UEG Week 2025 Semaglutide MASH benefits driven by weight loss and other metabolic pathways

medwireNews: The benefits of semaglutide therapy in patients with metabolic dysfunction-associated steatohepatitis (MASH) and moderate-to-advanced liver fibrosis are mediated by both weight loss-independent and dependent pathways, shows research presented at UEG Week 2025 in Berlin, Germany.

Jörn Schattenberg (Saarland University Medical Center, Homburg, Germany) presented a post-hoc analysis of the ongoing ESSENCE trial, in which a previously reported interim analysis showed that once weekly semaglutide 2.4 mg “delivered significant improvements in liver histology and substantial body weight reductions” compared with placebo over 72 weeks in the first 800 study participants.

The current analysis determined to what extent the benefits of semaglutide on liver histology are mediated by the indirect effect of weight loss versus the direct effects of the glucagon-like peptide-1 receptor agonist on the liver.

This included the impact of weight loss on the MASH-related histologic endpoint of steatohepatitis resolution without worsening liver fibrosis, and the responder endpoints of changes in alanine aminotransferase (ALT) and FibroScan–aspartate aminotransferase (FAST) score; and the fibrosis-related histologic endpoint of improvement in liver fibrosis without worsening of steatohepatitis, and the associated endpoints of changes in vibration-controlled transient elastography (VCTE) liver stiffness measurement and enhanced liver fibrosis (ELF) score.

Specifically, the team used logistic regression analysis where treatment (semaglutide vs placebo) was the exposure, the percentage weight loss from baseline to week 72 was the mediator, and baseline type 2 diabetes status, fibrosis stage, and bodyweight were covariates. This allowed calculation of the total, weight loss-independent, and weight loss-dependent effect sizes for each endpoint, where the odds ratio (OR) was considered statistically significant if the lower bound of the confidence interval (CI) was above 1.0, Schattenberg explained.

For histologic resolution of MASH without liver fibrosis worsening, the odds ratio (OR) for total effect of semaglutide versus placebo was 3.9 but this was only partially mediated by weight loss, with respective ORs for the independent and dependent effects of 2.0 and 1.9, all of which were significant.

This was also true for the likelihood of the MASH-related markers of ALT response, defined as a reduction of 17 U/L or greater, with total and weight loss-independent and dependent ORs of 4.7, 3.0 and 1.5, respectively, and FAST score response, defined as a reduction of 0.22 points or greater, with corresponding ORs of 6.9, 2.8, and 2.5. Again, all ORs were statistically significant.

Similarly, “the effect of semaglutide on fibrosis and related [non-invasive test] responder endpoints is only partially mediated by weight loss,” the presenter said.

The ORs for total and weight loss-independent and dependent improvements in liver fibrosis without MASH worsening with semaglutide versus placebo were 2.1, 1.5, and 1.4, respectively, with only the weight loss-independent effect nonsignificant with the lower bound of the CI at 1.0. There were significant ORs for VCTE liver stiffness response (defined as a 30% reduction) of 3.0, 1.7, and 1.7, respectively. For ELF score response (defined as ≥0.5 U reduction), the corresponding significant ORs were 4.5, 2.4 and 1.9.

Schattenberg observed that while knowing the underlying metabolic mechanisms for weight loss-independent and dependent effects with semaglutide “is not as important for the individual patient,” this analysis hints “towards effects that might be separated from weight loss.”

The presenter continued: “We've seen data in patients with bariatric surgery undergoing massive weight loss and not showing fibrosis regression, and there are certain aspects of this disease that are clearly weight loss independent.”

He concluded that MASH treatment is therefore “not all about weight loss” and understanding how semaglutide targets the weight loss-dependent effects will be useful to develop new treatments.

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United European Gastroenterology Week 2025; Berlin, Germany, 4-7 October