A Randomized Trial of Rosuvastatin in the Prevention

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 (hs. CRP): The JUPITER Trial Paul Ridker, Eleanor Danielson, Francisco Fonseca, Jacques Genest, Antonio Gotto, John Kastelein, Wolfgang Koenig, Peter Libby, Alberto Lorenzatti, Jean Mac. Fadyen, Borge Nordestgaard, James Shepherd, James Willerson, and Robert Glynn on behalf of the JUPITER Trial Study Group

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 Mac. Fadyen, 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)

JUPITER l 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 l 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 lipidlowering treatment according to current guidelines Adapted from Ridker et al. N Eng J Med 2008; 359: 2195 -207.

JUPITER - Rationale l Nearly half of all cardiovascular events occur in patients who are apparently healthy and who have low or normal levels of LDL-C l hs. CRP predicts cardiovascular disease independent of LDL-C levels l 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): 17 K-22 K.

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.

JUPITER: Background and Prior Work To improve detection of individuals at increased risk for cardiovascular disease, physicians often measure high sensitivity C-reactive protein (hs. CRP), 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 hs. CRP, 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 hs. CRP. Adapted from Ridker et al. NEJM 2008.

Efficacy of lovastatin in AFCAPS/Tex. CAPS subgroups by baseline LDL-C and hs. CRP Study group Rate of cardiovascular events NNT Lovastatin Placebo Low LDL-C/low hs. CRP 0. 025 0. 022 N/A Low LDL-C/high hs. CRP 0. 029 0. 051 48 High LDL-C/low hs. CRP 0. 020 0. 050 33 High LDL-C/high hs. CRP 0. 038 0. 055 58 Median LDL-C=3. 9 mmol/L (149 mg/d. L). Median hs. CRP=1. 6 mg/L AFCAPS/Tex. CAPS=Air Force/Texas Coronary Atherosclerosis Prevention Study; hs. CRP=highsensitivity 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.

JUPITER population compared with previous trials in patients without established CHD AFCAPS WOSCOPS JUPITER 6605 6595 17 802 % male 85 100 62 Duration, years 5. 2 4. 9 1. 9 6 1 0 total cholesterol 5. 72 7. 03 4. 73 LDL-C 3. 88 4. 97 2. 69 HDL-C 0. 93– 1. 03 1. 14 1. 32 1. 78 1. 85 1. 56 0. 2 NA 4. 3 Lovastatin Pravastatin Rosuvastatin 20– 40 mg 20 mg Patients, n Diabetes, % Baseline lipids, mmol/L* triglycerides hs. CRP, mg/L Statin CVD=cardiovascular disease; CHD=coronary heart disease; LDL-C=low-density lipoprotein cholesterol; HDL-C=highdensity lipoprotein cholesterol; hs. CRP=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.

Comparison of the JUPITER Trial Population to Previous Statin Trials of Primary Prevention JUPITER WOSCOPS AFCAPS 17, 802 6, 595 6, 605 Women (n) 6, 801 0 997 Minority (n) 5, 118 0 350 4. 9 5. 2 Sample size (n) Duration (yrs) Diabetes (%) 1. 9 (max 5) 0 1 6 Baseline LDL-C (mg/d. L) 108 192 150 Baseline HDL-C (mg/d. L) 49 44 36 -40 Baseline TG (mg/d. L) 118 164 158 Baseline hs. CRP (mg/L) >2 NA NA Intervention Rosuvastatin 20 mg Adapted from JUPITER Trial Study Group, Am J Cardiol 2007. Pravastatin 40 mg Lovastatin 10 -40 mg

JUPITER: Why Consider Statins for Low LDL, high hs. CRP Patients? In 2001, in an hypothesis generating analysis of apparently healthy individuals in the AFCAPS / Tex. CAPS trial*, we observed that those with low levels of both LDL and hs. CRP 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 hs. CRP 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/Tex. CAPS that among those with low LDL but high hs. CRP, 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.

JUPITER: Why Consider Statins for Low LDL, High hs. CRP Patients? AFCAPS/Tex. CAPS Low LDL Subgroups Low LDL, Low hs. CRP [A] Low LDL, High hs. CRP [B] 0. 5 Statin Effective 1. 0 RR 2. 0 Statin Not Effective However, while intriguing and of potential public health importance, the observation in AFCAPS/Tex. CAPS that statin therapy might be effective among those with elevated hs. CRP 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.

