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 symptomLiterature - 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’.
- 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.