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Crestor Presentation

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Crestor Presentation

  1. 1. Assurance of Cardiovascular Risk Reduction comes from broad Clinical Experience
  2. 2. GALAXY Presentation - suggested execution 1
  3. 3. Is Lower Better? Relationship between LDL-C and CV Event Rate Rosenson RS. Exp Opin Emerg Drugs 2004; 9 (2):269-279, LaRosa JC et al. N Engl J Med 2005; 352 :1425-1435. INTRO STELLAR PEPI METEOR ASTEROID JUPITER LDL-C achieved mg/dL (mmol/L) WOSCOPS – Pl AFCAPS - Pl ASCOT - Pl AFCAPS - Rx WOSCOPS - Rx ASCOT - Rx 4S - Rx HPS - Pl LIPID - Rx 4S - Pl CARE - Rx LIPID - Pl CARE - Pl HPS - Rx 0 5 10 15 20 25 30 40 (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 Secondary Prevention Primary Prevention Rx - Statin therapy Pl – Placebo Pra – pravastatin Atv - atorvastatin 200 (5.2) PROVE-IT - Pra PROVE-IT – Atv TNT – Atv10 TNT – Atv80
  4. 4. Half of patients on lipid lowering therapy are not reaching goal 2 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 EUROASPIRE II which reported in 2001 confirmed that half of treated CHD patients were still not at European total cholesterol goal Patients on lipid lowering therapy at European goal 50% 25% 75% 100% EUROASPIRE II: achievement of total cholesterol treatment goal 51%
  5. 5. NCEP ATP III: LDL-C Goals (2004 proposed modifications) *Therapeutic option 70 mg/dL =1.8 mmol/L; 100 mg/dL = 2.6 mmol/L; 130 mg/dL = 3.4 mmol/L; 160 mg/dL = 4.1 mmol/L Grundy SM et al. Circulation 2004; 110 :227-239. Existing LDL-C goals Proposed LDL-C goals LDL-C LEVEL High Risk CHD or CHD risk equivalents (10-yr risk >20%) 100 - 160 - 130 - 190 - Lower Risk < 2 risk factors Moderately High Risk ≥ 2 risk factors (10-yr risk 10-20%) goal 160 mg/dL goal 130 mg/dL 70 - goal 100 mg/dL or optional 70 mg/dL* Moderate Risk ≥ 2 risk factors (10-yr risk <10%) goal 130 mg/dL or optional 100 mg/dL*
  6. 6. Relationship Between Changes in LDL-C and HDL-C Levels and CHD Risk Third Report of the NCEP Expert Panel. NIH Publication No. 01-3670 2001. http://hin.nhlbi.nih.gov/ncep_slds/menu.htm 1% 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
  7. 7. Rosuvastatin versus Comparators: LDL-C Efficacy Across the Dose Range The STELLAR Study 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) 10 20 40 80 X X n=648 n=473 n=634 n=485 † ‡ Change in LDL-C from baseline (%) INTRO STELLAR PEPI METEOR ASTEROID JUPITER Jones PH et al. Am J Cardiol 2003;92:152–160
  8. 8. 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 10 20 40 10 20 40 80 10 20 40 * 7.7 † 9.5 ‡ 9.6 10 20 40 80 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 3.2 4.4 5.6 0 2 4 6 8 10 12 5.7 4.8 4.4 2.1 5.3 6.0 5.2 6.8
  9. 9. 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 <ul><li>Exclude: </li></ul><ul><li>Established statin users (prior statin use in last 12 months) </li></ul><ul><li>patients with CV event in previous 12 months </li></ul><ul><li>patients with <12 months history in PHARMO </li></ul><ul><li>cerivastatin and fluvastatin users* </li></ul><ul><li>Use of >1 statin simultaneously </li></ul><ul><li>patients under 18 </li></ul>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 2002. 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
  10. 10. <ul><li>Retrospective observational cohort study </li></ul><ul><li>Primary outcome: Cardiovascular (CV) Hospitalisations </li></ul><ul><ul><li>Fatal and non-fatal ischaemic heart disease, myocardial infarction (MI), fatal and non-fatal stroke, coronary and carotid revascularisation </li></ul></ul><ul><li>Secondary outcome </li></ul><ul><ul><li>Hospitalisations for MI </li></ul></ul><ul><li>Hazard ratios ¶ with 95% confidence intervals calculated </li></ul><ul><ul><li>Adjusted for patient characteristics, co-morbidities and co-medications </li></ul></ul>*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
