceride reduction was larger in the pravastatin group HDL increase was greater in the pravastatin group mg/dL Eishu Nango et al, lancet 2006;368:11555-63

MEGA Trial: Primary Composite Endpoint Primary composite endpoint of coronary heart disease events p = 0.01 3.3 vs 5.0 per 1000 patient years, hazard ratio 0.67, p=0.01 # per 1000 patient years Eishu Nango et al, lancet 2006;368:11555-63

MEGA Trial: Secondary Endpoints Total mortality was non-significantly lower in the pravastatin group (2.7 vs 3.8, HR 0.71, p=0.055) MI occurred less often in the pravastatin group (0.9 vs 1.6, p=0.03) No significant difference was observed in stroke (2.5 vs 3.0, p=0.33) or cerebral infarction plus TIA (2.0 vs 2.6, p=0.23) p=0.055 p=0.33 p=0.23 p=0.03 # per 1000 patient years Eishu Nango et al, lancet 2006;368:11555-63

MEGA Trial: Safety Data Frequency of cancer (per 1000 patient years) Frequency of elevated liver function abnormalities (%) % # per 1000 patient years There was no difference in the frequency of cancer or elevated liver function abnormalities and no cases of rhabdomyolysis. Eishu Nango et al, lancet 2006;368:11555-63

MEGA Trial: Summary Among Japanese patients with hypercholesterolemia, treatment with pravastatin was associated with a reduction in the primary composite endpoint of coronary heart disease The cardiac morbidity and mortality in Japan is much lower than in the U.S. and other western countries where statin therapy has been predominantly studied. The present study demonstrated that even in this lower risk population, primary prevention with low-dose statin therapy can be effective in reducing cardiac events, with a modest reduction in lipid parameters. Eishu Nango et al, lancet 2006;368:11555-63

Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial and ALLHAT–Lipid-Lowering Trial (ALLHAT) ALLHAT: N = 42,418: stage 1/2 hypertension + >1 CV risk factor Chlorthalidone 12.5–25 mg/d n = 15,255 Amlodipine 2.5–10 mg/d n = 9048 Lisinopril 10–40 mg/d n = 9054 Doxazosin* 2–8 mg/d n = 9061 Step 1: titration Step 2: open-label atenolol 25–100 mg/d, clonidine 0.1–0.3 mg bid, reserpine 0.05–0.2 mg/d Step 3: open-label hydralazine 25–100 mg bid ALLHAT-LLT: N = 10,355; CHD, LDL-C 100 to 129 mg/dL or no CHD, LDL-C 120 to 189 mg/dL Pravastatin 40 mg/d (n = 5170) Usual care (n = 5185) ALLHAT Collaborative Research Group. JAMA. 2002;288:2981-2997, 2998-3007. *Arm discontinued

ALLHAT-LLT: Effects of statin or usual care on outcomes N = 10,355 with treated hypertension, baseline LDL-C 120–189 mg/dL (no CHD) or LDL-C 100–129 mg/dL (CHD) At 4 yrs, LDL-C  by 28% (statin) and 11% (usual care) All-cause mortality CHD death + nonfatal MI 3 6 9 12 15 18 3 6 9 12 15 18 RR = 0.99 (95% CI, 0.89–1.11) RR = 0.91 (95% CI, 0.79–1.04) Cumulative rate (%) 6 5 4 3 2 1 6 5 4 3 2 1 Time to death (years) Time to event (years) Pravastatin Usual care

ALLHAT: Clinical implications BP-lowering trial Diuretic, ACEI, CCB equivalent in  CHD death and MI Lipid-lowering trial (ALLHAT-LLT) Statin, usual care equivalent in  all-cause mortality Modest differential in on-treatment cholesterol levels may have contributed to result ALLHAT BP results support importance of BP lowering, regardless of drug class used ALLHAT-LLT results are consistent with other statin trials

Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) 5804 patients aged 70–82 years with a history of vascular disease or with cardiovascular risk factors Randomized to pravastatin 40 mg/d or placebo Baseline TC 155–348 mg/dL Follow-up 3.2 years (mean) Primary endpoint (composite): coronary death, nonfatal MI, fatal or nonfatal stroke Shepherd J et al. Lancet 2002;360:1623–1630

