Ezetimibe-associated rhabdomyolysis: A comprehensive assessment of the USFDA adverse event reporting system using disproportionality analysis, case reviews, and meta-analysis of randomized clinical trials

Abstract

BACKGROUND

Ezetimibe, a Niemann-Pick C1-like 1 inhibitor, is widely prescribed as a monotherapy or in combination with statins to reduce cholesterol levels. Although generally well-tolerated, concerns have emerged regarding the risk of rhabdomyolysis, particularly with combination therapies. This study aims to evaluate the association between ezetimibe and rhabdomyolysis using data from the United States Food and Drug Administration’s Adverse Event Reporting System (USFDA AERS), case reviews, and a meta-analysis of clinical trials.

METHODS

We analyzed reports from the USFDA AERS between Q1 2004 and Q2 2024, focusing on cases with rhabdomyolysis with ezetimibe alone or in combination with statins or bempedoic acid. Disproportionality analysis using both frequentist and Bayesian methods was conducted. We also reviewed published case reports and performed a meta-analysis of randomized clinical trials comparing ezetimibe monotherapy with placebo.

RESULTS

Of 29,153,222 reports in AERS, 668 cases met the inclusion criteria. Frequentist and Bayesian analyses indicated an increased risk of rhabdomyolysis with ezetimibe alone and with statin combinations, particularly with simvastatin and atorvastatin. Interaction signal scores suggested statistically significant interactions between ezetimibe and certain statins (atorvastatin and rosuvastatin). Case reviews identified 9 published cases, most of which involved ezetimibe in patients on a stable background therapy of statins. The meta-analysis of 3 trials did not show a significant risk for rhabdomyolysis with ezetimibe monotherapy.

CONCLUSION

This study suggests a potentially possible association between ezetimibe (monotherapy and in combination), and rhabdomyolysis risk. Clinicians should monitor patients closely, particularly those on combination therapies. Further prospective studies are needed to elucidate causality and inform safe prescribing practices.