Assurance of Cardiovascular Risk Reduction comes from broad Clinical Experience

Is Lower Better? La relation entre le LDL-c et les evenements cardiovasculaires Rosenson RS. Exp Opin Emerg Drugs 2004;9(2): , LaRosa JC et al. N Engl J Med 2005;352: LDL-C atteint mg/dL (mmol/L) WOSCOPS – Pl AFCAPS - Pl ASCOT - Pl AFCAPS - RxWOSCOPS - Rx ASCOT - Rx 4S - Rx HPS - Pl LIPID - Rx 4S - Pl CARE - Rx LIPID - Pl CARE - Pl HPS - Rx (1.0) 60 (1.6) 80 (2.1) 100 (2.6) 120 (3.1) 140 (3.6) 160 (4.1) 180 (4.7) Event rate (%) 6 Prevention secondaire Prevention Primaire Rx - Statin therapy Pl – Placebo Pra – pravastatin Atv - atorvastatin 200 (5.2) PROVE-IT - Pra PROVE-IT – Atv TNT – Atv10 TNT – Atv80 INTRO STELLAR PEPI METEOR ASTEROID JUPITER

La moitié des patients n’atteignent pas leur objectif lipidique EUROASPIRE II:51% des patients n’ont pas atteint l’objectif Patients sous hypolipémiants qui ont atteint leur objectif 50%25%75%100% EUROASPIRE II: Atteinte d’objectif cholesterol total 51% Lipid management assessed in 5556 patients with CHD at least 6 months after discharge who qualify for treatment EUROASPIRE II. Eur Heart J 2001;22:554–572

La relation entre le taux du LDL-c et HDL ET LE RISUE CARDIOVASCULAIRE Third Report of the NCEP Expert Panel. NIH Publication No % decrease in LDL-C reduces CHD risk by 1% 1% increase in HDL-C reduces CHD risk by 1-3% INTRO STELLAR PEPI METEOR ASTEROID JUPITER

Rosuvastatin Atorvastatin Simvastatin Pravastatin *p<0.002 vs atorvastatin 10 mg; simvastatin 10, 20, 40 mg; pravastatin 10, 20, 40 mg †p<0.002 vs atorvastatin 20, 40 mg; simvastatin 20, 40, 80 mg; pravastatin 20, 40 mg ‡p<0.002 vs atorvastatin 40 mg; simvastatin 40, 80 mg; pravastatin 40 mg * X X X –60 –50 –40 –30 –20 –10 0 Dose, mg (log scale) X X n=648 n=473 n=634 n=485 † ‡ Change in LDL-C from baseline (%) Rosuvastatin versus Comparators: LDL-C Efficacy Across the Dose Range The STELLAR Study INTRO STELLAR PEPI METEOR ASTEROID JUPITER Jones PH et al. Am J Cardiol 2003;92:152–160

Rosuvastatin versus other statins - change in HDL-C The STELLAR Study *p<0.002 vs pravastatin 10 mg †p<0.002 vs atorvastatin 20, 40, 80 mg; simvastatin 40 mg; pravastatin 20, 40 mg ‡p<0.002 vs atorvastatin 40, 80 mg; simvastatin 40 mg; pravastatin 40 mg Observed data in ITT population * 7.7 † 9.5 ‡ Dose (mg) Rosuvastatin Atorvastatin Pravastatin Simvastatin Change in HDL-C from baseline (%) INTRO STELLAR PEPI METEOR ASTEROID JUPITER Jones PH et al. Am J Cardiol 2003;92:152–160

CV Risk Reduction – Head-to- head comparison In ‘’Real Life’’ All statin users between January 2000 and September 2005 rosuvastatin N = 8,088 atorvastatin N = 25,777 simvastatin N = 27,752 pravastatin N = 14,530 Exclude: Established statin users (prior statin use in last 12 months) patients with CV event in previous 12 months patients with <12 months history in PHARMO cerivastatin and fluvastatin users* Use of >1 statin simultaneously patients under 18 N = 76,147 Followed until first CV event or cessation of initial statin use or loss to follow-up in the database * Cerivastatin was withdrawn from the market in There were too few fluvastatin users for any meaningful analyses Heintjes et al, Current Medical Opinion and Research, July 2008 PEPI INTRO STELLAR PEPI METEOR ASTEROID JUPITER

