This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 26/6/1350    most recent 01.ATV.0000219695.84644.56v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Millar, J. S. Articles by Rader, D. J. Search for Related Content PubMed PubMed Citation Articles by Millar, J. S. Articles by Rader, D. J. Related Collections Risk Factors Other Treatment Lipid and lipoprotein metabolism

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:1350.)
© 2006 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Effects of the Cholesteryl Ester Transfer Protein Inhibitor Torcetrapib on Apolipoprotein B100 Metabolism in Humans

John S. Millar; Margaret E. Brousseau; Margaret R. Diffenderfer; P. Hugh; R. Barrett; Francine K. Welty; Aisha Faruqi; Megan L. Wolfe; Chorthip Nartsupha; Andres G. Digenio; James P. Mancuso; Gregory G. Dolnikowski; Ernst J. Schaefer; Daniel J. Rader

From the Institute for Translational Medicine and Therapeutics (J.S.M., A.F., M.L.W., D.J.R.), University of Pennsylvania School of Medicine, Philadelphia; Lipid Metabolism Laboratory (M.E.B., M.R.D., F.K.W., C.N., E.J.S.), JM-USDA-HNRCA at Tufts University, and Tufts-New England Medical Center, Boston, Mass; Schools of Medicine and Pharmacology (P.H.R.B.), University of Western Australia, Perth, Australia; Division of Cardiology (F.K.W.), Beth Israel Deaconess Medical Center, Boston, Mass; Clinical Research and Development (A.G.D., J.P.M.), Pfizer, Inc., Groton, Conn; and Mass Spectrometry Laboratory (G.G.D.), JM-USDA-HNRCA at Tufts University, Boston, Mass.

Correspondence to John S. Millar, PhD, 644 BRB II/III, 421 Curie Blvd, Philadelphia, PA 19104. E-mail jsmillar{at}mail.med.upenn.edu

Objective— Cholesteryl ester transfer protein (CETP) inhibition with torcetrapib not only increases high-density lipoprotein cholesterol levels but also significantly reduces plasma triglyceride, low-density lipoprotein (LDL) cholesterol, and apolipoprotein B (apoB) levels. The goal of the present study was to define the kinetic mechanism(s) by which CETP inhibition reduces levels of apoB-containing lipoproteins.

Methods and Results— Nineteen subjects, 9 of whom were pretreated with 20 mg atorvastatin, received placebo for 4 weeks, followed by 120 mg torcetrapib once daily for 4 weeks. Six subjects in the nonatorvastatin group received 120 mg torcetrapib twice daily for an additional 4 weeks. After each phase, subjects underwent a primed-constant infusion of deuterated leucine to endogenously label newly synthesized apoB to determine very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL) and LDL apoB100 production, and fractional catabolic rates (FCRs). Once-daily 120 mg torcetrapib significantly reduced VLDL, IDL, and LDL apoB100 pool sizes by enhancing the FCR of apoB100 within each fraction. On a background of atorvastatin, 120 mg torcetrapib significantly reduced VLDL, IDL, and LDL apoB100 pool sizes. The reduction in VLDL apoB100 was associated with an enhanced apoB100 FCR, whereas the decreases in IDL and LDL apoB100 were associated with reduced apoB100 production.

Conclusions— These data indicate that when used alone, torcetrapib reduces VLDL, IDL, and LDL apoB100 levels primarily by increasing the rate of apoB100 clearance. In contrast, when added to atorvastatin treatment, torcetrapib reduces apoB100 levels mainly by enhancing VLDL apoB100 clearance and reducing production of IDL and LDL apoB100.

The CETP inhibitor torcetrapib reduces apoB-containing lipoproteins in plasma. Torcetrapib alone reduces VLDL, IDL, and LDL apoB100 pool size primarily through increased apoB100 clearance. In contrast, addition of torcetrapib to background treatment with atorvastatin was associated with enhanced VLDL apoB100 clearance and reduced production of IDL and LDL apoB100.

Key Words: very low-density lipoproteins • triglyceride • low-density lipoproteins • cholesteryl ester transfer protein • CETP inhibition • lipoprotein kinetics

This article has been cited by other articles:

				M. J. Chapman, W. Le Goff, M. Guerin, and A. Kontush Cholesteryl ester transfer protein: at the heart of the action of lipid-modulating therapy with statins, fibrates, niacin, and cholesteryl ester transfer protein inhibitors Eur. Heart J., October 12, 2009; (2009) ehp399v1. [Abstract] [Full Text] [PDF]

				J. S. Millar, D. Duffy, R. Gadi, L. T. Bloedon, R. L. Dunbar, M. L. Wolfe, R. Movva, A. Shah, I. V. Fuki, M. McCoy, et al. Potent and Selective PPAR-{alpha} Agonist LY518674 Upregulates Both ApoA-I Production and Catabolism in Human Subjects With the Metabolic Syndrome Arterioscler Thromb Vasc Biol, January 1, 2009; 29(1): 140 - 146. [Abstract] [Full Text] [PDF]

				J. S. Millar, M. E. Brousseau, M. R. Diffenderfer, P. H. R. Barrett, F. K. Welty, J. S. Cohn, A. Wilson, M. L. Wolfe, C. Nartsupha, P. M. Schaefer, et al. Effects of the cholesteryl ester transfer protein inhibitor torcetrapib on VLDL apolipoprotein E metabolism J. Lipid Res., March 1, 2008; 49(3): 543 - 549. [Abstract] [Full Text] [PDF]

				K. G. Parhofer and P. H. R. Barrett Thematic review series: Patient-Oriented Research. What we have learned about VLDL and LDL metabolism from human kinetics studies J. Lipid Res., August 1, 2006; 47(8): 1620 - 1630. [Abstract] [Full Text] [PDF]