Abstract 120: Effects of Anacetrapib Treatment on CETP Metabolism
Background Cholesteryl ester transfer protein (CETP) is required for the exchange of core lipids, cholesteryl esters and triglycerides (TG), between lipoproteins. This results in net exchanges of TG in very-low-density (VLDL) or low-density lipoproteins (LDL) for cholesteryl esters in high-density lipoproteins (HDL). Treatment with anacetrapib, a CETP inhibitor in phase 3 development, is associated with an increased HDL-C and apo AI, and reduced both LDL-C and triglycerides. There are no published data on the regulation of CETP levels in humans. CETP mass has been reported to increase following CETP inhibition which prompted us to examine CETP kinetics. We developed a novel method using stable isotopes and LC-MS analysis to study the effects of anacetrapib on CETP turnover.
Methods Thirty-nine moderately hyperlipidemic participants were enrolled in a fixed-sequence study: 75% (N=29) were on atorvastatin (20mg/day) plus placebo for four weeks followed by atorvastatin plus anacetrapib (100 mg/day) for 8 weeks (S-ANA). Twenty-Five percent (N=10) of participants received double placebo for four weeks followed by placebo plus anacetrapib for 8 weeks (P-ANA). At the end of each period, we measured CETP mass, and kinetic studies were performed using D3 leucine to determine the fractional clearance and production rates of CETP.
Results Eight weeks of anacetrapib treatment was associated with 129% increase in CETP plasma levels and an 18% decrease in CETP activity (RFU/sec) in both groups. The increase in CETP mass was associated with a significant reduction in the fractional clearance of CETP from plasma (0.48 vs. 0.23 pools/day) p <.001. The decrease in fractional clearance of CETP was similar in Panel A and Panel B (Panel A 57%, Panel B 55%). There were no significant changes in the production rate of CETP.
Conclusions Using a novel method, we demonstrated significant effects of CETP inhibition with anacetrapib on the metabolism of CETP in plasma.
- © 2013 by American Heart Association, Inc.