Retrospective observational cohort study Primary outcome: Cardiovascular (CV) Hospitalisations Fatal and non-fatal ischaemic heart disease, myocardial infarction (MI), fatal and non-fatal stroke, coronary and carotid revascularisation Secondary outcome Hospitalisations for MI Hazard ratios ¶ with 95% confidence intervals calculated Adjusted for patient characteristics, co-morbidities and co- medications *I.e. CV events counted whilst on original statin ¶ The ‘hazard ratio’ was the ratio of the incidence of CV events on rosuvastatin versus that on other statins CV Risk Reduction – Head-to- head comparison In ‘’Real Life’’ PEPI INTRO STELLAR PEPI METEOR ASTEROID JUPITER Heintjes et al, Current Medical Opinion and Research, July 2008

Primary Outcome Rates of CV events were 28% lower on CRESTOR compared with other statins CRESTOR vs. other statins CRESTOR (10.8 mg) vs. ATV (17.3 mg) RSV betterRSV worse CRESTOR (10.8 mg) vs. SMV (22.1 mg) CRESTOR (10.8 mg) vs. PRV (33.8 mg) * A 95% CI that does not exceed 1 indicates a statistically significant hazard ratio 0.72 ( ) * 0.83 ( ) NS 0.71 ( ) * 0.60 ( ) * Hazard ratios of CV were adjused for age, gender, nitrates, classic antihypertensives and diabetes Adjusted hazard ratio of CV hospitalisations (95% CI) 28% 17% 29% 40% Reductio n in CV events PEPI INTRO STELLAR PEPI METEOR ASTEROID JUPITER Heintjes et al, Current Medical Opinion and Research, July 2008

US Study Patient selection All statin users between August 2003 and December 2005 rosuvastatin N = 45,510 atorvastatin N = 196,523 simvastatin N = 73,884 pravastatin N = 25,055 Exclude: established statin users (prior statin use in last 12 months) serious non-CV disease or immunosuppression with <12 months history in database patients under 18 N = 395,056 Followed until: first CV event, switch to another statin therapy or switch/add another lipid-lowering therapy or 90 days after end of statin supply or loss to follow-up in the database lovastatin N = 45,483 fluvastatin N = 8,584 INTRO STELLAR PEPI METEOR ASTEROID JUPITER Heintjes et al, Current Medical Opinion and Research, July 2008

US Study Results: Reduction in CV events >=90 days >=180 days >=270 days 0.95 ( ) 0.88 ( ) 0.76 ( ) ‡ RSV betterOther statins† better ( ) 0.91 ( ) 0.80 ( ) ‡ MPR>0.8 ‡ A 95% CI that does not exceed 1 indicates a statistically significant hazard ratio Adjusted* hazard ratio of CV events (95% CI) 20% Reductio n in CV events In patients with higher compliance ¶ and longer exposure times, a trend of a higher decreased CV event rate with RSV as compared to other statins was found INTRO STELLAR PEPI METEOR ASTEROID JUPITER N = 395,056 Heintjes et al, Current Medical Opinion and Research, July 2008

What about efficacy in atherosclerosis? Which is the Most Effective Statin in Regression of athersclerosis? INTRO STELLAR PEPI METEOR ASTEROID JUPITER

ENHANCEMETEOR PatientsHigh-risk FH (n=720) Lower risk asymptomatic subjects at low risk of CHD (n=984) LDL-C Baseline LDL-C 319mg/dL; 8.3mmol/L Mean baseline LDL-C 155mg/dL; 4mmol/L CIMT analysed Mean change from baseline in CIMT using composite measures from the right + left far wall CCA, carotid bulb and ICA 6 sites – far wall only Max CIMT, based on 12 carotid artery segments (near & far wall of the right and left CCA, carotid bulb and ICA) 12 sites – near and far walls Status Completed April ‘06, press release 14 Jan 08. Likely to jeopardise presentation of results at ACC Mar ’08 (23 months later). Completed May ’06, data at ACC Mar ’07 (10 months later) ResultsNo statistical difference in mean CIMT (primary endpoint), or in individual components of primary endpoint, including CCA. CRESTOR 40 mg slowed the rate of progression of maximum CIMT vs placebo ….and with significant regression of CIMT in the CCA ENHANCE vs METEOR INTRO STELLAR PEPI METEOR ASTEROID JUPITER Kasteline J et al, NEJM April, 2008 Crouse J et al, JAMA, 2007

