VOYAGER An indiVidual patient data meta- analysis Of statin therapY in At risk Groups: Effects of Rosuvastatin, atorvastatin and simvastatin Please see slide 27 for prescribing information

VOYAGER A unique Individual Patient Data Meta-analysis (of patients) Review of individual patient data from comparative randomised studies comparing rosuvastatin with either atorvastatin or simvastatin in high-risk populations Studies were identified by a comprehensive search of the Cochrane Controlled Trials Registry, Medline, EMBASE, Citeline, Trialtrove, and collection of all published research on rosuvastatin. 37 randomised comparative studies >4 weeks duration were identified as suitable for inclusion in the VOYAGER database, in which baseline and on-treatment lipids were recorded for each patient, as well as lab methods for determining these parameters Integrated database of > patients

VOYAGER Whole population and high-risk goal analysis Meta-analysis of comparative efficacy of increasing dose of atorvastatin versus rosuvastatin versus simvastatin on lowering levels of atherogenic lipids (from VOYAGER) Nicholls SJ et al. Am J Cardiol 2010; 105: 69–76

Background Statins are used widely to reduce cardiovascular risk in primary and secondary prevention Consequently, treatment guidelines have been developed which take into account a patient’s estimated risk of cardiovascular disease However, the incremental benefit of increasing statin dose on lipid levels and goal attainment has not been fully established Nicholls SJ et al. Am J Cardiol 2010; 105: 69–76

Objectives To use the VOYAGER individual patient data meta-analysis to explore relationships between increasing dose of rosuvastatin, atorvastatin and simvastatin, and the ability of these agents to –decrease the levels of atherogenic lipids –allow patients to achieve treatment goals Nicholls SJ et al. Am J Cardiol 2010; 105: 69–76

Patient baseline characteristics Whole population ParameterCohort (n=32 258) Mean (SD) age (y)60.0 ± 11.1 Males (%)56.7 Race (%) Caucasian Black Oriental Asian High-risk patients (%) † Diabetes mellitus Atherogenic dyslipidaemia Atherosclerotic disease Mean (SD) lipid levels (mg/dL) LDL-C HDL-C NonHDL-C ApoB ± ± ± ± 37.2 Median (IQR) TG (mg/dL)161.2 (120.4–215.0) Median (IQR) C-reactive protein (mg/L)0.38 (0.15–0.93) ApoB=apolipoprotein B; HDL-C=high-density lipoprotein cholesterol; IQR=interquartile range; LDL-C=low-density lipoprotein cholesterol; SD=standard deviation † Defined as established atherosclerotic disease, diabetes or atherogenic dyslipidaemia (TG ≥ 150 mg/dL or HDL-C <40 mg/dL) Nicholls SJ et al. Am J Cardiol 2010; 105: 69–76 Adapted by permission from Elsevier Inc.

Change in LDL-C levels with increasing dose of each statin Results from the whole population VOYAGER individual patient data meta-analysis *p<0.001 rosuvastatin 10 mg vs atorvastatin 10 mg and 20 mg; simvastatin 10 mg, 20 mg and 40 mg †p<0.001 rosuvastatin 20 mg vs atorvastatin 20 mg and 40 mg; simvastatin 20 mg,40 mg and 80mg ‡p<0.001 rosuvastatin 40 mg vs atorvastatin 40 mg and 80 mg; simvastatin 40 mg and 80 mg # p<0.05 atorvastatin 20 mg vs rosuvastatin 5 mg ## p<0.05 atorvastatin 80 mg vs rosuvastatin 5 mg and 10 mg Change in LDL-C from baseline (%) Dose (log scale) 5 mg10 mg20 mg40 mg80 mg -27 (n=365) -33 (n=2929) -39 (n=548) -45 (n=479) -50 ## (n=2072) -55 ‡ (n=2983) -50 † (n=3554) -44 * (n=11690) -39 (n=670) -36 (n= 7837) -41 # (n=3908) -46 (n=1324) Nicholls SJ et al. Am J Cardiol 2010; 105: 69–76 Adapted by permission from Elsevier Inc.

