6. A Randomized Trial of Rosuvastatin in the Prevention of Cardiovascular Events Among 17,802 Apparently Healthy Men and Women With Elevated Levels of C-Reactive Protein (hsCRP): The JUPITER Trial Paul Ridker, Eleanor Danielson, Francisco Fonseca, Jacques Genest, Antonio Gotto, John Kastelein, Wolfgang Koenig, Peter Libby, Alberto Lorenzatti, Jean MacFadyen, Borge Nordestgaard, James Shepherd, James Willerson, and Robert Glynn on behalf of the JUPITER Trial Study Group

7. Independent Steering Committee : P Ridker (Chair), F Fonseca, J Genest, A Gotto, J Kastelein, W Koenig, P Libby, A Lorenzatti, B Nordestgaard, J Shepherd, J Willerson Independent Academic Clinical Coordinating Center: P Ridker, E Danielson, R Glynn, J MacFadyen, S Mora (Boston) Independent Academic Study Statistician: R Glynn (Boston) Independent Data Monitoring Board: R Collins (Chair), K Bailey, B Gersh, G Lamas, S Smith, D Vaughan Independent Academic Clinical Endpoint Committee: K Mahaffey (Chair), P Brown,D Montgomery, M Wilson, F Wood (Durham)

8. 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 It assessed the long-term impact of rosuvastatin in individuals potentially at increased cardiovascular risk due to elevated CRP levels who do not qualify for lipid- lowering treatment according to current guidelines Adapted from Ridker et al. N Eng J Med 2008;359: 2195-207.

9. JUPITER - Rationale 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 Along with improved screening there is a need to examine the use of lipid-lowering agents as a method of reducing the risk of cardiovascular events Adapted from: Ridker PM. Circulation 2003; 108: 2292-97. Ridker PM. Am J Cardiol 2007; 100: 1659-64. Ridker PM. New Engl J Med 2002; 347: 1557-65. Ridker PM. Am J Cardiol 2003;92(suppl):17K-22K.

10. JUPITER: Background and Prior Work Current guidelines for the prevention of myocardial infarction stroke, and cardiovascular death endorse statin therapy among patients with established vascular disease, diabetes, and among those with hyperlidemia. However, these screening and treatment strategies are insufficient as half of all heart attack and stroke events occur among apparently healthy men and women with average or even low levels of cholesterol. Adapted from Ridker et al.NEJM 2008.

11. JUPITER: Background and Prior Work To improve detection of individuals at increased risk for cardiovascular disease, physicians often measure high sensitivity C-reactive protein (hsCRP), an inflammatory biomarker that reproducibly and independently predicts future vascular events and improves global risk classification, even when cholesterol levels are low. Prior work has shown that statin therapy reduces hsCRP, and that among stable coronary disease patients as well as those with acute ischemia, the benefit associated with statin therapy relates not only to achieving low levels of LDL, but also to achieving low levels of hsCRP. Adapted from Ridker et al. NEJM 2008.

12. Efficacy of lovastatin in AFCAPS/TexCAPS subgroups by baseline LDL-C and hsCRP Study group Rate of cardiovascular events NNT LovastatinPlacebo Low LDL-C/low hsCRP0.0250.022N/A Low LDL-C/high hsCRP0.0290.05148 High LDL-C/low hsCRP0.0200.05033 High LDL-C/high hsCRP0.0380.05558 Median LDL-C=3.9 mmol/L (149 mg/dL). Median hsCRP=1.6 mg/L AFCAPS/TexCAPS=Air Force/Texas Coronary Atherosclerosis Prevention Study; hsCRP=high- sensitivity C-reactive protein; LDL-C=low-density lipoprotein cholesterol; N/A=not applicable; NNT=number needed to treat to prevent one coronary event Adapted from Ridker et al. N Engl J Med 2001;344:1959-65.

