Effects of CETP inhibition with anacetrapib on metabolism of VLDL-TG and plasma apolipoproteins C-II, C-III, and E.
Cholesteryl ester transfer protein (CETP) mediates the transfer of HDL cholesteryl esters for triglyceride (TG) in VLDL/LDL. CETP inhibition, with anacetrapib, increases HDL-cholesterol, reduces LDL-cholesterol, and lowers TG levels. This study describes the mechanisms responsible for TG lowering by examining the kinetics of VLDL-TG, apoC-II, apoC-III, and apoE. Mildly hypercholesterolemic subjects were randomized to either placebo (N = 10) or atorvastatin 20 mg/qd (N = 29) for 4 weeks (period 1) followed by 8 weeks of anacetrapib, 100 mg/qd (period 2). Following each period, subjects underwent stable isotope metabolic studies to determine the fractional catabolic rates (FCRs) and production rates (PRs) of VLDL-TG and plasma apoC-II, apoC-III, and apoE. Anacetrapib reduced the VLDL-TG pool on a statin background due to an increased VLDL-TG FCR (29%;P= 0.002). Despite an increased VLDL-TG FCR following anacetrapib monotherapy (41%;P= 0.11), the VLDL-TG pool was unchanged due to an increase in the VLDL-TG PR (39%;P= 0.014). apoC-II, apoC-III, and apoE pool sizes increased following anacetrapib; however, the mechanisms responsible for these changes differed by treatment group. Anacetrapib increased the VLDL-TG FCR by enhancing the lipolytic potential of VLDL, which lowered the VLDL-TG pool on atorvastatin background. There was no change in the VLDL-TG pool in subjects treated with anacetrapib monotherapy due to an accompanying increase in the VLDL-TG PR.
University of Pennsylvania, Philadelphia, PA 19104 jsmillar@upenn.edu gr2104@cumc.columbia.edu.
John S
JS
Millar
Merck & Co., Inc., Kenilworth, NJ 07033.
Michael E
ME
Lassman
Columbia University, New York, NY 10032.
Tiffany
T
Thomas
Columbia University, New York, NY 10032.
Rajasekhar
R
Ramakrishnan
Merck & Co., Inc., Kenilworth, NJ 07033.
Patricia
P
Jumes
University of Pennsylvania, Philadelphia, PA 19104.
Richard L
RL
Dunbar
University of Pennsylvania, Philadelphia, PA 19104.
Emil M
EM
deGoma
University of Pennsylvania, Philadelphia, PA 19104.
Amanda L
AL
Baer
Columbia University, New York, NY 10032.
Wahida
W
Karmally
Columbia University, New York, NY 10032.
Daniel S
DS
Donovan
University of Pennsylvania, Philadelphia, PA 19104.
Hashmi
H
Rafeek
Merck & Co., Inc., Kenilworth, NJ 07033.
John A
JA
Wagner
Columbia University, New York, NY 10032.
Stephen
S
Holleran
New York City College of Technology, CUNY, Brooklyn, NY 11201.
Joseph
J
Obunike
Merck & Co., Inc., Kenilworth, NJ 07033.
Yang
Y
Liu
University of Pennsylvania, Philadelphia, PA 19104.
Soumia
S
Aoujil
University of Pennsylvania, Philadelphia, PA 19104.
Taylor
T
Standiford
Merck & Co., Inc., Kenilworth, NJ 07033.
David E
DE
Gutstein
Columbia University, New York, NY 10032.
Henry N
HN
Ginsberg
University of Pennsylvania, Philadelphia, PA 19104.
Daniel J
DJ
Rader
Columbia University, New York, NY 10032 jsmillar@upenn.edu gr2104@cumc.columbia.edu.
Gissette
G
Reyes-Soffer
D053304:Apolipoprotein C-II / Q000097:blood; D053305:Apolipoprotein C-III / Q000097:blood; D001053:Apolipoproteins / Q000097:blood*; D001057:Apolipoproteins E / Q000097:blood; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors*; D004347:Drug Interactions; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D008079:Lipoproteins, VLDL / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D023303:Oxazolidinones / Q000494:pharmacology*; D014280:Triglycerides / Q000378:metabolism*
D053304:Apolipoprotein C-II; D053305:Apolipoprotein C-III; D001053:Apolipoproteins; D001057:Apolipoproteins E; D053480:Cholesterol Ester Transfer Proteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008079:Lipoproteins, VLDL; D023303:Oxazolidinones; D014280:Triglycerides; C030106:very low density lipoprotein triglyceride; C530884:anacetrapib
cholesteryl ester transfer protein; drug therapy; kinetics; lipoprotein metabolism; plasma lipid transfer proteins; statins; triglyceride; very low density lipoprotein