Liver Lineup: GLP-1 RAs and FGF21s for MASH, with Mary Rinella, MD

In this episode of Liver Lineup: Updates and Unfiltered Insights, hosts Nancy Reau, MD, and Kimberly Brown, MD, sit down with Mary (Maru) Rinella, MD, a professor of medicine and director of Clinical Trials and the Metabolic and Fatty Liver Program at the University of Chicago, to discuss the rapidly evolving therapeutic landscape for metabolic dysfunction-associated steatohepatitis (MASH).1

The conversation opens with a discussion about GLP-1 receptor agonists, which Rinella notes are already ubiquitous in her practice, with nearly 60% of patients being on one by the time they see her because of the overlap of comorbidities like diabetes and obesity with MASLD. She explains that the liver benefits of these agents appear to be primarily mediated by weight loss, though findings from the ESSENCE trial of Novo Nordisk’s semaglutide have demonstrated resolution of steatohepatitis and improvements in fibrosis.

Editors’ note: This episode was recorded prior to the FDA approval of semaglutide (Wegovy) injection 2.4 mg for the treatment of noncirrhotic MASH on August 15, 2025.

The conversation then shifts to strategies for integrating GLP-1 receptor agonists with resmetirom (Rezdiffra), the first FDA-approved agent for MASH. Rinella emphasizes the importance of staggering initiation, typically waiting 3 to 6 months before layering therapies, to both monitor for side effects and determine which drug is driving clinical response. She highlights the need for individualized, patient-centered strategies based on comorbidities and disease severity.

Looking ahead, the discussion turns to next-generation incretin therapies, including dual and triple agonists such as tirzepatide, survodutide, and retatrutide. While early-phase studies suggest significant weight loss and metabolic benefits, all 3 experts note phase 3 data are needed to establish their antifibrotic efficacy. The group also notes challenges in advanced liver disease: while weight loss can improve fibrosis, it also poses important implications for sarcopenia risk and acceleration, a trade-off that is particularly concerning in the context of cirrhosis, where malnutrition already heightens risk.

The experts also delve into FGF21 analogues, a class Rinella describes as one of the most promising in development with agents such as efruxifermin and pegozafermin showing some of the largest antifibrotic signals to date. Although recent cirrhosis trials were limited by short follow-up periods, Rinella expresses confidence that longer studies will confirm meaningful fibrosis improvements, additionally pointing to emerging research suggesting possible effects on alcohol consumption, opening new avenues for treatment in patients with overlapping metabolic and alcohol-related liver disease.

Finally, the group considers where the field is headed. Within the next decade, Rinella says she anticipates a much richer therapeutic armamentarium that could allow most patients with MASH to receive targeted treatment. However, she cautions that decompensated cirrhosis remains an area of unmet need, with no therapies yet convincingly effective.

References

1. Brooks A. Semaglutide Improves Steatohepatitis, Fibrosis in Phase 3 MASH Trial. HCPLive. April 30, 2025. Accessed August 20, 2025. https://www.hcplive.com/view/semaglutide-improves-steatohepatitis-fibrosis-phase-3-mash-trial

2. Brooks A. FDA Approves Semaglutide (Wegovy) Injection 2.4 mg for Noncirrhotic MASH. HCPLive. August 15, 2025. Accessed August 20, 2025. https://www.hcplive.com/view/fda-approves-semaglutide-wegovy-injection-2-4-mg-for-noncirrhotic-mash

3. Brooks A. Efruxifermin Shows Potential for Fibrosis Reduction in Phase 2b MASH Cirrhosis Trial. HCPLive. May 9, 2025. Accessed August 20, 2025. https://www.hcplive.com/view/exfruxifermin-misses-primary-endpoint-phase-2b-compensated-mash-cirrhosis-trial