Favours rosuvastatinFavours atorvastatin Dosage RSV 5 mg versus: RSV 10 mg versus: RSV 20 mg versus: RSV 40 mg versus: Difference between treatments in mean % change from baseline (95% CI) n ATV 40 mg80 ATV 40 mg399 ATV 80 mg 1651 ATV 10 mg861 *** ATV 10 mg *** ATV 20 mg4583 *** ATV 20 mg 4624 *** ATV 40 mg1316 *** ATV 40 mg 2182 *** ATV 80 mg3358 *** ATV 20 mg77 † ATV 80 mg79 ††† ATV 80 mg406 ††† ***p<0.001 vs ATV; † p<0.05 vs RSV; ††† p<0.001 vs RSV Effect of increasing statin dose on reduction of LDL-C Results from the whole population VOYAGER individual patient data meta-analysis rosuvastatin (RSV) versus atorvastatin (ATV) Nicholls SJ et al. Am J Cardiol 2010; 105: 69–76 Reprinted by permission from Elsevier Inc.

Favours rosuvastatinFavours simvastatin ***p<0.001 vs SIM RSV 5 mg versus: RSV 10 mg versus: RSV 20 mg versus: RSV 40 mg versus: SIM 10 mg 0 SIM 40 mg 0 SIM 80 mg SIM 10 mg 321 *** SIM 20 mg 6001 *** SIM 40 mg 314 *** SIM 20 mg 1090 *** SIM 40 mg 1084 *** SIM 80 mg 323 *** SIM 80 mg 943 *** SIM 40 mg 315 *** SIM 20 mg 489 *** Difference between treatments in mean % change from baseline (95% CI) Dosagen Nicholls SJ et al. Am J Cardiol 2010; 105: 69–76 Reprinted by permission from Elsevier Inc. Effect of increasing statin dose on reduction of LDL-C Results from the whole population VOYAGER individual patient data meta-analysis rosuvastatin (RSV) versus simvastatin (SIM)

High-risk patients achieving LDL-C goals <100 mg/dL, stratified according to baseline LDL-C levels ≤160mg/dL † Represents <10 patients. NA=no data available Nicholls SJ et al. Am J Cardiol 2010; 105: 69–76 Adapted by permission from Elsevier Inc. Baseline LDL-C level (mg/dL): < –160 NA Rosuvastatin Atorvastatin Simvastatin † NA NA † Dose (mg)

High-risk patients with baseline LDL-C ≥160mg/dL achieving LDL-C goals <100 mg/dL Rosuvastatin Atorvastatin Simvastatin Nicholls SJ et al. Am J Cardiol 2010; 105: 69–76 Adapted by permission from Elsevier Inc. Rosuvastatin Atorvastatin Simvastatin Dose (mg)

NA 0 High-risk patients achieving LDL-C goals <70 mg/dL, stratified according to baseline LDL-C levels ≤160 mg/dL Rosuvastatin Atorvastatin Simvastatin † NANA NA 0 † Dose (mg) Baseline LDL-C level (mg/dL): < –160 † Represents <10 patients. NA=no data available Nicholls SJ et al. Am J Cardiol 2010; 105: 69–76 Adapted by permission from Elsevier Inc. NA 0 Rosuvastatin Atorvastatin Simvastatin † NA NA 0 † Dose (mg) Baseline LDL-C level (mg/dL): < –160

High-risk patients with baseline LDL-C ≥160mg/dL achieving LDL-C goals <70 mg/dL Rosuvastatin Atorvastatin Simvastatin 0 Dose (mg) Nicholls SJ et al. Am J Cardiol 2010; 105: 69–76 Adapted by permission from Elsevier Inc. Rosuvastatin Atorvastatin Simvastatin 0 Dose (mg)

