Why does Rosuvastatin (HMG-CoA reductase inhibitor) cause myalgia (muscle pain)?

Why Rosuvastatin Causes Myalgia

The exact mechanism of statin-induced myalgia remains incompletely understood, but the most compelling evidence points to direct cholesterol depletion from skeletal muscle cell membranes causing structural damage, particularly to the T-tubular system and subsarcolemmal regions. 1

Primary Mechanism: Cholesterol Depletion and Membrane Damage

• Statins directly damage skeletal muscle ultrastructure through cholesterol extraction from muscle cell membranes, even in asymptomatic patients 1
• The characteristic pattern of damage includes breakdown of the T-tubular system and subsarcolemmal rupture, which was experimentally reproduced by extracting cholesterol from skeletal muscle fibers in vitro 1
• The specific lipid/protein organization of skeletal muscle cells renders them particularly vulnerable to cholesterol lowering, explaining why muscle tissue is disproportionately affected compared to other tissues 1

Clinical Presentation and Risk Factors

Myalgia is the most common statin-associated side effect, occurring in 1-5% of patients in randomized controlled trials but 5-10% in real-world clinical practice 2

Key Risk Factors for Myopathy:

• Age ≥65 years 3
• Female sex 2
• Asian ancestry (due to increased rosuvastatin plasma concentrations) 3
• Low body mass index 2
• Uncontrolled hypothyroidism 2, 3
• Renal impairment 2, 3
• Hepatic dysfunction 2
• Higher rosuvastatin dosages (particularly 40 mg daily) 3
• Concomitant use of CYP3A4 inhibitors, OATP1B1 inhibitors, fibrates, niacin, or colchicine 2, 3

Pharmacogenetic Factors:

• Genetic variants in SLCO1B1, SLCO1B3, ABCB11, and CYP3A5 can contribute to both increased myalgia risk and altered statin response through effects on drug pharmacokinetics 4
• Low-activity variants in these genes may lead to increased systemic statin exposure and muscle tissue accumulation 4

Clinical Characteristics of Statin-Associated Myalgia

Myalgia is more likely to be statin-related if it is bilateral, involves proximal muscles, begins within weeks to months after statin initiation, and resolves after discontinuation 2

Spectrum of Muscle Toxicity (in order of severity):

1. Myalgia: Muscle ache or weakness without creatine kinase (CK) elevation 2
2. Myositis: Muscle symptoms with increased CK levels 2
3. Rhabdomyolysis: Muscle symptoms with marked CK elevation (typically >10× upper limit of normal) and creatinine elevation 2, 3
4. Immune-mediated necrotizing myopathy (IMNM): Rare autoimmune myopathy with persistent proximal muscle weakness, elevated CK, and positive anti-HMG-CoA reductase antibodies despite statin discontinuation 3

Important Clinical Pitfalls

• Most muscle symptoms in statin-treated patients are NOT actually caused by the statin - the SAMSON trial demonstrated that 90% of adverse symptoms experienced with statin therapy also occur with placebo, suggesting a strong nocebo effect 2
• Myalgia can occur with normal CK levels, and the absence of CK elevation does not rule out statin-related muscle toxicity 2
• Structural muscle damage can occur even in asymptomatic patients, indicating that lack of symptoms does not guarantee absence of muscle injury 1
• Rosuvastatin 40 mg daily carries 2.5-fold increased risk of abnormal liver function tests compared to 10 mg daily 5

Dose-Dependent Effects

• The myopathy risk is greater with rosuvastatin 40 mg daily compared with lower dosages 3
• Most patients (72.7%) are appropriately started on rosuvastatin 10 mg daily 5
• Myalgia was the most frequent reason for stopping rosuvastatin in post-marketing surveillance 5