Efficacy of Initiation of Semaglutide versus SGLT2 Inhibitors in Metabolic Dysfunction-Associated Steatotic Liver Disease: A Multicenter Propensity-Matched Real-World Study.

OBJECTIVES

Metabolic dysfunction-associated steatotic liver disease (MASLD) is common and linked to cardiometabolic comorbidities, with few direct comparisons between glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors (SGLT2is).

METHODS

This multicenter, retrospective, propensity score-matched cohort study utilized data from the TriNetX U.S. Collaborative Network. Adults with MASLD and at least one metabolic comorbidity were identified as new initiators of semaglutide (n = 128,332) or SGLT2is (n = 100,542), excluding alternative exposures and confounding liver etiologies. One-to-one propensity score matching on >50 covariates yielded balanced cohorts of 55,525 patients each. Time-to-event outcomes, including all-cause mortality, hospitalization, major adverse cardiovascular events, major adverse liver outcomes, major adverse kidney events, ascites, hepatic failure, and hepatic encephalopathy, were evaluated at 1-year and 5-year follow-ups using Kaplan-Meier analysis and Cox proportional hazards models.

RESULTS

Semaglutide was linked to significant risk reductions compared to SGLT2is. At 1-year, hazard ratios (HRs) were 0.382 (95% CI 0.338-0.430) for all-cause mortality, 0.444 (95% CI 0.429-0.459) for all-cause hospitalization, 0.502 (95% CI 0.476-0.530) for major adverse cardiovascular events, and 0.361 (95% CI 0.316-0.412) for major adverse liver outcomes. At 5-years, the corresponding HRs were 0.494 (95% CI 0.459-0.531), 0.565 (95% CI 0.551-0.579), 0.584 (95% CI 0.560-0.609), and 0.494 (95% CI 0.452-0.540). Major adverse kidney events showed no difference at 1-year (HR 0.998), but a reduction at 5-years (HR 0.858; 95% CI 0.789-0.933). Individual liver events (ascites, hepatic failure) followed similar patterns.

CONCLUSIONS

In this large real-world MASLD cohort, initiating semaglutide was linked to potential reductions in mortality, hospitalization, and adverse cardiometabolic, liver, and kidney outcomes compared to SGLT2is.