GLP‐1 RA Plus SGLT2i Versus Monotherapy in MASLD and Type 2 Diabetes: Three Pairwise Target Trial Emulations

Introduction Glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) and sodium‐glucose cotransporter‐2 inhibitors (SGLT2is) have demonstrated cardiovascular and metabolic benefits individually; however, the comparative effectiveness of combination therapy versus monotherapy in patients with metabolic dysfunction‐associated steatotic liver disease (MASLD) and type 2 diabetes mellitus (T2DM) remains incompletely characterized. Methods We conducted three pairwise target trial emulations using the TriNetX Research Network. Adults with MASLD and T2DM initiating GLP‐1 RA plus SGLT2i combination therapy, GLP‐1 RA monotherapy, or SGLT2i monotherapy were identified. Primary outcomes were all‐cause mortality, major adverse cardiovascular events (MACE), and composite liver outcomes. Propensity score matching (PSM) (1:1) was performed for each pairwise comparison. Cox proportional hazards regression with Bayesian hierarchical bias‐effect (BHBE) correction was utilized to address residual confounding. Results Following PSM, 42423 combination versus 42 423 GLP‐1 RA, 40349 combination versus 40 349 SGLT2i, and 51 826 GLP‐1 RA versus 51 826 SGLT2i patients were analyzed. Combination therapy significantly reduced all‐cause mortality versus SGLT2i monotherapy (hazard ratio [HR] 0.522, 95% confidence interval [CI] 0.488–0.559), with probable benefit after bias correction (corrected HR 0.655, posterior probability 92.4%; credible interval includes the null). Combination therapy demonstrated increased MACE risk versus GLP‐1 RA (HR 1.106, 95% CI 1.045–1.170), remaining significant after correction (corrected HR 1.111). Composite liver outcomes favored combination therapy versus SGLT2i (corrected HR 0.907, probability of benefit 81.9%). Conclusions GLP‐1 RA and SGLT2i combination therapy significantly reduced mortality and liver outcomes versus SGLT2i monotherapy in MASLD with T2DM; however, increased MACE risk versus GLP‐1 RA monotherapy warrants consideration in management decisions.