Major Endpoints: PROSPER Pravastatin (%) Placebo (%) Hazard ratio p Primary endpoint: CHD death/MI/stroke 14.1 16.2 0.85 0.014 Secondary endpoints: CHD death/MI 10.1 12.2 0.81 0.006 Fatal or nonfatal stroke 4.7 4.5 1.03 Other outcomes: Nonfatal MI 7.7 8.7 0.86 0.10 Nonfatal stroke 4.0 4.1 0.98 Transient ischemic attack 2.7 3.5 0.75 0.051 All CV events 15.7 18.0 0.012 Shepherd J et al. Lancet 2002;360:1623–1630

Mortality by Cause: PROSPER Cause of death Pravastatin (%) Placebo (%) Hazard ratio p CHD 3.3 4.2 0.76 0.043 Stroke 0.8 0.5 1.57 0.19 Vascular 4.7 5.4 0.85 0.16 Nonvascular 5.6 5.1 1.11 0.38 Cancer 4.0 3.1 1.28 0.082 Trauma/suicide 0.1 0.2 NA All causes 10.3 10.5 0.97 0.74 Shepherd J et al. Lancet 2002;360:1623–1630 Shepherd J et al. Lancet 2002;360:1623–1630

PROSPER Conclusion Pravastatin given for 3 years reduced the risk of coronary disease in elderly individuals PROSPER therefore extends to elderly individuals the treatment strategy currently used in middle aged people Shepherd J et al. Lancet 2002;360:1623–1630

Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) Randomized, double-blind, placebo-controlled trial To compare lovastatin with placebo for prevention of the first acute major coronary event (UA, fatal and non-fatal MI and sudden cardiac death) 6605 pts without CHD , 5608 men and 997 women Average follow-up was 5.2 years Lovastatin (20-40 mg daily) or placebo Downs JR, et al, JAMA 1998;279:1615-1622

AFCAPS/TexCAPS Endpoints Primary First Acute Major Coronary Event (UA, Fatal or Non-fatal MI ,Sudden Cardiac Death) Secondary Fatal or Non-Fatal MI Unstable Angina Fatal or Non-Fatal Cardiovascular Events Fatal or Non-Fatal Coronary Events Tertiary Endpoints Total Mortality, Non-Cardiovascular Mortality Fatal and Non-Fatal Cancer Discontinuation of Medication because of Adverse Effects Downs JR, et al, JAMA 1998;279:1615-1622

Baseline Characteristics(AFCAPS) Downs JR, et al, JAMA 1998;279:1615-1622

Baseline Characteristics(AFCAPS) Downs JR, et al, JAMA 1998;279:1615-1622

Baseline Lipid Levels Compared with U. S Baseline Lipid Levels Compared with U.S. Reference Population Based Upon NHANES III 1 Percentile ranks from US NHANES III reference population for study population averages 2 Men aged 45-73, and women aged 55-73, without cardiovascular disease Downs JR, et al, JAMA 1998;279:1615-1622

AFCAPS Reduction in Lipids-year Placebo 228.1 + 27.7 156.4 + 24.5 37.5 + 7.9 162.8 + 82.1 4.3 + 1.1 6.3 + 2.5 Lovastatin 183.7 + 23.8 114.6 + 20.1 39.3 + 8.0 142.8 + 72.8 3.0 + 0.8 4.8 + 1.0 Mean TC Mean LDL-C Mean HDL-C Median TG Ratios Mean LDL-C/HDL-C Mean TC/HDL-C Downs JR, et al, JAMA 1998;279:1615-1622

Percent Change in Lipid Parameters Baseline to Year 1 p-value < 0.001 for all lovastatin treatment groups 42% of lovastatin patients achieved LDL-C goal of < 110 mg/dL (placebo 3%) 81% of lovastatin patients achieved LDL-C goal of < 130 mg/dL (placebo 12%) TC LDL HDL TG TC/HDL LDL/HDL Downs JR, et al, JAMA 1998;279:1615-1622