***p<0.001 vs ATV; † p<0.05 vs RSV; ††† p<0.001 vs RSV Favours rosuvastatinFavours atorvastatin Nicholls SJ et al. Am J Cardiol 2010; 105: 69–76 Reprinted by permission from Elsevier Inc. Effect of increasing statin dose on reduction of nonHDL-C Results from the whole population VOYAGER individual patient data meta-analysis rosuvastatin (RSV) versus atorvastatin (ATV)

Change in nonHDL-C levels with increasing dose of each statin Rosuvastatin Atorvastatin Simvastatin Dose (mg) ***p<0.001 rosuvastatin vs equivalent or double dose of atorvastatin and simvastatin and rosuvastatin 10 mg vs simvastatin 40 mg and rosuvastatin 20 mg vs simvastatin 80 mg; ‡p<0.05 atorvastatin 20 mg vs rosuvastatin 5 mg; †††p<0.001 atorvastatin 80 mg vs rosuvastatin 5 mg and rosuvastatin 10 mg Nicholls SJ et al. Am J Cardiol 2010; 105: 69–76 Adapted by permission from Elsevier Inc. Rosuvastatin Atorvastatin Simvastatin Dose (mg) *** ‡ †††

***p<0.001 vs SIM Favours rosuvastatinFavours simvastatin RSV 5 mg versus: 0 SIM 10 mg 0 SIM 40 mg 0 SIM 80 mg RSV 10 mg versus: RSV 20 mg versus: RSV 40 mg versus: 319 SIM 80 mg 321 SIM 10 mg *** 5992 SIM 20 mg *** 491 SIM 20 mg *** 314 SIM 40 mg *** 1091 SIM 20 mg *** 1090 SIM 40 mg *** 323 SIM 80 mg *** 944 SIM 80 mg *** 315 SIM 40 mg *** Difference between treatments in mean % change from baseline (95% CI) Dosagen Nicholls SJ et al. Am J Cardiol 2010; 105: 69–76 Reprinted by permission from Elsevier Inc. Effect of increasing statin dose on reduction of nonHDL-C Results from the whole population VOYAGER individual patient data meta-analysis rosuvastatin (RSV) versus simvastatin (SIM)

High-risk patients achieving nonHDL-C levels <130 mg/dL, stratified according to baseline levels Rosuvastatin Atorvastatin Simvastatin Adapted by permission from Elsevier Inc. Baseline nonHDL-C level (mg/dL): < ≥190 Rosuvastatin Atorvastatin Simvastatin NA † NA NA Dose (mg) Nicholls SJ et al. Am J Cardiol 2010; 105: 69–76

Change in TG levels with increasing dose of each statin Results from the whole population VOYAGER individual patient data meta-analysis Dose (mg) ***p<0.001 rosuvastatin 10 mg vs atorvastatin 10 mg and simvastatin 20 mg, rosuvastatin 20 mg vs simvastatin 20 and 40 mg and rosuvastatin 40 mg vs simvastatin 40 and 80 mg; § p<0.01 rosuvastatin 10 mg vs simvastatin 10 mg; ¶ p<0.05 rosuvastatin 20 mg vs simvastatin 80 mg; † p<0.05 atorvastatin 80 mg vs rosuvastatin 5 mg and 40 mg and atorvastatin 40 mg vs rosuvastatin 10 mg; ‡ p<0.01 atorvastatin 80 mg vs rosuvastatin 10 mg; # p<0.001 atorvastatin 80 mg vs rosuvastatin 20 mg *** § ¶ †‡#†‡# † Adapted by permission from Elsevier Inc. Rosuvastatin Atorvastatin Simvastatin Dose (mg) *** § ¶ †‡#†‡# † Nicholls SJ et al. Am J Cardiol 2010; 105: 69–76

