Reducing low-density lipoprotein (LDL) is known to lower cardiovascular disease risk. Despite the use of statin drugs, which inhibit the body’s production of cholesterol and lower LDL, complementary strategies are needed to further reduce cardiac risk. Ezetimibe increases elimination of endogenous cholesterol via the stool and reduces intestinal cholesterol absorption.
Xiaobo Lin, from the Division of Endocrinology, Metabolism, and Lipid Research at the Washington University School of Medicine, and colleagues hypothesized that the cardioprotective mechanism of Ezetimibe is the increased reverse transport of endogenous cholesterol into the stool. The process of reverse transport involves removing endogenous cholesterol from the body tissues into the rapidly mixing plasma and tissue pool and then fecal elimination of the cholesterol.
To test this hypothesis, 24 participants were randomized to receive ezetimibe 10 mg per day or placebo for 6 weeks. The results of this study were published in Arteriosclerosis, Thrombosis, and Vascular Biology. Patients were also administered cholesterol tracers orally or intravenously to label the cholesterol in the stool by origin: endogenous, dietary, or unlabeled, newly synthesized cholesterol. Participants were asked to follow a strict metabolic kitchen diet to control dietary cholesterol and phytosterol intake.
Treatment with ezetimibe over 6 weeks increased the total fecal cholesterol by 54% when compared with placebo. The majority of the fecal cholesterol content was of endogenous origin, as dietary and newly synthesized cholesterol comprised only 11% and 2.4% of the total fecal cholesterol content, respectively. The cholesterol rapidly mixing pool size was not altered by ezetimibe treatment, indicating that the increase in cholesterol excretion was due to the displacement of cholesterol from peripheral tissues and biosynthesis of cholesterol. Ezetimibe seems to favour the turnover of body cholesterol. As expected, intestinal absorption of cholesterol was reduced by 30% in patients receiving ezetimibe. From these findings, the researchers note that there was a larger effect of ezetimibe on cholesterol metabolism than on the intestinal absorption of cholesterol.
Treatment with ezetimibe offers a complimentary approach to reducing cardiac risk by favouring the overall efficiency of the reverse cholesterol transport pathway. The combination of statin drugs and Ezetimibe increases elimination of endogenous cholesterol, reduces LDL, inhibits the production of cholesterol by the body, and inhibits the absorption of cholesterol via the gut. It is unknown whether the increased RCT pathway, stimulated by ezetimibe, has significant implications for the reduction of cardiac risk. More studies are required to confirm the relation of the RCT pathway and cardiac risk.
Written by Jessica Caporuscio, PharmD
Reference: Lin X, Racette SB, Ma L, et al. Ezetimibe Increases Endogenous Cholesterol Excretion in Humans. ArteriosclerThrombVascBiol. 2017:990-996.