Metabolic dysfunction-associated steatohepatitis (MASH) is an important progressive liver disorder that can lead to hepatic decompensation, hepatocellular carcinoma (HCC), and premature death. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have demonstrated beneficial effects on metabolic dysfunction and liver histology; however, their relationship with major long-term hepatic outcomes in routine clinical practice has not been fully established. A retrospective multicenter cohort study was conducted using a large real-world health database. Adults with MASH were classified according to whether they had documented exposure to GLP-1 RAs. The 2 groups were balanced using 1:1 propensity score matching based on demographic variables, coexisting conditions, and concomitant therapies. The outcomes evaluated were ascites, HCC, and all-cause mortality, with comparative effects reported as risk differences (RDs) and 95% confidence intervals (CIs). The initial study population comprised 1434,086 individuals with MASH, including 168,740 GLP-1 RA users and 1265,346 individuals without GLP-1 RA exposure. After matching, 168,733 patients were retained in each cohort with comparable baseline characteristics. Exposure to GLP-1 RAs was associated with fewer cases of ascites (RD - 0.013; 95% CI - 0.014 to - 0.012; P < .001) and lower all-cause mortality (RD - 0.022; 95% CI - 0.023- - 0.021; P < .001). A statistically significant increase in HCC incidence was observed among GLP-1 RA users; however, the magnitude of the absolute difference was minimal (RD 0.000; 95% CI 0.000-0.001; P = .025). 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. While a statistically significant difference in HCC occurrence was detected, its negligible absolute magnitude suggests limited clinical relevance. These findings support the potential role of GLP-1 RAs as beneficial and hepatically safe therapies in patients with MASH.
