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

• Main Authors: Margaret E. Brousseau, John S. Millar, Margaret R. Diffenderfer, Chorthip Nartsupha, Bela F. Asztalos, Megan L. Wolfe, James P. Mancuso, Andres G. Digenio, Daniel J. Rader, Ernst J. Schaefer
• Format: Article
• Language: English
• Published: Elsevier 2009-07-01
• Series: Journal of Lipid Research
• Subjects: high density lipoproteins; lipoprotein kinetics; Torcetrapib; HDL subspecies
• Online Access: http://www.sciencedirect.com/science/article/pii/S0022227520307926

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 α-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 α-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.