The failure of torcetrapib: was it the molecule or the mechanism?

Hopes have been running high that treatments aimed at raising HDL levels would soon help to reduce the large burden of cardiovascular disease that remains in patients at high risk of CHD who are now treated with statins. The unexpected and premature termination of the ILLUMINATE study has dashed those hopes. This study was designed to determine the clinical outcome of raising HDL by treatment with the CETP inhibitor torcetrapib in combination with atorvastatin. It had enrolled approximately 15 000 patients at high CHD risk who were randomized to treatment with torcetrapib (60 mg) plus atorvastatin versus atorvastatin alone (10 to 80 mg). As reported in the Wall Street Journal (Dec 4th), the study was terminated abruptly and unexpectedly after a little more than a year of treatment, because of an excess of deaths in the torcetrapib/atorvastatin versus atorvastatin groups (82 versus 51, respectively). Increases in heart failure, angina, and revascularization procedures were also observed. So is this the awakening from a dream of a highly effective way to raise HDL, or is it simply a nightmare created by unintended pharmacological effects of this particular CETP inhibitor? There is no clear answer to this question yet, but it is of interest to trace the development of CETP inhibitors, to reflect on the potential underlying reasons for the failure, and to ask if there is a way forward. The idea of inhibiting CETP as a therapy to increase HDL and lower LDL levels emerged from studies that elucidated human genetic deficiency of CETP in the Japanese population.1,2 Heterozygotes with about 40% reductions in CETP had mean 30% increases in HDL levels and no changes in LDL-C, whereas homozygotes with complete deficiency had HDL increases of more than 100%, and 40% decreases in LDL-C and apoB levels, as well as decreased VLDL and IDL cholesterol levels, compared with unaffected family members.2,3 The HDL accumulating in CETP-deficient subjects was predominantly a larger HDL-2 particle, reflecting the decreased removal of HDL CE and slower catabolism of apoA-1.4 Although the lipoprotein profile resulting from genetic CETP deficiency was clear, it proved much more difficult to define the relationship between CETP deficiency and CHD. The existence of CHD in some CETP-deficient individuals with high HDL and multiple risk factors was clearly documented.5 A cross-sectional population study of elderly men (mean age 78) of Japanese ancestry living in Hawaii showed an increased risk of definite CHD (MI, angina and revascularization) among 193 individuals heterozygous for CETP gene mutations, compared with 3276 wild-type controls.6 After adjustment for other risk factors the excess overall risk was moderate (RR 1.55, P 0.024), and was concentrated among men with mutations and HDL-C 60 mg/dL; men with HDL-C 60 mg/dL enjoyed a similar low prevalence of CHD, whether they had mutations or not. Among men with mutations, plasma CETP levels were reduced by 35% and the mean increase in HDL-C was about 10%, whereas there was no change in LDL-C. After exclusion of men with CHD, a subsequent prospective 10-year analysis of the remaining very elderly men (n 2340, 118 with mutations) showed a nonsignificant trend to lower CHD incidence in men with CETP mutations compared with the wild-type controls.7 Although the results of CETP SNP-CHD association studies in Caucasian populations have yielded mixed results, a meta-analysis suggested that the CETP Taq1B polymorphism located in the first intron is associated with higher HDL levels and reduced CHD.8 In summary, although the earlier studies on genetic CETP deficiency suggested some concern that deficiency might result in increased CHD,5,6 these studies had limited statistical power and were neither clearly confirmed nor refuted in subsequent work.7,8 The relationship of CETP to atherosclerosis in animal studies also provided a mixed picture. Mice normally lack CETP and in CETP transgenic mouse models, CETP activity led to variable atherosclerosis results, while in rabbits CETP inhibition consistently led to reduced atherosclerosis. In the standard LDLR or apoE knock-out mouse atherosclerosis models, introduction of a CETP transgene led to a moderate less than 2-fold increase in atherosclerosis,9 whereas in the apoE*3 (Leiden) background, the increase in atherosclerosis was dramatic.10 However, in mice with hypertriglyceridemia attributable to apoCIII transgene overexpression, CETP activity led to either no change or a reduction in atherosclerosis.11 Moreover, in a “humanized” transgenic mouse with combined hyperlipidemia, containing human apoA-1, apoCIII, and LDLR KO transgenes, CETP expression markedly reduced overall HDL levels, increased small HDL particles, and increased non-HDL cholesterol but did not increase atherosclerosis.12 These findings are of interest because in the setting of hypertriglyceridemia, CETP activity leads to profound remodeling of HDL particles, especially on a human apoA-1 transgenic background, apparently leading to release of lipid-poor apoA-1.13 This is a dynamic in vivo process that depends on a continuous cycle of CETP-mediated exchange of VLDL TG for HDL-CE, followed by activity of hepatic From the College of Physicians and Surgeons, Columbia University, New York. Correspondence to Alan R. Tall, Columbia University, College of Physicians and Surgeons, New York, NY 10032. E-mail [email protected] (Arterioscler Thromb Vasc Biol. 2007;27:257-260.) © 2007 American Heart Association, Inc.