Primary Endpoint ~ First Acute Major Coronary Event* 0.06 *Includes unstable angina, fatal and non-fatal MI & sudden cardiac death 0.05 Placebo 37% Risk Reduction (p < 0.001) 0.04 Cumulative Incidence 0.03 Lovastatin 0.02 0.01 0.00 1 2 3 4 5 5+ Years # At Risk Years of Follow-up Lovastatin N=3304 N=3270 N=3228 N=3184 N=3134 N=1688 Placebo N=3301 N=3251 N=3211 N=3159 N=3092 N=1644 Downs JR, et al, JAMA 1998;279:1615-1622

Primary Endpoint ~ First Acute Major Coronary Event* Fatal & Non-fatal MI, Unstable Angina, Sudden Cardiac Death reduced by 37% (p < 0.0008) Downs JR, et al, JAMA 1998;279:1615-1622

Lovastatin Reduced the Risk of First Acute Major Coronary Events > Median by Age N=3180 Men N=5608 Women N=997 Smokers N=818 Hypertension N=1448 Diabetes N=156 Downs JR, et al, JAMA 1998;279:1615-1622

Lovastatin Reduced the Risk of First Acute Major Coronary Events in All Baseline LDL Tertiles Downs JR, et al, JAMA 1998;279:1615-1622

AFCAPS/TexCAPS Role of Baseline LDL on Outcomes Baseline LDL Level (mg/dL) Downs JR, et al, JAMA 1998;279:1615-1622

AFCAPS/TexCAPS Role of Baseline HDL on Outcomes Baseline HDL Level (mg/dL) Downs JR, et al, JAMA 1998;279:1615-1622

Secondary Endpoint Analyses Cardiovascular Events* Fatal and Non-Fatal MI 0.03 0.08 0.07 Placebo 25% Risk Reduction (p = 0.003) Placebo 40% Risk Reduction (p = 0.002) 0.06 0.02 0.05 Cumulative Incidence Cumulative Incidence 0.04 Lovastatin 0.03 Lovastatin 0.01 0.02 0.01 0.00 0.00 1 2 3 4 5 5+ years 1 2 3 4 5 5+ years Years of Follow-up N=3304 N=3260 N=3206 N=3147 N=3088 N=1651 N=3301 N=3242 N=3187 N=3124 N=3045 N=1615 # At Risk Lovastatin Placebo Years of Follow-up N=3304 N=3281 N=3249 N=3214 N=3174 N=1717 N=3301 N=3270 N=3237 N=3200 N=3148 N=1692 # At Risk Lovastatin Placebo Unstable Angina Coronary Events* 0.03 0.07 Placebo 32% Risk Reduction (p = 0.02) 0.06 Placebo 25% Risk Reduction (p = 0.006) 0.05 0.02 0.04 Cumulative Incidence Cumulative Incidence 0.03 Lovastatin 0.01 Lovastatin 0.02 0.01 0.00 0.00 1 2 3 4 5 5+ years 1 2 3 4 5 5+ years Years of Follow-up Years of Follow-up N=3304 N=3281 N=3250 N=3217 N=3174 N=1707 N=3301 N=3267 N=3240 N=3205 N=3150 N=1678 # At Risk Lovastatin Placebo N=3304 N=3264 N=3215 N=3160 N=3106 N=1666 N=3301 N=3246 N=3201 N=3141 N=3069 N=1634 # At Risk Lovastatin Placebo Downs JR, et al, JAMA 1998;279:1615-1622

AFCAPS/TexCAPS Coronary Revascularizations 0.05 0.04 33% Risk Reduction (p = 0.001) Placebo 0.03 Cumulative Incidence 0.02 Lovastatin 0.01 0.00 1 2 3 4 5 5+ Years Years of Follow-up N=3304 N=3277 N=3237 N=3192 N=3148 N=1691 N=3301 N=3258 N=3221 N=3174 N=3108 N=1659 # At Risk Lovastatin Placebo Downs JR, et al, JAMA 1998;279:1615-1622

