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Torcetrapib does not reduce atherosclerosis beyond atorvastatin and induces more proinflammatory lesions than atorvastatin

Author: Haan, W. de · Vries-van der Weij, J. de · Hoorn, J.W.A. van der · Gautier, T. · Hoogt, C.C. van der · Westerterp, M. · Romijn, J.A. · Jukema, J.W. · Havekes, L.M. · Princen, H.M.G. · Rensen, P.C.N.
Type:article
Date:2008
Source:Circulation, 19, 117, 2515-2522
Identifier: 240771
doi: doi:10.1161/CIRCULATIONAHA.107.761965
Keywords: Biology · Biomedical Research · Atherosclerosis · Cholesteryl ester transfer proteins · Drugs · Lipids · Lipoproteins · Apolipoprotein E · Atorvastatin · Cholesterol · Cholesterol ester transfer protein · Collagen · High density lipoprotein cholesterol · Monocyte chemotactic protein 1 · Torcetrapib · Atherosclerosis · Cholesterol blood level · Drug activity · Evaluation · Female · Inflammation · Macrophage · Monocyte · Mouse · Nonhuman · Phenotype · Sham feeding · Statistical significance · Animals · Atherosclerosis · Cholesterol Ester Transfer Proteins · Drug Synergism · Heptanoic Acids · Inflammation · Mice · Mice, Inbred Strains · Pyrroles · Quinolines

Abstract

BACKGROUND - Although cholesteryl ester transfer protein (CETP) inhibition is regarded as a promising strategy to reduce atherosclerosis by increasing high-density lipoprotein cholesterol, the CETP inhibitor torcetrapib given in addition to atorvastatin had no effect on atherosclerosis and even increased cardiovascular death in the recent Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events trial. Therefore, we evaluated the antiatherogenic potential and adverse effects of torcetrapib in humanized APOE*3-Leiden.CETP (E3L.CETP) mice. METHODS AND RESULTS - E3L.CETP mice were fed a cholesterol-rich diet without drugs or with torcetrapib (12 mg·kg·d), atorvastatin (2.8 mg·kg·d), or both for 14 weeks. Torcetrapib decreased CETP activity in both the absence and presence of atorvastatin (-74% and -73%, respectively; P<0.001). Torcetrapib decreased plasma cholesterol (-20%; P<0.01), albeit to a lesser extent than atorvastatin (-42%; P<0.001) or the combination of torcetrapib and atorvastatin (-40%; P<0.001). Torcetrapib increased high-density lipoprotein cholesterol in the absence (30%) and presence (34%) of atorvastatin. Torcetrapib and atorvastatin alone reduced atherosclerotic lesion size (-43% and -46%; P<0.05), but combination therapy did not reduce atherosclerosis compared with atorvastatin alone. Remarkably, compared with atorvastatin, torcetrapib enhanced monocyte recruitment and expression of monocyte chemoattractant protein-1 and resulted in lesions of a more inflammatory phenotype, as reflected by an increased macrophage content and reduced collagen content. CONCLUSIONS - CETP inhibition by torcetrapib per se reduces atherosclerotic lesion size but does not enhance the antiatherogenic potential of atorvastatin. However, compared with atorvastatin, torcetrapib introduces lesions of a less stable phenotype. © 2008 American Heart Association, Inc. Chemicals / CAS: atorvastatin, 134523-00-5, 134523-03-8; cholesterol, 57-88-5; collagen, 9007-34-5; torcetrapib, 262352-17-0; atorvastatin, 110862-48-1; Cholesterol Ester Transfer Proteins; Heptanoic Acids; Pyrroles; Quinolines; torcetrapib, 262352-17-0