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

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-(2)H(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 (-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 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 alpha-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.

Fig. 1.

Effect of torcetrapib on the percentage of change in plasma concentrations of apoA-II versus placebo. Relative to placebo, torcetrapib increased plasma apoA-II levels by a mean of 10%, from 30 ± 4 to 33 ± 4 mg/dl, in the atorvastatin group, by 12%, from 29 ± 2 to 33 ± 5 mg/dl, in the 120 mg torcetrapib once daily group, and by 21%, from 30 ± 1 to 36 ± 3 mg/dl, in the 120 mg torcetrapib twice daily group. *P < 0.001 and **P = 0.01 for the comparison of absolute concentrations of apoA-II with the placebo phase. QD, once daily; BID, twice daily.

Fig. 2.

Effect of torcetrapib on the percentage of distribution of apoA-II among HDL subpopulations (mean ± SD). Relative to placebo, the percentage of distribution of apoA-II within the α-2 subpopulation of HDL increased from 58 ± 6 to 67 ± 10% (17%, P < 0.04) in the atorvastatin cohort, from 54 ± 7 to 65 ± 11% (16%, P < 0.01) in the 120 mg torcetrapib once daily cohort, and from 53 ± 8 to 69 ± 4% (31%, P < 0.01) in the 120 mg torcetrapib twice daily cohort. Conversely, torcetrapib significantly reduced the percentage of distribution of apoA-II within the α-3 subpopulation of HDL in each of the cohorts. *P < 0.01 and **P = 0.04 for comparison with placebo phase. QD, once daily; BID, twice daily; PBO, placebo; TOR, torcetrapib.