HDL biology
Case report finds pemafibrate paradoxically lowers HDL cholesterol in a patient with CETP deficiency (J Clin Lipidol 2025)
Original title: Effect of pemafibrate on high-density lipoprotein cholesterol levels and subspecies in a patient with cholesteryl ester transfer protein deficiency: A case report with mechanistic insights
CETP deficiency, the molecular basis of familial hyperalphalipoproteinemia, causes dysfunctional CETP to leave HDL cholesterol markedly elevated, with HDL particles that are abnormally large and enriched in cholesteryl esters, apolipoprotein CIII and apolipoprotein E, while LDL particles become small and triglyceride-enriched, with both HDL and LDL functionally abnormal. Pemafibrate, a selective PPAR-alpha modulator, has consistently raised HDL cholesterol by 16% to 22% in dyslipidemic patients with low baseline HDL cholesterol in clinical trials. This case report describes the unexpected opposite response, a marked reduction in HDL cholesterol following pemafibrate treatment in a patient with CETP deficiency, and investigates the clinical data and potential mechanisms underlying this paradoxical effect on HDL metabolism.
Original abstract
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.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.