AFCAPS/TexCAPS Mortality Placebo Lovastatin Event n=3301 n=3304 P-value Total Mortality 77 80 N.S. Cardiovascular 25 17 too few* Non-cardiovascular 52 63 N.S. *Too few for survival analyses Downs JR, et al, JAMA 1998;279:1615-1622

Tertiary Analysis Fatal and Non-Fatal Cancer* 0.08 *Excludes non-melanoma skin cancer 0.07 P = NS Placebo 0.06 0.05 Lovastatin Cumulative Incidence 0.04 0.03 0.02 0.01 0.00 1 2 3 4 5 5+ years Years of Follow-up # At Risk Lovastatin N=3304 N=3249 N=3188 N=3117 N=3059 N=1626 Placebo N=3301 N=3234 N=3171 N=3105 N=3043 N=1603 Downs JR, et al, JAMA 1998;279:1615-1622

AFCAPS/TexCAPS Summary of Results Clinical benefit appeared within the first year of treatment and continued was apparent for all LDL-C tertiles Range 90-235 mg/dl was consistent for subgroups Women Risk Factors - Age, DM, HTN, Smokers Downs JR, et al, JAMA 1998;279:1615-1622

AFCAPS/TexCAPS Conclusions In conjunction with a prudent diet, regular exercise and risk factor modification Lovastatin 20-40 mg/day could be used to lower the risk of the first acute major coronary event for primary prevention candidates - Men > 45 years, Women > 55 years HDL < 50 mg/dl LDL > 130 mg/dl Downs JR, et al, JAMA 1998;279:1615-1622

The Anglo-Scandinavian Cardiac outcomes Trial (ASCOT ) Multicenter trial with 2 treatment comparison A prospective, randomized, open, blinded end point design comparing 2 antihypertensive regimen A double blind placebo controlled trial of atorvastatin 10mg/day in the substrate of patients with total cholesterol ≤250mg/dl Primary end point: nonfatal MI or CHD death Planned follow up average of 5yr

The Anglo-Scandinavian Cardiac outcomes Trial Sever PS et al, Lancet 2003; 361:1149.

ASCOT-LLA trial Sever PS et al, Lancet 2003; 361:1149.

ASCOT-LLA trial Sever PS et al, Lancet 2003; 361:1149.

ASCOT-LLA trial Sever PS et al, Eur Heart J 2008;29:499–508

ASCOT-LLA trial Sever PS et al, Eur Heart J 2008;29:499–508

ASCOT-LLA trial Extension Sever PS et al, Eur Heart J 2008;29:499–508

The Anglo-Scandinavian Cardiac Outcomes Trial: 11-year mortality follow-up of the lipid-lowering arm in the UK The aim of this study was to determine the outcome benefits in those originally assigned atorvastatin in ASCOT Trial—8 years after closure of the lipid-lowering arm of the trial among the UK population Post trial mortality data were collected every 2-3months Sever PS et al, Eur Heart J August 28, 2011

ASCOT-LLA 11 year mortality study profile Sever PS et al, Eur Heart J August 28, 2011

ASCOT-LLA trial Extension Sever PS et al, Eur Heart J August 28, 2011

ASCOT-LLA trial Extension Sever PS et al, Eur Heart J August 28, 2011

ASCOT-LLA trial Extension Sever PS et al, Eur Heart J August 28, 2011

ASCOT-LLA trial Extension Sever PS et al, Eur Heart J August 28, 2011

Collaborative Atorvastatin Diabetes Study (CARDS) Patient Population Atorvastatin 10 mg (n=1428) Type 2 diabetes mellitus Men and women 40–75 years of age LDL-C 160 mg/dL (4.14 mmol/L) TG 600 mg/dL (6.78 mmol/L) 1 additional RF HTN (or on HTN treatment) Retinopathy Albuminuria Current smoking 2838 patients 4-year follow-up Double-blind placebo (n=1410) Primary endpoint: time to first major CV event (CHD death, nonfatal MI, unstable angina, resuscitated cardiac arrest, coronary revascularization, stroke Secondary endpoints: total mortality, any CV endpoint, lipids, and lipoproteins Colhoun HM et al. Lancet 2004;364:685-696.

