Abstract 69: Anacetrapib Dose-dependently Decreases Atherosclerosis Development and Adds to the Beneficial Effects of Atorvastatin in APOE*3Leiden.CETP Mice

Introduction The residual risk of cardiovascular disease that remains after statin treatment has triggered the search for a secondary treatment target. Epidemiological studies propose HDL-cholesterol (HDL-C) as a possible candidate. Cholesteryl ester transfer protein (CETP) transfers cholesteryl esters from atheroprotective HDL to atherogenic (V)LDL. In human intervention trials, the CETP inhibitor anacetrapib decreases (V)LDL-C by 30-40% and increases HDL-C by 40-140%. Hypothesis Complete inhibition of CETP activity may result in adverse effects as compared to partial inhibition due to the appearance of a dysfunctional HDL. We, therefore, evaluated the effect of a broad treatment window of anacetrapib-induced CETP inhibition with partial to full inhibition, as well as the combination of atorvastatin and anacetrapib on atherosclerosis development in APOE*3Leiden.CETP mice. Methods Female mice were fed a Western-type diet containing 0.1% cholesterol without or with incremental dosages of anacetrapib (0.03; 0.3; 3; 30 mg/kg/d), atorvastatin (2.4 mg/kg/d) or a combination of anacetrapib (0.3 mg/kg/d) and atorvastatin (2.4 mg/kg/d) for 20 weeks. Effects on plasma lipids, CETP activity and levels, as well as atherosclerotic lesion size and severity were assessed. Results Anacetrapib dose-dependently reduced CETP activity (-60% to -100%, P<0.001) and increased CETP levels (+13% to +31%, P<0.05), thereby decreasing nonHDL-C (-23% to -44%, P<0.001) and increasing HDL-C (+32% to +88%, P<0.001). Atorvastatin decreased CETP activity (-29%, P<0.001) and nonHDL-C (-36%, P<0.001). Anacetrapib dose-dependently decreased atherosclerotic lesion size (-36%, P<0.05 to -92%, P<0.001) and the percentage severe lesions. Anacetrapib added to the effects of atorvastatin by further reducing nonHDL-C (-36%, P<0.001), increasing HDL-C (+72%, P<0.001) and decreasing lesion size (-86%, P<0.001) and severity. Results on lesion composition are pending. Conclusions Anacetrapib dose-dependently decreases atherosclerosis development and adds to the beneficial effects of atorvastatin in APOE*3Leiden.CETP mice. Total blockage of CETP activity does not reveal adverse effects as compared to partial blockage.