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.

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.