13. JUPITER population compared with previous trials in patients without established CHD AFCAPSWOSCOPSJUPITER Patients, n6605 659517 802 % male8510062 Duration, years5.24.91.9 Diabetes, %610 Baseline lipids, mmol/L* total cholesterol5.727.034.73 LDL-C3.884.972.69 HDL-C0.93–1.031.141.32 triglycerides1.781.851.56 hsCRP, mg/L0.2NA4.3 Statin Lovastatin 20–40 mg Pravastatin 40 mg Rosuvastatin 20 mg CVD=cardiovascular disease; CHD=coronary heart disease; LDL-C=low-density lipoprotein cholesterol; HDL-C=high- density lipoprotein cholesterol; hsCRP=high sensitivity C-reactive protein; AFCAPS=Airforce/Texas Coronary Atherosclerosis Prevention Study; WOSCOPS=West of Scotland Coronary Prevention Study; *Baseline lipid levels are mean values. Adapted from: Ridker et al. Am J Cardiol 2007;100:1659-64. Ridker et al. N Engl J Med. 2001;344:1959-65.

14. JUPITERWOSCOPS AFCAPS Sample size (n)17,8026,595 6,605 Women (n) 6,801 0 997 Minority (n) 5,118 0 350 Duration (yrs)1.9 (max 5) 4.9 5.2 Diabetes (%) 0 1 6 Baseline LDL-C (mg/dL) 108 192 150 Baseline HDL-C (mg/dL) 49 44 36-40 Baseline TG (mg/dL) 118 164 158 Baseline hsCRP (mg/L) > 2 NA NA InterventionRosuvastatinPravastatinLovastatin 20 mg40 mg10-40 mg Adapted from JUPITER Trial Study Group, Am J Cardiol 2007. Comparison of the JUPITER Trial Population to Previous Statin Trials of Primary Prevention

15. JUPITER: Why Consider Statins for Low LDL, high hsCRP Patients? In 2001, in an hypothesis generating analysis of apparently healthy individuals in the AFCAPS / TexCAPS trial*, we observed that those with low levels of both LDL and hsCRP had extremely low vascular event rates and that statin therapy did not reduce events in this subgroup (N=1,448, HR 1.1, 95% CI 0.56-2.08). Thus, a trial of statin therapy in patients with low cholesterol and low hsCRP would not only be infeasible in terms of power and sample size, but would be highly unlikely to show clinical benefit. In contrast, we also observed within AFCAPS/TexCAPS that among those with low LDL but high hsCRP, vascular event rates were just as high as rates among those with overt hyperlipidemia, and that statin therapy significantly reduced events in this subgroup (N=1,428, HR 0.6, 95% CI 0.34-0.98). Adapted from *Ridker et al. N Engl J Med 2001;344:1959-65.

16. JUPITER: Why Consider Statins for Low LDL, High hsCRP Patients? However, while intriguing and of potential public health importance, the observation in AFCAPS/TexCAPS that statin therapy might be effective among those with elevated hsCRP but low cholesterol was made on a post hoc basis. Thus, a large-scale randomized trial of statin therapy was needed to directly test this hypotheses. Adapted from Ridker et al. New Engl J Med 2001;344:1959-65. Low LDL, Low hsCRP Low LDL, High hsCRP Statin EffectiveStatin Not Effective 1.0 2.0 0.5 [A] [B] Low LDL, Low hsCRP Low LDL, High hsCRP Statin EffectiveStatin Not Effective 1.0 2.0 0.5 AFCAPS/TexCAPS Low LDL Subgroups RR

17. JUPITER - Objective The primary objective was to investigate whether long-term treatment with rosuvastatin 20 mg decreases the rate of first major cardiovascular events compared with placebo in patients with low to normal LDL-C but at increased cardiovascular risk as identified by elevated CRP levels. Adapted from Ridker et al. Circulation 2003;108:2292-97.

