Ezetimibe blocks intestinal absorption of
sterols via interaction with the Neimann-Pick C1-Like 1 (NPC1L1) transporter and is approved for use in the treatment of primary
hyperlipidemia (heterozygous familial and non-familial),
homozygous familial hypercholesterolemia, and homozygous
sitosterolemia. A recently completed randomized clinical trial [
simvastatin and
ezetimibe in
aortic stenosis (SEAS)] testing the effectiveness of
Vytorin (a combination of
simvastatin and
ezetimibe) in patients with
aortic stenosis reported an unexpected safety finding: an increase in overall
cancer incidence and
cancer-associated mortality (all types) in the treated groups relative to the placebo control. A subsequent meta-analysis utilizing a much larger database from two ongoing clinical trials indicated that the observed findings in the SEAS trial were likely due to chance and not a true
drug-induced effect. Nonetheless, it has been suggested by various commentators on the SEAS trial that
ezetimibe may be carcinogenic. The extensive nonclinical database for
ezetimibe was used to test the hypothesis that
ezetimibe may be a direct or indirect
carcinogen. Using two different in silico approaches,
ezetimibe showed no structural alerts for genetic toxicity or carcinogenicity.
Ezetimibe was not genotoxic in two reverse mutation assays, one in vitro clastogenicity assay, and two mouse micronucleus assays. No evidence of proliferative lesions was observed in three species in studies of 1-12 months in duration.
Ezetimibe was not carcinogenic in standard 2-year bioassays in mice and rats. Additionally, in these 2-year bioassays, no
drug-related non-neoplastic lesions were noted. The absence of
drug-induced non-neoplastic or proliferative lesions in these studies indicates that
ezetimibe treatment was not associated with findings characteristic of
carcinogens (i.e.,
DNA reactivity or cell proliferation) Administration of pharmacologic doses of
ezetimibe to mice did not alter hepatic expression patterns of genes associated with apoptosis, cell proliferation, or epithelial-mesenchymal transition. No evidence of
drug-induced
tumors was observed in mice in which the molecular target of
ezetimibe (NPC 1L1) was knocked out over the life span of the animal. In conclusion, the nonclinical data do not support the proposed hypothesis based on the single observation from the SEAS trial and, rather, support the conclusion that
ezetimibe does not represent a carcinogenic hazard to humans using this
drug in a therapeutic setting.