  11. 11. Primary Outcome Rates of CV events were 28% lower on CRESTOR compared with other statins 0.4 0.6 0.8 1.0 1.2 1.4 CRESTOR vs. other statins CRESTOR (10.8 mg) vs. ATV (17.3 mg) RSV better RSV 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 (0.56-0.94) * 0.83 (0.63-1.10) NS 0.71 (0.54-0.94) * 0.60 (0.45-0.80) * 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% Reduction in CV events PEPI INTRO STELLAR PEPI METEOR ASTEROID JUPITER Heintjes et al, Current Medical Opinion and Research, July 2008
  12. 12. 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 <ul><li>Exclude: </li></ul><ul><li>established statin users (prior statin use in last 12 months) </li></ul><ul><li>serious non-CV disease or immunosuppression </li></ul><ul><li>with <12 months history in database </li></ul><ul><li>patients under 18 </li></ul>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
  13. 13. US Study Results: Reduction in CV events >=90 days >=180 days >=270 days 0.95 (0.84-1.08) 0.88 (0.74-1.05) 0.76 (0.59-0.97) ‡ RSV better Other statins† better 0.6 0.8 1.0 1.2 0.97 (0.86-1.08) 0.91 (0.78-1.06) 0.80 (0.64-1.00) ‡ MPR>0.8 MPR>0.8 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% Reduction 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
  14. 14. What about efficacy in atherosclerosis? Which is the Most Effective Statin in Regression of athersclerosis? INTRO STELLAR PEPI METEOR ASTEROID JUPITER
  15. 15. ENHANCE vs METEOR INTRO STELLAR PEPI METEOR ASTEROID JUPITER Kasteline J et al, NEJM April, 2008 Crouse J et al, JAMA, 2007 ENHANCE METEOR Patients High-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) Results No 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
  16. 16. METEOR primary endpoint: Rate of change of maximum IMT at 12 carotid sites Rosuvastatin vs placebo Time (years) -0.01 +0.01 0.00 +0.02 2 1 +0.03 Progression Regression P=NS (CRESTOR vs. zero slope Placebo +0.0131 mm/yr (n=252) Rosuvastatin 40 mg -0.0014 mm/yr (n=624) Placebo; Change in CIMT (95% CI) Rosuvastatin 40 mg; Change in CIMT (95% CI) 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 P<0.001 (CRESTOR vs. placebo)
  17. 17. ENHANCE results 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 Time (years) -0.01 +0.01 0.00 +0.02 +0.03 Primary Endpoint Change in mean IMT at 6 carotid sites (mm) SMV 80 + EZE +0.0111 mm p=0.29 (ns) SMV 80 +0.0058 mm <ul><li>720 patients with familial hypercholesteraemia </li></ul><ul><li>1 ° endpoint: Absolute change in m ean cIMT </li></ul><ul><li>Measured at 6 carotid sites </li></ul><ul><li>Most patients established statin users </li></ul>2 1
  18. 18. <ul><li>ENHANCE failed to meet its primary and secondary endpoints and showed that adding ezetimibe to simvastatin provides no benefit on the treatment of atherosclerosis </li></ul><ul><li>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 </li></ul><ul><li>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 </li></ul>Summary : METEOR & ENHANCE Results
  19. 19. A S tudy T o evaluate the E ffect of R osuvastatin O n I ntravascular ultrasound- D erived coronary atheroma burden     Nissen S et al. JAMA 2006;295 (13):1556-1565; Ballantyne C et al. Circulation 2008 DOI: 10.1161/CIRCULATIONAHA.108.773747. 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