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.

JUPITER: Trial Design JUPITER Multi-National Randomized Double Blind Placebo Controlled Trial of Rosuvastatin in the Prevention of Cardiovascular Events Among Individuals With Low LDL and Elevated hs. CRP Rosuvastatin 20 mg (N=8901) No Prior CVD or DM Men >50, Women >60 LDL <130 mg/d. L hs. CRP >2 mg/L 4 -week run-in 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 Adapted from Ridker et al. Circulation 2003; 108: 2292 -97. MI Stroke Unstable Angina CVD Death CABG/PTCA

JUPITER – Study Design No history of CAD Rosuvastatin 20 mg (n=8901) men ≥ 50 yrs Placebo women ≥ 60 yrs run-in LDL-C <130 mg/d. L Placebo (n=8901) CRP ≥ 2. 0 mg/L Visit: Week: 1 – 6 2 – 4 Lead-in/ eligibility 3 0 4 13 6 -monthly Final Randomisation Lipids CRP Tolerability Hb. A 1 C Median follow-up 1. 9 years CAD=coronary artery disease; LDL-C=low-density lipoprotein cholesterol; CRP=C-reactive protein; Hb. A 1 c=glycated haemoglobin Adapted from Ridker et al. N Eng J Med 2008; 359: 2195 -207.

U r Sw ug itz uay e R rlan om d an C ia h Es ile to n Is ia El rae Sa l l Bu vad lg or Pa aria na N ma o Ve rwa ne y G zue er la Ar ma ge ny C nti os na ta R Ric us a s Br ia D azil en C ma ol rk om Be bi lg a i M um ex Th P ico e ola N et nd he C rlan So ana ds U uth da ni te Af d r U Ki ica ni ng te d d o St m at es Randomizations (% Total. ) JUPITER: 17, 802 Patients, 1, 315 Sites, 26 Countries 25% 4021 20% Total Randomized = 17, 802 0% 14 15 32 327 336 345 197 202 204 209 222 253 270 273 83 85 143 162 Adapted from Ridker et al. NEJM 2008. 2873 15% 2497 2020 10% 5% 741 804 987 487

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

JUPITER: Inclusion and Exclusion Criteria, Study Flow 89, 863 Screened 89, 890 Screened Men > 50 years Women > 60 years No CVD, No DM LDL < 130 mg/d. L hs. CRP > 2 mg/L 4 week Placebo Run-In 17, 802 Randomized 8, 901 Assigned to 8, 901 Assignedto Rosuvastatin 20 mg Reason for Exclusion LDL > 130 mg/d. L 52 LDL-C > 130 mg/d. L 53 hs. CRP < 2. 0 mg/L 36 hs. CRP 37 Withdrew Consent 5 Withdrew Consent 4 Diabetes 1 Hypothyroid <1 Hypothyroid Liver Disease <1 TG > 500 mg/d. L <1 TG <1 Age out of range Current Use of HRT <1 Current Cancer <1 Poor Compliance/Other 3 8, 901 Assigned to Placebo 8, 600 Completed Study 8, 857 Completed Study 120 Lost follow-up 44 Lost toto follow-up 8, 864 Completed. Study 8, 600 Completed Study 120 Lost to follow-up 37 Lost to follow-up 8, 901 Included in Efficacy and Safety Analyses Adapted from Ridker et al. NEJM 2008. (%)

JUPITER - Major Exclusion Criteria l Current use of statins or other lipid-lowering therapies l Current use of post menopausal hormone replacement therapy l Prior history of cardiovascular or cerebrovaascular events, such as MI, unstable angina, prior arterial revascularisation or stroke, or CHD-risk equivalents l Chronic inflammatory condition, such as severe arthritis, lupus or inflammatory bowel disease and/or treatment with immunosuppressants l Uncontrolled: – hypertension: SBP > 190 mm. Hg or DBP > 100 mm. Hg – hypothyroidism: TSH > 1. 5 x ULN l CK 3 x ULN l Serum creatinine > 2. 0 mg/d. L l Evidence of hepatic dysfunction (ALT > 2 x ULN) l 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.