CARDS: Patient Baseline Characteristics Placebo (n = 1410) Atorvastatin (n = 1428) Age Mean (SD) years 61.8 (8.0) 61.5 (8.3) <60 529 (38%) 558 (39%) 60–70 708 (50%) 703 (49%) >70 173 (12%) 167 (12%) Women 453 (32%) 456 (32%) White ethnicity 1326 (94%) 1350 (95%) BMI Mean (SD), kg/m2 28.8 (3.5) 28.7 (3.6) Obese (BMI >30 kg/m2) 538 (38%) 515 (36%) Colhoun HM et al. Lancet 2004;364:685-696.

CARDS: Patient Baseline Lipids Placebo (n = 1410) Mean (SD) Atorvastatin (n = 1428) Mean (SD) Total cholesterol (mg/dL) (mmol/L) 207 (32) 5.35 (0.82) 207 (32) 5.36 (0.83) LDL cholesterol (mg/dL) (mmol/L) 117 (27) 3.02 (0.70) 118 (28) 3.04 (0.72) HDL cholesterol (mg/dL) (mmol/L) 55 (13) 1.42 (0.34) 54 (12) 1.39 (0.32) Triglycerides* (mg/dL) (mmol/L) 148 (104–212) 1.67 (1.17–2.40) 150 (106–212) 1.70 (1.20–2.40) *Median (interquartile range) Colhoun HM et al. Lancet 2004;364:685-696.

CARDS: Lipid Levels by Treatment Total Cholesterol (mg/dL) Average difference 26%, 54 mg/dL; P<0.0001 LDL Cholesterol (mg/dL) Average difference 40%, 46 mg/dL; P<0.0001 Placebo Placebo Median LDL-C (mg/dL)* Median TC (mg/dL)* Atorvastatin Atorvastatin 1 2 3 4 4.5 1 2 3 4 4.5 Years of Study Years of Study Colhoun HM et al. Lancet 2004;364:685-696.

Relative Risk Reduction 37% (95% CI, 17–52) P = 0.001 CARDS: Effect of Atorvastatin on the Primary Endpoint: Major CV Events Including Stroke Relative Risk Reduction 37% (95% CI, 17–52) P = 0.001 Placebo 127 events Cumulative Hazard, (%) Atorvastatin 83 events 1 2 3 4 4.75 Years Placebo Atorvastatin 1410 1428 1351 1392 1306 1361 1022 1074 651 694 305 328 Colhoun HM et al. Lancet 2004;364:685-696.

CARDS: Adverse and Serious Adverse Events Type of Event Patients (%) with Event Placebo (n = 1410) Atorvastatin 10 mg (n = 1428) Serious adverse event possibly associated with study drug 20 (1.1%) 19 (1.1%) Discontinued for AE 145 (10%) 122 (9%) Rhabdomyolysis Myopathy AE report 1 (0.1%) CPK 10  ULN 10 (0.7%) 2 (0.1%) ALT 3  ULN 14 (1%) 17 (1%) AST 3  ULN 4 (0.3%) 6 (0.4%) Colhoun HM et al. Lancet 2004;364:685-696.

CARDS Implications and Clinical Relevance In patients with Type 2 DM with lower LDL-C levels, atorvastatin 10 mg daily was safe, well tolerated & significantly efficacious in reducing the risk of first CHD events  CARDS supports recommendations that made by the ADA that patients with Type 2 DM should be considered as candidates for statin treatment—even at lower LDL-C levels Colhoun HM et al. Lancet 2004;364:685-696.