  20. 20. 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 Lumen area EEM area Atheroma area
  21. 21. 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
  22. 22. 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;354:1253-1263 . 2 Tardif J et al. Circulation 2004;110:3372-3377. 3 Nissen S et al. JAMA 2006;295 (13):1556-1565 4 Nissen S et al . JAMA 2004;292: 2217–2225. 5 Nissen S et al. JAMA 2004; 291 : 1071–1080 -1 -0.5 0 0.5 1 1.5 50 60 70 80 90 100 110 120 A-Plus 2 placebo ACTIVATE 1 placebo CAMELOT 4 placebo REVERSAL 5 pravastatin REVERSAL 5 atorvastatin Mean LDL-C (mg/dL) INTRO STELLAR PEPI METEOR ASTEROID JUPITER Progression Regression ASTEROID 3 rosuvastatin
  23. 23. 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 40 60 80 100 120 140 160 180 MARS MAAS PLAC I LCAS PLAC I CCAIT LCAS MAAS MARS On-Treatment LDL-C (mg/dL) CCAIT Placebo Statin * Nissen S et al. JAMA 2006;295 (13):1556-1565; Ballantyne C et al. Circulation 2008 DOI: 10.1161/CIRCULATIONAHA.108.773747. INTRO STELLAR PEPI METEOR ASTEROID JUPITER -1 -0.8 -0.6 -0.4 -0.2 0 0.2 0.4 0.6 0.8 1 1.2 1.4 Progression Regression ASTEROID 3 rosuvastatin
  24. 24. <ul><li>Atherosclerosis is the underlying cause of heart disease - the World’s number one killer </li></ul><ul><li>Rosuvastatin is the only statin to show regression of coronary atherosclerosis in a major clinical study </li></ul><ul><li>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 </li></ul>CRESTOR Clinical Perspective in Atherosclerosis INTRO STELLAR PEPI METEOR ASTEROID JUPITER METEOR ASTEROID DISEASE PROGRESSION OVER TIME EARLY DISEASE ESTABLISHED DISEASE US FDA approval for atherosclerosis as an indication- Nov. 2007
  25. 25. CRESTOR - Withdrawals due to Adverse Events Percentage of patients with an adverse event leading to withdrawal 0 2 4 6 8 rosuvastatin simvastatin pravastatin Patients (%) 1 3 5 7 2.9% 2.5% 2.5% (n=3074) (n=1457) (n=1278) 3.2% atorvastatin (n=2899) 10–40 mg 10–80 mg 10–80 mg 10–40 mg Brewer HB. Am J Cardiol 2003;92(Suppl):23K–29K Shepherd J et al. Am J Cardiol 2004;94:882-888
  26. 26. CRESTOR – Liver Effects ALT >3 × ULN: Frequency by LDL-C Reduction 0.0 0.5 1.0 1.5 2.0 2.5 3.0 20 30 40 50 60 70 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
  27. 27. CRESTOR - Muscle Effects CK >10 x ULN: Frequency by LDL-C Reduction Brewer HB. Am J Cardiol 2003;92(Suppl):23K–29K 0.0 0.5 1.0 1.5 2.0 2.5 3.0 20 30 40 50 60 70 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)
  28. 28. J ustification for the U se of statins in P rimary prevention: an I ntervention T rial E valuating R osuvastatin 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
  29. 29. 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
  30. 30. Landmark Statin Trial - Highlights *Relative risk of experiencing a major CV event INTRO STELLAR PEPI METEOR ASTEROID JUPITER Trial Year published Population Treatment % LDL-C RRR* 4S 1994 High cholesterol CHD S 20-40 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 20-40 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%
  31. 31. Lipids CRP Tolerability Lipids CRP Tolerability HbA 1C Placebo run-in 1 –6 2 –4 3 0 4 13 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
  32. 32. 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 Randomised (n=17,802) mmol/L mg/dL Total cholesterol 4.79 185 LDL-C 2.79 108 HDL-C 1.27 49 nonHDL-c 3.47 134 Triglycerides 1.33 118 Glucose 5.2 94 hsCRP, mg/L 4.3 HbA 1c , % 5.7
  33. 33. 0 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 Years Placebo Rosuvastatin 20 mg JUPITER - Primary Endpoint 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 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
