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

摘要

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 spite of the higher HDL cholesterol. Regieli et al. ( 2008 ) had come to a similar conclusion in the REGRESS study. After following 812 men with CHD on statins for 10 years, the B2 allele was associated with a hazard ratio for CVD death of 1.59 ( P = 0.01) despite the expected low CETP activity and high HDL cholesterol.Four additional meta-analyses looked at the impact of CETP inhibitors on CVD risk as part of larger studies of the effects of HDL cholesterol-raising agents in patients taking statins. All four concluded that the trials have not demonstrated a beneficial effect (Keene et al., 2014 ; Hourcade-Potelleret et al., 2015 ; Ip et al., 2015 ; Verdoia et al., 2015 ). In clinical studies, Gu et al. ( 2014 ) reported that although the A allele of the ?629°C/A polymorphism of the CETP gene was associated with a lower plasma CETP concentration than the C allele, it had not reduced CVD events in patients taking atorvastatin. Kastelein et al. ( 2015 ) observed no significant effect of anacetrapib on CVD incidence (four events vs. zero in the treated and placebo groups, respectively) during 12 months of follow-up in patients with heterozygous familial hypercholesterolemia already on lipid-lowering treatment. Scharnagl et al. ( 2014 ) confirmed earlier reports that human plasma samples with low CETP concentrations were less effective in promoting cholesterol efflux from cultured macrophages than samples with high concentrations. In animal studies, Kühnast et al. ( 2015 ) found that anacetrapib reduced atherosclerosis in APOE~(*)3Leiden.CETP transgenic mice. Briand et al. ( 2014 ) compared anacetrapib with dalcetrapib in hamsters, a species with natural CETP. In normal animals, neither drug at doses equipotent for CETP inhibition (by 60%) had any effect on macrophage-to-feces RCT, although they did lower equally the fractional clearance rate of HDL-CE. In dyslipidaemic animals, anacetrapib increased RCT, whereas an equipotent dose of dalcetrapib reduced it. Liu et al. ( 2015 ) found that inhibition of DNA topoisomerase II (Topo II) by etoposide, tenipooside or Topo II siRNA increased CETP gene expression and CETP secretion in HepG2 cells. When given to CETP transgenic mice, teniposide induced CETP expression in the liver, and increased macrophage-to-feces RCT to a greater degree than in wild-type mice with no CETP. Using a computer model of lipoprotein metabolism to analyze the on/off kinetics of the short-acting potent CETP inhibitor RG7232, Lu et al. (