1. Statins and CAD Prevention: Rosuvastatin

2. Rising burden of CVD in India (2005) Lancet 2005;366:1744-9 Estimated proportions of total deaths and DALYs lost by cause in India (all ages, 2005)

3. CAD risk factors in Indians J Assoc Physicians India. 2004 Feb;52:103-8 Fraction of CAD patients with various risk factors (n=5748) Dyslipidaemia is a major CVD risk factor in Indians

4. Secondary Prevention NCEP ATP 3. Circulation 2002; 106;3143 “NCEP-ATP III specifies an LDL cholesterol <100 mg/dL as the goal of therapy in secondary prevention” LDL-C is the primary target “NCEP-ATP III identifies the sum of LDL+VLDL [termed non-HDL cholesterol (Total-CL minus HDL-CL)] <130 mg/dL as a secondary target of therapy in persons with high triglycerides (≥200 mg/dL)” Non-HDL-C as the secondary target

5. “The Lower, the Better” Relative Risk for CHD (Log Scale) 3.7 2.9 2.2 1.7 1.3 1.0 LDL-C 4070100130160190 0 1 Grundy SM et al. Circulation 2004;110:227–239. mg/dL 1.05 1.80 2.60 3.35 4.10 4.90 mmol/L 1% decrease in LDL-C reduces CHD risk by 1%

6. NCEP-ATP 3 Guidelines for LDL Cholesterol NCEP ATP 3. Circulation 2002; 106;3143 *

7. NCEP-ATP 3 Update Circulation. 2004;110:227-239 *When LDL-lowering drug therapy is employed in high-risk or moderately high-risk persons, it is advised that intensity of therapy be sufficient to achieve at least a 30% to 40% reduction in LDL-C levels

8. Drugs for hyperlipidaemia LDL ↓18-55% HDL ↑5-15% TG ↓7-30% Statins LDL ↓15-30% HDL ↑3-5% TG No change Fibrates LDL ↓5-25% HDL ↑15-35% TG ↓20-50% Nicotinic acid LDL ↓5-20% HDL ↑10-20% TG ↓20-50% Bile acid sequestrants

9. LDL-C goal: an unmet need

10. The lipid treatment assessment project (L-TAP) 63% of patients with  2 risk factors and no CHD did not reach NCEP goal 63%82% 82% of CHD patients did not reach NCEP goal Arch Intern Med. 2000;160:459-467

11. Many Patients With CHD Fail to Achieve LDL-C and Non-HDL-C Goals Even With Dose Titration ACCESS STUDY. Ballantyne CM, et al. Am J Cardiol. 2001;88:265-269 n = 2,543 † At Wk 54 GAP

12. Reasons for the unmet gap Variations in drug potency Variations in drug potency Drug interactions Drug interactions Variations in drug tolerability affecting compliance Variations in drug tolerability affecting compliance

13. Rosuvastatin “Superstatin”

14. Statins: Comparison of standard doses † For every doubling of the dose above standard dose, an approximate 6% decrease in LDL-C level can be obtained Circulation. 2004;110:227-239

15. Change from baseline LDL-C level according to rosuvastatin dose Olsson AG 2000

16. LDL-C: % Change From Baseline at week 6 Rosuvastatin 10 to 40 mg vs Comparators P <0.001 vs comparators on a mg-to-mg basis. Data presented as means. http://www.fda.gov/OHRMS/DOCKETS/ac/03/slides/3968S1_01_B-AstraZeneca-Efficacy.ppt#14 STELLAR Study. Am J Cardiol 2003;92:152–160)

17. Rosuvastatin “Less drug interactions”

18. Statins: Differences in Pharmacokinetics NaturalSynthetic Lovastatin Simvastatin Pravastatin Atorvastatin Fluvastatin Rosuvastatin Lipophilic Hydrophilic Metabolized by cyt P (450) 3A4/2C9 Limited metabolism by cyt P (450) Schachter M. Fundam Clin Pharmacol 2005; 19: 117-125 Rosuvastatin: less chance of drug interaction

