Details

Autor(en) / Beteiligte

• Reyes-Soffer, Gissette
• Millar, John S
• Ngai, Colleen
• Jumes, Patricia
• Coromilas, Ellie
• Asztalos, Bela
• Johnson-Levonas, Amy O
• Wagner, John A
• Donovan, Daniel S
• Karmally, Wahida
• Ramakrishnan, Rajasekhar
• Holleran, Stephen
• Thomas, Tiffany
• Dunbar, Richard L
• deGoma, Emil M
• Rafeek, Hashmi
• Baer, Amanda L
• Liu, Yang
• Lassman, Michael E
• Gutstein, David E
• Rader, Daniel J
• Ginsberg, Henry N

Titel

Cholesteryl Ester Transfer Protein Inhibition With Anacetrapib Decreases Fractional Clearance Rates of High-Density Lipoprotein Apolipoprotein A-I and Plasma Cholesteryl Ester Transfer Protein

Ist Teil von

• Arteriosclerosis, thrombosis, and vascular biology, 2016-05, Vol.36 (5), p.994

Ort / Verlag

United States

Erscheinungsjahr

2016

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• Anacetrapib (ANA), an inhibitor of cholesteryl ester transfer protein (CETP) activity, increases plasma concentrations of high-density lipoprotein cholesterol (HDL-C), apolipoprotein A-I (apoA)-I, apoA-II, and CETP. The mechanisms responsible for these treatment-related increases in apolipoproteins and plasma CETP are unknown. We performed a randomized, placebo (PBO)-controlled, double-blind, fixed-sequence study to examine the effects of ANA on the metabolism of HDL apoA-I and apoA-II and plasma CETP. Twenty-nine participants received atorvastatin (ATV) 20 mg/d plus PBO for 4 weeks, followed by ATV plus ANA 100 mg/d for 8 weeks (ATV-ANA). Ten participants received double PBO for 4 weeks followed by PBO plus ANA for 8 weeks (PBO-ANA). At the end of each treatment, we examined the kinetics of HDL apoA-I, HDL apoA-II, and plasma CETP after D3-leucine administration as well as 2D gel analysis of HDL subspecies. In the combined ATV-ANA and PBO-ANA groups, ANA treatment increased plasma HDL-C (63.0%; P<0.001) and apoA-I levels (29.5%; P<0.001). These increases were associated with reductions in HDL apoA-I fractional clearance rate (18.2%; P=0.002) without changes in production rate. Although the apoA-II levels increased by 12.6% (P<0.001), we could not discern significant changes in either apoA-II fractional clearance rate or production rate. CETP levels increased 102% (P<0.001) on ANA because of a significant reduction in the fractional clearance rate of CETP (57.6%, P<0.001) with no change in CETP production rate. ANA treatment increases HDL apoA-I and CETP levels by decreasing the fractional clearance rate of each protein.