Can Rosuvastatin and Ezetimibe Worsen Restless Legs Syndrome?
There is no established evidence linking rosuvastatin or ezetimibe to worsening of restless legs syndrome (RLS), and these medications are not listed among the known pharmacological triggers for RLS.
Known Medication Triggers for RLS
The most recent American Academy of Sleep Medicine (AASM) guidelines and comprehensive RLS reviews identify specific medication classes that can worsen RLS, but statins and cholesterol absorption inhibitors are notably absent from these lists 1, 2:
- Serotonergic antidepressants (SSRIs, SNRIs) are documented RLS triggers and should be discontinued when possible 2
- Dopamine antagonists (antipsychotics, antiemetics) consistently worsen RLS symptoms 2
- Centrally acting H1 antihistamines (e.g., diphenhydramine) are known to exacerbate RLS 2
- Bupropion is specifically recommended against for RLS treatment by the AASM 1
Statin-Related Muscle Symptoms vs. RLS
The muscle-related adverse effects of statins are distinct from RLS and should not be confused 1:
- True statin-induced myopathy occurs in only approximately 1% of patients and presents as muscle pain, weakness, or cramping—not the characteristic urge to move with relief by movement that defines RLS 1
- The European Society of Cardiology consensus panel emphasizes that most perceived statin intolerance is subjective rather than representing true cause-and-effect muscle toxicity 1
- Rosuvastatin/ezetimibe combination therapy has comparable safety to rosuvastatin monotherapy with no increased incidence of muscle-related adverse events 3, 4, 5
Clinical Approach When RLS and Lipid-Lowering Therapy Coexist
If a patient on rosuvastatin and ezetimibe reports worsening RLS symptoms, the appropriate evaluation should focus on 1, 2:
- Iron status assessment: Check serum ferritin and transferrin saturation, as iron deficiency (ferritin ≤100 ng/mL or transferrin saturation <20%) is a primary treatable cause of RLS 1, 2
- Review other medications: Systematically evaluate for serotonergic antidepressants, dopamine antagonists, or antihistamines that are established RLS triggers 2
- Assess comorbid conditions: Screen for end-stage renal disease (24% RLS prevalence), peripheral neuropathy (21.5%), diabetes, or iron deficiency anemia (23.9%) 2
- Continue lipid-lowering therapy: There is no evidence-based rationale to discontinue or modify rosuvastatin/ezetimibe for RLS symptoms 1, 2
First-Line RLS Management
When RLS requires treatment in a patient on lipid-lowering therapy 1, 2:
- Iron supplementation with ferrous sulfate 325-650 mg daily or intravenous iron 1000 mg for appropriate iron parameters 1, 2
- Gabapentinoids (gabapentin, gabapentin enacarbil, pregabalin) are first-line pharmacologic therapy, with approximately 70% of patients achieving much or very much improved symptoms versus 40% with placebo 1, 2
- Avoid dopamine agonists as first-line therapy due to 7-10% annual incidence of augmentation (iatrogenic worsening) 2, 6
Common Pitfall to Avoid
Do not attribute RLS symptoms to statin therapy based on temporal association alone, as this may lead to inappropriate discontinuation of evidence-based cardiovascular risk reduction therapy 1. The combination of rosuvastatin and ezetimibe reduces cardiovascular events and mortality in high-risk patients, with 94% achieving LDL-C goals <100 mg/dL 3, 7.