19. Rosuvastatin “Ease of administration”

20. Longer half-life Hepatic cholesterol synthesis is maximal between midnight and 2:00 A.M Hepatic cholesterol synthesis is maximal between midnight and 2:00 A.M Most statins attain peak plasma concentrations 1-4 hours after oral administration and have a half-life of 1- 4 hours requiring them to be administered in the evening Most statins attain peak plasma concentrations 1-4 hours after oral administration and have a half-life of 1- 4 hours requiring them to be administered in the evening Rosuvastatin has a long half-life like atorvastatin (approximately 20 hrs) which permits it to be administered any time in a day Rosuvastatin has a long half-life like atorvastatin (approximately 20 hrs) which permits it to be administered any time in a day

21. Rosuvastatin “Effects on other atherogenic lipid parameters”

22. Effect on total cholesterol Mean % change in TC from baseline * * p<0.001 vs. other statins Rosuvastatin 10mgAtorvastatin 10mgSimvastatin 20mgPravastatin 20mg n=389n=393 n=249n=252 Coron Artery Dis 2004;15:115-23.

23. Effect on triglycerides Mean % change in TG from baseline * * p<0.001 vs. simvastatin & pravastatin Rosuvastatin 10mgAtorvastatin 10mgSimvastatin 20mgPravastatin 20mg n=389n=393 n=249n=252 Am J Cardiol 2003;91(Suppl):3C-10C.

24. Effect on small dense LDL-C: % change from baseline after 6 weeks of treatment * * p< 0.001 vs. atorvastatin STELLAR Trial. Am J Cardiol 2008;101:315–318.

25. Effect on HDL-C: % Change From Baseline at week 6 P <.002 RSV 10 mg vs PRA 10 mg. P <.002 RSV 20 mg vs ATV 20 mg, 40 mg, 80 mg; PRA 20 mg, 40 mg; SIM 40 mg. P <.002 RSV 40 mg vs ATV 40 mg, 80 mg; PRA 40 mg; SIM 40 mg. Data presented as LS means ± SE. N = 156 160 157 158 155 156 165 160 164 161 165 162 158 163 STELLAR Study. Am J Cardiol 2003;92:152–160)

26. 10mg 20mg 40mg10mg 20mg 40mg 80mg 10mg 20mg 40mg RosuvastatinAtorvastatinSimvastatinPravastatin Mean % change from baseline in LDL-C:HDL-C * †# *p<0.002 rosuvastatin 10mg vs. atorvastatin 10mg, simvastatin and pravastatin 10, 20, and 40mg †p<0.002 rosuvastatin 20mg vs. atorvastatin 20 and 40mg, simvastatin 20, 40, and 80mg and pravastatin 20 and 40mg #p<0.002 rosuvastatin 40mg vs. atorvastatin and simvastatin 40 and 80mg and pravastatin 40mg Clin Ther. 2004;26:1388-1399

27. 10mg 20mg 40mg10mg 20mg 40mg 80mg 10mg 20mg 40mg RosuvastatinAtorvastatinSimvastatinPravastatin Mean % change from baseline in TC:HDL-C * †# *p<0.002 rosuvastatin 10mg vs. atorvastatin 10mg, simvastatin and pravastatin 10, 20, and 40mg †p<0.002 rosuvastatin 20mg vs. atorvastatin 20 and 40mg, simvastatin 20, 40, and 80mg and pravastatin 20 and 40mg #p<0.002 rosuvastatin 40mg vs. atorvastatin and simvastatin 40 and 80mg and pravastatin 40mg Clin Ther. 2004;26:1388-1399

28. 10mg 20mg 40mg10mg 20mg 40mg 80mg 10mg 20mg 40mg RosuvastatinAtorvastatinSimvastatinPravastatin Mean % change from baseline in Non HDL-C:HDL-C * †# *p<0.002 rosuvastatin 10mg vs. atorvastatin 10mg, simvastatin and pravastatin 10, 20, and 40mg †p<0.002 rosuvastatin 20mg vs. atorvastatin 20 and 40mg, simvastatin 20, 40, and 80mg and pravastatin 20 and 40mg #p<0.002 rosuvastatin 40mg vs. atorvastatin and simvastatin 40 and 80mg and pravastatin 40mg Clin Ther. 2004;26:1388-1399

