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

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-H-2(3)] 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 (29.4%, P, 0.003) and nonatorvastatin once-(29.9%, P 5 0.02) and twice-(213.2%, P 5 0.02) daily cohorts. Torcetrapib significantly increased the amount of apoA-II in the alpha-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 a-3-migrating HDL, with mean reductions of 214% (P 5 0.23), 218% (P, 0.02), and 218% (P, 0.01) noted during the atorvastatin and nonatorvastatin 120 mg onceand 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.-Brousseau, M. E., 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. Effects of cholesteryl ester transfer protein inhibition on apolipo-protein A-II-containing HDL subspecies and apolipoprotein A-II metabolism. J. Lipid Res. 2009. 50: 1456-1462.