I read with great interest the recent review article by J. M. Schattenberg et al. on the therapeutic targeting of peroxisome proliferator-activated receptors (PPARs) in primary biliary cholangitis (PBC) 1. The manuscript provides a comprehensive and generally well-balanced overview of the field. In the interest of transparency, the authors appropriately disclose support from a pharmaceutical company that markets a PPAR agonist currently conditionally approved as a second-line therapy for PBC. They also note that several co-authors have affiliations with this company or with the company that originally developed the agent. Here, I would like to offer a few additional observations that may further complement and strengthen the review. First, I was somewhat surprised that the authors did not refer to non-invasive markers of fibrosis, which are likely to become integral to the therapeutic evaluation of PBC as surrogate endpoints of long-term efficacy, alongside biochemical response and patient-reported outcomes 2. In this regard, it is noteworthy that bezafibrate is currently the only PPAR agonist to have demonstrated, in a randomized placebo-controlled trial, concomitant improvements in liver stiffness measured by elastography (FibroScan) and in the Enhanced Liver Fibrosis (ELF) score 3. This finding is supported by real-world observational data showing improvements in both Ludwig stage and Ishak fibrosis score after 5 years of combination therapy with ursodeoxycholic acid 4 and is consistent with the survival benefit observed in the Japanese national registry study, which reported a reduction of more than 60% in mortality and the need for liver transplantation among patients receiving combination therapy 5. Second, the authors appear to place particular emphasis on the adverse effects associated with the established PPAR agonists, bezafibrate and fenofibrate, in comparison with the newer agents elafibranor and seladelpar, notably citing the relatively high discontinuation rate (26% within the first year) reported in a UK real-world cohort 6. However, the more recent nationwide Dutch study evaluating the effectiveness and tolerability of bezafibrate in a real-world setting is not discussed—perhaps reflecting its very recent publication 7. This study closely replicates the favourable biochemical effects observed in the bezafibrate arm of the BEZURSO trial—namely, significant and sustained reductions in serum alkaline phosphatase, total bilirubin, gamma-glutamyl transferase, and transaminases—and reports an overall 13% rate of treatment discontinuation due to documented adverse events over a mean follow-up of 30 months. For context, in the Japanese national registry—the largest and longest-running real-world study of bezafibrate published to date—the corresponding rate was 6% 5. It may also be worth noting that—unlike in the ELATIVE (elafibranor) and RESPONSE (seladelpar) trials—no signal for increased fracture risk was observed in the BEZURSO trial 8. Finally, in the absence of head-to-head trials directly comparing the various PPAR agonists used in PBC, two recent meta-analyses not referenced in this review warrant careful consideration. These studies offer a comparative assessment of biochemical and symptomatic outcomes across these agents, accounting for baseline characteristics—particularly serum alkaline phosphatase levels and worst itch numerical rating scale—and applying standardized endpoints across the major published trials 9, 10. Sincerely, Dr. Christophe Corpechot. Christophe Corpechot: conceptualization, validation, writing – review and editing. Artificial intelligence–assisted tools (ChatGPT, OpenAI) were used to assist with language editing and improve the clarity of the manuscript. The author has nothing to report. The author reports research grants from Intercept and Arrow, and consulting work for Cymabay, Gilead, Ipsen, Calliditas, GSK, Mirum, Advanz, and Intercept. This article is linked to Schattenberg et al. paper. To view this article, visit https://doi.org/10.1111/apt.70598. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.
Christophe Corpechot (Tue,) studied this question.