Ezetimibe is NOT Contraindicated After Statin-Induced Rhabdomyolysis
Ezetimibe should be considered as a first-line nonstatin therapy for patients who develop rhabdomyolysis on statins, as it works through a completely different mechanism (cholesterol absorption inhibition rather than HMG-CoA reductase inhibition) and is explicitly recommended by major guidelines for this clinical scenario. 1
Guideline-Based Recommendations
The 2022 ACC Expert Consensus Decision Pathway specifically addresses this situation and provides clear guidance:
For patients who experience severe statin-associated muscle symptoms or rhabdomyolysis, nonstatin therapies should be considered, with ezetimibe as the first-line option. 1
The ACC guidelines explicitly state that "treatment for these patients may include PCSK9 inhibitors or ezetimibe" when patients have documented statin-induced rhabdomyolysis. 1
Ezetimibe is recommended as first-line nonstatin therapy for patients with statin-associated adverse effects (SASEs) who still require LDL-C lowering. 1
Mechanistic Rationale
The key distinction that makes ezetimibe safe in this context:
Ezetimibe inhibits the NPC1L1 protein in the small intestine, blocking cholesterol absorption—a completely different mechanism from statins, which inhibit HMG-CoA reductase in the liver. 2
Since rhabdomyolysis from statins is related to their specific effect on the HMG-CoA reductase pathway, ezetimibe does not share this risk mechanism. 3
Safety Profile of Ezetimibe
Rhabdomyolysis Risk with Ezetimibe Monotherapy
The FDA label notes that cases of myopathy and rhabdomyolysis have been reported with ezetimibe, but emphasizes that "most patients who developed rhabdomyolysis were taking a statin or other agents known to be associated with an increased risk of rhabdomyolysis, such as fibrates." 4
A 2018 Cochrane review found it uncertain whether ezetimibe increases or decreases the risk of myopathy when added to statins (RR 1.31,95% CI 0.72 to 2.38), with very low-quality evidence due to wide confidence intervals and low event rates. 5
A 2024 analysis of FDA adverse event data suggested a potentially possible association between ezetimibe monotherapy and rhabdomyolysis, but a meta-analysis of randomized trials did not show significant risk with ezetimibe monotherapy. 6
Clinical Experience
A 2008 study in heart transplant patients found that ezetimibe was generally well-tolerated in patients who had previously experienced statin intolerance, including 3 patients (8%) who had prior rhabdomyolysis from statins. However, one patient experienced asymptomatic recurrence of rhabdomyolysis with ezetimibe, suggesting CPK surveillance is recommended. 7
A 2008 review concluded that ezetimibe has not been associated with increased rates of myopathy or rhabdomyolysis in most studies, whether used alone or with statins, though rare case reports exist. 8
Clinical Algorithm for Management
When a patient develops rhabdomyolysis on statins:
Immediately discontinue the statin permanently—patients with documented statin-induced rhabdomyolysis should not be re-exposed to any statin. 1
Assess ongoing need for LDL-C lowering based on cardiovascular risk, ASCVD status, and LDL-C levels. 1
If LDL-C lowering is still indicated, initiate ezetimibe 10 mg daily as first-line nonstatin therapy. 1, 2
Monitor creatine kinase (CK) levels during ezetimibe therapy, particularly in the first few months, given the rare case reports of recurrent myopathy. 7
If ezetimibe alone is insufficient or not tolerated, consider PCSK9 inhibitors, bempedoic acid, or bile acid sequestrants as alternative options. 1
Important Caveats
Statin-associated autoimmune myopathy is a distinct entity requiring chronic immunosuppressive therapy; these patients should never be re-exposed to statins but can receive ezetimibe or PCSK9 inhibitors. 1
The European guidelines note that 5-10% of patients on statins develop myopathy, but rhabdomyolysis is extremely rare (1.6 per 100,000 patient-years). 1
Risk factors for statin-induced rhabdomyolysis include age, sex, diabetes, renal impairment, cardiovascular disease, certain interacting drugs (especially gemfibrozil), and SLCO1B1 gene mutations. 1
While ezetimibe can cause hepatic transaminase elevations (particularly when combined with statins), this is distinct from the muscle toxicity concern and should be monitored separately. 4, 2