Ezetimibe Increases Endogenous Cholesterol Excretion in Humans

Abstract

Objective Ezetimibe improves cardiovascular outcomes when added to optimum statin treatment. It lowers LDL 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 LDL cholesterol 100–200 mg/dL, we measured cholesterol metabolism before and after a 6-week treatment period with ezetimibe 10 mg/day or placebo. Plasma cholesterol was labeled by intravenous infusion of cholesterol-d7 in a lipid emulsion and dietary cholesterol with cholesterol-d5 and sitostanol-d4 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, P < 0.0001) and LDL cholesterol 19.8 ± 1.9% (P = 0.0001). Body cholesterol pool size was unchanged, but fecal endogenous cholesterol excretion increased 66.6 ± 12.2% (P < 0.0001) and percent cholesterol excretion from body pools into the stool increased 74.7 ± 14.3% (P < 0.0001) while plasma cholesterol turnover rose 26.2 ± 3.6% (P = 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.

Endothelial Functions

“…70 These findings are consistent with those of the IMPROVE-IT trial (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) that demonstrated that ezetimibe provided an additional beneficial prognostic effect to statin therapy. 71 Lin et al 72 demonstrated that a 6-week treatment of ezetimibe in a standard dose not only reduced intestinal cholesterol absorption but also promoted reverse cholesterol transport from endogenous cholesterol pools into the stool. Ezetimibe did not affect the plasma concentration of high-density lipoprotein-a beneficial cholesterol with vasoprotective property of enhancing endothelial NO production through activation of eNOS.…”

“…Ezetimibe did not affect the plasma concentration of high-density lipoprotein-a beneficial cholesterol with vasoprotective property of enhancing endothelial NO production through activation of eNOS. 72 Denimal et al 73 showed that this beneficial effect of high-density lipoprotein was impaired by the sphingosine-1-phosphate depletion of high-density lipoprotein in patients with metabolic syndrome. On the basis of the premise that targeting glucagon-like peptide (GLP)-1 could provide better treatment of diabetes mellitus via pleiotropic cardiovascular protective effects beyond glycemic control, many clinical trials of GLP-1-based therapies have been conducted with variable effects on cardiovascular outcomes, and others are ongoing.…”

Endogenous Cholesterol Excretion Is Negatively Associated With Carotid Intima–Media Thickness in Humans

“…31 This is likely due to inter-individual differences in metabolic regulation rather than analytical error because our previous work shows that repeated FEEC measurements in the same individual have a coefficient of variation of about 10%. 8 …”

“…36 Although the result has been attributed to LDL cholesterol lowering, the actual mechanism is unknown and recent work shows that FEEC is increased about 70% by ezetimibe. 8 Further work is needed to establish the utility of treatments directed toward whole body cholesterol metabolism.…”

“…Using multiple stable isotopic tracers to label both dietary and endogenous cholesterol and employing a metabolic kitchen diet to provide a constant baseline for measurement, it is possible to quantitate total fecal cholesterol excretion and to characterize it as originating from the endogenous pool, the diet, or unlabeled hepatobiliary components. 8 The final common pathway for RCT is the fecal excretion of endogenous cholesterol (FEEC). That measurement, along with related cholesterol fluxes, forms the basis for this report.…”