JUPITER - Baseline Characteristics* Rosuvastatin n=8901 Age (years) Male sex (%) Race (%) White Black Hispanic Other BMI (kg/m 2) Systolic BP (mm. Hg) Diastolic BP (mm. Hg) Placebo n=8901 66 (60 -71) 61. 5 66 (60 -71) 62. 1 71. 4 12. 6 3. 6 28. 3 (25. 3 -32. 0) 134 (124 -145) 80 (75 -87) 71. 1 12. 6 12. 8 3. 5 28. 4 (25. 3 -32. 0) 134 (124 -145) 80 (75 -87) *All values are median (interquartile range) or N (%). Adapted from Ridker et al. N Eng J Med 2008; 359: 2195 -207.

JUPITER: Baseline Blood Levels (median, interquartile range) Rosuvastatin (N = 8901) Placebo (n = 8901) hs. CRP, mg/L 4. 2 (2. 8 - 7. 1) 4. 3 (2. 8 - 7. 2) LDL, mg/d. L 108 (94 - 119) HDL, mg/d. L 49 (40 – 60) Triglycerides, mg/L 118 (85 - 169) 118 (86 - 169) Total Cholesterol, mg/d. L 186 (168 - 200) 185 (169 - 199) Glucose, mg/d. L 94 (87 – 102) 94 (88 – 102) Hb. A 1 c, % 5. 7 (5. 4 – 5. 9) 5. 7 (5. 5 – 5. 9) All values are median (interquartile range). Adapted from Ridker et al. NEJM 2008. [ Mean LDL = 104 mg/d. L ]

JUPITER - Baseline laboratory parameters* Rosuvastatin n=a 8901 Total cholesterol (mmol/L) LDL cholesterol (mmol/L) HDL cholesterol (mmol/L) Triglycerides (mmol/L) hs. CRP (mg/L) Glucose (mmol/L) Hb. A 1 c(%) Glomerular filtration rate, (ml/min/1. 73 m 2) Placebo n=8901 4. 81 (4. 34 -5. 17) 2. 79 (2. 43 -3. 08) 1. 27 (1. 03 -1. 55) a 1. 33 (0. 96 -1. 91) 4. 2 (2. 8 -7. 1) 5. 2 (4. 8 -5. 7) 5. 7 (5. 4 -5. 9) 4. 78 (4. 37 -5. 15) 2. 79 (2. 43 -3. 08) 1. 27 (1. 03 -1. 55) 1. 33 (0. 97 -1. 91) 4. 3 (2. 8 -7. 2) 5. 2 (4. 9 -5. 7) 5. 7 (5. 5 -5. 9) 73. 3 (64. 6 -83. 7) 73. 6 (64. 6 -84. 1) For hs. CRP, 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.

JUPITER - Medical History Current smoker (%) Family history CHD† (%) Metabolic syndrome‡ (%) Aspirin use (%) Rosuvastatin n=8901 15. 7 11. 2 41. 0 16. 6 Placebo n=8901 16. 0 11. 8 41. 8 16. 6 †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.

JUPITER - Study End Points l Primary End Point – Time to the first occurrence of a major cardiovascular event, composite of: • cardiovascular death • Stroke • MI • unstable angina • arterial revascularisation l 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.

JUPITER: Primary Objectives Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin 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 < 130 mg/d. L (3. 36 mmol/L) who are nonetheless at increased vascular risk on the basis of an enhanced inflammatory response, as determined by hs. CRP > 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. Adapted from Ridker et al. NEJM 2008.

hs. CRP decrease 37 percent at 12 months 0 12 24 Months Adapted from Ridker et al. NEJM 2008. 36 HDL (mg/d. L) LDL decrease 50 percent at 12 months HDL increase 4 percent at 12 months TG (mg/d. L) hs. CRP (mg/L) LDL (mg/d. L) JUPITER: Effects of Rosuvastatin 20 mg on LDL, HDL, TG, and hs. CRP TG decrease 17 percent at 12 months 48 Months

Placebo 251/8901 0. 06 HR 0. 56, 95% CI 0. 46 -0. 69 P<0. 00001 0. 04 - 44 % Rosuvastatin 142 / 8901 0. 00 0. 02 Cumulative Incidence 0. 08 JUPITER Primary Trial End Point: MI, Stroke, UA/Revascularization, CV Death 0 1 2 4 Follow-up (years) Number at Risk Rosuvastatin Placebo 3 8, 901 8, 631 8, 621 8, 412 8, 353 Adapted from Ridker et al. NEJM 2008. 6, 540 6, 508 3, 893 3, 872 1, 958 1, 963 1, 353 1, 333 983 955 544 534 157 174

