No association between myopathy risk score and other muscle symptoms in patients on simvastatin

Independent risk factors for simvastatin-related myopathy and relevance to different types of muscle symptom

Literature - Hopewell JC, Offer A, Haynes R, et al. - Eur Heart J 2020, 41: 3336–3342, doi:10.1093/eurheartj/ehaa574

Introduction and methods

Statin therapy is effective in reducing MI, coronary revascularization and ischemic stroke and evidence from RCTs have demonstrated that statins are safe and well-tolerated [1-3]. Myopathy, characterized by muscle pain or weakness related with elevated creatine kinase (CK) levels (>10x upper limit of normal) are rarely caused by statin therapy [3-7]. However, muscle pain or weakness without elevated CK levels are as often reported by patients receiving statins as by patients receiving matching placebo (the nocebo effect) [3,5]. Incidence of myopathy is ~1 per 10.000 person-years, but some factors increasing blood statin levels can increase the risk of myopathy [3,7,8].

This observational study examined the relevance of independent risk factors for myopathy using data of three large trial populations and assessed the association between risk factors for myopathy and risk of other muscle symptoms.

The study population consisted of 58.390 participants receiving simvastatin: 9808 patients in the Heart Protection Study (HPS) trial, 11.538 patients in de SEARCH trial and 25.673 patients in the HPS2-THRIVE trial and 11371 patients in the run-in period of the HPS2-THRIVE trial. During follow-up visits, participants were asked about any new muscle pain or weakness and ALT and CK were measured. Myopathy was defined as unexplained muscle pain or weakness with CK >10x ULN. Unexplained muscle pain or weakness not associated with a diagnosis of myopathy was defined as ‘other muscle symptoms’.

Main results

  • During 196.521 person-years of exposure (representing mean of 3.4 years of treatment), 171 participants developed myopathy. Mean time from initiation of simvastatin to myopathy was 18 months. Rate of myopathy per 10.000 person-years was 9.
  • Rate of myopathy was higher in the first year vs. later years (19 vs. 5).
  • Other muscle symptoms (not myopathy) were common, occurring in at least 26% of participants, with 981 events per 10.000 person-years.
  • Simvastatin dose was the strongest predictor of myopathy. Other independent risk factors were Chinese descent (compared to European), older age, lower BMI and female sex.
  • Concomitant use of hypoglycemic medication, verapamil, niacin-laropiprant, diltiazem, beta-blockers and diuretics also independently influenced myopathy risk.
  • A weighted myopathy risk score was developed using the independent risk factors. In myopathy cases the risk score had a median of 7.2 (IQR 6.1-8.0) and 4.2 (IQR: 3.1-5.6) in other participants. It was a strong predictor of myopathy between the top and bottom thirds of the risk score (HR 34.35, 95%CI; 12.73-92.69, Ptrend=9.1 x 10⁻⁴⁸). In those reporting muscle symptoms other than confirmed myopathy, there was no association with the risk score.
  • Individuals carrying an rs4149056 C allele had a 3-fold higher risk of myopathy (OR 3.10, 95%CI: 2.09-4.59, P=1.5 x 10⁻⁸), not of other muscle symptoms.


This observational study of three large trials with simvastatin showed that absolute risk of myopathy due to statin therapy is low. A myopathy risk score with input from independent risk factors can identify those at high risk of myopathy. No association of risk score with other muscle symptoms was found, demonstrating consistency with findings from RCTs that statin therapy does not typically cause these symptoms.


1. Cholesterol Treatment Trialists’ (CTT) Collaboration. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet 2012;380: 581–590.

2. Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010;376:1670–1681.

3. Newman CB, Preiss D, Tobert JA, et al. Statin safety and associated adverse events: a scientific

statement from the American Heart Association. Arterioscler Thromb Vasc Biol 2019;39:e38–e81.

4. Ballantyne CM, Corsini A, Davidson MH, Holdaas H, Jacobson TA, Leitersdorf E, Marz W, Reckless JP, Stein EA. Risk for myopathy with statin therapy in high-risk patients. Arch Intern Med 2003;163:553–564.

5. Collins R, Reith C, Emberson J, et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet 2016;388:2532–2561.

6. Mach F, Baigent C, Catapano AL, 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J 2020;41:111–188.

7 . Stroes ES, Thompson PD, Corsini A, et al. Statin-associated muscle symptoms: impact on statin therapy-European Atherosclerosis Society consensus panel statement on assessment, aetiology and management. Eur Heart J 2015;36:1012–1022.

8. Kashani A, Sallam T, Bheemreddy S, et al. Review of side-effect profile of combination ezetimibe and statin therapy in randomized clinical trials. Am J Cardiol 2008;101:1606–1613.

Find this article online at Eur Heart J

Facebook Comments


We’re glad to see you’re enjoying PACE-CME…
but how about a more personalized experience?

Register for free