Lipid-Altering Drug, mg/d CHD* Risk vs Placebo in Diabetic Patients, % Primary Prevention Trials of Lipid-Altering Therapy Including Patients with Diabetes Trial Diabetic,* n Total N in Study Lipid-Altering Drug, mg/d CHD* Risk vs Placebo in Diabetic Patients, % CARDS † 2,838 Atorvastatin 10 –37 (p=.001) AFCAPS 155 6,605 Lovastatin 20–40 ‡ –44 (NS) HPS § 2,912 7,150 Simvastatin 40 –33 (p=.0003) ASCOT 2,532 10,305 –16 (NS) PROSPER 623 5,804 Pravastatin 40 +27 (NS) HHS 135 4,081 Gemfibrozil 1200 –68 (NS) * By history † Prospective trial in diabetic subjects; others are subgroup analyses ‡ Mean 30 mg/d § Type 1 or 2 diabetes Bays H et al. Future Cardiology 2005;1:39-59. | Colhoun HM et al. Lancet 2004;364:685-696. | Downs JR et al. JAMA 1998;279:1615-1622. | HPS Collaborative Group. Lancet 2003;361:2005-2016. | Sever PS et al. Lancet 2003;361:1149-1158. | Shepherd J et al. Lancet 2002;360:1623-1630. | Koskinen P et al. Diabetes Care 1992;15:820-825.

Measuring Effects of Intima-Media Thickness: An Evaluation of Rosuvastatin METEOR Trial Evaluated the effect of rosuvastatin compared with placebo on carotid intima-media thickness (CIMT) among asymptomatic patients at low risk for cardiovascular disease Study period was two-year Randomized controlled trial Rosuvastatin 40 mg daily vs placebo Crouse JR 3rd, et al, JAMA 2007; 297:1344.

METEOR Trial: Study Design 984 asymptomatic patients with moderately elevated cholesterol and low risk of CVD according to the National Cholesterol Education Program Adult Treatment Panel III guidelines criteria (0-1 risk factor and LDL 120-190mg/dL or > 2 risk factors and LDL 120 to <160mg/dL with a 10-year coronary heart disease risk < 10%); HDL-C <60mg/dL; triglycerides <500mg/dL; evidence of thickening of the walls of the extracranial carotid arteries as measured by B-mode ultrasound (max CIMT between 1.2 and <3.5mm) 5:2 Randomized. Double-blinded. Placebo-controlled. Mean age = 57 years. 40% Female. R Rosuvastatin (40mg) n=702 Placebo n=282 6, 12, 18 and 24 mos. follow-up Primary Endpoint: Annualized rate of change in maximum CIMT Secondary Endpoint: Annualized rate of change in maximum CIMT derived from the near and far walls of the right and left common carotid artery; the right and left carotid bulb; the right and left internal carotid artery; and annualized rate of change in mean CIMT for the near and far walls of the right and left common carotid artery.

METEOR Trial: Primary Endpoint Change in maximum CIMT with rosuvastatin vs. placebo After two years, treatment with rosuvastatin was associated with a statistically significant reduction in the rate of progression of CIMT thickening in overall carotid segments, while the placebo group displayed progression (p<0.001). p < 0.001 Change in CIMT for 12 Carotid Artery sites (mm/year) Rosuvastatin n = 282 n = 702 Placebo

METEOR Trial: Secondary Endpoint Change in maximum CIMT with rosuvastatin vs. placebo After two years, treatment with rosuvastatin was associated with a statistically significant reduction in the rate of progression of CIMT thickening in common carotid sites, while the placebo group displayed progression (p<0.001). p < 0.001 Change in CIMT for common carotid sites (mm/year) Rosuvastatin n = 282 n = 702 Placebo

METEOR Trial: Secondary Endpoint Change in maximum CIMT with rosuvastatin vs. placebo After two years, treatment with rosuvastatin was associated with a statistically significant reduction in the rate of progression of CIMT thickening in carotid bulb sites, while the placebo group displayed progression (p<0.001). p < 0.001 Change in CIMT for carotid bulb sites (mm/year) Rosuvastatin n = 282 n = 702 Placebo

METEOR Trial: Secondary Endpoint Change in maximum CIMT with rosuvastatin vs. placebo After two years, treatment with rosuvastatin was associated with a statistically significant lower progression in CIMT thickening in internal carotid sites as compared with the placebo group (p=0.02) p = 0.02 Change in CIMT for internal carotid artery sites (mm/year) n = 702 n = 282 Rosuvastatin Placebo