Dosage n ***p<0.001 vs ATV; † p<0.05 vs RSV; †† p<0.01 vs RSV; ††† p<0.001 vs RSV Favours rosuvastatinFavours atorvastatin 80 RSV 5 mg versus: 864 ATV 10 mg 77 ATV 20 mg ATV 40 mg † 79 ATV 80 mg RSV 10 mg versus: *** ATV 10 mg 4591ATV 20 mg † 399 ATV 40 mg †† 407ATV 80 mg 4636ATV 20 mg 1317 ATV 40 mg ††† 1650 ATV 80 mg RSV 40 mg versus: 2182 ATV 40 mg † 3362 ATV 80 mg RSV 20 mg versus: Difference between treatments in mean % change from baseline (95% CI) Nicholls SJ et al. Am J Cardiol 2010; 105: 69–76 Reprinted by permission from Elsevier Inc. Effect of increasing statin dose on reduction of TG Results from the whole population VOYAGER individual patient data meta-analysis rosuvastatin (RSV) versus atorvastatin (ATV)

*p<0.05 vs SIM; **p<0.01 vs SIM; ***p<0.001 vs SIM Favours rosuvastatinFavours simvastatin Dosagen Difference between treatments in mean % change from baseline (95% CI) RSV 5 mg versus: 0 SIM 10 mg 491 SIM 20 mg 0 SIM 40 mg 0 SIM 80 mg RSV 10 mg versus: ** 321 SIM 10 mg *** 6014 SIM 20 mg 314 SIM 40 mg 319 SIM 80 mg RSV 20 mg versus: *** 1091 SIM 20 mg *** 1091 SIM 40 mg * 323 SIM 80 mg RSV 40 mg versus: *** 315 SIM 40 mg *** 944 SIM 80 mg Nicholls SJ et al. Am J Cardiol 2010; 105: 69–76 Reprinted by permission from Elsevier Inc. Effect of increasing statin dose on reduction of TG Results from the whole population VOYAGER individual patient data meta-analysis rosuvastatin (RSV) versus simvastatin (SIM)

Baseline TG level (mg/dL): High-risk patients achieving TG levels <150 mg/dL, stratified according to baseline TG levels † Represents less than 10 patients Rosuvastatin Atorvastatin Simvastatin Dose (mg) † Nicholls SJ et al. Am J Cardiol 2010; 105: 69–76 Adapted by permission from Elsevier Inc. Baseline TG level (mg/dL): Rosuvastatin Atorvastatin Simvastatin Dose (mg) †

Rosuvastatin Atorvastatin Simvastatin Dose (mg) ***p<0.001 rosuvastatin vs equivalent or double doses of atorvastatin or simvastatin, except rosuvastatin 10 mg vs atorvastatin 20 mg (p<0.01) and p<0.001 rosuvastatin 10 mg vs simvastatin 40 mg and rosuvastatin 20 mg vs simvastatin 80 mg; ††† p<0.001 atorvastatin 80 mg vs rosuvastatin 5 mg and 10 mg; ‡ p<0.01 atorvastatin 80 mg vs rosuvastatin 20 mg. ApoB levels were determined in (75.5%) of patients only *** ††† ‡ Nicholls SJ et al. Am J Cardiol 2010; 105: 69–76 Adapted by permission from Elsevier Inc. Rosuvastatin Atorvastatin Simvastatin Dose (mg) *** ††† ‡ Change in ApoB levels with increasing dose of each statin Results from the whole population VOYAGER individual patient data meta-analysis

**p<0.01 vs ATV; ***p<0.001 vs ATV; †† p<0.01 vs RSV; ††† p<0.001 vs RSV Favours rosuvastatinFavours atorvastatin Difference between treatments in mean % change from baseline (95% CI) RSV 5 mg versus: *** 833 ATV 10 mg 76 ATV 20 mg 79 ATV 40 mg ††† 76 ATV 80 mg RSV 10 mg versus: *** 7631ATV 10 mg ** 4436ATV 20 mg 370 ATV 40 mg ††† 379ATV 80 mg *** 3905ATV 20 mg *** 1251 ATV 40 mg †† 1562 ATV 80 mg RSV 40 mg versus: *** 1542 ATV 40 mg *** 3230 ATV 80 mg Dosagen RSV 20 mg versus: Nicholls SJ et al. Am J Cardiol 2010; 105: 69–76 Reprinted by permission from Elsevier Inc. Effect of increasing statin dose on reduction of ApoB Results from the whole population VOYAGER individual patient data meta-analysis rosuvastatin (RSV) versus atorvastatin (ATV)

