A meta-analysis of individual patient data on all adverse events in large-scale, long-term trials of statin therapy found increases in hepatic transaminase and other liver function tests related to statin intensity, but found no evidence that statins cause the majority (62 of 66) of other adverse effects listed in statin labeling, according to findings from the Cholesterol Treatment Trialists' Collaboration published Feb. 14 in The Lancet.

Researchers identified 19 double-blind trials comparing a statin (atorvastatin, fluvastatin, pravastatin, rosuvastatin, simvastatin) vs. placebo, for a total of 123,940 participants (mean age 63 years, 28% women) with a median follow-up of 4.5 years. Of these individuals, 48% had previous vascular disease and 18% had a history of diabetes. The researchers calculated 95% confidence intervals (Cis) and event rate ratios (RR) for all undesirable effect terms listed in statin Summary of Product Characteristics, with statistical significance assessed after controlling the false discovery rate (FDR) at 5%.

Additionally, four trials with 30,724 participants that compared a more intensive vs. less intensive statin regimen were identified. All the participants had vascular disease, their mean age was 62 years and the median follow-up was five years.

Results showed that only four of the 66 undesirable effects were FDR significant for the statin vs. placebo, respectively: abnormal liver transaminases (0.30% per annum vs. 0.22% per annum; RR 1.41); other liver function test abnormalities (0.25% per annum vs. 0.20% per annum; RR 1.26), with an absolute annual excess of 0.13%; urinary composition alterations (0.21% per annum vs. 0.18% per annum; RR 1.07); and edema (1.38% per annum vs. 1.31% per annum; RR 1.07).

Additionally, significant excesses were found for abnormal liver transaminases and other liver function tests, suggesting a dose-response pattern, but not for urinary composition alteration or edema, in the analysis of the four trials comparing more vs. less intensive statin regimens.

The authors emphasize their findings "reinforce previous conclusions that any risks associated with statin therapy are greatly outweighed by their cardiovascular benefits." Looking ahead, "…there is a pressing need for regulatory authorities to require revision of statin labels and for other official sources of health information to be updated, so that clinicians, patients, and the public can make informed decisions regarding the balance of the benefits and risks of statin therapy."

In an accompanying editorial comment, Timo E. Strandberg, MD, PhD, and Raul Santos, MD, PhD, note that statins have been considered very safe before the present analysis, and "the results are still most valuable for public health and drug policy." They hope these results "help to improve patient adherence with statin therapy, and, importantly, lead to a profound revision of drug labeling of statins to be more evidence based."