JUPITER: Grouped Components of the Primary End Point HR 0. 53, CI 0. 40 -0. 69 P<0. 00001 HR 0. 53, CI 0. 40 -0. 70 P<0. 00001 0. 06 Arterial Revascularization or Hospitalization for Unstable Angina 0. 05 Myocardial Infarction, Stroke, or Cardiovascular Death 0. 04 0. 03 0. 02 Rosuvastatin 0. 00 - 47 % 0. 01 Rosuvastatin Cumulative Incidence 0. 04 0. 03 0. 02 - 47 % 0. 01 Cumulative Incidence Placebo 0. 05 Placebo 0 1 2 3 Follow-up (years) Adapted from Ridker et al. NEJM 2008. 4 0 1 2 3 Follow-up (years) 4

JUPITER: Individual Components of the Primary End Point Endpoint Rosuvastatin Placebo HR 95%CI P Primary Endpoint* 142 251 0. 56 0. 46 -0. 69 <0. 00001 Non-fatal MI Any MI 22 31 62 68 0. 35 0. 46 0. 22 -0. 58 0. 30 -0. 70 <0. 00001 <0. 0002 Non-fatal Stroke Any Stroke 30 33 58 64 0. 52 0. 33 -0. 80 0. 34 -0. 79 0. 003 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 Adapted from Ridker et al. NEJM 2008.

JUPITER: Primary End Point – Subgroup Analysis I N Men Women P for Interaction 11, 001 6, 801 0. 80 Age < 65 Age > 65 8, 541 9, 261 0. 32 Smoker Non-Smoker 2, 820 14, 975 0. 63 Caucasian Non-Caucasian 12, 683 5, 117 0. 57 USA/Canada Rest of World 6, 041 11, 761 0. 51 Hypertension No Hypertension 10, 208 7, 586 0. 53 All Participants 17, 802 0. 25 0. 5 Rosuvastatin Superior Adapted from Ridker et al. NEJM 2008. 1. 0 2. 0 Rosuvastatin Inferior 4. 0

JUPITER - Primary End Point Time to first occurrence of a CV death, non-fatal stroke, non-fatal MI, unstable angina or arterial revascularisation Hazard Ratio 0. 56 (95% CI 0. 46 -0. 69) P<0. 00001 Cumulative Incidence 0. 08 Placebo 0. 06 Rosuvastatin 20 mg 0. 04 NNT for 2 yrs = 95 5 yrs* = 25 0. 02 0. 00 0 Number at risk Rosuvastatin 8901 Placebo 8901 1 8412 8353 2 Years 3893 3872 *Extrapolated figure based on Altman and Andersen method Adapted from Ridker et al. N Eng J Med 2008; 359: 2195 -207. 3 1353 1333 4 5 538 531 157 174

JUPITER - Primary End Point Components Placebo Rosuvastatin n (rate**) [n=8901] HR 95% CI P value Primary Endpoint 251 (1. 36) 142 (0. 77) 0. 56 0. 46 -0. 69 <0. 001* (Time to first occurrence of CV death, MI, stroke, unstable angina, arterial revascularisation) Non-fatal MI Fatal or non-fatal MI 62 (0. 33) 68 (0. 37) 22 (0. 12) 31 (0. 17) 0. 35 0. 46 0. 22 -0. 58 <0. 001* 0. 30 -0. 70 0. 0002 Non-fatal stroke Fatal or non-fatal stroke 58 (0. 31) 64 (0. 34) 30 (0. 16) 33 (0. 18) 0. 52 0. 33 -0. 80 0. 34 -0. 79 Arterial Revascularization 131 (0. 71) 71 (0. 38) 0. 54 0. 41 -0. 72 <0. 0001 Unstable angina† 27 (0. 14) 16 (0. 09) 0. 59 0. 32 -1. 10 CV death, stroke, MI 157 (0. 85) 83 (0. 45) 0. 53 0. 40 -0. 69 <0. 001* Revascularization or unstable angina 143 (0. 77) 76 (0. 41) 0. 53 0. 40 -0. 70 <0. 001* ** Rates are per 100 person years; † Hospitalisation due to unstable angina; *Actual P-value was <0. 00001 HR=Hazard Ratio; CI =Confidence Interval Adapted from Ridker et al. N Eng J Med 2008; 359: 2195 -207. 0. 003 0. 002 0. 09

