Ezetimibe, a potent cholesterol absorption inhibitor, normalizes combined dyslipidemia in obese hyperinsulinemic hamsters

Ezetimibe potently and selectively inhibits cholesterol absorption in tape intestine, thereby reducing plasma cholesterol in preclinical models of hyp ercholesterolemia. Clinical trials have demonstrated that ezetimibe lowers LDL cholesterol and raises HDL cholesterol in humans. The effect of ezetimi be on other dyslipidemias, particularly hypertriglyceridemia, is not yet kn own. In the present studies, we assessed the effect of ezetimibe on combine d hypercholesterolemia and hypertriglyceridemia in obese hyperinsulinemic h amsters. Hamsters were fed chow, chow with cholesterol (0.12%), or the same cholesterol diet containing different dietary triglycerides (15%) in the a bsence or presence of 1 mg/kg ezetimibe (in diet) for up to 84 days. Body w eight, serum insulin, leptin, glucose, cholesterol, and triglyceride levels were analyzed. Cholesterol and triglyceride levels were also determined in VLDL+IDL, LDL, and HDL. Hamsters maintained on high-fat diets became obese , hyperinsulinemic, hyperleptinemic, hypercholesterolemic, and hyper-trigly ceridemic. Ezetimibe did not affect body weight, insulin, or leptin, but ab lated the combined hypercholesterolemia and hypertriglyceridemia induced by high-fat diets. Ezetimibe normalized VLDL+IDL cholesterol and triglyceride and significantly decreased LDL cholesterol to below chow-fed levels. The ratio of HDL to LDL cholesterol increased significantly with the addition o f ezetimibe. Ezetimibe completely eliminated the accumulation of cholestery l eater and free cholesterol in liver that was induced under the various di etary conditions in the absence of drug. In conclusion, ezetimibe is very e ffective in correcting the combined dyslipidemia in diet-induced obese hype rinsulinemic hamsters and may be an effective therapy for ameliorating comb ined dyslipidemia in obese insulin-resistant and/or type 2 diabetic humans.