  34. 34. JUPITER - Total Mortality Death from any cause 20% Reduction INTRO STELLAR PEPI METEOR ASTEROID JUPITER 0 1 2 3 4 5 6 7 0 1 2 3 4 5 Years Placebo Rosuvastatin 20mg 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
  35. 35. JUPITER - Primary Endpoint Components 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 62 (0.33) 22 (0.12) 0.35 0.22-0.58 <0.001 * Fatal or non-fatal MI 68 (0.37) 31 (0.17) 0.46 0.30-0.70 0.0002 Non-fatal stroke 58 (0.31) 30 (0.16) 0.52 0.33-0.80 0.003 Fatal or non-fatal stroke 64 (0.34) 33 (0.18) 0.52 0.34-0.79 0.002 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 0.09 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 * <ul><ul><ul><ul><ul><li>Placebo Rosuvastatin HR 95% CI p-value [n=8901] [n=8901] </li></ul></ul></ul></ul></ul><ul><li>n (rate ** ) n (rate ** ) </li></ul>** Rates are per 100 person years; † Hospitalisation due to unstable angina; *Actual p-value was < 0.00001 INTRO STELLAR PEPI METEOR ASTEROID JUPITER
  36. 36. Tolerability and safety data <ul><li>Adverse Events, (%) </li></ul><ul><li>Any serious adverse event 15.5 15.2 0.60 </li></ul><ul><li>Muscle weakness, stiffness, pain 15.4 16.0 0.34 </li></ul><ul><li>Myopathy 0.1 0.1 0.82 </li></ul><ul><li>Rhabdomyolysis 0.0 <0.1 * ---- </li></ul><ul><ul><li>Newly diagnosed cancer 3.5 3.4 0.51 </li></ul></ul><ul><ul><li>Death from cancer 0.7 0.4 0.02 </li></ul></ul><ul><ul><li>Gastrointestinal disorders 19.2 19.7 0.43 </li></ul></ul><ul><ul><li>Renal disorders 5.4 6.0 0.08 </li></ul></ul><ul><ul><li>Bleeding 3.1 2.9 0.45 </li></ul></ul><ul><ul><li>Hepatic disorders 2.1 2.4 0.13 </li></ul></ul><ul><li>Other events, (%) </li></ul><ul><ul><li>Newly diagnosed diabetes ** 2.4 3.0 0.01 </li></ul></ul><ul><ul><li>Haemorrhagic stroke 0.1 0.1 0.44 </li></ul></ul> Placebo Rosuvastatin p-value [n=8901] [n=8901] *Occurred after trial completion; **physician reported newly diagnosed diabetes INTRO STELLAR PEPI METEOR ASTEROID JUPITER
  37. 37. Laboratory Safety Data <ul><li>Laboratory Values, N (%) </li></ul><ul><li>Serum creatinine ‡ 10 (0.10) 16 (0.20) 0.24 </li></ul><ul><ul><li>ALT > 3 x ULN # 17 (0.20) 23 (0.30) 0.34 </li></ul></ul><ul><li>Glycosuria † 32 (0.40) 36 (0.50) 0.64 </li></ul><ul><li>Laboratory Values, median values (IQR) </li></ul><ul><li>GFR * , (mL/min/1.73m 2 ) 66.6 (58.8-76.2) 66.8 (59.1-76.5) 0.02 </li></ul><ul><li>% HbA1c ** 5.8 (5.6-6.1) 5.9 (5.7-6.1) 0.001 </li></ul><ul><li>Fasting plasma glucose ** , (mg/dL) 98 (90-106) 98 (91-107) 0.12 </li></ul>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
  38. 38. JUPITER – summary and perspectives <ul><li>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 </li></ul><ul><li>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) </li></ul><ul><li>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 </li></ul><ul><li>In JUPITER, long-term treatment with rosuvastatin 20 mg was well tolerated in nearly 9000 study participants </li></ul><ul><li>There was no difference between treatment groups for muscle weakness, cancer, haematological disorders, gastrointestinal, hepatic or renal systems </li></ul><ul><li>The results from JUPITER highlight the importance of highly effective statin treatment for these patients with an increased risk of CV disease </li></ul>INTRO STELLAR PEPI METEOR ASTEROID JUPITER
  39. 39. Assurance of Cardiovascular Risk Reduction comes from broad Clinical Experience CRESTOR - Offers Comprehensive Lipid Management 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

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