Objective: To estimate relative risk of statin-associated musculoskeletal symptoms (SAMS) by statin therapy intensity. Setting: Network meta-analysis assessing multi-center RCTs across several countries. Participants: Pubmed, Web of Science, Cochrane database, and clinicaltrials.gov were searched through January 2021 for doubled-blinded RCTs testing the effect of statin therapy on lipids with at least 1000 participants and two years of intended treatment. Two coders assessed articles for final inclusion, quality, and outcomes. Treatment intensity was categorized according to American Heart Association definitions.

Outcomes: Pairwise and network meta-analysis (NMA) estimated relative risk (RR) and risk difference (RD) with random effects modeling. Heterogeneity was evaluated with the I2 statistic. Outcomes included muscle symptoms (any, myalgia, and attrition due to muscle symptoms), rhabdomyolysis, and elevated creatine kinase (>10x upper limit of normal).

Results: Of 2801 RCTs, 24 (N=152,461) met inclusion criteria. NMA results indicated risk was significantly greater for high compared to moderate intensity statin therapy for any muscle problem (RR=1.04, 95% CI: 1.00,1.07; I2=0% ), myalgia (RR=1.04, 95% CI: 1.00,1.08; I2=0%, NNH=173), attrition due to muscle problems (RR=1.37, 95% CI: 1.09,1.73, I2=0%, NNH=218), and elevated CK (RR=4.69, CI: 2.50, 8.80; I2=7%, NNH=527). Risk also was significantly higher for high intensity compared to placebo for any muscle problem (RR=1.05, 95% CI: 1.01,1.09, I2=0% ), myalgia (RR=1.13, 95% CI: 1.05,1.23; I2=0%, NNH=182), attrition due to muscle problems (RR=1.55, 95% CI: 1.15,2.08, I2=0%, NNH=187), and elevated CK (RR=5.37, CI: 2.48, 11.61; I2=7%, NNH=589). Due to inconsistency of results across sensitivity analyses, estimates were inconclusive for rhabdomyolysis and CK. There were no significant differences in risk between moderate-intensity therapy and placebo for all outcomes.

Conclusions: For approximately 200 patients on high-intensity statins, one additional patient may experience myalgia or discontinue therapy due to muscle problems compared to moderate-intensity therapy.

Trial Registration: Prospero #CRD42019112758

From the manuscript:

The Trials.  PubMed, Cochrane Database, Web of Science, and clinicaltrials.gov were searched (Prospero #CRD42019112758 for search terms and strategy) from January 1, 2010 to October 1, 2018 to identify eligible trials. Double-blinded RCTs to improve lipid levels that comparing statin therapy to placebo or higher-lower dose statin therapy were selected. In order to detect most adverse events, RCTs were selected that had at least 1,000 participants with two years of intended follow-up, where statin treatment was not given with other prescription drug therapies, and results contained reports on muscle-related adverse events. All included trials were coded for quality with Oxford Center for Evidence-based Medicine ratings¹⁴ and a five-point Jadad quality score.

Exposure Variable.  Studies were classified by intensity of statin treatment (“high” or “moderate”)  according to American Heart Association definitions for potency in reduction of lipid levels.¹⁵ High intensity signifies an expected 50% or greater reduction in LDL-C levels when taking that statin (i.e., 80 mg atorvastatin) and moderate signifies 30-50% reduction in LDL-C.¹⁵

Outcome Variables. Adverse muscle-related events were coded into five main outcomes.  The first outcome was for any patient-reported muscle complaint coded from reports of “muscle aches”, “pains”, “cramps”, “stiffness,” “musculoskeletal disorders,” etc.  The second focused on only myalgia or muscle pain. The third focused on attrition due to musculoskeletal complaints. A fourth captured explicit reporting of rhabdomyolysis, with or without a trial definition. The fifth was elevated creatine kinase, greater than ten times the upper limit of normal (CK >10x ULN). This threshold was used to distinguish this outcome from less meaningful CK increases and also because CK>10xULN is commonly reported in RCTs. All outcomes were coded as reported by original investigators in published and online reports, and were independently coded by two people (JD, SW). Trial investigators were contacted for clarification, where needed.