Abstract 397: Changes in Lipoprotein Subfraction Concentrations After Treatment with the Cholesteryl Ester Transfer Protein Inhibitor Anacetrapib Alone or in Combination with Atorvastatin

Abstract

Background Anacetrapib (ANA), a cholesteryl ester transfer protein inhibitor, has been shown to increase plasma HDL cholesterol and reduce LDL cholesterol, both as monotherapy and in combination with atorvastatin (ATORVA). The effects of these regimens on lipoprotein subfractions have not been reported. Methods ApoB-containing lipoprotein particle subfractions were measured by ion mobility in a post-hoc analysis of baseline and 8 week on-treatment samples from 464 dyslipidemic participants who had been randomized to placebo, ATORVA 20 mg/d, or to ANA at several doses administered with and without ATORVA ( clinicaltrials.gov NCT00325455 ). Results ANA (combined 150 mg/d and 300 mg/d groups) significantly reduced total LDL particle concentration by 51%, and levels of large, medium, and small LDL particles (LDL 1, 2, and 3a) by 43-72% but significantly increased levels of the less abundant cholesterol-depleted very small LDL 4a and 4b species by ~64%. In contrast, ATORVA, despite producing a similar reduction of total LDL particle concentration (50%), reduced the levels of all LDL particle subfractions, although the magnitude was smaller for LDL 4a, with a much smaller non-significant reduction for LDL 4b. Compared with ANA monotherapy, results for combination treatment were generally consistent with additive effects. Notably, for individuals with baseline triglyceride (TG) above the median (>154 mg/dL), increases of very small LDL after ANA were markedly attenuated, whereas after ATORVA there was greater reduction of LDL 4a in the higher TG group. Conclusions Similar reductions of LDL levels after ANA or ATORVA were not associated with comparable effects on all LDL particle subfractions, and neither drug was effective in lowering levels of the smallest LDL particles. Assessment of the clinical impact of the effects of ANA on LDL subfractions, and the differential changes in very small LDL in individuals with normal versus elevated TG, await cardiovascular outcome data from REVEAL.