Cholesteryl ester transfer protein inhibition as a strategy to reduce cardiovascular risk

Abstract

Human and rabbit plasma contain a cholesteryl ester transfer protein (CETP) that promotes net mass transfers of cholesteryl esters from high density lipoproteins (HDL) to other plasma lipoprotein fractions. As predicted, inhibition of CETP in both humans and rabbits increases the concentration of cholesterol in the potentially protective HDL fraction, while decreasing it in potentially proatherogenic non-HDL fractions. Inhibition of CETP in rabbits also inhibits the development of diet-induced atherosclerosis. However, use of the CETP inhibitor torcetrapib in humans did not reduce atheroma in three imaging trials and caused an excess of deaths and cardiovascular events in a large clinical outcome trial. The precise explanation for the harm caused by torcetrapib is unknown but may relate to documented, potentially harmful effects unrelated to inhibition of CETP. More recently, a trial using the weak CETP inhibitor dalcetrapib, which raises HDL levels less effectively than torcetrapib and does not lower non-HDL lipoprotein levels, was terminated early for reasons of futility. There was no evidence that dalcetrapib caused harm in that trial. Despite these setbacks, the hypothesis that CETP inhibitors will be antiatherogenic in humans is still being tested in studies with anacetrapib and evacetrapib, two CETP inhibitors that are much more potent than dalcetrapib and that do not share the off-target adverse effects of torcetrapib.

Fig. 1.

Proposed shuttle mechanism for cholesteryl ester transfer by CETP. CETP collides randomly with particles in all lipoprotein fractions to form transient complexes that facilitate an exchange of both CE and TG between the lipoprotein particles and CETP. The CETP (with its associated CE and TG) subsequently dissociates from lipoprotein particles to circulate in a free state until it collides with another lipoprotein particle (either in the same or in a different lipoprotein fraction) to form a new transient complex with further exchange of CE and TG between lipoprotein particle and CETP molecule. In this way, CETP promotes an equilibration of both CE and TG between all lipoprotein particles.

Fig. 2.

Proposed tunnel mechanism for cholesteryl ester transfer by CETP. The N-terminal of CETP initially penetrates the HDL surface and forms a binary complex in which the CETP interacts with the cholesteryl ester core of HDL. The binary complex then interacts with LDL or VLDL via the C-terminal domain of CETP to form a ternary complex consisting of HDL, CETP, and VLDL/LDL. Molecular forces introduced by the lipoproteins at either end of the CETP molecule cause twisting of the CETP molecule that results in the formation of a tunnel through which cholesteryl esters are transferred from HDL to LDL or VLDL. The ternary complex then dissociates to form VLDL/LDL particles that are enriched in cholesteryl esters and HDL particles that are depleted of cholesteryl esters and reduced in size.

Fig. 3.

Net effect of CETP on plasma lipoproteins. As most of the CE in plasma originates in HDL in the LCAT reaction, while the majority of the triglyceride enters plasma as a component of TRL, the net effect of the equilibration promoted by CETP as shown in Fig. 1 is a mass transfer of CE from HDL to LDL and TRL and of TG from TRL to HDL.

Fig. 4.

Protective properties of HDL. HDL has multiple properties with the potential to protect against the development of atherosclerosis.

Fig. 5.

Effects of torcetrapib on diabetic control. The ILLUMINATE trial included 6,661 patients with type 2 diabetes. At baseline, there were no differences between the two treatment arms with respect to plasma glucose, insulin, HbA1C, or HOMA-IR. Compared with the patients taking atorvastatin alone (A), those taking the combination of torcetrapib plus atorvastatin (T/A) had a highly significant improvement in diabetic control.

Fig. 6.

Cardiovascular end points in the DEFINE (31) and ILLUMINATE (3) trials. The hazard ratios and 95% confidence intervals are shown. The primary end point in ILLUMINATE was time to first occurrence of a major cardiovascular event (MCVE), comprising a composite of death from coronary heart disease, nonfatal myocardial infarction, stroke, and hospitalization for unstable angina. A pre-specified end point in DEFINE was time to first occurrence of a MCVE, comprising death from cardiovascular causes, nonfatal myocardial infarction, hospitalization for unstable angina, and nonfatal stroke. CETP-I, CETP inhibitor.