Available online 22 July 2025

Cholesteryl ester transfer protein (CETP) deficiency impairs reverse cholesterol transport (RCT) and leads to the abnormal accumulation of high-density lipoprotein cholesterol (HDL-C).

Pemafibrate increases HDL-C in patients with dyslipidemia and low HDL-C levels.

Pemafibrate reduces HDL-C in CETP deficiency by decreasing large HDL particles.

Pemafibrate may promote hepatic cholesterol uptake through CETP-independent pathways.

Considering available evidence, pemafibrate appears to comprehensively enhance RCT.

Cholesteryl ester transfer protein (CETP) deficiency is a representative molecular abnormality in familial hyperalphalipoproteinemia, a hereditary disorder of lipid metabolism characterized by markedly elevated plasma high-density lipoprotein cholesterol (HDL-C) levels. In this condition, dysfunction of CETP, which mediates the transfer of cholesteryl esters from HDL particles to apolipoprotein (Apo)B-containing lipoproteins, leads to the abnormal accumulation of HDL-C. These HDL particles are unusually large and enriched in cholesteryl esters, ApoCIII, and ApoE, whereas low-density lipoprotein (LDL) particles are small, depleted of cholesteryl esters, and enriched in triglycerides. Both HDL and LDL particles in CETP deficiency are functionally abnormal.

Pemafibrate, a selective peroxisome proliferator-activated receptor α modulator, has consistently been demonstrated in clinical trials to increase HDL-C levels by 16% to 22% in patients with dyslipidemia and low baseline HDL-C. Herein, we describe the unexpected finding of a marked reduction in HDL-C levels in a patient with CETP deficiency following pemafibrate treatment. To better understand this paradoxical response, we analyzed the patient’s clinical data and investigated potential mechanisms underlying pemafibrate's effects on HDL metabolism.

Pemafibrate

Peroxisome proliferator-activated receptor alpha

Cardiovascular disease

High-density lipoprotein cholesterol

Reverse cholesterol transport

Cholesterol efflux

Cholesteryl ester transfer proteins

© 2025 The Authors. Published by Elsevier Inc. on behalf of National Lipid Association.