What proportion of symptomatic side effects in patients taking statins are genuinely caused by the drug? Systematic review of randomized placebo-controlled trials to aid individual patient choice.

OBJECTIVE Discussions about statin efficacy in cardiovascular prevention are always based on data from blinded randomized controlled trials (RCTs) comparing statin to placebo; however, discussion of side effects is not. Clinicians often assume symptoms occurring with statins are caused by statins, encouraging discontinuation. We test this assumption and calculate an evidence-based estimate of the probability of a symptom being genuinely attributable to the statin itself. METHODS We identified RCTs comparing statin to placebo for cardiovascular prevention that reported side effects separately in the two arms. RESULTS Among 14 primary prevention trials (46,262 participants), statin therapy increased diabetes by absolute risk of 0.5% (95% CI 0.1-1%, p = 0.012), meanwhile reducing death by a similar extent: -0.5% (-0.9 to -0.2%, p = 0.003). In the 15 secondary prevention RCTs (37,618 participants), statins decreased death by 1.4% (-2.1 to -0.7%, p < 0.001). There were no other statin-attributable symptoms, although asymptomatic liver transaminase elevation was 0.4% more frequent with statins across all trials. Serious adverse events and withdrawals were similar in both arms. CONCLUSIONS Only a small minority of symptoms reported on statins are genuinely due to the statins: almost all would occur just as frequently on placebo. Only development of new-onset diabetes mellitus was significantly higher on statins than placebo; nevertheless only 1 in 5 of new cases were actually caused by statins. Higher statin doses produce a detectable effect, but even still the proportion attributable to statins is variable: for asymptomatic liver enzyme elevation, the majority are attributable to the higher dose; in contrast for muscle aches, the majority are not.