18. Rosuvastatin 20 mg (N=8901) MIStrokeUnstable Angina Angina CVD Death CABG/PTCA JUPITER Multi-National Randomized Double Blind Placebo Controlled Trial of Rosuvastatin in the Prevention of Cardiovascular Events Among Individuals With Low LDL and Elevated hsCRP 4-week run-in Adapted from Ridker et al. Circulation 2003;108:2292-97. No Prior CVD or DM Men >50, Women >60 LDL <130 mg/dL hsCRP >2 mg/L JUPITER: Trial Design Placebo (N=8901) Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica, Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands, Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland, United Kingdom, Uruguay, United States, Venezuela

19. JUPITER – Study Design Lipids CRP Tolerability Lipids CRP Tolerability HbA 1C Placebo run-in 1 –6 2 –4 3030 4 13 Final 6-monthly Visit: Week: Randomisation Lipids CRP Tolerability Rosuvastatin 20 mg (n=8901) Placebo (n=8901) Lead-in/ eligibility No history of CAD men ≥50 yrs women ≥60 yrs LDL-C <130 mg/dL CRP ≥2.0 mg/L CAD=coronary artery disease; LDL-C=low-density lipoprotein cholesterol; CRP=C-reactive protein; HbA 1c =glycated haemoglobin Median follow-up 1.9 years Adapted from Ridker et al. N Eng J Med 2008;359:2195-207.

20. JUPITER: 17,802 Patients, 1,315 Sites, 26 Countries 4021 2873 2497 2020 987 804 741 487 345 336 327 273270 253 222 209 204202197 162 143 8583 32 1514 0% 5% 10% 15% 20% 25% Uruguay Switzerland Romania Chile Estonia Israel El Salvador Bulgaria Panama Norway Venezuela Germany Argentina Costa Rica Russia Brazil Denmark Colombia Belgium Mexico Poland The Netherlands Canada South Africa United Kingdom United States Randomizations (% Total.) Total Randomized = 17,802 Adapted from Ridker et al. NEJM 2008.

21. JUPITER - Patient Flow 89,890 subjects screened 17,802 randomised Rosuvastatin 20mg n=8,901 Placebo n=8,901 Lost to follow up n=44 Completed study n=8,857 Lost to follow up n=37 Completed study n=8,864 Adapted from Ridker et al. N Eng J Med 2008;359: 2195-207.

22. JUPITER: Inclusion and Exclusion Criteria, Study Flow 89,863 Screened 17,802 Randomized 8,901 Assigned to Rosuvastatin 20 mg 8,901 Assigned to Placebo Reason for Exclusion (%) LDL-C > 130 mg/dL 53 hsCRP < 2.0 mg/L 37 Withdrew Consent 4 Diabetes 1 Hypothyroid <1 Liver Disease <1 TG > 500 mg/dL <1 Age out of range <1 Current Use of HRT <1 Cancer <1 Poor Compliance/Other 3 8,600 Completed Study 120 Lost to follow-up 8,600 Completed Study 120 Lost to follow-up 8,901 Included in Efficacy and Safety Analyses 8,901 Included in Efficacy and Safety Analyses 89,890 Screened Men > 50 years Women > 60 years No CVD, No DM LDL < 130 mg/dL hsCRP > 2 mg/L 17,802 Randomized Reason for Exclusion (%) LDL > 130 mg/dL 52 hsCRP < 2.0 mg/L 36 Withdrew Consent 5 Diabetes 1 Hypothyroid <1 Liver Disease <1 TG > 500 mg/dL <1 Age out of range <1 Current Use of HRT <1 Cancer <1 Poor Compliance/Other 3 4 week Placebo Run-In 8,857 Completed Study 44 Lost to follow-up 8,901 Assigned to Rosuvastatin 20 mg 8,901 Assigned to Placebo 8,864 Completed Study 37 Lost to follow-up 8,901 Included in Efficacy and Safety Analyses 8,901 Included in Efficacy and Safety Analyses Adapted from Ridker et al. NEJM 2008.

