Cholesteryl ester transfer protein inhibition and endothelial function: enough with the surrogates

This editorial refers to ‘Vascular effects and safety of dalcetrapib in patients with or at risk of coronary heart disease: the dal-VESSEL randomized clinical trial’, by T.F. Luscher et al. , doi:10.1093/eurheartj/ehs019 Statins significantly reduce cardiovascular events in a broad category of patients at risk for or with established atherosclerotic cardiovascular disease; however, a substantial residual risk remains even when LDL-cholesterol (LDL-C) levels are lowered to 70 mg/dL.1 A part of this residual risk is related to low HDL-C levels.1 Epidemiological studies, the known favourable biological actions of HDL and its key constituents, as well as experimental studies have suggested beneficial athero-protective effects of HDL, making HDL a suitable therapeutic target.2 However, unlike LDL-C lowering, HDL-C-raising interventions with currently available agents, such as niacin, fibrates, or peroxisome proliferator-activated receptor γ agonists, have not been conclusively or consistently demonstrated to reduce cardiovascular events.3 In the last several years, inhibition of a key enzyme, CETP (cholesteryl ester transfer protein), involved in HDL metabolism, has become a focus of attention since CETP inhibition leads to increases in HDL-C levels.4CETP is a glycoprotein, present in humans, rabbits, primates, and hamsters, but absent in rodents, dogs, horses, cows, and pigs, that facilitates transfer of cholesterol ester from HDL particles to LDL/very low-density lipoprotein (VLDL) particles in exchange for triglycerides, thereby participating in reverse cholesterol transport and regulating circulating HDL-C levels.4 Recent observations have also highlighted the fact that CETP remodels HDL particles to generate pre-β-HDL particles that participate as initial acceptors of ABCA-1-mediated cholesterol transfer from peripheral tissues.5 Despite the inverse relationship between CETP activity and HDL-C levels, epidemiological and genetic association studies have provided somewhat conflicting and inconsistent results with respect to the relationship between CETP activity and coronary heart disease (CHD) risk.4,6 Therefore, …