METEOR Trial: Limitations & Summary Compared with placebo, subjects treated with rosuvastatin had a marked reduction in LDL-cholesterol (-49 versus -0.3 percent) The study was not designed to evaluate clinical events, It is uncertain how well changes in CIMT predict clinical events, particularly in this low risk population. This study does not convincingly support the use of high dose statins (such as rosuvastatin 40 mg daily) for primary prevention in patients at low risk for CHD events

Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) JUPITER is the first large-scale, prospective study to examine the role of statin therapy in individuals with low to normal LDL-C levels, but with increased cardiovascular risk identified by elevated CRP Nearly half of all cardiovascular events occur in patients who are apparently healthy and who have low or normal levels of LDL-C hsCRP predicts cardiovascular disease independent of LDL-C levels Ridker et al, NEJM 2008359:2195-07

JUPITER Rosuvastatin 20 mg (N=8901) Placebo (N=8901) MI Stroke Unstable Angina CVD Death CABG/PTCA Rosuvastatin 20 mg (N=8901) No Prior CVD or DM Men >50, Women >60 LDL <130 mg/dL hsCRP >2 mg/L Placebo (N=8901) 4-week run-in Baseline LDLC 104 mg/dL Baseline HDLC 49 mg/dL Baseline hsCRP 4.2 mg/L Women 6,800 Non-Caucasian 5,000 Ridker et al, NEJM 2008359:2195-07

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death JUPITER Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death HR 0.56, 95% CI 0.46-0.69 P < 0.00001 Placebo 251 / 8901 0.08 Number Needed to Treat (NNT5) = 25 - 44 % 0.06 Cumulative Incidence 0.04 Rosuvastatin 142 / 8901 0.02 0.00 1 2 3 4 Follow-up (years) Number at Risk Rosuvastatin 8,901 8,631 8,412 6,540 3,893 1,958 1,353 983 544 157 Placebo 8,901 8,621 8,353 6,508 3,872 1,963 1,333 955 534 174 Ridker et al, NEJM 2008359:2195-07

JUPITER Grouped Components of the Primary Endpoint Myocardial Infarction, Stroke, or Cardiovascular Death Arterial Revascularization or Hospitalization for Unstable Angina HR 0.53, CI 0.40-0.69 P < 0.00001 HR 0.53, CI 0.40-0.70 P < 0.00001 0.05 Placebo 0.06 Placebo 0.04 0.05 0.04 0.03 - 47 % Cumulative Incidence Cumulative Incidence 0.03 - 47 % 0.02 0.02 Rosuvastatin 0.01 Rosuvastatin 0.01 0.00 0.00 1 2 3 4 1 2 3 4 Follow-up (years) Follow-up (years) Ridker et al, NEJM 2008359:2195-07

JUPITER Individual components of the Primary Endpoint Endpoint Rosuvastatin Placebo HR 95%CI P Primary Endpoint* 142 251 0.56 0.46-0.69 <0.00001 Non-fatal MI 22 62 0.35 0.22-0.58 <0.00001 Any MI 31 68 0.46 0.30-0.70 <0.0002 Non-fatal Stroke 30 58 0.52 0.33-0.80 0.003 Any Stroke 33 64 0.52 0.34-0.79 0.002 Revascularization or Unstable Angina 76 143 0.53 0.40-0.70 <0.00001 MI, Stroke, CV Death 83 157 0.53 0.40-0.69 <0.00001 *Nonfatal MI, nonfatal stroke, revascularization, unstable angina, CV death Ridker et al, NEJM 2008359:2195-07

JUPITER Primary Endpoint – Subgroup Analysis P for Interaction Men 11,001 0.80 Women 6,801 Age < 65 8,541 0.32 Age > 65 9,261 Smoker 2,820 0.63 Non-Smoker 14,975 Caucasian 12,683 0.57 Non-Caucasian 5,117 USA/Canada 6,041 0.51 Rest of World 11,761 Hypertension 10,208 0.53 No Hypertension 7,586 All Participants 17,802 0.25 0.5 1.0 2.0 4.0 Rosuvastatin Superior Rosuvastatin Inferior Ridker et al, NEJM 2008359:2195-07

