Cholesteryl ester transfer protein inhibitors: from high-density lipoprotein cholesterol to low-density lipoprotein cholesterol lowering agents?

Abstract

Cholesteryl ester transfer protein (CETP) is a liver-synthesized glycoprotein whose main functions are facilitating transfer of both cholesteryl esters from high-density lipoprotein (HDL) particles to apolipoprotein B (apoB)-containing particles as well as transfer of triglycerides from apoB-containing particles to HDL particles. Novel crystallographic data have shown that CETP exchanges lipids in the circulation by a dual molecular mechanism. Recently, it has been suggested that the atherosclerotic cardiovascular disease (ASCVD) benefit from CETP inhibition is the consequence of the achieved low-density lipoprotein cholesterol (LDL-C) and apoB reduction, rather than through the HDL cholesterol (HDL-C) increase. The use of CETP inhibitors is supported by genetic evidence from Mendelian randomization studies, showing that LDL-C lowering by CETP gene variants achieves equal ASCVD risk reduction as LDL-C lowering through gene proxies for statins, ezetimibe, and proprotein convertase subtilisin-kexin Type 9 inhibitors. Although first-generation CETP inhibitors (torcetrapib, dalcetrapib) were mainly raising HDL-C or had off-target effects, next generation CETP inhibitors (anacetrapib, evacetrapib) were also effective in reducing LDL-C and apoB and have been proven safe. Anacetrapib was the first CETP inhibitor to be proven effective in reducing ASCVD risk. In addition, CETP inhibitors have been shown to lower the risk of new-onset diabetes, improve glucose tolerance, and insulin sensitivity. The newest-generation CETP inhibitor obicetrapib, specifically designed to lower LDL-C and apoB, has achieved significant reductions of LDL-C up to 45%. Obicetrapib, about to enter phase III development, could become the first CETP inhibitor as add-on therapy for patients not reaching their guideline LDL-C targets.

Keywords: ASCVD; CETP inhibitor; HDL-C; LDL-C; CETP.

Figure 1

Overview of working mechanisms of CETP inhibition and traditional lipid-lowering therapies. Simplified overview of cholesterol metabolism. Cholesteryl ester transfer protein (CETP) facilitates transfer of cholesteryl esters (CE) and triglycerides (TG) between lipoproteins. Transfer of CE to VLDL particles contributes to maturation to LDL particles, which contribute to foam cell formation in the atherosclerotic plaque. Cholesteryl ester transfer protein inhibitors (CETPi) impair transfer of cholesterol esters from high-density lipoprotein (HDL) to apoB particles and transfer of triglycerides from apoB to HDL particles. Proprotein convertase subtilisin–kexin Type 9 inhibiting (PCSK9i) monoclonal antibodies block PCSK9 binding to low-density lipoprotein receptor (LDLR). Statins block 3-hydroxy-3-methylglutaryl coenzyme reductase (HMGCR). Ezetimibe inhibits Niemann-Pick-like protein 1C1 (NPC1L1), preventing transport of sterols into enterocytes.

Figure 2

Mechanisms of cholesteryl esters and triglycerides transfer by CETP. CETP facilitates bidirectional transfer of cholesteryl esters and triglycerides via two known mechanisms. The first (A) is a shuttle mechanism where CETP binds a lipoprotein (shown is HDL) particle, exchanging cholesteryl esters and triglycerides (for HDL: cholesteryl esters out, triglycerides in). After detaching, the CETP molecule binds to a second lipoprotein particle (shown is LDL/VLDL), again exchanging cholesteryl esters and triglycerides (for LDL/VLDL: cholesteryl esters in, triglycerides out). The second (B) mechanism is a tunnel mechanism. The N-terminal domain binds to an HDL particle forming a CETP–HDL complex, which binds to either an LDL or VLDL particle through the C-terminal domain, forming a ternary complex between HDL, CETP, and LDL or VLDL. CETP, cholesteryl ester transfer protein; HDL, high-density lipoprotein; LDL, low-density lipoprotein; VLDL, very low-density lipoprotein.

Figure 3

REVEAL trial and statins in the CTT meta-analysis. Reduction in rate of coronary death or myocardial infarction from the REVEAL trial, compared reduction in statin trials from the CTT, plotted according to the size of the absolute reduction in non-HDL cholesterol. Adapted from Bowman et al., Copyright © 2021 Massachusetts Medical Society. Reprinted with permission from REVEAL, Randomized EValuation of the Effects of Anacetrapib through Lipid-modification. CTT, Cholesterol Treatment Trialists’; HDL, high-density lipoprotein.

Figure 4

REVEAL—components of major coronary event during 6.4 years of follow-up. Depicted is the primary outcome and its components of the in-trial and post-trial follow-up of the REVEAL study. Adapted from REVEAL Collaborative Group, MDP477. The Effects of Anacetrapib Therapy on Occlusive Vascular Events During Post-Trial Follow-Up of the REVEAL Randomized Trial, 2019 American Heart Association Scientific Sessions. Reprinted with permission from REVEAL, Randomized EValuation of the Effects of Anacetrapib through Lipid-modification.

Figure 5

REVEAL—effect on mortality during 6.4 years of follow-up. Depicted are the secondary outcomes and their components of the post-trial follow-up of the REVEAL study. Adapted from REVEAL Collaborative Group, MDP477. The Effects of Anacetrapib Therapy on Occlusive Vascular Events During Post-Trial Follow-Up of the REVEAL Randomized Trial, 2019 American Heart Association Scientific Sessions. Reprinted with permission from REVEAL, Randomized EValuation of the Effects of Anacetrapib through Lipid-modification.