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

PainSci » bibliography » Cholesterol Treatment Trialists' Collaboration 2022
updated Sep 5, 2023

Tags: medications, chronic pain, harms, muscle, self-treatment, treatment, pain problems

Four pages on PainSci cite Cholesterol Treatment Trialists' Collaboration 2022: 1. 38 Surprising Causes of Pain 2. Vitamins, Minerals & Supplements for Pain & Healing 3. Vitamin D for Pain 4. Sign me up for mild muscle pain? The statins dilemma

PainSci commentary on Cholesterol Treatment Trialists' Collaboration 2022: ?This page is one of thousands in the PainScience.com bibliography. It is not a general article: it is focused on a single scientific paper, and it may provide only just enough context for the summary to make sense. Links to other papers and more general information are provided wherever possible.

This is an enormous review of nineteen placebo controlled tests of the side effects of statins, following over 30,000 patients for about 4 years on average. A data set like that makes a typical little musculoskeletal medicine study look like a shack in the shadow of the Burj Khalifa.

There was no major difference in the rates of muscle pain and weakness in statins versus placebo. They saw a modest signal in the first year, and for more intensive statin therapy: slightly more myopathy with statins, and mostly mild. Only about 1 in 15 cases of allegedly statin-induced myopathy reported by patients were actually related to statins, according to this data, and those were pretty tame. The researchers concluded:

“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.”

This statin evidence cuts both ways: it undermines the Legend of Statin Associated Myopathy, but it also confirms that there is indeed an unpleasant side effect. Even a 5% risk of very mild-but-chronic muscle pain might seem unacceptable to many people. One in twenty is not “rare,” and no amount of chronic pain is cool. So even as it fights excessive hype about SAM, it’s not particularly reassuring either.

For a more detailed report on this paper, see “Sign me up for mild muscle pain? The statins dilemma.”

~ Paul Ingraham

original abstract †Abstracts here may not perfectly match originals, for a variety of technical and practical reasons. Some abstacts are truncated for my purposes here, if they are particularly long-winded and unhelpful. I occasionally add clarifying notes. And I make some minor corrections.

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.

original abstract †Abstracts here may not perfectly match originals, for a variety of technical and practical reasons. Some abstacts are truncated for my purposes here, if they are particularly long-winded and unhelpful. I occasionally add clarifying notes. And I make some minor corrections.

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