JUPITER: Primary Endpoint – Subgroup Analysis II N Family HX of CHD No Family HX of CHD P for Interaction 2, 045 15, 684 0. 07 BMI < 25 kg/m BMI 25 -29. 9 kg/m 2 2 BMI > 30 kg/m 4, 073 7, 009 6, 675 0. 70 Metabolic Syndrome No Metabolic Syndrome 7, 375 10, 296 0. 14 Framingham Risk < 10% Framingham Risk > 10% 8, 882 8, 895 0. 99 hs. CRP > 2 mg/L Only 6, 375 2 All Participants 17, 802 0. 25 0. 5 1. 0 Rosuvastatin Superior Adapted from Ridker et al. NEJM 2008. 2. 0 Rosuvastatin Inferior 4. 0

0. 06 JUPITER: Secondary End Point – All Cause Mortality Placebo 247 / 8901 HR 0. 80, 95%CI 0. 67 -0. 97 P= 0. 02 0. 04 0. 03 0. 02 Rosuvastatin 198 / 8901 0. 00 0. 01 Cumulative Incidence 0. 05 - 20 % 0 Number at Risk Rosuvastatin 8, 901 Placebo 8, 901 1 2 3 4 Follow-up (years) 8, 847 8, 852 Adapted from Ridker et al. NEJM 2008. 8, 787 8, 775 6, 999 6, 987 4, 312 4, 319 2, 268 2, 295 1, 602 1, 614 1, 192 1, 196 683 684 227 246

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 1. 11 (0. 67– 1. 83) VS Pravastatin JUPITER Rosuvastatin 1. 25 (1. 05– 1. 54) 0. 25 0. 5 Statin Better Adapted from Ridker et al. NEJM 2008. 1. 0 2 Statin Worse 4

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

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

Prevalence of conventional risk factors† in male patients with CHD Four Three (0. 9%) None 8. 9% 19. 4% Two 27. 8% 43. 0% One Total male patients=87 869 CHD=coronary heart disease †smoking, hypertension, hypercholesterolaemia and diabetes mellitus Adapted from Khot et al. JAMA 2003; 290: 898 -904.

CRP is a strong independent predictor of CV events in women Lp(a) Homocysteine IL-6 TC LDL-C s. ICAM-1 SAA Apo. B TC/HDL-C CRP + TC/HDL-C 0 1. 0 2. 0 4. 0 6. 0 Relative risk of future CV events 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; s. ICAM-1=soluble intercellular adhesion molecule 1; TC=total cholesterol Adapted from Blake GJ, Ridker PM. Circ Res 2001; 89: 763 -71.

CRP predicts risk of MI and stroke in apparently healthy men 3. 5 2. 0 *** 3. 0 1. 5 2. 5 Relative risk of MI * Relative risk of ischaemic stroke 2. 0 1. 5 1. 0 0. 5 0 1 2 3 4 Quartile of 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 Adapted from Ridker et al. N Engl J Med 1997; 336: 973 -79. 0 1 2 3 Quartile of CRP 4

CV event-free survival in women using combined LDL-C and hs. CRP measures 1. 00 0. 99 Probability of eventfree survival 0. 98 Low LDL-C, low hs. CRP High LDL-C, low hs. CRP Low LDL-C, high hs. CRP 0. 97 0. 96 High LDL-C, high hs. CRP 0 CV=cardiovascular; hs. CRP=high-sensitivity C-reactive protein; LDL-C=low-density lipoprotein cholesterol Median LDL-C=3. 2 mmol/L (124 mg/d. L) Median CRP=1. 5 mg/L Adapted from Ridker et al. N Engl J Med 2002; 347: 1557 -65.

