Recently published results of large clinical trials have shown that although the cholesteryl ester transfer protein (CETP) inhibitor torcetrapib had a positive effect on plasma HDL cholesterol level, torcetrapib failed to improve atherosclerosis. In order to investigate the possible antiatherogenic vs. adverse effects of torcetrapib in humanized APOE*3-Leiden. CETP transgenic mice, de Haan et al. treated mice with atorvastatin, torcetrapib, or both for 14 weeks. As expected, they reported that torcetrapib decreased CETP activity and increased HDL cholesterol levels. However, mice treated with torcetrapib had an increased expression of monocyte chemoattractant protein-1, which enhanced monocyte recruitment. Consequently, those mice had atherosclerotic lesions containing more macrophages and less collagen and therefore were characterized by “unstable” plaques. Based on the observation that torcetrapib induced a regression of the atheroma, but that this atheroma was less stable and more “inflamed”, the authors suggested that this mechanism could partly explain why CETP inhibition was tied to increased cardiovascular deaths in humans.
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