Clinical applications of a novel selective PPARα modulator, pemafibrate, in dyslipidemia and metabolic diseases

Abstract

Fasting and postprandial hypertriglyceridemia is a risk factor for atherosclerotic cardiovascular diseases (ASCVD). Fibrates have been used to treat dyslipidemia, particularly hypertriglyceridemia, and low HDL-cholesterol (HDL-C). However, conventional fibrates have low selectivity for peroxisome proliferator-activated receptor (PPAR)α. Fibrates’ clinical use causes side effects such as worsening liver function and elevating the creatinine level. Large-scale clinical trials of fibrates have shown negative results for prevention of ASCVD. To overcome these issues, the concept of the selective PPARα modulator (SPPARMα), with a superior balance of efficacy and safety, has been proposed. A SPPARMα, pemafibrate (K-877), was synthesized by Kowa Company, Ltd. for better efficacy and safety. Clinical trials conducted in Japan confirmed the superior effects of pemafibrate on triglyceride reduction and HDL-C elevation. Conventional fibrates showed elevated liver function test values and worsened kidney function test values, while pemafibrate demonstrated improved liver function test values and was less likely to increase serum creatinine or decrease the estimated glomerular filtration rate. There were extremely few drug interactions even when it was used concomitantly with various statins. Furthermore, unlike many of the conventional fibrates that are renal excretory-type drugs, pemafibrate is excreted into the bile, so it can be safely used even in patients with impaired renal function and there is no increase in its blood concentration. This novel SPPARMα, pemafibrate, has superior benefit-risk balance compared to conventional fibrates and can be used for patients for whom it was difficult to use existing fibrates, including those who are taking statins and those with renal dysfunction. A large-scale trial PROMINENT using pemafibrate for patients with type 2 diabetes is in progress. In the current review, the latest data on pemafibrate will be summarized.