Can statins (HMG-CoA reductase inhibitors) cause muscle weakness?

Statin-Associated Muscle Weakness

Yes, statins can cause muscle weakness, which is part of a spectrum of statin-associated muscle symptoms (SAMS) that ranges from mild myalgia to severe rhabdomyolysis. 1

Types of Statin-Associated Muscle Effects

Statin-associated muscle symptoms occur along a spectrum:

• Myalgia: Muscle ache or weakness without creatine kinase (CK) elevation
• Myositis: Muscle symptoms with increased CK levels
• Myopathy: General term referring to any disease of muscles
• Rhabdomyolysis: Muscle symptoms with marked CK elevation (typically >10 times the upper limit of normal) and creatinine elevation 1

Frequency and Clinical Presentation

• Myalgia occurs in 5-10% of patients in observational studies, though only 1-5% in randomized controlled trials 1
• Myositis/myopathy with CK elevation and objective weakness is rare 1
• Rhabdomyolysis is extremely rare (approximately 0.08% with lovastatin and simvastatin) 1
• Muscle symptoms typically:
  • Are bilateral
  • Involve proximal muscles
  • Begin within weeks to months after starting statins
  • Resolve after discontinuation 1

Evidence of Muscle Damage

Importantly, muscle damage can occur even with normal CK levels:

• Biopsy-confirmed myopathy has been documented in patients with normal CK levels 2
• Ultrastructural damage to skeletal muscle, including breakdown of the T-tubular system and subsarcolemmal rupture, has been observed even in asymptomatic patients 3
• In one study, 25 of 44 patients with statin-associated myopathy showed evidence of structural muscle damage on biopsy, with only one having significantly elevated CK levels 4

Risk Factors for Statin-Associated Muscle Weakness

Several factors increase the risk of statin-associated myopathy:

• Advanced age (especially >80 years)
• Female sex
• Small body frame and frailty
• Multisystem disease (e.g., chronic renal insufficiency, especially due to diabetes)
• Multiple medications
• Perioperative periods
• Asian ancestry
• High levels of physical activity
• Concomitant use of medications that interact with statins 1, 5

Drug Interactions That Increase Risk

Certain medications significantly increase the risk of statin-associated muscle symptoms:

• Fibrates (especially gemfibrozil)
• Cyclosporine
• Macrolide antibiotics (erythromycin, clarithromycin)
• Azole antifungals (itraconazole, ketoconazole)
• HIV protease inhibitors
• Amiodarone
• Large quantities of grapefruit juice 5, 6, 7

Monitoring and Management

If muscle weakness is suspected:

1. Evaluate symptoms thoroughly:

   • Assess for bilateral proximal muscle weakness
   • Determine timing in relation to statin initiation
   • Check for resolution after discontinuation 1

2. Measure CK levels if muscle symptoms occur, but be aware that normal CK does not rule out structural muscle damage 1, 4

3. Check for other causes of muscle weakness:

   • Hypothyroidism (measure TSH)
   • Reduced renal or hepatic function
   • Vitamin D deficiency
   • Rheumatologic disorders 5

4. If statin-associated muscle weakness is confirmed:

   • Temporarily discontinue the statin until symptoms resolve
   • Consider rechallenge with a lower dose or different statin
   • Try less lipophilic statins or alternative dosing regimens (e.g., alternate-day dosing) 5

5. For severe symptoms or significantly elevated CK (>10× ULN):

   • Discontinue statin immediately
   • Monitor renal function
   • Check for myoglobinuria 5, 6

Mechanism of Statin-Associated Muscle Weakness

The exact mechanism is not fully understood, but several theories exist:

• Inhibition of ubiquinone (CoQ10) synthesis affecting mitochondrial function
• Interaction with the cytochrome P-450 hepatic enzyme system
• Exacerbation of exercise-induced muscle injury
• Cholesterol depletion affecting T-tubular system and muscle membrane integrity 1, 3

Conclusion

Statin-associated muscle weakness is a real phenomenon that can occur with or without CK elevation. While severe myopathy is rare, milder forms of muscle symptoms are relatively common and can significantly impact quality of life and medication adherence. Clinicians should take patient reports of muscle symptoms seriously, even when laboratory values are normal, as structural muscle damage may still be present.