Efficacy

The objectives of the rosuvastatin clinical development programme was to demonstrate that rosuvastatin:

• fulfills the unmet medical need by providing greater beneficial effects on key lipid parameters compared with other currently marketed statins
• has a similar safety profile compared to other currently marketed statins
• has a low potential for significant drug/drug interactions.

Rosuvastatin has undergone evaluation for efficacy and safety in a worldwide comprehensive programme of pre-approval trials. This programme involved a greater number of patients than any other statin at the time of their FDA approval. The NDA clinical programme included:

• 33 phase I trials/27 phase II/III trials/doses of 5–80 mg studied in phase III/10,275 patients in completed studies/12,569 patients in safety database (including real time laboratory data (RTLD) from ongoing studies)
• phase III trial designs: Comparisons with placebo, atorvastatin, simvastatin, pravastatin, niacin, fenofibrate/Combinations with niacin, fenofibrate and cholestyramine/Open-label extension trials
• patient types studied: type IIa or IIb dyslipidaemia, heterozygous or homozygous FH, type IV dyslipidaemia (isolated hypertriglyceridaemia).

This programme has successfully demonstrated the very favourable benefit–risk profile of rosuvastatin by showing greater beneficial effects on key lipid parameters compared with currently marketed statins, while at the same time showing a similar safety profile.

Additionally, the programme has confirmed a low potential for significant drug–drug interactions. It remains ongoing and includes the largest number of outcomes studies ongoing at launch compared to other statins. This shows AZ confidence in the efficacy of rosuvastatin and the difference it will make to the lives of people at risk of cardiovascular disease.

Rosuvastatin reduces LDL-C by up to 63%

Efficacy results are given for rosuvastatin doses of 5 to 40 mg and are shown as mean percentage change in observed data from the intention-to-treat (ITT) population.

The data here is from the initial dose-ranging study¹. This was a 6-week randomised, placebo-controlled study involving 206 patients with:

• LDL-C >160mg/dL and <220mg/dL (4.14 and 5.69 mmol/L)
• triglycerides <300mg/dL (<3.39mmol/L)

At week 6, patients receiving rosuvastatin exhibited marked dose-related reductions in LDL-C, compared with those receiving placebo (p<0.001). Reductions were 45% in the rosuvastatin 5 mg group, 52% in the 10 mg group, 55% in the 20 mg group, 63% in the 40 mg group versus 7% in the placebo group. The 63% reduction achieved with 40 mg surpasses the maximum LDL-C reduction previously reported for any other statin.

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*p<0.001 vs placebo
Adapted from Olsson A. Cardiovasc Drug Rev 2002;20:303–328

Rosuvastatin versus comparators: LDL-C efficacy across the dose range

The figure below shows the percentage change from baseline in LDL-C at week 6 at each dose across respective dose ranges.¹

• rosuvastatin 10 mg reduced LDL-C to a significantly greater extent than atorvastatin 10 mg; simvastatin 10, 20 or 40 mg; or pravastatin 10, 20 or 40 mg (p<0.002).
• rosuvastatin 20 mg reduced LDL-C to a significantly greater extent than atorvastatin 20 or 40 mg (p<0.002); pravastatin 20 or 40 mg, or simvastatin 20, 40 or 80 mg (p<0.002).
• rosuvastatin 40 mg reduced LDL-C to a significantly greater extent than atorvastatin 40 mg, pravastatin 40 mg, or simvastatin 40 or 80 mg (p<0.002).

Results from the STELLAR study

Click to enlarge

*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

Adapted from Jones PH et al. Am J Cardiol 2003;92:152–160

Rosuvastatin versus comparators: LDL-C efficacy at 10mg Dose

Rosuvastatin 10 mg reduced LDL-C to a significantly greater extent than atorvastatin 10 mg; simvastatin 10, 20 or 40 mg; and pravastatin 10, 20 or 40 mg (p<0.002).¹

Results from the STELLAR study:

Click to enlarge

*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
Adapted from Jones PH et al. Am J Cardiol 2003;92:152–160

Rosuvastatin versus other statins - achievement of LDL-C goals across dose range

Additionally, data from STELLAR demonstrates the greater efficacy of rosuvastatin in bringing patients to their 2003 European LDL-C goals compared to the same and some higher doses of atorvastatin, simvastatin and pravastatin.²¹

Patients achieving 2003 European LDL-C goals‡

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‡LDL-C <3mmol/l (115mg/dl) in general; <2.5mmol/l (97mg/dl) for patients with clinically established CVD or type 2 diabetes
*p<0.002 vs atorvastatin 10 mg; simvastatin 10, 20, 40 mg; pravastatin 10, 20, 40 mg
†p<0.002 vs atorvastatin 20 mg; simvastatin 20, 40 mg; pravastatin 20, 40 mg
#p<0.002 vs atorvastatin 40 mg; simvastatin 40, 80 mg; pravastatin 40 mg

Kritharides L. Eur Heart J Suppl 2004;6(Suppl A):A12-A18

Additionally, data from STELLAR demonstrates the greater efficacy of rosuvastatin in bringing patients to their NCEP ATP III LDL-C goals compared to the same and some higher doses of atorvastatin, simvastatin and pravastatin.¹