Time (years) Progression Regression P=NS (CRESTOR vs. zero slope Placebo mm/yr (n=252) Rosuvastatin 40 mg mm/yr (n=624) P<0.001 (CRESTOR vs. placebo) Placebo; Change in CIMT (95% CI) Rosuvastatin 40 mg; Change in CIMT (95% CI) METEOR primary endpoint: Rate of change of maximum IMT at 12 carotid sites Rosuvastatin vs placebo Crouse JR III, et al. JAMA 2007;297 (12):1344–1353 INTRO STELLAR PEPI METEOR ASTEROID JUPITER 48% reduction LDL-C 8% Increase HDL-C

ENHANCE results Time (years) Primary Endpoint Change in mean IMT at 6 carotid sites (mm) SMV 80 + EZE mm p=0.29 (ns) SMV mm 720 patients with familial hypercholesteraemia 1° endpoint: Absolute change in mean cIMT Measured at 6 carotid sites Most patients established statin users 2 1 Ezetimibe/simvastatin 10/80mg showed no significant difference to simvastatin 80mg on the primary endpoint (mean CIMT), on any component of the primary endpoint, or on any of the secondary imaging endpoints INTRO STELLAR PEPI METEOR ASTEROID JUPITER Kasteline J et al, NEJM April, 2008

 ENHANCE failed to meet its primary and secondary endpoints and showed that adding ezetimibe to simvastatin provides no benefit on the treatment of atherosclerosis  CRESTOR has the proven efficacy to lower LDL-C, raise HDL-C, and has been shown to slow the progression of atherosclerosis at any stage of the disease  CRESTOR significantly slowed the progression of atherosclerosis in the METEOR study (which employed very similar methodology to ENHANCE). These results were pivotal to achieving the unique atherosclerosis indication granted by US FDA Summary : METEOR & ENHANCE Results

A Study To evaluate the Effect of Rosuvastatin On Intravascular ultrasound-Derived coronary atheroma burden Nissen S et al. JAMA 2006;295 (13): ; Ballantyne C et al. Circulation 2008 DOI: /CIRCULATIONAHA ASTEROID used intravascular ultrasound (IVUS) and quantitative coronary angiography (QCA) to evaluate the effect of rosuvastatin (CRESTOR™) on atherosclerotic disease in patients with coronary artery disease (CAD) INTRO STELLAR PEPI METEOR ASTEROID JUPITER

Lumen area EEM area Atheroma area Ultrasound Determination of Atheroma Area Precise planimetry of EEM and lumen borders with calculation of atheroma cross-sectional area INTRO STELLAR PEPI METEOR ASTEROID JUPITER

Example of regression of atherosclerosis with rosuvastatin in ASTEROID, measured by IVUS Images courtesy of Cleveland Clinic Intravascular Ultrasound Core Laboratory Effects of Rosuvastatin on intravascular ultrasound (IVUS) - derived coronary artery atheroma burden The ASTEROID study INTRO STELLAR PEPI METEOR ASTEROID JUPITER 53% reduction LDL-C 14% Increase HDL-C

2 The relationship between mean LDL-C and change in percent atheroma volume (PAV) in IVUS studies † Change in Percent Atheroma Volume* (%) 1 Nissen S et al. N Engl J Med 2006;354: Tardif J et al. Circulation 2004;110: Nissen S et al. JAMA 2006;295 (13): Nissen S et al. JAMA 2004;292: 2217– Nissen S et al. JAMA 2004; 291:1071– A-Plus 2 placebo ACTIVATE 1 placebo CAMELOT 4 placebo REVERSAL 5 pravastatin REVERSAL 5 atorvastatin Mean LDL-C (mg/dL) Progression Regression ASTEROID 3 rosuvastatin INTRO STELLAR PEPI METEOR ASTEROID JUPITER

