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.