29. 10mg 20mg 40mg10mg 20mg 40mg 80mg 10mg 20mg 40mg RosuvastatinAtorvastatinSimvastatinPravastatin Mean % change from baseline in ApoB:ApoA-1 * †# *p<0.002 rosuvastatin 10mg vs. atorvastatin 10mg, simvastatin and pravastatin 10, 20, and 40mg †p<0.002 rosuvastatin 20mg vs. atorvastatin 20, simvastatin 20, 40, and 80mg and pravastatin 20 and 40mg #p<0.002 rosuvastatin 40mg vs. atorvastatin and simvastatin 40 and 80mg and pravastatin 40mg Clin Ther. 2004;26:1388-1399

30. Rosuvastatin “Clinical implications”

31. Earlier achievement of targets POLARIS study. Atherosclerosis 194 (2007) e154–e164

32. 984 asymptomatic patients with moderately elevated cholesterol and low risk of CVD acc to NCEP-ATP 3 criteria Rosuvastatin 40mg (n=702) Vs Placebo (n=282) for 2 years Change in CIMT for 12 Carotid Artery sites (mm/year) Change in CIMT for 12 Carotid Artery sites (mm/year) Change in CIMT n = 702 n = 282 p < 0.001 METEOR Trial. ACC 2007 Rosuvastatin Placebo

33. ASTEROID: Effect on atheroma volume measured by IVUS Nissen SE et al. JAMA. 2006;295:1556-65. mm 3 P < 0.001 %

34. Primary Prevention With LDL-Lowering Therapy Reduced intakes of saturated fat and cholesterol Reduced intakes of saturated fat and cholesterol Increased physical activity Increased physical activity Weight control Weight control Statins Statins

35. JUPITER trial Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin Ridker et al, N Engl J Med 2008

36. JUPITER Multi-National Randomized Double Blind Placebo Controlled Trial of Rosuvastatin in the Prevention of Cardiovascular Events Among Individuals With Low LDL and Elevated hsCRP Ridker et al, Circulation 2003;108:2292-2297. JUPITER Trial Design Rosuvastatin 20 mg (N=8901) MIStrokeUnstable Angina Angina CVD Death CABG/PTCA 4-week run-in No Prior CVD or DM Men >50, Women >60 LDL <130 mg/dL hsCRP >2 mg/L Placebo (N=8901)

37. hsCRP (mg/L) LDL (mg/dL) Months 012243648 TG (mg/dL) HDL (mg/dL) Months JUPITER Effects of rosuvastatin 20 mg on LDL, HDL, TG, and hsCRP LDL decrease 50 percent at 12 months hsCRP decrease 37 percent at 12 months HDL increase 4 percent at 12 months TG decrease 17 percent at 12 months Ridker et al NEJM 2008 0 12 24 36 48 ______ PlaceboRosuvastatin LDL-C decrease 50 percent at 12 months

38. JUPITER Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death Placebo 251 / 8901 Rosuvastatin 142 / 8901 HR 0.56, 95% CI 0.46-0.69 P < 0.00001 - 44 % 01234 0.00 0.02 0.04 0.06 0.08 Cumulative Incidence Number at Risk Follow-up (years) Rosuvastatin Placebo 8,9018,6318,4126,5403,8931,9581,353983544157 8,9018,6218,3536,5083,8721,9631,333955534174 Ridker et al NEJM 2008 Number Needed to Treat (NNT 5 ) = 25

39. JUPITER Secondary Endpoint – All Cause Mortality Placebo 247 / 8901 Rosuvastatin 198 / 8901 HR 0.80, 95%CI 0.67-0.97 P= 0.02 - 20 % 01234 0.00 0.01 0.02 0.03 0.04 0.05 0.06 Cumulative Incidence Number at Risk Follow-up (years) Rosuvastatin Placebo 8,9018,8478,7876,9994,3122,2681,6021,192683227 8,9018,8528,7756,9874,3192,2951,6141,196684246 Ridker et al NEJM 2008

40. JUPITER Primary Endpoint – Subgroup Analysis 0.250.51.02.04.0 Rosuvastatin SuperiorRosuvastatin Inferior Men Women Age< 65 Age > 65 Smoker Non-Smoker Caucasian Non-Caucasian USA/Canada Rest of World Hypertension No Hypertension All Participants NP for Interaction 11,001 0.80 6,801 8,541 0.32 9,261 2,820 0.63 14,975 12,683 0.57 5,117 6,041 0.51 11,761 10,208 0.53 7,586 17,802 Ridker et al NEJM 2008

41. FDA has approved rosuvastatin to reduce the risk of stroke, MI and arterial revascularization procedures in individuals without clinically evident CHD but with an increased risk of CVD based on age (men ≥50 and women ≥60), hsCRP ≥ 2 mg/L, and the presence of at least one additional CVD risk factor, such as hypertension, low HDL-C, smoking, or a family history of premature coronary heart disease.

