Efficacy of tirzepatide versus SGLT2 inhibitors in metabolic dysfunction-associated steatotic liver disease (MASLD): a multicenter propensity-matched real-world study.

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent condition with significant cardiometabolic and hepatic risks. Tirzepatide, a dual GLP-1/GIP receptor agonist, shows promise in MASLD, but real-world comparative data against sodium-glucose cotransporter-2 inhibitors (SGLT2is) are lacking. METHODS: In this multicenter, retrospective, propensity score-matched cohort study using the TriNetX US Collaborative Network, we compared outcomes in 43,743 new tirzepatide initiators versus 43,743 matched SGLT2i users with MASLD and ≥ 1 metabolic comorbidity. Propensity Score Matching (1:1, caliper 0.1) balanced > 50 covariates. Primary outcomes included all-cause mortality, hospitalization, major adverse cardiovascular events (MACE), major adverse liver outcomes (MALO), and major adverse kidney events (MAKE) at 1- and 3-year follow-up, analyzed via Kaplan-Meier estimation and Cox proportional hazards models. RESULTS: Tirzepatide was associated with significantly lower risks versus SGLT2is. At 1-year follow-up (n = 43,743 per group), all-cause mortality events were 144 (cumulative incidence 0.48%, KM event-free survival 99.52%) with tirzepatide versus 533 (1.38%, 98.62%) with SGLT2i (HR 0.328, 95% CI 0.272-0.394; log-rank p < 0.0001). All-cause hospitalization occurred in 3033 versus 7143 (HR 0.460, 95% CI 0.441-0.480). MACE events were 1064 versus 2376 (HR 0.506, 95%CI 0.471-0.544). MALO events were 149 versus 465 (HR 0.379, 95% CI 0.315-0.456). Hepatic failure and ascites also favored tirzepatide, while MAKE, varices, and hepatic encephalopathy showed no significant differences. Benefits persisted at 3 years (n = 39,838 per group): mortality 208 versus 963 (HR 0.374, 95% CI 0.321-0.436); hospitalization 3723 versus 9548 (HR 0.528, 95%CI 0.508-0.549); MACE 1260 versus 3282 (HR 0.545, 95%CI 0.510-0.582); and MALO 220 versus 726 (HR 0.478, 95%CI 0.410-0.558). CONCLUSIONS: In this large real-world MASLD cohort, tirzepatide was associated with substantial reductions in mortality, hospitalizations, cardiovascular, and liver-related events compared to SGLT2is. These observational findings suggest potential advantages of tirzepatide and warrant prospective validation in randomized trials.