Abstract
AimsStatins are widely used to prevent cardiovascular events, but little is known about the impact of different risk factors for statin-related myopathy or their relevance to reports of other types of muscle symptom.Methods and resultsAn observational analysis was undertaken of 171 clinically adjudicated cases of myopathy (defined as unexplained muscle pain or weakness with creatine kinase >10× upper limit of normal) and, separately, of 15 208 cases of other muscle symptoms among 58 390 individuals with vascular disease treated with simvastatin for a mean of 3.4 years. Cox proportional hazards models were used to identify independent predictors of myopathy. The rate of myopathy was low: 9 per 10 000 person-years of simvastatin therapy. Independent risk factors for myopathy included: simvastatin dose, ethnicity, sex, age, body mass index, medically treated diabetes, concomitant use of niacin-laropiprant, verapamil, beta-blockers, diltiazem and diuretics. In combination, these risk factors predicted more than a 30-fold risk difference between the top and bottom thirds of a myopathy risk score (hazard ratio : 34.35, 95% CI: 12.73–92.69, P across thirds = 9·1 × 10−48). However, despite the strong association with myopathy, this score was not associated with the other reported muscle symptoms (P across thirds = 0.93). Likewise, although SLCO1B1 genotype was associated with myopathy, it was not associated with other muscle symptoms.ConclusionsThe absolute risk of simvastatin-related myopathy is low, but individuals at higher risk can be identified to help guide patient management. The lack of association of the myopathy risk score with other muscle symptoms reinforces randomized placebo-controlled evidence that statins do not cause the vast majority of reported muscle symptoms.
Highlights
Large-scale meta-analyses of randomized controlled trials show that statin therapy reduces the risks of myocardial infarction, coronary revascularization, and ischaemic stroke by about one-fifth for each mmol/L LDL-C reduction, largely irrespective of patient characteristics.[1,2] As a consequence, statins are prescribed to millions of people worldwide, with simvastatin still constituting $40% of all statin prescriptions in the UK in 2019 and being the second most commonly prescribed statin in the USA.[3,4]Evidence from randomized controlled trials indicates that statin therapy is safe and well-tolerated.[5]
Statin therapy does rarely cause myopathy, which is a potentially serious side-effect characterized by muscle pain or weakness associated with markedly elevated creatine kinase (CK) levels (e.g. >10Â upper limit of normal [ULN]).[5,6,7,8,9]
The absolute risk of myopathy due to standard statin regimens is low, but individuals can be identified who are at elevated risk by combining a number of independent risk factors in a myopathy risk score
Summary
Evidence from randomized controlled trials indicates that statin therapy is safe and well-tolerated.[5] Statin therapy does rarely cause myopathy, which is a potentially serious side-effect characterized by muscle pain or weakness associated with markedly elevated creatine kinase (CK) levels >10Â upper limit of normal [ULN]).[5,6,7,8,9] In contrast, muscle pain or weakness without elevated blood levels of CK is reported as often by patients receiving a statin as by patients receiving matching placebo, suggesting almost all such reports are not caused pharmacologically by the statin (i.e. they are a ‘nocebo’ effect).[5,7] The incidence of myopathy is typically $1 per 10 000 person-years with standard statin regimens (such as simvastatin 40 mg daily), but factors that increase blood statin levels—such as higher statin doses, concomitant use of certain drugs (e.g. strong CYP3A4 inhibitors, amiodarone), Chinese ethnicity,[10] and SLCO1B1 genotype11,12—can increase the risk.[5,9,13] As myopathy is rare, there is little reliable information about the independent relevance of these or other risk factors, or of the relative strength of their associations.[6,8,9,12,14,15] Statin therapy does rarely cause myopathy, which is a potentially serious side-effect characterized by muscle pain or weakness associated with markedly elevated creatine kinase (CK) levels (e.g. >10Â upper limit of normal [ULN]).[5,6,7,8,9] In contrast, muscle pain or weakness without elevated blood levels of CK is reported as often by patients receiving a statin as by patients receiving matching placebo, suggesting almost all such reports are not caused pharmacologically by the statin (i.e. they are a ‘nocebo’ effect).[5,7] The incidence of myopathy is typically $1 per 10 000 person-years with standard statin regimens (such as simvastatin 40 mg daily), but factors that increase blood statin levels—such as higher statin doses, concomitant use of certain drugs (e.g. strong CYP3A4 inhibitors, amiodarone), Chinese ethnicity,[10] and SLCO1B1 genotype11,12—can increase the risk.[5,9,13] As myopathy is rare, there is little reliable information about the independent relevance of these or other risk factors, or of the relative strength of their associations.[6,8,9,12,14,15]
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