23. JUPITER - Major Exclusion Criteria Current use of statins or other lipid-lowering therapies Current use of post menopausal hormone replacement therapy Prior history of cardiovascular or cerebrovaascular events, such as MI, unstable angina, prior arterial revascularisation or stroke, or CHD-risk equivalents Chronic inflammatory condition, such as severe arthritis, lupus or inflammatory bowel disease and/or treatment with immunosuppressants Uncontrolled: –hypertension: SBP > 190 mmHg or DBP > 100 mmHg –hypothyroidism: TSH > 1.5 x ULN CK  3 x ULN Serum creatinine > 2.0 mg/dL Evidence of hepatic dysfunction (ALT > 2 x ULN) History of prior malignancy, alcohol or drug abuse CHD = coronary heart disease; CK = creatinine kinase; ULN = upper limit of normal; SBP = systolic blood pressure; DBP = diastolic blood pressure Adapted from: Ridker et al. N Eng J Med 2008;359:2195-207. Ridker PM. Circulation 2003;108:2292-97.

24. Age (years) 66 (60-71) 66 (60-71) Male sex (%) 61.562.1 Race (%) White71.471.1 Black12.412.6 Hispanic12.612.8 Other3.63.5 BMI (kg/m 2 ) 28.3 (25.3-32.0) 28.4 (25.3-32.0) Systolic BP (mmHg) 134 (124-145) 134 (124-145) Diastolic BP (mmHg) 80 (75-87) 80 (75-87) Rosuvastatin Placebo n=8901 n=8901 JUPITER - Baseline Characteristics * *All values are median (interquartile range) or N (%). Adapted from Ridker et al. N Eng J Med 2008;359:2195-207.

25. JUPITER: Baseline Blood Levels (median, interquartile range) RosuvastatinPlacebo (N = 8901)(n = 8901) hsCRP, mg/L4.2(2.8 - 7.1)4.3 (2.8 - 7.2) LDL, mg/dL 108 (94 - 119)108(94 - 119) HDL, mg/dL49(40 – 60)49(40 – 60) Triglycerides, mg/L118(85 - 169)118 (86 - 169) Total Cholesterol, mg/dL186 (168 - 200)185(169 - 199) Glucose, mg/dL94(87 – 102)94(88 – 102) HbA1c, %5.7(5.4 – 5.9)5.7 (5.5 – 5.9) All values are median (interquartile range). [ Mean LDL = 104 mg/dL ] Adapted from Ridker et al. NEJM 2008.

26. Total cholesterol (mmol/L) 4.81 (4.34-5.17) 4.78 (4.37-5.15) LDL cholesterol (mmol/L) 2.79 (2.43-3.08) 2.79 (2.43-3.08) HDL cholesterol (mmol/L) 1.27 (1.03-1.55) 1.27 (1.03-1.55) Triglycerides (mmol/L) a1.33 (0.96-1.91) 1.33 (0.97-1.91) hsCRP (mg/L) 4.2 (2.8-7.1) 4.3 (2.8-7.2) Glucose (mmol/L) 5.2 (4.8-5.7) 5.2 (4.9-5.7) HbA 1c (%) 5.7 (5.4-5.9) 5.7 (5.5-5.9) Glomerular filtration rate, (ml/min/1.73m 2 ) 73.3 (64.6-83.7) 73.6 (64.6-84.1) Rosuvastatin Placebo n=a8901 n=8901 JUPITER - Baseline laboratory parameters * For hsCRP, values are the average of the values obtained at two screening visits *All values are median (interquartile range) or N (%). Adapted from Ridker et al. N Eng J Med 2008;359: 2195-207.

27. Current smoker (%) 15.716.0 Family history CHD † (%) 11.211.8 Metabolic syndrome ‡ (%) 41.041.8 Aspirin use (%) 16.616.6 Medical History Rosuvastatin Placebo n=8901 n=8901 JUPITER - Medical History †Family history of premature coronary heart disease (CHD) defined as first degree relative with CHD at age < 55 yrs (male), < 65 yrs (female); ‡ Metabolic syndrome defined according to consensus criteria of American Heart Association and the National Heart, Lung, and Blood Institute Adapted from Ridker et al. N Eng J Med 2008;359: 2195-207.