42. AURORA AURORA Trial. N Engl J Med 2009;360:1395-407 4D study. N Engl J Med 2005;353:238-48 2776 patients, 50-80 years age, undergoing maintenance hemodialysis Rosuvastatin 10 mg Vs placebo Median follow-up of 3.8 yrs Rosuvastatin lowered LDL-C level but had no significant effect on the composite primary end point of death from cardiovascular causes, nonfatal MI, or nonfatal stroke Similar results with atorvastatin observed in 4D study

43. Rosuvastatin “Safety”

44. Adverse events Equal or even lower risk of myopathy compared to other statins because of the lower dose requirement and option of non-daily dosing Equal or even lower risk of myopathy compared to other statins because of the lower dose requirement and option of non-daily dosing Mild transaminitis might occur – Self limiting Mild transaminitis might occur – Self limiting Small but significant increases in the rate of physician- reported diabetes and glycated hemoglobin values noted in JUPITER trial Small but significant increases in the rate of physician- reported diabetes and glycated hemoglobin values noted in JUPITER trial Hematuria, proteinuria, ARF only in very high doses (≥80mg) Hematuria, proteinuria, ARF only in very high doses (≥80mg) Ann Intern Med. 2009;150:858-868. Am J Cardiol. 2000;85:15E-19E

45. Adverse events % subjects with adverse events Rosuvastatin (n = 700) Placebo (n = 281) Myalgia12.712.1 CK > 10 X ULN 0.1‡ 0.7 Rhabdomyolysis00 ALT > 3 X ULN 0.60.4 Hepatitis00 Proteinuria shift * 0.30.4 Renal failure 00 Cardiac SAEs 0.90 Neoplasms1.61.1 Deaths1/702†0/282 *Shift in dipstick urine protein from none/trace at baseline to ≥ 2+ post baseline. †Creutzfeldt-Jakob disease, not related to study treatment. ‡Exercise-associated. METEOR Trial ACC 2007

46. Summary Lipid abnormalities are proportionately associated with CAD morbidity and mortality Lipid abnormalities are proportionately associated with CAD morbidity and mortality Failure rate in achieving NCEP ATP III goal in CHD patients is very high Failure rate in achieving NCEP ATP III goal in CHD patients is very high Rosuvastatin is more effective in reducing LDL- C and achieving NCEP ATP III goal Rosuvastatin is more effective in reducing LDL- C and achieving NCEP ATP III goal

47. Summary Effective in reducing plaque volume, and hence may be useful for secondary prevention of CAD Effective in reducing plaque volume, and hence may be useful for secondary prevention of CAD May also be useful for primary prevention in select populations May also be useful for primary prevention in select populations Being a hydrophilic, associated with less chances of drug interactions Being a hydrophilic, associated with less chances of drug interactions Safe and well tolerated Safe and well tolerated

51. Cost comparison ZYROVA – Zydus Cadila; 5 mg x 10's (IRP: rupee 90), 10 mg x 10's (IRP: rupee 150), 20 mg x 10's (IRP: rupee 280) ZYROVA – Zydus Cadila; 5 mg x 10's (IRP: rupee 90), 10 mg x 10's (IRP: rupee 150), 20 mg x 10's (IRP: rupee 280) ATORVA – Zydus Cadila; 10 mg x 10's (IRP: rupee 94), 40 mg x 10's (IRP: rupee 190.03) ATORVA – Zydus Cadila; 10 mg x 10's (IRP: rupee 94), 40 mg x 10's (IRP: rupee 190.03) ORVAS – Systopic; 5 mg x 10's (IRP: rupee 16)10 mg x 10's (IRP: rupee 24.5)20 mg x 10's (IRP: rupee 48) ORVAS – Systopic; 5 mg x 10's (IRP: rupee 16)10 mg x 10's (IRP: rupee 24.5)20 mg x 10's (IRP: rupee 48) Source – CIMS (http://cimsasia.com)