Abstract 18072: A Model to Predict Clinical Efficacy of CETP Inhibition: Anacetrapib Elevates HDL, Lowers LDL and Increases Sterol Excretion in the Syrian Golden Hamster
Cholesteryl ester transfer protein (CETP) is a target for dyslipidemia and coronary artery disease. Anacetrapib (ANA), a reversible inhibitor of CETP, raises HDL cholesterol and lowers LDL cholesterol in dyslipidemic patients. However, a preclinical model which recapitulates both the HDL and LDL-modulating effects of ANA observed in humans has not been reported. Based upon the similarity in lipoprotein profiles between dyslipidemic Syrian golden hamsters and humans, this study tested the hypothesis that treatment of dyslipidemic hamsters with ANA would result in HDL raising and lowering of LDL similar to what is observed in humans, in order to facilitate development of an animal model in which reverse cholesterol transport might be studied in vivo. Hamsters were placed on a high fat diet (45% kcal from fat, 0.12% cholesterol) for 3 weeks to induce dyslipidemia and treated with ANA (60mg/kg in diet) or high fat diet alone for 2 weeks. ANA-treated animals showed higher HDL and lower LDL compared to control (max effect 60mg/kg, HDL 67±9%, LDL -54±7% P<0.001), measured with FPLC-cholesterol analysis. Concentrations of unconjugated bile acids were increased in bile and feces from ANA-treated animals compared to control, and fecal free cholesterol was increased with ANA treatment (max effect 60mg/kg, 43±19%, P<0.05 vs. control), suggesting increased sterol excretion resulting from CETP inhibition. The significant increases in HDL and reductions of LDL in the Syrian golden hamster model observed in this study are in line with prior data from ANA-treated dyslipidemic patients, suggesting that the hamster constitutes a robust model in which to investigate the fate of cholesterol with CETP inhibition. Furthermore, this study demonstrates that ANA induces increased sterol excretion, suggesting that CETP inhibition in the hamster may stimulate reverse cholesterol transport. Therefore, this model may serve as a predictive tool to further characterize the beneficial effects of CETP inhibition on lipid metabolism and coronary artery disease in the clinic.
- © 2010 by American Heart Association, Inc.