GLP-1 Receptor Agonists Cut Ascites, Mortality in MASH

Adults with metabolic dysfunction–associated steatohepatitis (MASH) who received glucagon-like peptide-1 receptor agonists (GLP-1 RAs) had significantly fewer cases of ascites and lower all-cause mortality than similar patients who did not receive the drugs, according to a new multinational, propensity-matched cohort study published in Medicine (Baltimore).¹

The findings, drawn from more than 1.4 million patients in a global real-world database, offer some of the largest-scale evidence to date that a drug class already reshaping obesity and diabetes care may also blunt the most severe downstream consequences of fatty liver disease.

MASH is a progressive form of metabolic dysfunction–associated steatotic liver disease that can advance to hepatic decompensation, hepatocellular carcinoma (HCC), and premature death.² Although GLP-1 RAs have shown metabolic and histological benefits in clinical trials, their association with these major long-term hepatic outcomes in routine practice is not fully established, prompting the multinational research team to turn to the large real-world database.¹

Identifying the Study Population

Investigators used the TriNetX Global Health Research Network to gather de-identified electronic health record data on 110 participating health organizations; analyses were conducted on January 4, 2026. The initial study population comprised 1,434,086 individuals with MASH; of this group, 168,740 (11.8%) had documented GLP-1 RA exposure (dulaglutide, exenatide, liraglutide, lixisenatide, or semaglutide), and 1,265,346 (88.2%) had no exposure.

Before matching, the 2 groups differed substantially. Patients receiving GLP-1 RAs were younger (mean [SD] age, 57.1 [14.1] vs 59.3 [16.7] years) and more often female (63.5% vs 56.4%) vs those without GLP-1 RA exposure, and they carried a heavier burden of endocrine and metabolic comorbidities. To control for these differences, the researchers applied 1:1 propensity score matching on demographic characteristics, comorbidities, and concomitant medications, ultimately retaining 168,733 patients in each cohort with standardized differences below 0.01 for all matched covariates.

What Clinical Outcomes Did GLP-1 RA Use Affect?

In the matched population, ascites—excess fluid build-up in the abdomen³—occurred in 3091 patients in the GLP-1 RA cohort compared with 5263 in the non–GLP-1 RA cohort, for a risk difference (RD) of –0.013 (95% CI, –0.014 to –0.012; P < .001) and an absolute risk reduction of 1.3%. All-cause mortality was likewise lower among GLP-1 RA users, with 4248 vs 7957 deaths (RD, –0.022; 95% CI, –0.023 to –0.021; P < .001), an absolute risk reduction of 2.2%.

HCC was the exception. It occurred slightly more often among GLP-1 RA users (713 vs 631 cases; RD, 0.000; 95% CI 0.000-0.001; P = .025), reaching statistical significance despite a negligible difference that the authors said carried limited clinical relevance.

“Among patients with MASH, GLP-1 RA exposure was associated with a lower incidence of ascites and reduced mortality in this large real-world matched cohort,” the authors wrote. “The reduced occurrence of ascites among GLP-1 RA users is particularly noteworthy, as ascites represents a major manifestation of hepatic decompensation and is associated with substantial morbidity and poor prognosis.”

The authors pointed to the drugs’ broader metabolic effects—weight loss, improved insulin sensitivity, and potential reductions in hepatic steatosis and inflammation—as plausible mechanisms, alongside cardiometabolic benefits that could lower mortality risk beyond the liver itself.

These findings echo previous research showing that GLP-1 RAs can reduce liver fat, slow fibrosis progression, and help resolve MASH, with semaglutide, diraglutide, and liraglutide all linked to improvements in liver enzymes or hepatic fat.⁴ They also follow the FDA’s 2025 accelerated approval of semaglutide for MASH with moderate to advanced fibrosis, based on ESSENCE trial (NCT02970942) data showing 63% of treated patients achieved steatohepatitis resolution without worsening fibrosis vs 34% on placebo.⁵

The Study’s Limitations and What Comes Next

The study could not establish causality, and the authors acknowledged that dietary habits, physical activity, socioeconomic status, disease severity, medication adherence, and GLP-1 RA dose or duration were not fully captured. The database also lacked detailed histological staging of fibrosis severity, and reliance on electronic health record coding raises the possibility of misclassified exposures or outcomes.

Even so, the authors called the sample size, multicenter design, and propensity matching important strengths that provided evidence difficult to generate in conventional trials given MASH’s prolonged natural history.

“Further prospective studies and randomized trials with long-term follow-up are warranted to clarify the causal effects of GLP-1 RAs on hepatic decompensation, HCC development, and survival,” they concluded.

References

1. Khan SA, Subedi A, Marasni A, et al. Clinical outcomes associated with GLP-1 receptor agonist use in metabolic dysfunction-associated steatohepatitis: a multinational cohort study. Medicine (Baltimore). 2026;105(37):e50733. doi:10.1097/MD.0000000000050733
2. Metabolic dysfunction–associated steatohepatitis. Cleveland Clinic. Updated May 5, 2025. Accessed September 17, 2026. https://my.clevelandclinic.org/health/diseases/22988-nonalcoholic-steatohepatitis
3. Ascites. Mayo Clinic. March 21, 2026. Accessed September 17, 2026. https://www.mayoclinic.org/diseases-conditions/ascites/symptoms-causes/syc-20596724
4. Munz K. GLP-1 RAs may offer broad hepatic benefits in MASH. AJMC^®. March 27, 2025. Accessed September 17, 2026. https://www.ajmc.com/view/glp-1-ras-may-offer-broad-hepatic-benefits-in-mash
5. Klein HE. FDA approves semaglutide for MASH with fibrosis. AJMC. August 18, 2025. Accessed September 17, 2026. https://www.ajmc.com/view/fda-approves-semaglutide-for-mash-with-fibrosis