Ezetimibe Increases Endogenous Cholesterol Excretion in Humans

Objective: Ezetimibe improves cardiovascular outcomes when added to optimum statin treatment. It lowers low-density lipoprotein cholesterol and percent intestinal cholesterol absorption, but the exact cardioprotective mechanism is unknown. We tested the hypothesis that the dominant effect of ezetimibe is to increase the reverse transport of cholesterol from rapidly mixing endogenous cholesterol pool into the stool.

Approach And Results: In a randomized, placebo-controlled, double-blind parallel trial in 24 healthy subjects with low-density lipoprotein cholesterol 100 to 200 mg/dL, we measured cholesterol metabolism before and after a 6-week treatment period with ezetimibe 10 mg/d or placebo. Plasma cholesterol was labeled by intravenous infusion of cholesterol-d in a lipid emulsion and dietary cholesterol with cholesterol-d and sitostanol-d solubilized in oil. Plasma and stool samples collected during a cholesterol- and phytosterol-controlled metabolic kitchen diet were analyzed by mass spectrometry. Ezetimibe reduced intestinal cholesterol absorption efficiency 30±4.3% (SE, <0.0001) and low-density lipoprotein cholesterol 19.8±1.9% (=0.0001). Body cholesterol pool size was unchanged, but fecal endogenous cholesterol excretion increased 66.6±12.2% (<0.0001) and percent cholesterol excretion from body pools into the stool increased 74.7±14.3% (<0.0001), whereas plasma cholesterol turnover rose 26.2±3.6% (=0.0096). Fecal bile acids were unchanged.

Conclusions: Ezetimibe increased the efficiency of reverse cholesterol transport from rapidly mixing plasma and tissue pools into the stool. Further work is needed to examine the potential relation of reverse cholesterol transport and whole body cholesterol metabolism to coronary events and the treatment of atherosclerosis.

Clinical Trials Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01603758.