Risk of muscle symptoms while taking statins

Clinical question

What are the effects of statins on muscles?

Bottom line

Statins increase the risk of muscle symptoms (pain, cramps, weakness) in the first year of use, from 14.0% (placebo) to 14.8%, but are similar to placebo after 1 year. Only 1 patient-reported muscle symptom in 15 is due to the statin. Statins may increase muscle symptoms with creatine kinase rising to 10 times normal levels for 1 in about 3000 patients over placebo.

Evidence

Seven systematic reviews (11 to 135 RCTs; N=18,192 to 192,977) from the past 5 years examine this.^1-7 We focus on the most recent (23 RCTs; 154,664 patients over 4.3 years).¹ Results are statistically significant unless indicated.

• Any muscle symptoms for statin versus placebo …

  • - Anytime: 27.1% versus 26.6% (placebo).¹

    • — Within the first year: 14.8% versus 14.0%, number needed to harm of 125.

    • — After the first year: 14.8% versus 15.0% (not statistically different).

  • - Other systematic reviews^2-7 had similar but not statistically different results for myalgia,⁵ those 65 and older,⁴ and intensity versus placebo.² No difference by statin type,³ lipophilic or hydrophilic statins,⁶ or age group.^1,5,6

• Any muscle symptoms, more- versus less-intense statin …

  • - Any time point: 36.1% versus 34.8% (less intense).¹

  • - Other systematic reviews found similar results.²

• Creatine kinase level more than 10 times the upper limit of normal (myopathy): 0.077% versus 0.044% (placebo).¹

  • - Four other systematic reviews^2-5 found no difference.

  • - More- versus less-intense statin^1,2: No difference for approved statins and doses (excluding simvastatin 80 mg).

• Rhabdomyolysis: 3 systematic reviews^4,5 found no difference.

• Discontinuation for muscle symptoms^2,4 or any adverse event^4,5,7 was not statistically increased.

Two large n-of-1 trials (60 to 200 patients with previous statin intolerance due to muscle symptoms) randomized to 3 to 4 cycles of about 4 to 8 weeks each of statin,^8,9 placebo,^8,9 and no pill.⁸

• Muscle symptom scores …

  • - Statin versus placebo^8,9: no difference.

  • - Statin versus no pill⁸: pain score of 16 versus 8 (no pill) (scale of 0 to 100, with higher scores being worse).

Context

• Mean creatine kinase rise¹ with statins was about 2%.

• Myopathy and rhabdomyolysis are too infrequent to discern statin effects in meta-analysis of more than 100,000 RCT participants. Statin-induced rhabdomyolysis is estimated to be 2 to 3 excess cases per 100,000 patient-years.¹

Implementation

Statins are the most effective lipid-lowering drugs to prevent cardiovascular (CV) diseases, with a relative risk reduction of 25% to 35% for CV events and about 10% for mortality.^10,11 For nonsevere muscle symptoms possibly caused by a statin, other causes should be excluded.¹² If none is identified, stop the statin and try a rechallenge in a few weeks with the same dose, a lower dose, a different statin, or alternate-day dosing, as most patients will tolerate rechallenge.^8-10,12 Non-statin therapies appear to have fewer CV benefits and no mortality effect and should be considered only if statin intolerance is severe or unmanageable.^10,11