Cholesteryl Ester Transfer Protein Inhibition for Preventing Cardiovascular Events: JACC Review Topic of the Week

Abstract

Cholesteryl ester transfer protein (CETP) facilitates exchange of triglycerides and cholesteryl ester between high-density lipoprotein (HDL) and apolipoprotein B100-containing lipoproteins. Evidence from genetic studies that variants in the CETP gene were associated with higher blood HDL cholesterol, lower low-density lipoprotein cholesterol, and lower risk of coronary heart disease suggested that pharmacological inhibition of CETP may be beneficial. To date, 4 CETP inhibitors have entered phase 3 cardiovascular outcome trials. Torcetrapib was withdrawn due to unanticipated off-target effects that increased risk of death, and major trials of dalcetrapib and evacetrapib were terminated early for futility. In the 30,000-patient REVEAL (Randomized Evaluation of the Effects of Anacetrapib through Lipid Modification) trial, anacetrapib doubled HDL cholesterol, reduced non-HDL cholesterol by 17 mg/dl (0.44 mmol/l), and reduced major vascular events by 9% over 4 years, but anaceptrapib was found to accumulate in adipose tissue, and regulatory approval is not being sought. Therefore, despite considerable initial promise, CETP inhibition provides insufficient cardiovascular benefit for routine use.

Keywords: CETP; CETP inhibitor; HDL cholesterol; LDL cholesterol; Mendelian randomization; cardiovascular disease; randomized trial.

Graphical abstract

Central Illustration

Effects of Cholesteryl Ester Transfer Protein Inhibitors and Genetic Variants on Major Cardiovascular Outcomes in the Context of Relevant Observational Epidemiology and Statin Therapy ↑ = increase; ↓ = decrease; ↔ = unchanged; BP = blood pressure; CETP = cholesteryl ester transfer protein; HDL-C = high-density lipoprotein cholesterol; HMG CoA = 3-hydroxy-3-methyl-glutaryl-coenzyme A; HMGCR = HMG CoA reductase; LDL-C = low-density lipoprotein cholesterol; MVE = major vascular events; N/A = not available; OR = odds ratio.

Figure 1

The role of CETP in Lipid Metabolism and the Effect of CETP Inhibition on Circulating Lipoproteins (A) CETP in lipid metabolism and (B) the effect of CETP inhibition on circulating lipoprotein. CE = cholesteryl ester; CETP = cholesteryl ester transfer protein, HDL = high-density lipoprotein; IDL = intermediate-density lipoprotein; LDL = low-density lipoprotein; trig = triglycerides; VLDL = very low-density lipoprotein.

Figure 2

Associations of Clinical Trials of Lipid-Modifying Therapies, the Corresponding Genetic Proxies, and Risk of Coronary Heart Disease Clinical trials results are scaled to a 40-mg/dl lower non–HDL cholesterol and genetic associations are scaled to a 40-mg/dl lower apolipoprotein B100. Clinical trial data are taken from the original trials, with the exception of the CTT estimate, which is derived from Supplementary Figure 5 of the REVEAL trial. Genetic data are obtained from Ference et al. . Endpoints for the clinical trials are: 1) REVEAL: myocardial infarction or coronary death; 2) FOURIER: myocardial infarction; 3) CTT: myocardial infarction or coronary death; and 4) IMPROVE-IT: myocardial infarction. Endpoints for the genetic estimates are myocardial infarction, coronary death, coronary revascularization, or stroke. apo B = apolipoprotein B100; CTT = Cholesterol Treatment Trialists Collaboration; HMGCR = HMG CoA reductase; NPC1L1 = Niemann-Pick C1-Like 1; OR = odds ratio; PCSK9 = Proprotein Convertase Subtilisin/Kexin type 9; other abbreviations as in Figure 1.