Tirzepatide versus SGLT2 inhibitors for MASLD: a multi-institutional propensity score-matched cohort study

Tirzepatide (TZP) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) have both shown promise in managing metabolic dysfunction-associated steatotic liver disease (MASLD). However, direct comparative data are limited. This study aimed to evaluate the real-world effectiveness of TZP versus SGLT2i in adults with MASLD.

We conducted a retrospective, multi-institutional cohort study using the TriNetX global research network. Adults (≥ 18 years) with a diagnosis of MASLD who were newly initiated on TZP or SGLT2i between January 1, 2022, and June 30, 2025, were included. The primary outcome was a composite of all-cause mortality, major adverse cardiovascular events (MACEs), and major adverse liver outcomes (MALOs). Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs).

After 1:1 propensity score matching, 23,106 patients were included in each group. Compared to SGLT2i, TZP use was associated with a significantly lower risk of the primary composite outcome (HR, 0.72; 95% CI, 0.63-0.83). TZP was also associated with lower risks of all-cause mortality (HR, 0.55; 95% CI, 0.43-0.71), MACEs (HR, 0.68; 95% CI, 0.58-0.80), and MALOs (HR, 0.66; 95% CI, 0.54-0.80). These associations were consistent across subgroups stratified by age, sex, BMI, and comorbidities.

In this large real-world study, TZP was associated with significantly better clinical outcomes than SGLT2i in adults with MASLD. These findings support TZP as a preferred treatment option and highlight the need for prospective trials to validate these results.