Novel Selective PPARα Modulator Pemafibrate for Dyslipidemia, Nonalcoholic Fatty Liver Disease (NAFLD), and Atherosclerosis

Abstract

Statins, the intestinal cholesterol transporter inhibitor (ezetimibe), and PCSK9 inhibitors can reduce serum LDL-C levels, leading to a significant reduction in cardiovascular events. However, these events cannot be fully prevented even when maintaining very low LDL-C levels. Hypertriglyceridemia and reduced HDL-C are known as residual risk factors for ASCVD. Hypertriglyceridemia and/or low HDL-C can be treated with fibrates, nicotinic acids, and n-3 polyunsaturated fatty acids. Fibrates were demonstrated to be PPARα agonists and can markedly lower serum TG levels, yet were reported to cause some adverse effects, including an increase in the liver enzyme and creatinine levels. Recent megatrials of fibrates have shown negative findings on the prevention of ASCVD, which were supposed to be due to their low selectivity and potency for binding to PPAR α. To overcome the off-target effects of fibrates, the concept of a selective PPARα modulator (SPPARMα) was proposed. Kowa Company, Ltd. (Tokyo, Japan), has developed pemafibrate (K-877). Compared with fenofibrate, pemafibrate showed more favorable effects on the reduction of TG and an increase in HDL-C. Fibrates worsened liver and kidney function test values, although pemafibrate showed a favorable effect on liver function test values and little effect on serum creatinine levels and eGFR. Minimal drug–drug interactions of pemafibrate with statins were observed. While most of the fibrates are mainly excreted from the kidney, pemafibrate is metabolized in the liver and excreted into the bile. It can be used safely even in patients with CKD, without a significant increase in blood concentration. In the megatrial of pemafibrate, PROMINENT, for dyslipidemic patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia, and low HDL-C and LDL-C levels, the incidence of cardiovascular events did not decrease among those receiving pemafibrate compared to those receiving the placebo; however, the incidence of nonalcoholic fatty liver disease was lower. Pemafibrate may be superior to conventional fibrates and applicable to CKD patients. This current review summarizes the recent findings on pemafibrate.

Design and Synthesis of Novel Indole Ethylamine Derivatives as a Lipid Metabolism Regulator Targeting PPARα/CPT1 in AML12 Cells

“…The therapeutic effects of most clinical PPARα agonists on NAFLD are typically achieved by lowering the TG levels in patients. [ 41 ] To screen the indole-based PPARα agonists for their lipid-modifying effects, we investigated the effects of four new compounds ( 4 , 5 , 8 , 9 ) on lipid accumulation in hepatocytes via an in vitro model of oleic acid (OA)-induced triglyceride-accumulated murine hepatic AML12 cells by applying 500 µM of OA for 24 h. Adipogenesis was evaluated both by measuring the intracellular TG levels and by using fenofibrate as a positive control ( Figure 5 a). At the same concentration of 20 µM, all the compounds showed effects.…”

Non-alcoholic fatty liver disease and risk of cardiovascular diseases: clinical association, pathophysiological mechanisms, and management

“…However, they were reported to cause some adverse effects, including an increase in liver enzyme and creatinine levels [75] . Two meta-analyses provided supportive evidence of fibrate use in both primary and secondary CVD prevention [76] . The highly potent and selective PPARα agonist K-877 has shown beneficial effects on atherogenic dyslipidemia and the absence of some adverse effects seen with fibrates [77] .…”

An Overview of the Role of Peroxisome Proliferator-activated Receptors in Liver Diseases

“… 159 In another clinical study, pemafibrate was assessed in NAFLD and atherosclerosis (AS), and was reported that pemafibrate was superior to conventional fibrates and might even be used for chronic kidney disease. 160 …”