Physicians' Academy for Cardiovascular Education

Small minority of side-effects on statins are truly pharmacologically mediated by the drug

Literature - Finegold JA et al. Eur J Prev Cardiol. 2014 - Eur J Prev Cardiol. 2014 Mar 12


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

Finegold JA, Manisty CH, Goldacre B, et al.
Eur J Prev Cardiol. 2014 Mar 12.


The benefit of statin therapy on death, stroke and heart attack has been quantified against placebo control, but information on side effects has not. Many sources that list adverse events are unable to differentiate between events caused by the drug and spontaneous events.
Patients who report symptoms during statin therapy need straightforward information about the likelihood that this symptom is truly caused by the drug. For example in the case of myopathy and rhabdomyolysis, conflicting data have been published.
The majority of meta-analyses of RCT data have supported the relative safety of statins with regard to muscle-related side effects [1-3]. Side effects that are pharmacologically caused by statins may sometimes be difficult to distinguish from spontaneous effects or those attributable to the nocebo effect: experiencing unpleasant effects through negative expectations [4,5].
This study combines the placebo-controlled evidence on adverse events pharmacologically mediated by statins. A clear, understandable metric is presented for everyday clinical use, to advise patients on whether experienced symptoms are truly pharmacologically caused by the statin: the proportion of symptoms nonpharmacological (PSN) [6]. 14 primary prevention RCTs (46262 subjects) and 15 secondary prevention RCTs (37618 subjects) were included in the final analysis.

Main results

  • When statins are used for primary prevention, randomization to statins significantly increased the rate of diabetes by 0.5% (95%CI: 0.1-1%, P=0.012), as compared with placebo. Deaths were significantly reduced by statins by a similar rate (0.5%, 95%CI: -0.9 to 0.2%, P=0.003).
  • As secondary prevention, statins did not significantly change the rate of development of diabetes. Randomisation to statins reduced mortality by 1.4% (95%CI: -2.1 to -0.7%, P<0.001).
  • No other symptom was significantly altered as a result of randomisation to statins as compared with placebo.
  • An asymptomatic rise in liver transaminases was more common with statins as compared with placebo, both in primary prevention trials (+0.4%, 95%CI: 0.2-0.6%, P=0.024) and secondary prevention trials (+0.4%, 95%CI: 0.2-0.7%, P=0.006).  
  • None of the studies showed a higher rate of serious adverse events in the statin arm, as compared with placebo. Withdrawals occurred less frequently in statin-treated patients than in placebo-treated patients.
  • PSN was calculated for symptoms that were statistically significantly increased in statin-treated patients. PSN was 76.1% in primary and 77.0% in secondary prevention trials, for liver transaminases more than three times upper limit of normal. For new diagnosis of diabetes in primary prevention trials, PSN was 80.2%.


This study examined data of 83880 patients receiving blinded placebo-controlled statin therapy, and found little evidence that statins cause symptomatic side effects beyond placebo.
The rate of developing diabetes was significantly higher with statins than with placebo; across primary and secondary prevention trials: 3% vs 2.4%, giving a PSN of 80%. Thus, 20% of all new diabetes diagnoses were directly pharmacologically attributable to statins. Asymptomatic raised liver enzymes was the only adverse events that occurred significantly more often with statins in both primary and secondary prevention trials. It is unclear whether this is harmful.
Importantly, many side effects commonly attributed to statins, such as myopathy, fatigue, muscle aches, rhabdomyolysis, or rise in creatinin kinase > 10 upper limit of normal, were no more common in the statin-treated, as opposed to the placebo-treated group.
The PSN may help judge the risk-benefit trade off for statin treatment, and would be useful information on the patient information leaflet.
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