1. JUPITER Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin Ridker P et al. N Eng J Med 2008;359: 2195-2207

2. 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 (CRESTOR™) in individuals potentially at increased cardiovascular (CV) risk due to elevated CRP levels who do not qualify for lipid-lowering treatment according to current guidelines Ridker P et al. N Eng J Med 2008;359: 2195-2207

3. 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 Ridker PM. New Engl J Med 2002; 347: 1557–1565

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

5. 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 Blake GJ, Ridker PM. Circ Res 2001; 89: 763–771

6. CRP predicts risk of MI and stroke in apparently healthy men CRP=C-reactive protein; MI=myocardial infarction *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 *** Ridker PM et al. N Engl J Med 1997; 336: 973–979

7. 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 Ridker PM et al. N Engl J Med 2002; 347: 1557–1565

8. 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 Ridker PM et al. N Engl J Med 2001; 344: 1959–1965

9. 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 Ridker PM. Circulation 2003; 108: 2292–2297

10. 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 Ridker P et al. N Eng J Med 2008;359: 2195-2207

11. JUPITER - Study Endpoints Primary Endpoint –Time to the first occurrence of a major cardiovascular event, composite of: cardiovascular death Stroke MI unstable angina arterial revascularisation Secondary Endpoints: –total mortality –non-cardiovascular mortality –development of diabetes mellitus –development of venous thromboembolic events –bone fractures –discontinuation of study medication due to adverse effects. Ridker PM. Circulation 2003; 108: 2292–2297

12. JUPITER - Major inclusion criteria Men aged ≥50 years; women aged ≥60 years Fasting LDL-C levels  130 mg/dL (3.4 mmol/L), CRP levels ≥2.0 mg/L and TG levels  500 mg/dL (5.7 mmol/L) on initial screening Ridker PM. Circulation 2003; 108: 2292–2297

13. JUPITER - Major exclusion criteria Current use of statins or other lipid-lowering therapies Current use of hormone replacement therapy Prior history of cardiovascular or cerebrovascular 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 Ridker PM. Circulation 2003; 108: 2292–2297 CHD = coronary heart disease; CK = creatinine kinase; ULN = upper limit of normal; SBP = systolic blood pressure; DBP = diastolic blood pressure Ridker P et al. N Eng J Med 2008;359: 2195-2207

14. JUPITER - Patient Flow 89,890 subjects screened 17,802 randomized 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 Ridker P et al. N Eng J Med 2008;359: 2195-2207

15. 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 (%). Ridker P et al. N Eng J Med 2008;359: 2195-2207

16. Total cholesterol (mg/dL) 186 (168-200) 185 (169-199) LDL cholesterol (mg/dL) 108 (94-119) 108 (94-119) HDL cholesterol (mg/dL) 49 (40-60) 49 (40-60) Triglycerides (mg/dL) 118 (85-169) 118 (86-169) hsCRP (mg/L) 4.2 (2.8-7.1) 4.3 (2.8-7.2) Glucose (mg/dL) 94 (87-102) 94 (88-102) 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) RosuvastatinPlacebo n=8901 n=8901 JUPITER - Baseline laboratory parameters * For hsCRP, values are the average of the values obtained at two screening and visits *All values are median (interquartile range) or N (%). Ridker P et al. N Eng J Med 2008;359: 2195-2207

17. 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 CHD defined as first degree relative with CHD at age < 55 yrs (male), < 65 yrs (female); ‡ Metabolic syndrome defined according to consensus criteria of AHA/NHLBI Ridker P et al. N Eng J Med 2008;359: 2195-2207

18. JUPITER population compared with previous trials in patients without established CHD AFCAPSWOSCOPSJUPITER Patients, n6605 659517 802 % male, n8510062 Duration, years5.24.91.9 Diabetes, %610 Baseline lipids, mg/dL* total cholesterol221272183 LDL-C150192104 HDL-C36–404451 triglycerides158164138 hsCRP, mg/L0.2NA4.3 StatinLovastatin 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; *Baseline lipid levels are mean values. Ridker PM et al. Am J Cardiol 2007; 100: 1659–1664 Ridker PM et al. N Engl J Med. 2001 344: 1959-65