JUPITER Primary Endpoint – Subgroup Analysis P for Interaction Family HX of CHD 2,045 0.07 No Family HX of CHD 15,684 BMI < 25 kg/m 2 4,073 0.70 BMI 25-29.9 kg/m 7,009 2 BMI > 30 kg/m 2 6,675 Metabolic Syndrome 7,375 0.14 No Metabolic Syndrome 10,296 Framingham Risk < 10% 8,882 0.99 Framingham Risk > 10% 8,895 hsCRP > 2 mg/L Only 6,375 hsCRP > 2 mg/L Only 6,375 All Participants 17,802 0.25 0.5 1.0 2.0 4.0 Rosuvastatin Superior Rosuvastatin Inferior Ridker et al, NEJM 2008359:2195-07

JUPITER Adverse Events and Measured Safety Parameters Event Rosuvastatin Placebo P Muscle weakness 1,421 (16.0) 1,375 (15.4) 0.34 Myopathy 10 (0.1) 9 (0.1) 0.82 Rhabdomyolysis 1 (0.01)* 0 (0.0) -- Incident Cancer 298 (3.4) 314 (3.5) 0.51 Cancer Deaths 35 (0.4) 58 (0.7) 0.02 Hemorrhagic stroke 6 (0.1) 9 (0.1) 0.44 GFR (ml/min/1.73m2 at 12 mth) 66.8 (59.1-76.5) 66.6 (58.8-76.2) 0.02 ALT > 3xULN 23 (0.3) 17 (0.2) 0.34 Fasting glucose (24 mth) 98 (91-107) 98 (90-106) 0.12 HbA1c (% at 24 mth) 5.9 (5.7-6.1) 5.8 (5.6-6.1) 0.01 Glucosuria (12 mth) 36 (0.5) 32 (0.4) 0.64 Incident Diabetes** 270 (3.0) 216 (2.4) 0.01 *Occurred after trial completion, trauma induced. All values are median (interquartile range) or N (%) **Physician reported Ridker et al, NEJM 2008359:2195-07

JUPITER Statins and the Development of Diabetes HR (95% CI) WOSCOPS Pravastatin 0.70 (0.50–0.98) PROSPER Pravastatin 1.34 (1.06–1.68) HPS Simvastatin 1.20 (0.98–1.35) ASCOT-LLA Atorvastatin 1.20 (0.91–1.44) PROVE-IT Atorvastatin VS Pravastatin 1.11 (0.67–1.83) JUPITER Rosuvastatin 1.25 (1.05–1.54) 0.25 0.5 1.0 2 4 Statin Better Statin Worse Ridker et al, NEJM 2008359:2195-07

JUPITER Secondary Endpoint – All Cause Mortality HR 0.80, 95%CI 0.67-0.97 P= 0.02 Placebo 247 / 8901 0.06 - 20 % 0.05 0.04 Cumulative Incidence 0.03 Rosuvastatin 198 / 8901 0.02 0.01 0.00 1 2 3 4 Follow-up (years) Number at Risk Rosuvastatin 8,901 8,847 8,787 6,999 4,312 2,268 1,602 1,192 683 227 Placebo 8,901 8,852 8,775 6,987 4,319 2,295 1,614 1,196 684 246 Ridker et al, NEJM 2008359:2195-07

JUPITER Conclusions In this trial of low LDL/high hsCRP individuals who do not currently qualify for statin therapy, rosuvastatin significantly reduced All-cause mortality by 20 percent Incident myocardial infarction, stroke, and cardiovascular death by 47 percent Ridker et al, NEJM 2008359:2195-07

CONCLUDE Statin trials in primary prevention, starting with the landmark WOSCOPS trial, have found substantial relative reductions in cardiovascular events without an increase in noncardiovascular mortality In view of the evidence, statins should be seriously considered in people with diabetes at least by age 50 in men and 60 in women Also, men aged 55 years or above with multiple risk factors, and women aged 65 years or above, should be seriously considered for generic statin use.

THANK YOU