CETP inhibitors and cardiovascular disease: Time to think again.

Inhibition of cholesteryl ester transfer protein (CETP) lowers plasma low-density lipoprotein cholesterol concentration and raises high-density lipoprotein (HDL) cholesterol, suggesting it might prevent cardiovascular disease (CVD). From the outset, however, the concept has been controversial owing to uncertainty about its effects on HDL function and reverse cholesterol transport (RCT). Although there has long been good evidence that CETP inhibition reduces atherosclerosis in rabbits, the first information on CETP as a CVD risk factor in a prospectively followed cohort was not published until after the first Phase 3 trial of a CETP inhibitor had begun. The worrying finding that CVD incidence was related inversely to plasma CETP has since been reproduced in each of five further prospective cohort studies. Similar results were obtained in subjects on or off statin therapy, for first and second CVD events, and for mortality as well as CVD morbidity. Additionally, two recent studies have found alleles of the CETP gene that lower hepatic CETP secretion to be associated with an increased risk of myocardial infarction. Meanwhile, CETP gene transfer in mice was found to increase RCT from peripheral macrophages in vivo, and human plasma with high CETP activity was shown to have a greater capacity to remove cholesterol from cultured cells than plasma with low activity. This mounting evidence for a protective function of CETP has been given remarkably little attention, and indeed was not mentioned in several recent reviews.  It appears to show that CETP inhibition does not test the HDL hypothesis as originally hoped, and raises a pressing ethical issue regarding two Phase 3 trials of inhibitors, involving more than forty thousand subjects, which are currently in progress. As the weight of evidence now clearly supports an adverse effect of CETP inhibition on CVD, an urgent review is needed to determine if these trials should be discontinued.