The BMJ recently reported the results of a multicenter, randomized, placebo-controlled n-of-1 trial (n = 200) that showed no overall effects of atorvastatin 20 mg once a day on muscle symptoms compared with placebo in individuals who previously reported severe muscle symptoms when taking statins [1]. In this study, participants who recently stopped or were considering stopping statins because of muscle symptoms were randomized to a sequence of six double-blinded treatment periods (two months each) of atorvastatin 20 mg once a day or placebo. About 70% of participants had known cardiovascular disease requiring statin for secondary cardiovascular risk reduction. The primary analysis compared participants’ rated muscle symptoms on a visual analogue scale (0-10) during the statin and placebo periods. The 151 participants included in the primary analysis showed no difference in muscle symptom scores between statin and placebo periods (mean difference statin minus placebo -0.11, 95% confidence interval -0.36 to 0.14; p = 0.40). Medication withdrawal because of intolerable muscle symptoms was 9% during the statin period and 7% during the placebo period. Two-thirds of participants who completed the trial reported restarting long-term treatment with statins.

This study is an important addition to the expanding evidence busting the myth of the need to stop statin therapy because of vague non-severe muscle symptoms, which as the BMJ study shows, are common in both placebo and statin-treated patients. Optimal treatment of dyslipidemia, a serious, globally prevalent cardiovascular disease risk factor, is an important public health priority, and high-quality evidence accumulated over several decades consistently shows that statins significantly reduce atherosclerotic cardiovascular disease events across all age groups. Statins are generally well tolerated with a good safety profile. Severe statin-associated adverse effects on muscle such as myopathy (1 in 10,000 people treated annually) and rhabdomyolysis (0.2 in 10,000 people treated annually) are rare [2]. However, as the BMJ study suggests, the causal relationship between statins and less severe muscle symptoms is unclear. The findings from unblinded observational studies and controversial media reports have raised unfounded concerns about statins in the general population. This has led to resistance to initiating statin and non-adherence to prescribed therapy despite its profound benefits, exposing patients to unnecessary and increased risk of cardiovascular disease. Hence, large, well-controlled, randomized trials assessing statin-associated muscle symptoms have become the focus of research attention to address this literature gap.

This study appears to be well conducted, and the results are likely valid. The findings are consistent with other studies assessing similar research endpoints. The n-of-1 randomized SAMSON trial (n = 60) showed no significant difference in symptoms between participants given placebo and those given 20 mg of atorvastatin once a day (p = 0.39) [3]. Pooled results showed 90% of the symptoms attributable to the nocebo effect. In the GAUSS-3 trial, during re-challenge with a statin, 26.5% in the placebo group (but not statin group) reported muscle symptoms, suggesting that symptoms are not always related to statin use [4].

These findings do not mean that clinicians can dismiss muscle symptoms reported by patients taking a statin. A comprehensive evaluation to identify possible etiologies of reported symptoms must be performed. The pattern of symptoms, timing of onset, and timing of improvement after statin discontinuation can help identify true statin-associated adverse effects. However, the findings of clinical trials such as this study provide a strong foundation for discussion of low-dose statin re-challenge and might help clinicians reassure patients with mild non-specific muscle symptoms.

References

1. Herrett E, Williamson E, Brack K, et al: Statin treatment and muscle symptoms: series of randomized, placebo-controlled n-of-1 trials. BMJ. 2021;372:n135. Published 2021 Feb 24. doi:10.1136/bmj.n135

2. Collins R, Reith C, Emberson J, et al: Interpretation of the evidence for the efficacy and safety of statin therapy [published correction appears in Lancet. 2017 Feb 11;389(10069):602]. Lancet. 2016;388(10059):2532-2561. doi:10.1016/S0140-6736(16)31357-5

3. Wood FA, Howard JP, Finegold JA, et al: N-of-1 Trial of a statin, placebo, or no treatment to assess side effects. N Engl J Med 2020;383(22):2182-2184. doi:10.1056/NEJMc2031173

4. Nissen SE, Stroes E, Dent-Acosta RE, et al: Efficacy and tolerability of evolocumab vs ezetimibe in patients with muscle-related statin intolerance: The GAUSS-3 randomized clinical trial. JAMA 2016;315(15):1580-1590. doi:10.1001/jama.2016.3608