Effect of Statin Therapy on Muscle Symptoms

Quick Takes

  • The small excess risk of muscle symptoms due to statin therapy largely occurred within the first year of treatment.
  • Clinicians can suggest to patients taking statins that the probability of muscle symptoms actually caused by the statin is <1 in 10.
  • In clinical practice, muscle cramps or spasms are often the complaint and the reason for stopping statins; much more frequently than the 3% in this very large study group. Expert reviews suggest that cramps are not statin related. The authors support this conclusion. There was a 0.2% greater incidence of cramps on statins vs. placebo (HR, 1.09; 95% CI, 1.00-1.1) and a 0.1% greater incidence in more intensity vs. lower-intensity statin dosing (HR, 1.04; 95% CI, 0.89-1.22).
  • A significant number of patients begin to complain about muscle symptoms several years after tolerating a statin and then appear to be intolerant to other statins—a clinical dilemma that needs clarity.

Study Questions:

What is the frequency of statin therapy causing muscle pain or weakness, as determined in an individual participant data meta-analysis of all recorded adverse muscle events in large, long-term, randomized, double-blind trials of statin therapy?


Randomized trials of statin therapy were eligible if they aimed to recruit ≥1,000 participants with a scheduled treatment duration of ≥2 years, and involved a double-blind comparison of statin versus placebo or of a more intensive versus a less intensive statin regimen. The analyzed individual participant data was derived 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.


Among 19 placebo-controlled trials conducted between 1990–2021 (mean age 63 years [standard deviation 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% confidence interval [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 1,000 person-years, which indicates that only 1 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 (i.e., 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 (CK) values of approximately 0.02 times the upper limit of normal (ULN).


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.


The normal rise in CK (about 20 U/L) in healthy persons on statins, and statin myopathy [~1 extra case per 10,000 person-years] and rhabdomyolysis [~2–3 cases per 100,000 person-years] are found in the first few years of statin use. The great majority of serious myopathies and elevation of CK to >5x ULN are due to drug interactions. The widespread publicity of these rare occurrences led to fear among patients and physicians alike that continues 30 years after, despite the nearly 25% decrease in cardiovascular events for every 40 mg/dL decrease in LDL-C.

Clinicians can suggest to patients taking statins that ‘the probability of muscle symptoms actually caused by the statin is <10%,’ and that this conclusion is based on >150,000 patients who were randomized to statin versus placebo or high-intensity versus low-intensity statin and followed for muscle-related symptoms for ≥2 years.

Clinical Topics: Dyslipidemia, Prevention, Lipid Metabolism, Nonstatins, Novel Agents, Statins

Keywords: Atorvastatin, Cholesterol, LDL, Creatine Kinase, Diabetes Mellitus, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Muscle Cramp, Muscles, Myalgia, Primary Prevention, Rhabdomyolysis, Rosuvastatin Calcium, Vascular Diseases

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