19. 0 1 2 3 4 5 6 7 8 9 012345 Years Placebo Rosuvastatin 20 mg JUPITER - Primary Endpoint Time to first occurrence of a CV death, non-fatal stroke, non-fatal MI, unstable angina or arterial revascularization Percent of patients with primary endpoint Number at risk RSV 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 Ridker P et al. N Eng J Med 2008;359: 2195-2207 NNT for 2y = 95 5y* = 25 *Extrapolated figure based on Altman and Andersen method

20. JUPITER - Primary Endpoint 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 Limit ** Rates are per 100 person years; † Hospitalisation due to unstable angina; *Actual p-value was < 0.00001 Ridker P et al. N Eng J Med 2008;359: 2195-2207

21. JUPITER – Subgroup analysis Rosuvastatin better Placebo better NP- value* Age 0.32 ≤ 65 years8,541 >65 yrs9,261 Gender 0.80 Males11,001 Females6,801 Race 0.57 White12,683 Non-white5,117 Hypertension 0.53 Yes10,208 No 7,586 Region 0.51 US or Canada6,041 Other11,761 Metabolic syndrome 0.14 Yes7,375 No10,296 Family history of CHD 0.07 Yes 2,045 No15,684 Framingham risk score 0.99 ≤10%8,882 >10%8,895 0 0.20.40.60.8 1 1.2 Ridker P et al. N Eng J Med 2008;359: 2195-2207 Hazard ratio (95% CI)

22. 0 1 2 3 4 5 6 7 012345 Years Placebo Rosuvastatin 20mg JUPITER - Total Mortality Death from any cause Percent total mortality Number at risk RSV 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 Ridker P et al. N Eng J Med 2008;359: 2195-2207

23. JUPITER JUPITER Effects on LDL-C, HDL-C, TG and hsCRP at 12 months; Percentage change between rosuvastatin and placebo -60 -50 -40 -30 -20 -10 0 10 LDL-CHDL-CTGhsCRP Percentage change from baseline (%) 50% 4% 17% 37% p<0.001 p<0.001* p<0.001 *P-value at study completion (48 months) = 0.34 Ridker P et al. N Eng J Med 2008;359: 2195-2207

24. JUPITER Tolerability and safety data Adverse Events, (%) Any serious adverse event15.515.20.60 Muscle weakness, stiffness, pain15.416.00.34 Myopathy0.1 0.10.82 Rhabdomyolysis 0.0 <0.1 * ---- Newly diagnosed cancer3.53.40.51 Death from cancer0.70.40.02 Gastrointestinal disorders19.219.70.43 Renal disorders5.46.00.08 Bleeding3.12.90.45 Hepatic disorders2.12.40.13 Other events, (%) Newly diagnosed diabetes ** 2.43.00.01 Haemorrhagic stroke 0.10.10.44 Placebo Rosuvastatin p-value [n=8901] [n=8901] *Occurred after trial completion; **physician reported newly diagnosed diabetes Ridker P et al. N Eng J Med 2008;359: 2195-2207

25. 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 % HbA1c ** 5.8 (5.6-6.1) 5.9 (5.7-6.1) 0.001 Fasting plasma glucose **, (mg/dL) 98 (90-106) 98 (91-107) 0.12 Placebo Rosuvastatin p-value [n=8901] [n=8901] GFR = Glomerular filtration rate, HbA1c = Haemoglobin A1c # on consecutive visits, ‡ >100% increase from baseline, *at 12 months, **at 24 months, †>trace at 12 months Ridker P et al. N Eng J Med 2008;359: 2195-2207

26. JUPITER – summary and perspectives 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 Ridker P et al. N Eng J Med 2008;359: 2195-2207

27. 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 This study is supported by AstraZeneca