Change in Percent Diameter Stenosis vs On-Treatment LDL-C in QCA Trials * ASTEROID - rosuvastatin; MAAS - simvastatin; CCAIT - lovastatin; MARS – lovastatin; LCAS - fluvastatin; PLAC I - pravastatin Change in % Stenosis per year MARS MAAS PLAC I LCAS PLAC I CCAIT LCAS MAAS MARS On-Treatment LDL-C (mg/dL) CCAIT Placebo Statin* Progression Regression Nissen S et al. JAMA 2006;295 (13): ; Ballantyne C et al. Circulation 2008 DOI: /CIRCULATIONAHA INTRO STELLAR PEPI METEOR ASTEROID JUPITER ASTEROID 3 rosuvastatin

Atherosclerosis is the underlying cause of heart disease - the World’s number one killer Rosuvastatin is the only statin to show regression of coronary atherosclerosis in a major clinical study In ASTEROID, two imaging modalities that measure different parameters and focus on different segments of the coronary arteries have demonstrated concordant improvements in both IVUS measurements of atheroma volume and angiographic measurements of lumen dimension consistent with regression of atherosclerosis with intensive rosuvastatin therapy CRESTOR Clinical Perspective in Atherosclerosis METEORASTEROID DISEASE PROGRESSION OVER TIME EARLY DISEASE ESTABLISHED DISEASE US FDA approval for atherosclerosis as an indication- Nov INTRO STELLAR PEPI METEOR ASTEROID JUPITER

CRESTOR - Withdrawals due to Adverse Events Percentage of patients with an adverse event leading to withdrawal rosuvastatinsimvastatinpravastatin Patients (%) % 2.5% (n=3074)(n=1457) (n=1278) 3.2% atorvastatin (n=2899) 10–40 mg10–80 mg 10–40 mg Brewer HB. Am J Cardiol 2003;92(Suppl):23K–29K Shepherd J et al. Am J Cardiol 2004;94:

CRESTOR – Liver Effects ALT >3 × ULN: Frequency by LDL-C Reduction LDL-C reduction (%) Fluvastatin (20, 40, 80 mg) Rosuvastatin (10, 20, 40 mg) Lovastatin (20, 40, 80 mg) Atorvastatin (10, 20, 40, 80 mg) Simvastatin (40, 80 mg) Occurrence of ALT >3×ULN (%) Persistent elevation is elevation to >3 x ULN on 2 successive occasions Brewer HB. Am J Cardiol 2003;92(Suppl):23K–29K

CRESTOR - Muscle Effects CK >10 x ULN: Frequency by LDL-C Reduction Brewer HB. Am J Cardiol 2003;92(Suppl):23K–29K LDL-C reduction (%) Occurrence of CK >10 × ULN (%) Cerivastatin (0.2, 0.3, 0.4, 0.8 mg) Rosuvastatin (10, 20, 40 mg) Pravastatin (20, 40 mg) Atorvastatin (10, 20, 40, 80 mg) Simvastatin (40, 80 mg)

Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin CV Risk Reduction –CRESTOR Outcome Study Objective: The primary objective of the JUPITER study is 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 LDL-C but with increased risk as identified by elevated CRP levels Ridker PM et al. Am J Cardiol 2007; 100: 1659–1664. INTRO STELLAR PEPI METEOR ASTEROID JUPITER

20% Reduction Mortality 44% Reduction CV events 48% Reduction Stroke 47% Reduction Unstable angina CV Risk Reduction –CRESTOR Outcome Study INTRO STELLAR PEPI METEOR ASTEROID JUPITER 47% Reduction Combined CV risk 54% Reduction Heart attack

Landmark Statin Trial - Highlights Trial Year published PopulationTreatment % LDL- C RRR* 4S 1994 High cholesterol CHD S mg-35%-34% WOSCOPS 1995 High cholesterol No CHD P 40 mg-26%-31% CARE 1996 Average cholesterol CHD P 40 mg-32%-24% AFCAPS/ TexCAPS 1998 Average cholesterol, low HDL-C No CHD L mg-25%-37% HPS 2002 Average cholesterol CHD or a CHD risk equivalent S 40 mg-29%-24% JUPITER 2008 Low to normal LDL-C R20-50%-44% *Relative risk of experiencing a major CV event INTRO STELLAR PEPI METEOR ASTEROID JUPITER

