Changes in lipoprotein subfraction concentration and composition in healthy individuals treated with the CETP inhibitor anacetrapib

Abstract

We investigated the effects of the cholesteryl ester (CE) transfer protein inhibitor anacetrapib (ANA) on plasma lipids, lipoprotein subfraction concentrations, and lipoprotein composition in 30 healthy individuals. Participants (n = 30) were randomized to ANA 20 mg/day, 150 mg/day, or placebo for 2 weeks. Changes in concentration of lipoprotein subfractions were assessed using ion mobility, and compositional analyses were performed on fractions separated by density gradient ultracentrifugation. ANA 150 mg/day versus placebo resulted in significant decreases in LDL-cholesterol (26%) and apo B (29%) and increases in HDL-cholesterol (82%). Concentrations of medium and small VLDL, large intermediate density lipoprotein (IDL), and medium and small LDL (LDL2a, 2b, and 3a) decreased whereas levels of very small and dense LDL4b were increased. There was enrichment of triglycerides and reduction of CE in VLDL, IDL, and the densest LDL fraction. Levels of large buoyant HDL particles were substantially increased, and there was enrichment of CE, apo AI, and apoCIII, but not apoAII or apoE, in the mid-HDL density range. Changes in lipoprotein subfraction concentrations and composition with ANA 20 mg/day were similar to those for ANA 150 mg/day but were generally smaller in magnitude. The impact of these changes on cardiovascular risk remains to be determined.

Trial registration: ClinicalTrials.gov NCT01252953.

Fig. 1.

Placebo-adjusted differences in mean change from baseline ± 95% confidence intervals in % TG/mass and %CE/mass content for IDL and LDL subfractions in ANA 150 mg versus placebo groups. For nonparametrically distributed data (TG%: LDL F4; CE%: LDL total, F4), the Hodges-Lehman estimate of median difference and distribution-free confidence interval are presented; otherwise, the least squares mean difference and 95% confidence interval from an ANCOVA model with treatment as a factor and baseline lipid level as a covariate are presented.

Fig. 2.

Placebo-adjusted differences in median change from baseline ± 95% confidence intervals in % TG/mass and %CE/mass content for HDL subfractions in ANA 150 mg versus placebo groups. For normally distributed data (TG%: HDL total, F6; CE%: HDL F1, F2, F4, F5), the least squares mean difference and 95% confidence interval from an ANCOVA model with treatment as a factor and baseline lipid level as a covariate are presented; otherwise, the Hodges-Lehman estimate of median difference and distribution free confidence interval are presented.

Fig. 3.

Placebo-adjusted differences in median change from baseline ± 95% confidence intervals in ApoAI for IDL, LDL, and HDL subfractions in ANA 150 mg versus placebo groups. For normally distributed data (LDL F2, F5, F6, HDL F5), the least squares mean difference and 95% confidence interval from an ANCOVA model with treatment as a factor and baseline lipid level as a covariate are presented; otherwise, the Hodges-Lehman estimate of median difference and distribution free confidence interval are presented.