28. JUPITER - Study End Points Primary End Point –Time to the first occurrence of a major cardiovascular event, composite of: cardiovascular death Stroke MI unstable angina arterial revascularisation Secondary End Points: –total mortality –non-cardiovascular mortality –development of diabetes mellitus –development of venous thromboembolic events –bone fractures –discontinuation of study medication due to adverse effects. Adapted from Ridker et al. Circulation 2003;108:2292-97.

29. JUPITER: Primary Objectives To investigate whether rosuvastatin 20 mg compared to placebo would decrease the rate of first major cardiovascular events among apparently healthy men and women with LDL 2 mg/L. To enroll large numbers of women and individuals of Black or Hispanic ethnicity, groups for whom little data on primary prevention with statin therapy exists. Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin Adapted from Ridker et al. NEJM 2008.

30. hsCRP (mg/L) LDL (mg/dL) Months 012243648 TG (mg/dL) HDL (mg/dL) Months JUPITER: Effects of Rosuvastatin 20 mg on LDL, HDL, TG, and hsCRP LDL decrease 50 percent at 12 months hsCRP decrease 37 percent at 12 months HDL increase 4 percent at 12 months TG decrease 17 percent at 12 months Adapted from Ridker et al. NEJM 2008.

31. JUPITER: Adverse Events and Measured Safety Parameters Event RosuvastatinPlacebo P Any SAE1,352(15.2)1,337 (15.5)0.60 Muscle weakness1,421(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/1.73m 2 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 Adapted from Ridker et al. NEJM 2008.

32. JUPITER Primary Trial End Point: MI, Stroke, UA/Revascularization, CV Death Placebo 251/8901 Rosuvastatin 142 / 8901 HR 0.56, 95% CI 0.46-0.69 P<0.00001 - 44 % 01234 0.00 0.02 0.04 0.06 0.08 Cumulative Incidence Number at Risk Follow-up (years) Rosuvastatin Placebo 8,9018,6318,4126,5403,8931,9581,353983544157 8,9018,6218,3536,5083,8721,9631,333955534174 Adapted from Ridker et al. NEJM 2008.

33. JUPITER: Grouped Components of the Primary End Point HR 0.53, CI 0.40-0.70 P<0.00001 Rosuvastatin Placebo Myocardial Infarction, Stroke, or Cardiovascular Death Arterial Revascularization or Hospitalization for Unstable Angina HR 0.53, CI 0.40-0.69 P<0.00001 01234 0.00 0.01 0.02 0.03 0.04 0.05 0.06 Cumulative Incidence Follow-up (years) 01234 0.00 0.01 0.02 0.03 0.04 0.05 Cumulative Incidence Follow-up (years) Placebo Rosuvastatin - 47 % Adapted from Ridker et al. NEJM 2008.

34. JUPITER: Individual Components of the Primary End Point *Nonfatal MI, nonfatal stroke, revascularization, unstable angina, CV death Endpoint RosuvastatinPlaceboHR 95%CI P Primary Endpoint*1422510.56 0.46-0.69<0.00001 Non-fatal MI 22620.35 0.22-0.58<0.00001 Any MI31680.46 0.30-0.70 <0.0002 Non-fatal Stroke30580.52 0.33-0.80 0.003 Any Stroke33640.52 0.34-0.79 0.002 Revascularization or Unstable Angina761430.53 0.40-0.70<0.00001 MI, Stroke, CV Death831570.53 0.40-0.69<0.00001 Adapted from Ridker et al. NEJM 2008.

35. JUPITER: Primary End Point – Subgroup Analysis I 0.250.51.02.04.0 Rosuvastatin SuperiorRosuvastatin Inferior Men Women Age< 65 Age > 65 Smoker Non-Smoker Caucasian Non-Caucasian USA/Canada Rest of World Hypertension No Hypertension All Participants NP for Interaction 11,001 0.80 6,801 8,541 0.32 9,261 2,820 0.63 14,975 12,683 0.57 5,117 6,041 0.51 11,761 10,208 0.53 7,586 17,802 Adapted from Ridker et al. NEJM 2008.

