CETP inhibitors and cardiovascular disease: Time to think again

Abstract

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.

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“…The first observational prospective cohort study that has proven the role of CETP as a risk factor for cardiovascular diseases (CVDs) was in 2006. After that, CETP inhibitors have been evaluated in several randomized controlled trials . Elevated CETP levels were found to associate with dyslipidemia of metabolic diseases, insulin resistance, hypertriglyceridemia, and ultimately with premature atherosclerosis .…”

“…After that, CETP inhibitors have been evaluated in several randomized controlled trials. 32 Elevated CETP levels were found to associate with dyslipidemia of metabolic diseases, insulin resistance, hypertriglyceridemia, and ultimately with premature atherosclerosis. 33 The concept of CETP inhibition came into the field of atherosclerosis because of its immense potential to increase HDL level and also its anti-atherosclerotic activities.…”

The controversy over the use of cholesteryl ester transfer protein inhibitors: is there some light at the end of the tunnel?

“…Although the elevation of plasma high‐density lipoprotein (HDL) protects against atherosclerosis by mechanisms involving cellular removal of cholesterol, inhibition of oxidation, apoptosis, inflammation and restoration of endothelial function, raising HDL by inhibiting CETP has not been effective in the prevention of coronary vascular disease (CVD) . Nonetheless, although the elevation of HDL by inhibitors of CETP and niacin has increased activity on cellular cholesterol efflux and anti‐inflammatory properties , besides reducing concentrations of pro‐atherogenic lipoproteins (apoB‐LP), these pharmacological interventions have failed in preventing human atherosclerosis.…”

“…Higher frequency rate of cardiovascular disease was related to both high and low CETP concentration or CETP mRNA . However, in a 2014 review, Miller listed six population investigations where the concentration of CETP in plasma was reciprocally related to cardiovascular disease (CVD). On the other hand, a meta‐analysis by Thomson in 2008 , including 46 studies, concluded that CETP genotypes that are associated with moderate inhibition of the CETP activity showed weakly inverse correlation with coronary artery disease risk.…”

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

“…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.…”