As shown in this Figure, there are 2 further research results that should be borne in mind when reviewing the negative results from the clinical endpoint and imaging investigations with the first CETP inhibitor, torcetrapib.
An earlier paper by Matsuura et al[17] found that for people who were genetically deficient in CETP, their HDL particles had an enhanced ability to efflux cholesterol from macrophages in ApoE- and ABCG1 transporter-dependent pathways. In other words, in these genetically CETP-deficient humans, the HDL particles do not have impaired functionality; in fact, they have an enhanced functionality.
A second consideration comes from further analysis of the ILLUMINATE results, which revealed that despite the off-target, negative mortality effects of torcetrapib, nevertheless the drug showed a dose-dependent benefit for cholesterol efflux. As reported by Yvan- Charvet et al,[18] following CETP inhibition with 60 mg of torcetrapib, those patients’ HDL showed an increased ability to promote net cholesterol efflux, and this effect was “dramatically” increased at the 120 mg dose of torcetrapib – again, demonstrating increased HDL particle functionality with CETP inhibition.
J Clin Lipidol. 2011; 5(6).[17]Matsuura F, Want N, Wengen Chen, et al. HDL from CETP-deficient subjects shows enhanced ability to promote cholesterol efflux from macrophages in an apoE- and ABCG1-dependent pathway. J Clin Invest 2006: 116(5): 1435-1441.
[18]Yvan-Charvet L, Matsuura F, Wang N, et al. Inhibition of Cholesteryl Ester Transfer Protein by Torcetrapib Modestly Increases Macrophage Cholesterol Efflux to HDL. Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:1132