36. 0.00 0.02 0.04 0.06 0.08 012345 Years Placebo Rosuvastatin 20 mg JUPITER - Primary End Point Time to first occurrence of a CV death, non-fatal stroke, non-fatal MI, unstable angina or arterial revascularisation Cumulative Incidence Number at risk Rosuvastatin 8901 8412 3893 1353 538 157 Placebo 8901 8353 3872 1333 531 174 Hazard Ratio 0.56 (95% CI 0.46-0.69) P<0.00001 Adapted from Ridker et al. N Eng J Med 2008;359:2195-207. NNT for 2 yrs = 95 5 yrs* = 25 *Extrapolated figure based on Altman and Andersen method

37. JUPITER - Primary End Point Components Primary Endpoint 251 (1.36) 142 (0.77)0.560.46-0.69 <0.001 * (Time to first occurrence of CV death, MI, stroke, unstable angina, arterial revascularisation) Non-fatal MI 62 (0.33) 22 (0.12)0.350.22-0.58 <0.001 * Fatal or non-fatal MI 68 (0.37) 31 (0.17)0.460.30-0.700.0002 Non-fatal stroke 58 (0.31) 30 (0.16)0.520.33-0.800.003 Fatal or non-fatal stroke 64 (0.34) 33 (0.18)0.520.34-0.790.002 Arterial Revascularization 131 (0.71) 71 (0.38)0.540.41-0.72 <0.0001 Unstable angina † 27 (0.14) 16 (0.09)0.590.32-1.100.09 CV death, stroke, MI 157 (0.85) 83 (0.45)0.530.40-0.69 <0.001 * Revascularization or unstable angina 143 (0.77) 76 (0.41)0.530.40-0.70 <0.001 * PlaceboRosuvastatinHR95% CIP value [n=8901][n=8901] n (rate ** ) HR=Hazard Ratio; CI =Confidence Interval ** Rates are per 100 person years; † Hospitalisation due to unstable angina; *Actual P-value was <0.00001 Adapted from Ridker et al. N Eng J Med 2008;359:2195-207.

38. JUPITER: Primary Endpoint – Subgroup Analysis II 0.250.51.02.04.0 Rosuvastatin SuperiorRosuvastatin Inferior Family HX of CHD No Family HX of CHD BMI < 25 kg/m 2 BMI 25-29.9 kg/m BMI> 30 kg/m Metabolic Syndrome No Metabolic Syndrome Framingham Risk< 10% Framingham Risk > 10% hsCRP > 2 mg/L Only All Participants NP for Interaction 2,045 0.07 15,684 4,073 0.70 7,009 6,675 7,375 0.14 10,296 8,882 0.99 8,895 6,375 17,802 2 2 hsCRP > 2 mg/L Only 6,375 Adapted from Ridker et al. NEJM 2008.

39. JUPITER: Secondary End Point – All Cause Mortality Placebo 247 / 8901 Rosuvastatin 198 / 8901 HR 0.80, 95%CI 0.67-0.97 P= 0.02 - 20 % 01234 0.00 0.01 0.02 0.03 0.04 0.05 0.06 Cumulative Incidence Number at Risk Follow-up (years) Rosuvastatin Placebo 8,9018,8478,7876,9994,3122,2681,6021,192683227 8,9018,8528,7756,9874,3192,2951,6141,196684246 Adapted from Ridker et al. NEJM 2008.

40. JUPITER: Statins and the Development of Diabetes 0.250.51.024 WOSCOPSPravastatin HPSSimvastatin ASCOT-LLAAtorvastatin JUPITERRosuvastatin PROVE-ITAtorvastatin VS Pravastatin 0.70 (0.50–0.98) 1.20 (0.98–1.35) 1.20 (0.91–1.44) 1.11 (0.67–1.83) 1.25 (1.05–1.54) Statin BetterStatin Worse HR (95% CI) PROSPERPravastatin 1.34 (1.06–1.68) Adapted from Ridker et al. NEJM 2008.

