Cholesteryl Ester Transfer Protein Inhibitors and Cardiovascular Outcomes: A Systematic Review and Meta-Analysis

Abstract

Background: Atherosclerosis is a multi-factorial disease, and low-density lipoprotein cholesterol (LDL-C) is a critical risk factor in developing atherosclerotic cardiovascular disease (ASCVD). Cholesteryl-ester transfer-protein (CETP), synthesized by the liver, regulates LDL-C and high-density lipoprotein cholesterol (HDL-C) through the bidirectional transfer of lipids. The novelty of CETP inhibitors (CETPis) has granted new focus towards increasing HDL-C, besides lowering LDL-C strategies. To date, five CETPis that are projected to improve lipid profiles, torcetrapib, dalcetrapib, evacetrapib, anacetrapib, and obicetrapib, have reached late-stage clinical development for ASCVD risk reduction. Early trials failed to reduce atherosclerotic cardiovascular occurrences. Given the advent of some recent large-scale clinical trials (ACCELERATE, HPS3/TIMI55-REVEAL Collaborative Group), conducting a meta-analysis is essential to investigate CETPis' efficacy.

Methods: We conducted a thorough search of randomized controlled trials (RCTs) that commenced between 2003 and 2023; CETPi versus placebo studies with a ≥6-month follow-up and defined outcomes were eligible.

Primary outcomes: major adverse cardiovascular events (MACEs), cardiovascular disease (CVD)-related mortality, all-cause mortality.

Secondary outcomes: stroke, revascularization, hospitalization due to acute coronary syndrome, myocardial infarction (MI).

Results: Nine RCTs revealed that the use of a CETPi significantly reduced CVD-related mortality (RR = 0.89; 95% CI: 0.81-0.98; p = 0.02; I2 = 0%); the same studies also reduced the risk of MI (RR = 0.92; 95% CI: 0.86-0.98; p = 0.01; I2 = 0%), which was primarily attributed to anacetrapib. The use of a CETPi did not reduce the likelihood any other outcomes.

Conclusions: Our meta-analysis shows, for the first time, that CETPis are associated with reduced CVD-related mortality and MI.

Keywords: CETP inhibitors; HDL-C lipoproteins; LDL-C lipoproteins; anacetrapib; atherosclerosis; cholesterol ester transfer protein; dalceprapib; evacetrapib; obicetrapib; torcetrapib.

Figure 1

PRISMA flow diagram.

Figure 2

Forest plot of MACEs outcome [10,27,29,33,34,35,36,37,38,39,40] *. The values of each study (represented by black diamonds), in which the size is determined by 95% CI; the effect size of each individual study in the meta-analysis (represented by blue squares).

Figure 3

Forest plot of CVD mortality outcome [10,27,29,33,35,36,37,38,40] *. The values of each study (represented by black diamonds), in which the size is determined by 95% CI; the effect size of each individual study in the meta-analysis (represented by blue squares).

Figure 4

Forest plot of the all-cause mortality outcome [10,27,29,33,34,35,36,37,38,39,40] *. The values of each study (represented by black diamonds), in which the size is determined by 95% CI; the effect size of each individual study in the meta-analysis (represented by blue squares).

Figure 5

Forest plot of the myocardial infarction outcome [10,27,29,33,35,36,37,38,40] *. The values of each study (represented by black diamonds), in which the size is determined by 95% CI; the effect size of each individual study in the meta-analysis (represented by blue squares).