Effect of statin therapy on muscle symptoms: an individual participant data meta-analysis of large-scale, randomised, double-blind trials

Abstract

Background: Statin therapy is effective for the prevention of atherosclerotic cardiovascular disease and is widely prescribed, but there are persisting concerns that statin therapy might frequently cause muscle pain or weakness. We aimed to address these through an individual participant data meta-analysis of all recorded adverse muscle events in large, long-term, randomised, double-blind trials of statin therapy.

Methods: Randomised trials of statin therapy were eligible if they aimed to recruit at least 1000 participants with a scheduled treatment duration of at least 2 years, and involved a double-blind comparison of statin versus placebo or of a more intensive versus a less intensive statin regimen. We analysed individual participant data from 19 double-blind trials of statin versus placebo (n=123 940) and four double-blind trials of a more intensive versus a less intensive statin regimen (n=30 724). Standard inverse-variance-weighted meta-analyses of the effects on muscle outcomes were conducted according to a prespecified protocol.

Findings: Among 19 placebo-controlled trials (mean age 63 years [SD 8], with 34 533 [27·9%] women, 59 610 [48·1%] participants with previous vascular disease, and 22 925 [18·5%] participants with diabetes), during a weighted average median follow-up of 4·3 years, 16 835 (27·1%) allocated statin versus 16 446 (26·6%) allocated placebo reported muscle pain or weakness (rate ratio [RR] 1·03; 95% CI 1·01-1·06). During year 1, statin therapy produced a 7% relative increase in muscle pain or weakness (1·07; 1·04-1·10), corresponding to an absolute excess rate of 11 (6-16) events per 1000 person-years, which indicates that only one in 15 ([1·07-1·00]/1·07) of these muscle-related reports by participants allocated to statin therapy were actually due to the statin. After year 1, there was no significant excess in first reports of muscle pain or weakness (0·99; 0·96-1·02). For all years combined, more intensive statin regimens (ie, 40-80 mg atorvastatin or 20-40 mg rosuvastatin once per day) yielded a higher RR than less intensive or moderate-intensity regimens (1·08 [1·04-1·13] vs 1·03 [1·00-1·05]) compared with placebo, and a small excess was present (1·05 [0·99-1·12]) for more intensive regimens after year 1. There was no clear evidence that the RR differed for different statins, or in different clinical circumstances. Statin therapy yielded a small, clinically insignificant increase in median creatine kinase values of approximately 0·02 times the upper limit of normal.

Interpretation: Statin therapy caused a small excess of mostly mild muscle pain. Most (>90%) of all reports of muscle symptoms by participants allocated statin therapy were not due to the statin. The small risks of muscle symptoms are much lower than the known cardiovascular benefits. There is a need to review the clinical management of muscle symptoms in patients taking a statin.

Funding: British Heart Foundation, Medical Research Council, Australian National Health and Medical Research Council.

Figure 1

Effect on muscle adverse events in trials of any statin regimen versus placebo (A) and more versus less intensive statin regimens (B) Bold data are the totals or subtotals. O–E=observed minus expected. Var=variance.

Figure 2

Effect on any muscle pain or weakness, by duration of treatment, in trials of any statin regimen versus placebo Bold data are the totals or subtotals. White squares indicate months, black squares indicate years. The test for heterogeneity in the log rate ratio between the first year and all subsequent years combined: χ² =12·1, p=0·0005. For each risk period, percentages shown are of those alive and still at risk of a first report of muscle pain or weakness at the start of the risk period. O–E=observed minus expected. Var=variance.

Figure 3

Rate ratio and absolute rate difference for muscle adverse events by duration of treatment, in trials of any statin regimen versus placebo

Figure 4

Effect of less intensive or moderate-intensity statin regimens on any muscle pain or weakness, by participant characteristics Bold indicates the overall summary result. White squares indicate missing data. Tests of heterogeneity (or trend) listed after each prognostic characteristic are of the log rate ratio for each of the subgroups of that characteristic, and are uncorrected for multiple comparisons. GFR=glomerular filtration rate. LDL=low-density lipoprotein. O–E=observed minus expected. Var=variance.