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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:148.)
© 2008 American Heart Association, Inc.

Clinical and Population Studies

Inhibition of CETP by Torcetrapib Attenuates the Atherogenicity of Postprandial TG-Rich Lipoproteins in Type IIB Hyperlipidemia

Maryse Guerin; Wilfried Le Goff; Emilie Duchene; Zélie Julia; Tu Nguyen; Tom Thuren; Charles L. Shear; M. John Chapman

From INSERM U551 (M.G., W.L.G., E.D., Z.J., M.J.C.), Paris, France; Université Pierre et Marie Curie–Paris6 (M.G., W.L.G., E.D., Z.J., M.J.C.), UMR S551, Paris, France; and Pfizer Global Research and Development (T.N., T.T., C.L.S.), New London, Conn.

Correspondence to Dr Maryse Guerin, PhD, INSERM Unité 551, Hôpital de la Pitié, Pavillon Benjamin Delessert, 83, boulevard de l’Hôpital, 75651 Paris Cedex 13, France. E-mail mguerin{at}chups.jussieu.fr

Abstract

Objective— The purpose of this study was to evaluate the impact of torcetrapib on atherogenic TG-rich lipoprotein subfractions in the postprandial phase in Type IIB hyperlipidemia.

Methods and Results— The quantitative and qualitative features of the postprandial profile of TG-rich lipoproteins were determined at baseline, after treatment for 6 weeks with 10 mg/d atorvastatin, and subsequently with an atorvastatin/torcetrapib combination (10/60 mg/d) in Type IIB patients (n=18). After ingestion of a standardized mixed meal, TG-rich lipoprotein subfractions were evaluated over 8 hours after each experimental period. On a background of atorvastatin, torcetrapib significantly attenuated the incremental postprandial area under the curve (iAUC 0 to 8 hours) for VLDL-1 (–40%), and the AUC 0 to 8 hours for VLDL-2 (-53%), with minor effect on chylomicron iAUC (–24%); concomitantly, the CE/TG ratio in both VLDL-1 and VLDL-2 was significantly reduced (–27% to –42%). Such reduction was attributable to torcetrapib-mediated attenuation of postprandial CE transfer to Chylomicrons (–17%) and VLDL-1 (–33%). Marked reduction in postprandial VLDL-1 levels was associated with apoE enrichment.

Conclusions— On a background of atorvastatin, torcetrapib attenuated the quantitative and qualitative features of the atherogenic postprandial profile of chylomicrons, VLDL-1 and VLDL-2. Such changes reflect the sum of torcetrapib-mediated effects on TG-rich lipoprotein production, intravascular remodeling, and catabolism.

CETP inhibition via torcetrapib, on a background of atorvastatin, reduces the postprandial accumulation of atherogenic triglyceride-rich subspecies including chylomicrons and VLDL-1 in type IIB hyperlipidemia, but equally attenuates their atherogenicity by reducing core CE content.

Key Words: CETP • Torcetrapib • high-density lipoprotein • postprandial hypertriglyceridemia

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