Published Online
on May 5, 2008

A more recent version of this article appeared on May 13, 2008

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Submitted on December 19, 2007
Accepted on March 13, 2008

Torcetrapib Does Not Reduce Atherosclerosis Beyond Atorvastatin and Induces More Proinflammatory Lesions Than Atorvastatin

Willeke de Haan MSc, Jitske de Vries-van der Weij MSc, José W.A. van der Hoorn MSc, Thomas Gautier PhD, Caroline C. van der Hoogt PhD, Marit Westerterp PhD, Johannes A. Romijn PhD, MD, J. Wouter Jukema PhD, MD, Louis M. Havekes PhD, Hans M.G. Princen PhD, and Patrick C.N. Rensen PhD^*

From the Departments of General Internal Medicine, Endocrinology, and Metabolic Diseases (W.d.H., C.C.v.d.H., M.W., J.A.R., L.M.H., P.C.N.R.), Human Genetics (J.d.V.-v.d.W.), and Cardiology (J.W.A.v.d.H., L.M.H., J.W.J.), Leiden University Medical Center, Leiden; Netherlands Organization for Applied Scientific Research–Biosciences, Gaubius Laboratory, Leiden (J.d.V.-v.d.W., J.W.A.v.d.H., L.M.H., H.M.G.P.); and Center for Liver, Digestive, and Metabolic Diseases, Department of Pediatrics, University Medical Center Groningen, Groningen (T.G.), the Netherlands.

^* To whom correspondence should be addressed. E-mail: P.C.N.Rensen{at}lumc.nl.

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^-1 · d^-1), atorvastatin (2.8 mg · kg^-1 · d^-1), 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.

Key words: atherosclerosis • cholesteryl ester transfer proteins • drugs • lipids • lipoproteins

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