Future of Cholesteryl Ester Transfer Protein (CETP) Inhibitors: A Pharmacological Perspective

In almost 30 years since the introduction of HMG-CoA reductase inhibitors (statins), no other class of lipid modulators has entered the market. Elevation of high-density lipoprotein-cholesterol (HDL-C) via inhibiting cholesteryl ester transfer protein (CETP) is an attractive strategy for reducing the risk of cardiovascular events in high-risk patients. Triglyceride and cholesteryl ester (CE) transfer between lipoproteins is mediated by CETP; thus inhibition of this pathway increases the concentration of HDL-C. Torcetrapib was the first CETP inhibitor evaluated in Phase 3 clinical trials. Because of off-target effects, torcetrapib raised blood pressure and increased the concentration of serum aldosterone leading to higher cardiovascular events and mortality. Torcetrapib showed positive effects on the cardiovascular risk especially in patients with a greater increase in HDL-C and Apolipoprotein A-1 (apoA-1) levels. The Phase 3 clinical trial of dalcetrapib, the second CETP inhibitor that has entered clinical development, was terminated because of ineffectiveness. Dalcetrapib is a CETP modulator that elevated HDL-C level but did not reduce the concentration of low-density lipoprotein cholesterol (LDL-C). Both heterotypic and homotypic CE transfer between lipoproteins are mediated by some CETP inhibitors including torcetrapib, anacetrapib and evacetrapib while dalcetrapib only affect the heterotypic CE transfer. Dalcetrapib has a chemical structure that is distinct from other CETP inhibitors with smaller molecular weight and lack of trifluoride moieties. Dalcetrapib is a pro-drug that must be hydrolyzed to a pharmacologically active thiol form. Two other CETP inhibitors, anacetrapib and evacetrapib, are currently undergoing evaluation in Phase 3 clinical trial. Both molecules have shown beneficial effects by increasing HDL-C and decreasing LDL-C concentration. The success of anacetrapib and evacetrapib will remain to be confirmed upon the completion of Phase 3 clinical trials in 2017 and 2015, respectively. Generally, the concentration of HDL-C has been considered as biomarker for the activity of CETP inhibitors. However, it is not clear whether a fundamental relationship exist between HDL-C and the risk of coronary artery diseases (CAD). The most crucial role for HDL-C is cholesterol efflux capacity in which HDL can reverse transport cholesterol from foam cells in atherosclerotic plaques. In view of the heterogeneity in HDL-C particle size, charge, and composition, the mere concentration of HDL-C may not be a good surrogate marker for HDL functionality. Recent clinical studies reported that increased HDL-C functionality inversely correlate with the development of atherosclerotic plaque. Future development of CETP inhibitors may therefore benefit from the use of biomarkers that better predict HDL functionality