Investigational CETP antagonists for hyperlipidemia and atherosclerosis prevention

Reverse cholesterol transport (RCT) is a function of high-density lipoproteins (HDL) in humans and higher species. It is enabled by the cholesteryl ester transfer protein (CETP), a high molecular weight protein exchanging cholesteryl esters in HDL for triglycerides in very low-density lipoproteins (VLDL). Inhibition of CETP may provide a useful strategy to raise HDL, the protective lipoprotein fraction in plasma.

Evaluation based on clinical and experimental findings of the three drugs developed or in advanced development for CETP inhibition.

Inhibition of CETP, both inherited and drug induced, at times leads to dramatic elevations of HDL-cholesterol (HDL-C) levels. Epidemiological data presently available do not, however, provide convincing evidence that reduced CETP levels or activity due to genetic factors and associated with HDL-C elevations, reduce cardiovascular risk. Indeed, the opposite may be true in some instances. All the three CETP inhibitors were the object of experimental and clinical evaluation. Large clinical trials with torcetrapib led to very negative findings, that is, raised cardiovascular morbidity and mortality in addition to raised risk of cancer and sepsis. Off-target effects of the drug, such as aldosterone retention and raised blood pressure, were believed to provide an explanation for these negative findings. The two newer agents, dalcetrapib and anacetrapib, do not exert off-target effects. The two drugs differ because anacetrapib has a more dramatic effect on HDL cholesterolemia (+139%) versus more moderate effects of dalcetrapib (+20-30%). Anacetrapib, however, may impair formation of pre-β HDL, that is, the primary particles in the process of cholesterol removal. The initial large trial with anacetrapib (DEFINE study) in coronary patients on statin treatment, appeared to confirm a remarkable HDL raising property, together with some reduction in vascular end points, in particular coronary procedures. The issue of other potentially harmful effects of CETP inhibition (sepsis and others) has yet to be clarified. Large clinical end-point trials, however, will be necessary to provide convincing evidence that, in addition to raising HDL-C, CETP inhibitors provide a valid additional treatment, for example, to statins in patients with coronary heart disease (CHD) or at high risk of CHD.