Torcetrapib
Torcetrapib produces smaller but more inflamed, less stable plaques than atorvastatin in humanized transgenic mice (Circulation 2008)
Original title: Torcetrapib does not reduce atherosclerosis beyond atorvastatin and induces more proinflammatory lesions than atorvastatin
Following the finding of the ILLUMINATE trial that torcetrapib added to atorvastatin had no effect on atherosclerosis and increased cardiovascular death, researchers evaluated the antiatherogenic potential and adverse effects of torcetrapib in humanized APOE*3-Leiden.CETP mice fed a cholesterol-rich diet for 14 weeks with no drug, torcetrapib, atorvastatin, or both. Torcetrapib reduced CETP activity by 74% and 73% with and without atorvastatin (p < 0.001), lowered plasma cholesterol by 20% (less than the 42% seen with atorvastatin or the 40% combination effect), and raised HDL cholesterol by 30% and 34% alone and with atorvastatin. Torcetrapib and atorvastatin alone each reduced atherosclerotic lesion size by roughly 43-46%, but the combination did not reduce lesions further than atorvastatin alone. Compared with atorvastatin, torcetrapib increased monocyte recruitment and monocyte chemoattractant protein-1 expression and produced lesions with more macrophage content and less collagen, a more inflammatory, less stable phenotype.
Original 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 x kg(-1) x d(-1)), atorvastatin (2.8 mg x kg(-1) x 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.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.