41. JUPITER: Predicted Benefit Based on LDL Reduction vs Observed Benefit Adapted from Ridker et al. NEJM 2008. Proportional reduction in vascular event rate (95% CI) Mean LDL cholesterol difference between treatment groups (mmol/L) IDEAL TNT A-to-Z CTT PROVE-IT JUPITER PREDICTED

42. JUPITER: Predicted Benefit Based on LDL Reduction vs Observed Benefit Proportional reduction in vascular event rate (95% CI) Mean LDL cholesterol difference between treatment groups (mmol/L) IDEAL TNT A-to-Z CTT PROVE-IT JUPITER PREDICTED JUPITER OBSERVED Adapted from Ridker et al. NEJM 2008.

43. Prevalence of conventional risk factors † in male patients with CHD None One Two Three Four (0.9%) Total male patients=87 869 CHD=coronary heart disease † smoking, hypertension, hypercholesterolaemia and diabetes mellitus 19.4% 43.0% 27.8% 8.9% Adapted from Khot et al. JAMA 2003;290:898-904.

44. CRP is a strong independent predictor of CV events in women Apo=apolipoprotein; CRP=C-reactive protein; CV=cardiovascular; HDL-C=high-density lipoprotein cholesterol; IL=interleukin; LDL-C=low-density lipoprotein cholesterol; Lp(a)=lipoprotein (a); SAA=serum amyloid A; sICAM-1=soluble intercellular adhesion molecule 1; TC=total cholesterol 0 Lp(a) Homocysteine IL-6 TC LDL-C sICAM-1 SAA ApoB TC/HDL-C CRP CRP + TC/HDL-C Relative risk of future CV events 1.02.04.06.0 Adapted from Blake GJ, Ridker PM. Circ Res 2001;89:763-71.

45. CRP predicts risk of MI and stroke in apparently healthy men CRP=C-reactive protein; MI=myocardial infarction Quartile 1: ≤ 0.55 ; Quartile 2: ≤ 0.56-1.14; Quartile 3: 1.15-2.10 ; Quartile 4:  2.11. *P=0.02 versus quartile 1; ***P<0.001 versus quartile 1 Quartile of CRP Relative risk of ischaemic stroke 0 0.5 1.0 1.5 2.0 1234 * Quartile of CRP Relative risk of MI 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 1234 *** Adapted from Ridker et al. N Engl J Med 1997;336:973-79.

46. CV event-free survival in women using combined LDL-C and hsCRP measures CV=cardiovascular; hsCRP=high-sensitivity C-reactive protein; LDL-C=low-density lipoprotein cholesterol Median LDL-C=3.2 mmol/L (124 mg/dL) Median CRP=1.5 mg/L 1.00 0.99 0.98 0.97 0.96 0 Low LDL-C, low hsCRP High LDL-C, high hsCRP High LDL-C, low hsCRP Low LDL-C, high hsCRP Probability of event- free survival Adapted from Ridker et al. N Engl J Med 2002;347:1557-65.

47. 0.00 0.02 0.04 0.06 012345 Years Placebo Rosuvastatin 20 mg JUPITER - Total Mortality Death from any cause Cumulative Incidence Number at risk Rosuvastatin 8901 8787 4312 1602 676 227 Placebo 8901 8775 4319 1614 681 246 Hazard Ratio 0.80 (95% CI 0.67-0.97) P=0.02 Adapted from Ridker et al. N Eng J Med 2008;359: 2195-207.

48. JUPITER - Laboratory Safety Data Laboratory Values, N (%) Serum creatinine ‡ 10 (0.10) 16 (0.20)0.24 ALT > 3 x ULN # 17 (0.20) 23 (0.30)0.34 Glycosuria † 32 (0.40) 36 (0.50)0.64 Laboratory Values, median values (IQR) GFR *, (mL/min/1.73m 2 ) 66.6 (58.8-76.2) 66.8 (59.1-76.5) 0.02 % HbA 1c ** 5.8 (5.6-6.1) 5.9 (5.7-6.1) 0.001 Fasting plasma glucose ** (mmol/L) 5.4 (5.0-5.9) 5.4 (5.1-5.9) 0.12 Placebo Rosuvastatin P value [n=8901] [n=8901] GFR = Glomerular filtration rate, HbA 1c = Haemoglobin A 1c ; IQR = interquartile range ‡ >100% increase from baseline;# on consecutive visits; † >trace at 12 months; *at 12 months, **at 24 months Adapted from Ridker et al. N Eng J Med 2008;359: 2195-207.

