Trust the Blinded Randomized Evidence That Statin Therapy Rarely Causes Symptomatic Side Effects
Authors: Richard Peto, Rory Collins
Journal: Circulation (2018)

randomized trial ◼ safety ◼ statins M eta-analyses of randomized trials of statin therapy have shown that lowering low-density lipoprotein cholesterol levels reduces the risk of occlusive vascular events and improves overall survival, while refuting previous claims about adverse effects on cancer and nonvascular mortality. 1In recent years, however, it has been claimed-based largely on nonrandomized observational studies that are not consistent with the randomized evidence-that statin therapy commonly causes muscle-related and other adverse effects.There needs to be greater recognition of the weaknesses of observational studies (except where relative risks are extreme and outcomes otherwise rare) and the strengths of blinded randomized trials for assessing both efficacy and safety. 1 Statin therapy can cause myopathy (defined as muscle pain or weakness with large increases in creatine kinase levels), but this is rare and most muscle-related symptoms are not myopathy.Because myopathy can be serious, patients are warned about the possibility of muscle pain or weakness when prescribed statins, and because of those warnings, some may then report such symptoms.Consequently, observational studies involving the routine use of statin therapy, which necessarily cannot involve blinded control, may well misattribute symptoms to the statin.In contrast, randomized trials of adequate size with blinded control can be informative not only about the efficacy but also about the safety and tolerability of statin therapy (even if the trials did not seek predefined information about particular outcomes). 1Data-dependent emphasis on particular results in particular trials (especially small ones) or selected subgroups (especially involving small numbers of events) may, however, yield biased results.Instead, unbiased assessments can be achieved by analyzing a predefined set of the larger trials; such as those that involved ≥1000 participants and ≥2 years of statin treatment. 1he frequency of muscle-related symptoms recorded in each of those trials depends on whether such symptoms were systematically sought and on the questions asked.However, although the rates differ between the trials, the proportions reporting these symptoms within each of these trials were similar among patients assigned statin or placebo (Table ). 1 The highest rate was in the HPS trial (Heart Protection Study) of 40 mg simvastatin daily versus placebo among about 20 000 patients who were specifically asked about any muscle pain or weakness at every follow-up. 2An excess of 1.0% (standard error 0.5) disappeared after the first year, with similar proportions reporting muscle-related symptoms after about 5 years (32.9% statin versus 33.2% placebo), ruling out an excess >1%.The reported incidence during the first year was >3 times the annual rate during the later years, illustrating that the initial warnings increased reporting of symptoms that were not pharmacological.Before randomization, all potential participants in HPS took 1 month of placebo followed by 1 month of simvastatin daily.In addition to excluding patients who would report problems on placebo, statin use during this run-in phase may have