Favours rosuvastatinFavours simvastatin ***p<0.001 vs SIM Difference between treatments in mean % change from baseline (95% CI) RSV 5 mg versus: 0 SIM 10 mg *** 469 SIM 20 mg 0 SIM 40 mg 0 SIM 80 mg RSV 10 mg versus: *** 300 SIM 10 mg *** 1824 SIM 20 mg *** 291 SIM 40 mg 296 SIM 80 mg RSV 20 mg versus: *** 1052 SIM 20 mg *** 1049 SIM 40 mg *** 295 SIM 80 mg RSV 40 mg versus: *** 293 SIM 40 mg *** 888 SIM 80 mg Dosagen Nicholls SJ et al. Am J Cardiol 2010; 105: 69–76 Reprinted by permission from Elsevier Inc. Effect of increasing statin dose on reduction of ApoB Results from the whole population VOYAGER individual patient data meta-analysis rosuvastatin (RSV) versus simvastatin (SIM)

NA † NA 0 High-risk patients achieving ApoB levels <90 mg/dL, stratified according to baseline levels † Represents <10 patients. NA=no data available Rosuvastatin † † Dose (mg) Nicholls SJ et al. Am J Cardiol 2010; 105: 69–76 Adapted by permission from Elsevier Inc. Baseline ApoB level (mg/dL): 150 NA Rosuvastatin Atorvastatin Dose (mg)

Conclusions Increasing the dose of rosuvastatin, atorvastatin and simvastatin resulted in incremental greater reductions in atherogenic lipids and allowed patients to achieve treatment goals The VOYAGER large individual patient database of more than patients highlights the importance of choice of statin and dose when selecting treatment Nicholls SJ et al. Am J Cardiol 2010; 105: 69–76

CRESTOR (rosuvastatin) adverse events Undesirable effects (refer to the SmPC for a full list of side effects): Side effects most frequently reported in controlled clinical studies and post marketing experience: headache, dizziness, constipation, nausea, abdominal pain, myalgia, asthenia, and diabetes mellitus in patients with fasting glucose 5.6–6.9 mmol/L. Rarely: myopathy (including myositis), rhabdomyolysis with or without acute renal failure, hypersensitivity reactions including angioedema, pancreatitis. Very rarely: arthralgia, jaundice, hepatitis, polyneuropathy, haematuria, memory loss. Unknown frequency: diarrhoea, Stevens-Johnson syndrome. Other usually transient side effects: elevations in transaminases and CK levels, proteinuria. The following side effects have been reported with some statins: depression, sleep disturbances, sexual dysfunction and in exceptional cases, interstitial lung disease. MARKETING AUTHORISATION HOLDER: AstraZeneca UK Ltd., 600 Capability Green, Luton LU1 3LU United Kingdom. Telephone: +44 (0) Fax: +44 (0) Medical Information Direct Line: +44 (0) Medical Information Licensed from Shionogi & Co. Ltd., Osaka, Japan. Adverse events should be reported. Reporting forms and information can be found at Adverse events should also be reported to AstraZeneca on

CRESTOR™ (rosuvastatin) Summary of Product Characteristics February 2011 Click on the icon below to access the Summary of Product Characteristics. Consult full prescribing information for CRESTOR before prescribing. CRESTOR exhibition VOYAGER non EU ppt, 2011 CRESTOR is a trademark of the AstraZeneca group of companies