Efficacy and Safety of K-877 (Pemafibrate), a Selective PPARα Modulator, in European Patients on Statin Therapy

Diabetes Care. 2022 Apr 1;45(4):898-908. doi: 10.2337/dc21-1288.

Abstract

Objective: High plasma triglyceride (TG) is an independent risk factor for cardiovascular disease. Fibrates lower TG levels through peroxisome proliferator-activated receptor α (PPARα) agonism. Currently available fibrates, however, have relatively low selectivity for PPARα. The aim of this trial was to assess the safety, tolerability, and efficacy of K-877 (pemafibrate), a selective PPARα modulator, in statin-treated European patients with hypertriglyceridemia.

Research design and methods: A total of 408 statin-treated adults were recruited from 68 European sites for this phase 2, randomized, double-blind, placebo-controlled trial. They had fasting TG between 175 and 500 mg/dL and HDL-cholesterol (HDL-C) ≤50 mg/dL for men and ≤55 mg/dL for women. Participants were randomly assigned to receive placebo or one of six pemafibrate regimens: 0.05 mg twice a day, 0.1 mg twice a day, 0.2 mg twice a day, 0.1 mg once daily, 0.2 mg once daily, or 0.4 mg once daily. The primary end points were TG and non-HDL-C level lowering at week 12.

Results: Pemafibrate reduced TG at all doses (adjusted P value <0.001), with the greatest placebo-corrected reduction from baseline to week 12 observed in the 0.2-mg twice a day treatment group (54.4%). Reductions in non-HDL-C did not reach statistical significance. Reductions in TG were associated with improvements in other markers for TG-rich lipoprotein metabolism, including reductions in apoB48, apoCIII, and remnant cholesterol and an increase in HDL-C levels. Pemafibrate increased LDL-cholesterol levels, whereas apoB100 was unchanged. Pemafibrate was safe and well-tolerated, with only minor increases in serum creatinine and homocysteine concentrations.

Conclusions: Pemafibrate is effective, safe, and well-tolerated for the reduction of TG in European populations with hypertriglyceridemia despite statin treatment.

Publication types

  • Clinical Trial, Phase II
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Benzoxazoles
  • Butyrates
  • Double-Blind Method
  • Female
  • Fibric Acids / therapeutic use
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors* / therapeutic use
  • Hypertriglyceridemia* / drug therapy
  • Male
  • PPAR alpha / metabolism
  • Triglycerides

Substances

  • (R)-2-(3-((benzoxazol-2-yl-d4 (3-(4-methoxyphenoxy-d7)propyl)amino)methyl)phenoxy) butanoic acid
  • Benzoxazoles
  • Butyrates
  • Fibric Acids
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • PPAR alpha
  • Triglycerides

Associated data

  • EudraCT/2013-001517-32
  • figshare/10.2337/figshare.18028304