Effects of cholesteryl ester transfer protein inhibition on apolipoprotein A-II-containing HDL subspecies and apolipoprotein A-II metabolism

M. E Brousseau, J. S Millar, M. R Diffenderfer, C Nartsupha, B. F Asztalos, M. L Wolfe, J. P Mancuso, A. G Digenio, D. J Rader and E. J. Schaefer

Journal of Lipid Research, 2009, 50(7), 1456-1462. DOI: 10.1194/jlr.P800037-JLR200

Abstract

This study was designed to establish the mechanism responsible for the increased apolipoprotein (apo) A-II levels caused by the cholesteryl ester transfer protein inhibitor torcetrapib. Nineteen subjects with low HDL cholesterol (<40 mg/dl), nine of whom were also treated with 20 mg of atorvastatin daily, received placebo for 4 weeks, followed by 120 mg of torcetrapib daily for the next 4 weeks. Six subjects in the nonatorvastatin cohort participated in a third phase, in which they received 120 mg of torcetrapib twice daily for 4 weeks. At the end of each phase, subjects underwent a primed-constant infusion of [5,5,5-²H₃]l-leucine to determine the kinetics of HDL apoA-II. Relative to placebo, torcetrapib significantly increased apoA-II concentrations by reducing HDL apoA-II catabolism in the atorvastatin (–9.4%, P < 0.003) and nonatorvastatin once- (–9.9%, P = 0.02) and twice- (–13.2%, P = 0.02) daily cohorts. Torcetrapib significantly increased the amount of apoA-II in the -2-migrating subpopulation of HDL when given as monotherapy (27%, P < 0.02; 57%, P < 0.003) or on a background of atorvastatin (28%, P < 0.01). In contrast, torcetrapib reduced concentrations of apoA-II in -3-migrating HDL, with mean reductions of –14% (P = 0.23), –18% (P < 0.02), and –18% (P < 0.01) noted during the atorvastatin and nonatorvastatin 120 mg once- and twice-daily phases, respectively. Our findings indicate that CETP inhibition increases plasma concentrations of apoA-II by delaying HDL apoA-II catabolism and significantly alters the remodeling of apoA-II-containing HDL subpopulations.

ASCI-ID: 972-109