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

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.

Effects of the PPAR-δ agonist MBX-8025 on atherogenic dyslipidemia.

OBJECTIVE: Determine the effects of treatment with a selective PPAR-δ agonist±statin on plasma lipoprotein subfractions in dyslipidemic individuals. METHODS: Ion mobility analysis was used to measure plasma concentrations of subfractions of the full spectrum of lipoprotein particles in 166 overweight or obese dyslipidemic individuals treated with the PPAR-δ agonist MBX-8025 (50 and 100 mg/d)±atorvastatin (20 mg/d) in an 8-week randomized parallel arm double blind placebo controlled trial. RESULTS: MBX-8025 at both doses resulted in reductions of small plus very small LDL particles and increased levels of large LDL, with a concomitant reduction in large VLDL, and an increase in LDL peak diameter. This translated to reversal of the small dense LDL phenotype (LDL pattern B) in ∼90% of the participants. Modest increases in HDL particles were confined to the smaller HDL fractions. Atorvastatin monotherapy resulted in reductions in particles across the VLDL-IDL-LDL spectrum, with a significantly smaller reduction in small and very small LDL vs. MBX-8025 100 mg/d (-24.5±5.3% vs. -47.8±4.9%), and, in combination with MBX-8025, a reversal of the increase in large LDL. CONCLUSION: PPAR-δ and statin therapies have complementary effects in improving lipoprotein subfractions associated with atherogenic dyslipidemia.