The class
Yamashita argues CETP inhibition may backfire by generating small dense LDL and downregulating hepatic SR-BI (Curr Opin Lipidol 2016)
Original title: Re-evaluation of cholesteryl ester transfer protein function in atherosclerosis based upon genetics and pharmacological manipulation
This review re-evaluates the function of plasma CETP in atherosclerosis using recent human genetics and pharmacological manipulation findings. CETP transfers cholesteryl ester from HDL to apoB-containing lipoproteins, a key step of reverse cholesterol transport, and CETP inhibitors were developed to raise HDL-C and cut cardiovascular events. However, outcome trials of torcetrapib, dalcetrapib, and evacetrapib were all prematurely terminated for increased mortality or futility despite marked HDL-C increases and LDL-C decreases (except with dalcetrapib). CETP-deficient patients show striking HDL and LDL changes, sometimes with atherosclerotic disease, and recent prospective epidemiological studies suggested atheroprotective roles for CETP. The review argues CETP inhibition induces small dense LDL formation, possibly dysfunctional HDL, and downregulates hepatic scavenger receptor class B type I (SR-BI), potentially disrupting LDL-receptor- and SR-BI-mediated cholesterol delivery to the liver, and concludes that enhancing reverse cholesterol transport via CETP and SR-BI activation, or inducing apoA-I/HDL production, may be a more promising future strategy than CETP inhibition.
Original abstract
Purpose Of Review: To re-evaluate the functions of plasma cholesteryl ester transfer protein (CETP) in atherosclerosis based upon recent findings from human genetics and pharmacological CETP manipulation.
Recent Findings: CETP is involved in the transfer of cholesteryl ester from HDL to apolipoprotein B-containing lipoproteins, a key step of reverse cholesterol transport (RCT). CETP inhibitors have been developed to raise serum HDL-cholesterol (HDL-C) levels and reduce cardiovascular events. However, outcome studies of three CETP inhibitors (torcetrapib, dalcetrapib and evacetrapib) were prematurely terminated because of increased mortality or futility despite marked increases in HDL-cholesterol and decreases in LDL-cholesterol except for dalcetrapib. Patients with CETP deficiency show remarkable changes in HDL and LDL and are sometimes accompanied by atherosclerotic cardiovascular diseases. Recent prospective epidemiological studies demonstrated atheroprotective roles of CETP. CETP inhibition induces formation of small dense LDL and possibly dysfunctional HDL and downregulates hepatic scavenger receptor class B type I (SR-BI). Therefore, CETP inhibitors may interrupt LDL receptor and SR-BI-mediated cholesterol delivery back to the liver.
Summary: For future drug development, the opposite strategy, namely enhancers of RCT via CETP and SR-BI activation as well as the inducers of apolipoprotein A-I or HDL production might be a better approach rather than delaying HDL metabolism by inhibiting a main stream of RCT in vivo.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.