Abstract 196: Impact of Cholesteryl Ester Transfer Protein Inhibition With TA-8995 on High Density Lipoprotein Function

Abstract

Background: The effect of inhibiting cholesteryl ester transfer protein (CETP) activity on high density lipoprotein (HDL) function is poorly understood. Aim: To determine whether the CETP inhibitor, TA-8995, influences the cholesterol efflux capacity and anti-inflammatory properties of HDLs. Methods: Subjects were treated with TA-8995 (2.5 mg/day, n=14 or 10 mg/day, n=13), or placebo (n=14) for 12 weeks. Blood was collected prior to (Visit 2), and after TA-8995 treatment (Visit 5). The composition and size of ultracentrifugally isolated HDLs was determined. Serum cholesterol efflux was quantified in J774 macrophages and CHO cells. Inhibition of vascular cell adhesion molecule (VCAM)-1 and intercellular adhesion molecule (ICAM)-1 expression was determined by flow cytometry in tumor necrosis factor (TNF)-alpha activated human coronary artery endothelial cells (HCAECs) after pre-incubation with isolated HDLs. Results: Plasma HDL-cholesterol (HDL-C) levels, HDL composition and size were comparable at Visit 2 and Visit 5 in the placebo group. Treatment with 2.5 and 10 mg TA-8995 increased HDL-C levels by 113±0.6% and 153±0.5%, respectively. HDL composition in the placebo and treatment groups was comparable at Visit 2. At Visit 5 the apoA-I/apoA-II molar ratio, and wt% phospholipid, cholesteryl ester and unesterified cholesterol increased and the wt% triglyceride and total protein decreased in both treatment groups. TA-8995 treatment also increased HDL size. At Visit 5 versus Visit 2 cAMP-specific cholesterol efflux from J774 macrophages increased by 24±0.3% and 21±0.3%, respectively, in the 2.5 mg and 10 mg TA-8995 treatment groups while ABCA1-specific cholesterol efflux increased by 10±0.1% and 20±0.1%, respectively, and ABCG1-specific cholesterol efflux increased by 20±0.2% and 7±0.2%, respectively. Cholesterol efflux was comparable at Visit 2 and Visit 5 in the placebo group. Pre-incubation of HCAECs with HDLs from the placebo and both TA-8995 treatment groups inhibited TNF-alpha-induced ICAM-1 and VCAM-1 expression comparably at Visits 2 and 5. Conclusion: Inhibition of CETP with TA-8995 changes HDL composition. It also increases HDL size and cholesterol efflux and conserves the anti-inflammatory properties of HDLs.