JUPITER: Subgroup Analysis Placebo better Rosuvastatin better 0. 57 Race White Non-white 12, 683 5, 117 0. 53 Hypertension Yes No 10, 208 7, 586 0. 51 Region US or Canada Other 6, 041 11, 761 Metabolic syndrome Yes No 7, 375 10, 296 Family history of CHD Yes No 0. 07 2, 045 15, 684 Framingham risk score ≤ 10% >10% 0. 14 0. 99 8, 882 8, 895 Adapted from Ridker et al. N Eng J Med 2008; 359: 2195 -207. 1. 2 11, 001 6, 801 1 Males Females 0. 80 Gender 0. 6 8, 541 9, 261 0. 4 ≤ 65 years >65 yrs 0. 2 Age P- value 0. 32 0 N Hazard ratio (95% CI)

JUPITER - Total Mortality Cumulative Incidence Death from any cause Hazard Ratio 0. 80 (95% CI 0. 67 -0. 97) P=0. 02 0. 06 Placebo Rosuvastatin 20 mg 0. 04 0. 02 0. 00 0 Number at risk Rosuvastatin 8901 Placebo 8901 1 2 8787 8775 4312 4319 Years Adapted from Ridker et al. N Eng J Med 2008; 359: 2195 -207. 3 1602 1614 4 5 676 681 227 246

JUPITER Effects on LDL-C, HDL-C, TG and hs. CRP at 12 months Percentage change between rosuvastatin and placebo 10 LDL-C TG hs. CRP 4% 0 Percentage change from baseline (%) HDL-C P<0. 001* -10 17% -20 P<0. 001 -30 37% -40 -50 P<0. 001 50% P<0. 001 -60 *P-value at study completion (48 months) = 0. 34 Adapted from Ridker et al. N Eng J Med 2008; 359: 2195 -207.

JUPITER - Tolerability and Safety Data Placebo [n=8901] Adverse Events, (%) Any serious adverse event Muscle weakness, stiffness, pain Myopathy Rhabdomyolysis Newly diagnosed cancer Death from cancer Gastrointestinal disorders Renal disorders Bleeding Hepatic disorders Other events, (%) Newly diagnosed diabetes** Haemorrhagic stroke Rosuvastatin P value [n=8901] 15. 5 15. 4 0. 1 0. 0 3. 5 0. 7 19. 2 5. 4 3. 1 2. 1 15. 2 16. 0 0. 1 <0. 1* 3. 4 0. 4 19. 7 6. 0 2. 9 2. 4 0. 60 0. 34 0. 82 ---0. 51 0. 02 0. 43 0. 08 0. 45 0. 13 2. 4 0. 1 3. 0 0. 1 0. 01 0. 44 *Occurred after trial completion; **physician -reported Adapted from Ridker et al. N Eng J Med 2008; 359: 2195 -207.

JUPITER - Laboratory Safety Data Placebo [n=8901] Laboratory Values, N (%) Serum creatinine‡ ALT > 3 x ULN# Glycosuria† Rosuvastatin [n=8901] 10 (0. 10) 17 (0. 20) 32 (0. 40) Laboratory Values, median values (IQR) GFR*, (m. L/min/1. 73 m 2) 66. 6 (58. 8 -76. 2) % Hb. A 1 c** 5. 8 (5. 6 -6. 1) Fasting plasma glucose** (mmol/L) 5. 4 (5. 0 -5. 9) P value 16 (0. 20) 0. 24 23 (0. 30) 0. 34 36 (0. 50) 0. 64 66. 8 (59. 1 -76. 5) 0. 02 5. 9 (5. 7 -6. 1) 0. 001 5. 4 (5. 1 -5. 9)0. 12 ‡ >100% increase from baseline; # on consecutive visits; † >trace at 12 months; *at 12 months, **at 24 months GFR = Glomerular filtration rate, Hb. A 1 c = Haemoglobin A 1 c; IQR = interquartile range Adapted from Ridker et al. N Eng J Med 2008; 359: 2195 -207.

JUPITER: Conclusions – Efficacy I Among apparently healthy men and women with elevated hs. CRP 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 hs. CRP 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.

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 hs. CRP 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.

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/d. L (and 25 percent had LDL < 44 mg/d. L). 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 Hb. A 1 c and physician reported diabetes similar to that seen in other major statin trials. Adapted from Ridker et al. NEJM 2008.

JUPITER – Summary l 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. l 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). l 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. l In JUPITER, long-term treatment with rosuvastatin 20 mg was well tolerated in nearly 9000 study participants. l There was no difference between treatment groups for muscle weakness, cancer, haematological disorders, gastrointestinal, hepatic or renal systems. l 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.

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.

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

Acknowledgements l 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 l The JUPITER Independent Data Monitoring Board l The JUPITER investigators and participating patients

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