49. JUPITER: Conclusions – Efficacy I Among apparently healthy men and women with elevated hsCRP but low LDL, rosuvastatin reduced by 47 percent incident myocardial infarction, stroke, and cardiovascular death. Despite evaluating a population with lipid levels widely considered to be “optimal” in almost all current prevention algorithms, the relative benefit observed in JUPITER was greater than in almost all prior statin trials. 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. Adapted from Ridker et al. NEJM 2008.

50. JUPITER: Conclusions – Efficacy II Benefits of rosuvastatin were consistent in all sub-groups evaluated regardless of age, sex, ethnicity, or other baseline clinical characteristic, including those with elevated hsCRP and no other major risk factor. Rates of hospitalization and revascularization were reduced by 47 percent within a two-year period suggesting that the screening and treatment strategy tested in JUPITER is likely to be cost-effective, benefiting both patients and payers. The Number Needed to Treat in JUPITER was 25 for the primary endpoint, a value if anything smaller than that associated with treating hyperlipidemia in primary prevention. Adapted from Ridker et al. NEJM 2008.

51. JUPITER: Conclusions - Safety With regard to safety, the JUPITER results show no increase in serious adverse events among those allocated to rosuvastatin 20 mg as compared to placebo in a setting where half of the treated patients achieved levels of LDL< 55 mg/dL (and 25 percent had LDL < 44 mg/dL). show no increase in myopathy, cancer, hepatic disorders, renal disorders, or hemorrhagic stroke with treatment duration of up to 5 years. show no increase in systematically monitored glucose or glucosuria during follow-up, but small increases in HbA1c and physician reported diabetes similar to that seen in other major statin trials. Adapted from Ridker et al. NEJM 2008.

52. JUPITER – Summary The JUPITER study included patients with low to normal LDL-C who were at increased CV risk as identified by elevated CRP levels and who did not require statin treatment based on current treatment guidelines. A 44% reduction in the primary endpoint of major cardiovascular events (composite of: CV death, MI, stroke, unstable angina, arterial revascularisation) was observed in patients who received rosuvastatin 20 mg compared with placebo (P<0.00001). A 20% reduction in total mortality was observed in patients who received rosuvastatin 20 mg compared with placebo (P=0.02), a unique finding for statins in a population without established CHD. In JUPITER, long-term treatment with rosuvastatin 20 mg was well tolerated in nearly 9000 study participants. There was no difference between treatment groups for muscle weakness, cancer, haematological disorders, gastrointestinal, hepatic or renal systems. The results from JUPITER highlight the importance of highly effective statin treatment for these patients with an increased risk of CV disease. Adapted from Ridker et al. N Eng J Med 2008;359: 2195-207.

53. JUPITER: Public Health Implications Application of the simple screening and treatment strategy tested in the JUPITER trial over a five-year period could conservatively prevent more than 250,000 heart attacks, strokes, revascularization procedures, and cardiovascular deaths in the United States alone. We thank the 17,802 patients and the >1,000 investigators worldwide for their personal time, effort, and commitment to the JUPITER trial. www.brighamandwomens.org/jupitertrial Adapted from Ridker et al. NEJM 2008.

54. JUPITER: Implications for Primary Prevention Among men and women age 50 or over : If diabetic, treat If LDLC > 160 mg/dL, treat If hsCRP > 2 mg/L, treat A simple evidence based approach to statin therapy for primary prevention. Adapted from Ridker et al. NEJM 2008.

55. Acknowledgements The JUPITER Steering Committee –P Ridker (Chairman), Boston, MA, USA –A Gotto, New York, NY, USA –P Libby, Boston, MA, USA –J Willerson, Houston, TX, USA –J Genest, Montreal, Canada The JUPITER Independent Data Monitoring Board The JUPITER investigators and participating patients

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