Abstract 246: Anacetrapib Adds to the Antiatherogenic Effect of Atorvastatin, Mainly by Increasing the Clearance of Non-HDL Cholesterol

Abstract

Introduction: The residual risk that remains after statin treatment has stimulated the search for secondary treatment targets. Epidemiological studies propose HDL-C as a possible candidate. Cholesteryl ester transfer protein (CETP) transfers cholesteryl esters from atheroprotective HDL to atherogenic (V)LDL. The CETP inhibitor anacetrapib decreases (V)LDL-C by ~15-40% and increases HDL-C by ~40-140% in clinical trials. We evaluated the effects of anacetrapib on lipid metabolism, HDL function and atherosclerosis, and examined possible additive/synergistic effects of anacetrapib on top of atorvastatin in APOE*3Leiden.CETP mice. Methods and results: Mice were fed a diet without or with ascending dosages of anacetrapib (0.03; 0.3; 3; 30 mg/kg/d), atorvastatin (2.4 mg/kg/d) alone or in combination with anacetrapib (0.3 mg/kg/d) for 21 weeks. Anacetrapib dose-dependently reduced CETP activity (-59% to -100%, P<0.01), thereby decreasing nonHDL-C (-24% to -45%, P<0.001) and increasing HDL-C (+30% to +86%, P<0.001). Anacetrapib did not affect HDL function. Additionally, we showed that anacetrapib reduced nonHDL-C mainly by increasing the clearance by the liver. Anacetrapib dose-dependently reduced atherosclerotic lesion area (-41% to -92%, P<0.01) and severity, increased the plaque stability index and added to the effects of atorvastatin by further decreasing lesion size (-95%, P<0.001) and severity. Analysis of covariance showed that both anacetrapib (P<0.05) and nonHDL-C (P<0.001), but not HDL-C (P=0.76), independently decreased lesion size. Conclusions: Anacetrapib reduces atherosclerosis, and adds to the anti-atherogenic effect of atorvastatin. The anti-atherogenic effect is mainly ascribed to a reduction in nonHDL-C, as a consequence of an increased clearance. In addition, anacetrapib improves lesion stability.