Cholesteryl ester transfer protein: ace of spades, queen of hearts, or the joker?

Citation: Miller NE (2015) Cholesteryl ester transfer protein: ace of spades, queen of hearts, or the joker? Front. Pharmacol. 6:145. Plasma cholesteryl ester transfer protein (CETP) catalyzes the transfer of CEs from high-density lipoproteins (HDLs) to triglyceride-rich and low-density lipoproteins (LDLs). The hypothesis that CETP inhibition will prevent cardiovascular disease (CVD) was based on the fact that low activity increases HDL cholesterol and decreases LDL cholesterol. Early reports that CETP gene transfer increased atherosclerosis in mice, and that CETP inhibition reduced lesions in cholesterol-fed rabbits fuelled enthusiasm for the approach. Although some cautioned that the development of CETP inhibitors was premature owing to uncertainties about their impact on the remodeling of HDLs and reverse cholesterol transport (RCT) in humans (Fielding and Havel, 1996), drug discovery programmes proceeded. Two parallel research tracks then emerged. While industry progressed to clinical studies, academics sought to clarify the relations of CETP activity to RCT and atherosclerosis. Two drugs reached Phase 3 clinical trials. However, ILLUMINATE was terminated when torcetrapib was found to have had increased CVD. Five years later, Dal-OUTCOMES was aborted when it was evident dalcetrapib was not conferring any benefit. After reviewing the literature up to May 2014, Miller (2014) concluded that CETP inhibition is more likely to increase CVD than prevent it, and was of the opinion that ongoing trials should be stopped. Since then several further pertinent studies have been published. They include four meta-analyses of the Taq1B polymorphism of the CETP gene. Cao et al. (2014) concluded that B2B2 homozygotes (low CETP activity, high HDL cholesterol) have a lower risk of myocardial infarction (MI) than B1B1 subjects. Using Mendelian randomization, Wu et al. (2014) found the B2 allele to be associated with a lower risk of coronary heart disease (CHD). However, another Mendelian randomization (Niu and Qi, 2015) found the B2 allele to be associated with a higher risk of CVD than the B1 allele. In this context, an earlier meta-analysis by Dullaart and Sluiter (2008) is of interest. These authors found that B2B2 carriers were less frequent among cases drawn from samples at high CVD risk than among cases drawn from population-based samples. Furthermore, in the latter case the odds ratio for CVD was 1.45 (95% CI: 1.07–1.95) in B2B2 relative to B1B1, while in the former it was 0.84 (0.74–0.96), suggesting that in the general population the B2 allele is actually associated with higher CVD risk in …