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#LDL-C goal <100mg/dl for high-risk; <130 for medium risk & <160 for low-risk patients
*p<0.002 vs. simvastatin 10 mg and 20 mg; pravastatin 10 mg, 20 mg and 40 mg
†p<0.002 vs. atorvastatin 20 mg, simvastatin 20mg and 40 mg; pravastatin 20 mg and 40 mg
‡p<0.002 vs. simvastatin 40 mg and pravastatin 40 mg

Jones PH et al. Am J Cardiol 2003;92:152–160

Change in HDL-C

The HDL-C raising efficacy of rosuvastatin also compares very favourably with that of simvastatin and pravastatin. Rosuvastatin resulted in a statistically significant greater increase in HDL-C compared with atorvastatin for rosuvastatin 20-mg and 40-mg-dose comparisons (p<0.002).¹

• -rosuvastatin 10 mg raised HDL-C statistically significantly more than pravastatin 10 mg (p<0.002).
• rosuvastatin 20 mg raised HDL-C statistically significantly more than atorvastatin 20, 40 and 80 mg, simvastatin 40 mg, and pravastatin 20, 40 mg (p<0.002).
• rosuvastatin 40 mg raised HDL-C statistically significantly more than atorvastatin 40 and 80 mg, simvastatin 40 mg, and pravastatin 40 mg (p<0.002).

Mean baseline HDL-C for rosuvastatin group: 51 mg/dL.

Results from the STELLAR study:

Click to enlarge

*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

Adapted from Jones PH et al. Am J Cardiol 2003;92:152–160

Change in triglycerides

Dose for dose, there were no significant differences in reductions in TG levels from baseline between rosuvastatin and atorvastatin; however, rosuvastatin resulted in a statistically significant greater reduction in TG compared with simvastatin or pravastatin (p<0.002).¹

• rosuvastatin 10 mg decreased triglycerides statistically significantly more than pravastatin 10 and 20 mg (p<0.002).
• rosuvastatin 20 mg decreased triglycerides statistically significantly more than simvastatin 40 mg, pravastatin 20 and 40 mg (p<0.002).
• rosuvastatin 40 mg decreased triglycerides statistically significantly more than simvastatin 40 mg and pravastatin 40 mg (p<0.002).

Mean baseline TG for rosuvastatin group: 179 mg/dL.

Results from the STELLAR study:

Click to enlarge

*p<0.002 vs pravastatin 10, 20 mg
†p<0.002 vs simvastatin 40 mg; pravastatin 20, 40 mg
‡p<0.002 vs simvastatin 40 mg; pravastatin 40 mg

Adapted from Jones PH et al. Am J Cardiol 2003;92:152–160

Rosuvastatin efficacy summary

• Rosuvastatin is the most effective statin at lowering LDL-C^1-21
  • highly effective reductions in LDL-C of up to 63%²¹
  • superior LDL-C lowering versus atorvastatin in more than 17 comparative studies involving >16,000 patients^1-15,18-20
• Rosuvastatin 10 mg can cut LDL-C in half and produces:
  • greater reductions in LDL-C than the same and some higher doses of other statins^1-17
  • greater reductions in LDL-C than atorvastatin 10 and 20 mg^2,13-15
  • greater achievement of LDL-C goals than commonly prescribed doses of other statins, avoiding the need to titrate to higher doses^{1,4,5,10-14,22-24}
• Rosuvastatin produces a significant increase in HDL-C which, unlike atorvastatin, is maintained across the dose range¹

References:
1. Jones P et al. Am J Cardiol 2003;92:152–160
2. Schuster H et al. Am Heart J 2004;147:705–712.
3. Blasetto J et al. Am J Cardiol 2003;91(Suppl):3C–10C
4. Berne C et al. Cardiovascular Diabetology 2005;4 (1):7
5. Betteridge J et al. Atheroscler Suppl 2004;5(1):107, Abs M464
6. Davidson M et al. Am J Cardiol 2002;89:268–275
7. Schwartz G et al. Am Heart J 2004;148(1):P105, H1–H9 8. Olsson A et al. Am Heart J 2002;144:1044–1051
9. Stalenhoef A et al. Eur Heart J 2005 in press
10. Strandberg T et al. Clin Ther 2004;26(11):1821–1833
11. Gupta M et al. Atheroscler Suppl 2005;6(1):108-109 Abs W16-P-033
12. Fonseca F et al. Curr Med Res Opin 2005;21(8):1307-1315
13. Jukema J et al. Current Medical Research 2005 in press. 14. Clearfield M et al. Atheroscler Suppl 2005;6(1):104 Abs W16-P-014
15. Wolffenbuttel B et al. J Int Med 2005;257:531–539
16. Paoletti R et al. J Cardiovasc Risk 2001;8:383–390
17. Brown W et al. Am Heart J 2002;144:1036–1043
18. Stein E et al. H. Am J Cardiol 2003;92:1287–1293
19. Schneck D et al. Am J Cardiol 2003;91:33–41
20. Leiter L et al. Atheroscler Suppl 2005;6(1):113 Abs W16-P-051
21. Olsson A et al. Cardiovasc Drug Rev 2002;20:303–328 22. Kritharides L. Eur Heart J Suppl 2004;6(Suppl A):A12–A18.
23. Shepherd J et al. Am J Cardiol 2003;91(Suppl):11C–19C
24. Schuster H, Fox JC. Exp Opin Pharmacother 2004;5:1187–1200

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