Comparison of sequential rosuvastatin doses in hypercholesterolaemia: a meta-analysis of randomised controlled trials

Abstract

Background:

Rosuvastatin is an effective treatment for patients with hypercholesterolaemia. However, the incremental benefit and risk of increasing through the licensed dose range have not been comprehensively assessed across all available clinical trials.

Research design and methods:

The literature databases CENTRAL, EMBASE, and MEDLINE were searched in April 2008 for trials with comparisons of sequential licensed rosuvastatin dosages: 5 vs. 10 mg/day, 10 vs. 20 mg/day, and 20 vs. 40 mg/day. Clinical trial registries were also searched. For benefit outcomes, weighted mean differences were derived using the inverse variance method. For risk outcomes, the Mantel–Haenszel method was used to calculate a summary relative risk.

Results:

The meta-analysis included 26 trials. The results demonstrated significantly favourable changes in low-density lipoprotein cholesterol level with increasing dosage (by 6.25, 5.84, and 5.03 percentage points for 10 vs. 5 mg/day, 20 vs. 10 mg/day, and 40 vs. 20 mg/day, respectively), and also in the ratios of total cholesterol to high-density lipoprotein cholesterol (HDL-C) and apolipoprotein B to apolipoprotein A-I (all p < 0.00001). In addition, a significantly favourable change in HDL-C level was found with 20 mg/day over 10 mg/day (p = 0.02). Among the primary tolerability comparisons, no significant differences in risk were seen for muscular, hepatic, or renal adverse events, with only one exception: the risk of proteinuria by urine dipstick testing was significantly higher with rosuvastatin 40 mg/day than 20 mg/day (p = 0.01).

The efficacy outcomes assessed in this meta-analysis are limited to surrogate markers of morbidity and mortality.

Conclusions:

This meta-analysis provides evidence for improved efficacy in treating patients with hypercholesterolaemia with each sequential titration of rosuvastatin and a generally consistent tolerability profile across the dose range.

Keywords::

• Dose comparison
• Efficacy
• Meta-analysis
• Rosuvastatin
• Tolerability
• Surrogate markers

Transparency

Declaration of funding

JG and SJE are full-time employees of AstraZeneca UK Ltd, the manufacturer of rosuvastatin. GYHL received no support or funding from AstraZeneca UK Ltd for this work.

Declaration of financial/other relationships

GYHL has received honoraria from AstraZeneca for consultancy work on trial steering committees and in other areas.

Peer reviewers may receive honoraria from CMRO for their review work. Peer Reviewer 1 has disclosed that he/she has received sponsorship or research funding from; and has acted as an advisor to Amgen, Alcon, Wyeth, Merck & Co. Inc., Ipsen, Pneuma Partners, Kinex, Endo, Sanofi-Pasteur, Nycomed and Encysive. Peer Reviewer 2 has disclosed no relevant financial relationships.

Acknowledgements

The authors would like to thank Dr Emma Ashton of Monash University, Victoria, Australia, for supplying supplementary data to one of the studies included in the meta-analysis26.