PPAR Agonists in PBC: Hepatology | April 2026

Introduction

Primary biliary cholangitis is a chronic cholestatic liver disease that can progress to cirrhosis and liver failure if inadequately treated. While ursodeoxycholic acid remains the first-line therapy, a significant proportion of patients have incomplete response or intolerance. In this context, peroxisome proliferator–activated receptor agonists have emerged as promising second-line options, targeting metabolic and inflammatory pathways involved in cholestasis. However, comparative efficacy among different PPAR agents remains unclear due to lack of direct head-to-head trials.

Problem Statement

There is limited comparative evidence to guide the selection of the most effective and safest PPAR agonist as second-line therapy in PBC.

Summary

This network meta-analysis of eight randomized trials involving over 700 patients demonstrates that all PPAR agonists are superior to placebo in achieving biochemical response and alkaline phosphatase (ALP) normalization, key surrogate markers of disease control in PBC. Among available agents, bezafibrate ranked highest for overall biochemical response, while both bezafibrate and seladelpar showed the best performance for ALP normalization.

Interestingly, the magnitude of ALP reduction was consistent regardless of baseline disease severity, suggesting broad applicability across patient subgroups. Total bilirubin outcomes were similar across treatments, and adverse events leading to discontinuation were infrequent, supporting a favorable safety profile.

In the absence of direct comparative trials, this study provides valuable indirect evidence to guide clinical decision-making. However, differences in ranking should be interpreted cautiously due to variability in study design and populations.

Clinically, PPAR agonists represent an effective and safe second-line strategy in PBC, with bezafibrate and seladelpar emerging as leading options. Future research should focus on long-term outcomes and patient-centered benefits beyond biochemical response.