Lipids CRP Tolerability Lipids CRP Tolerability HbA 1C Placebo run-in 1 –6 2 – Final 3–4 y 6-monthly Randomisation Lipids CRP Tolerability Rosuvastatin 20 mg (n~7500) Placebo (n~7500) 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 CV Risk Reduction –CRESTOR Outcome Study Ridker PM et al. Am J Cardiol 2007; 100: 1659–1664. INTRO STELLAR PEPI METEOR ASTEROID JUPITER

Randomised (n=17,802) mmol/Lmg/dL Total cholesterol LDL-C HDL-C nonHDL-c Triglycerides Glucose5.294 hsCRP, mg/L4.3 HbA 1c, %5.7 Values expressed as median (interquartile range). For hsCRP, values are the mean of the screening and randomization visits. LDL-C=low-density lipoprotein cholesterol; HDL-C=high-density lipoprotein cholesterol; hsCRP=median high sensitivity C- reactive protein; HbA 1c =glycosylated haemoglobin Ridker PM et al. Am J Cardiol 2007; 100: 1659–1664. Laboratory parameters at baseline INTRO STELLAR PEPI METEOR ASTEROID JUPITER

Years Placebo Rosuvastatin 20 mg JUPITER - Primary Endpoint Percent of patients with primary endpoint Number at risk RSV Placebo Hazard Ratio 0.56 (95% CI ) P< NNT for 2y = 95 5y* = 25 44% Reduction Time to first occurrence of a CV death, non-fatal stroke, non-fatal MI, unstable angina or arterial revascularization INTRO STELLAR PEPI METEOR ASTEROID JUPITER

JUPITER - Total Mortality Death from any cause 20% Reduction INTRO STELLAR PEPI METEOR ASTEROID JUPITER

JUPITER - Primary Endpoint Components Primary Endpoint 251 (1.36) 142 (0.77) <0.001 * (Time to first occurrence of CV death, MI, stroke, unstable angina, arterial revascularisation) Non-fatal MI 62 (0.33) 22 (0.12) <0.001 * Fatal or non-fatal MI 68 (0.37) 31 (0.17) Non-fatal stroke 58 (0.31) 30 (0.16) Fatal or non-fatal stroke 64 (0.34) 33 (0.18) Arterial Revascularization 131 (0.71) 71 (0.38) < Unstable angina † 27 (0.14) 16 (0.09) CV death, stroke, MI 157 (0.85) 83 (0.45) <0.001 * Revascularization or unstable angina 143 (0.77) 76 (0.41) <0.001 * PlaceboRosuvastatinHR95% CIp-value [n=8901][n=8901] n (rate ** ) ** Rates are per 100 person years; † Hospitalisation due to unstable angina; *Actual p-value was < INTRO STELLAR PEPI METEOR ASTEROID JUPITER

Tolerability and safety data Adverse Events, (%) Any serious adverse event Muscle weakness, stiffness, pain Myopathy Rhabdomyolysis 0.0 <0.1 * ---- Newly diagnosed cancer Death from cancer Gastrointestinal disorders Renal disorders Bleeding Hepatic disorders Other events, (%) Newly diagnosed diabetes ** Haemorrhagic stroke Placebo Rosuvastatin p-value [n=8901] [n=8901] *Occurred after trial completion; **physician reported newly diagnosed diabetes INTRO STELLAR PEPI METEOR ASTEROID 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 ( ) 66.8 ( ) 0.02 % HbA1c ** 5.8 ( ) 5.9 ( ) 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 INTRO STELLAR PEPI METEOR ASTEROID JUPITER

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< ) 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 INTRO STELLAR PEPI METEOR ASTEROID JUPITER

Assurance of Cardiovascular Risk Reduction comes from broad Clinical Experience Best in class HDL-C increase, and LDL-C decrease 1 PEPI 2 Nearly 500,000 a million patients in real life, have shown CRESTOR is superior in CV risk reduction as compared to all statins First statin to show..treating dyslipidemia with Crestor halts the progression of atherosclerosis in low risk patients leading to US FDA approval in atherosclerosis indication 3 4 out of 5 patients showed coronary plaque regression in patients with established CHD 4 First positive outcome on CRESTOR – Study halted because of unequivocal superiority in cardiovascular morbidity and mortality 5 CRESTOR - Offers Comprehensive Lipid Management