Effects of Epeleuton, a Novel Synthetic Second-Generation n-3 Fatty Acid, on Non-Alcoholic Fatty Liver Disease, Triglycerides, Glycemic Control, and Cardiometabolic and Inflammatory Markers

Abstract

Background Epeleuton is 15-hydroxy eicosapentaenoic acid ethyl ester, a second-generation synthetic n-3 fatty acid derivative of eicosapentaenoic acid. The primary objective was to assess the effect of epeleuton on markers of nonalcoholic fatty liver disease (NAFLD) with post hoc analyses of cardiometabolic markers. Methods and Results In a multicenter, randomized, double-blind, placebo-controlled trial, 96 adults with nonalcoholic fatty liver disease and body mass index 25 to 40 were randomized in a 1:1:1 ratio to receive epeleuton 2 g/day, epeleuton 1 g/day, or placebo for 16 weeks. A total of 27% of patients had diabetes mellitus. Primary end points of changes in alanine aminotransferase and liver stiffness did not improve at week 16. Secondary and post hoc analyses investigated changes in cardiometabolic markers. Epeleuton 2 g/day significantly decreased triglycerides, very-low-density lipoprotein cholesterol, and total cholesterol without increasing low-density lipoprotein cholesterol. Despite a low mean baseline hemoglobin A1C (HbA_1C; 6.3±1.3%), epeleuton 2 g/day significantly decreased HbA_1c (-0.4%; P=0.026). Among patients with baseline HbA_1c >6.5%, epeleuton 2 g/day decreased HbA_1c by 1.1% (P=0.047; n=26). Consistent dose-dependent reductions were observed for fasting plasma glucose, insulin, and insulin resistance indices. Epeleuton 2 g/day decreased circulating markers of cardiovascular risk and endothelial dysfunction. Epeleuton was well tolerated, with a safety profile not different from placebo. Conclusions While epeleuton did not meet its primary end points on alanine aminotransferase or liver stiffness, it significantly decreased triglycerides, HbA_1C, plasma glucose, and inflammatory markers. These data suggest epeleuton may have potential for cardiovascular risk reduction and nonalcoholic fatty liver disease by simultaneously targeting hypertriglyceridemia, hyperglycemia, and systemic inflammation. Further trials are planned. Registration URL: https://www.clini​caltr​ials.gov; Unique identifier: NCT02941549.

Keywords: 15‐HEPE; DS102; epeleuton; n‐3 fatty acid.

Figure 1. Consolidated Standards of Reporting Trials flow diagram of subject disposition.

mITT indicates modified intention‐to‐treat.

Figure 2. Change in HbA_1c, glycemic, and insulin resistance parameters.

A, Change in HbA_1C (%) in placebo and epeleuton groups. B, Proportion of patients with HbA_1c >6.5% at baseline which is normal at week 16. C, Change in fasting plasma glucose in placebo and epeleuton groups. D, Change in plasma free fatty acids in placebo and epeleuton groups. E, Change in insulin in placebo and epeleuton groups. F, LS mean change in HOMA‐IR in placebo and epeleuton groups. G, LS mean change in Adipo‐IR in placebo and epeleuton groups. For (A, C, D and E) error bars denote standard error. For (F and G) error bars denote 95% CIs. Adipo‐IR indicates adipose tissue insulin resistance; HbA_1c, hemoglobin A_1c; HOMA‐IR, homeostatic model assessment for insulin resistance; and LS, least squares. * denotes nonsignificant P values (>0.05) compared with placebo.

Figure 3. Median percentage change in lipid levels in patients receiving placebo, epeleuton 1 g/day or epeleuton 2 g/day (intention‐to‐treat population).

A, Changes in lipid levels at week 16. B, Changes in triglycerides levels at week 16 in the mITT population and subgroups excluding outliers and with elevated triglycerides at baseline. P values are from the Wilcoxon rank‐sum test. Error bars denote 95% CIs. HDL‐C indicates high‐density lipoprotein cholesterol; LDL‐C, low‐density lipoprotein cholesterol; RLP‐C, remnant‐like particle cholesterol; and VLDL‐C, very‐low‐density lipoprotein cholesterol. *Denotes nonsignificant P values (>0.05) compared with placebo.