GLP-1 receptor agonist–SGLT-2 inhibitor combination and risk of major adverse liver and cardiovascular outcomes in adults with MASLD and type 2 diabetes

BACKGROUND AND AIMS: Glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter-2 (SGLT-2) inhibitors individually benefit patients with metabolic dysfunction-associated steatotic liver disease (MASLD). We aimed to evaluate the effect of GLP-1 receptor agonist-SGLT-2 inhibitor combination on the risk of major adverse liver and cardiovascular outcomes compared with either agent alone among patients with MASLD and type 2 diabetes (T2D). APPROACH AND RESULTS: This is a target trial emulation study using data from U.S. MarketScan databases. Propensity score-matched cohorts were built to compare (1) 4606 patients who received GLP-1 receptor agonist-SGLT-2 inhibitor combination with 18,424 who received only GLP-1 receptor agonist, and (2) 5368 patients who received this combination with 21,472 who received only SGLT-2 inhibitors. Cox regression models were conducted in on-treatment designs. Compared with GLP-1 receptor agonists, the GLP-1 receptor agonist-SGLT-2 inhibitor combination was associated with a 39% lower risk of major adverse liver outcomes [HR 0.61 (95% CI 0.49-0.77)] and a 35% lower risk of major adverse cardiovascular events [HR 0.65 (0.60-0.70)] during a median follow-up of 6.3 months. Compared with SGLT-2 inhibitors, the combination was associated with a 43% lower risk of major adverse liver outcomes [HR 0.57 (0.46-0.69)] and a 20% lower risk of major adverse cardiovascular events [HR 0.80 (0.75-0.86)] during a median follow-up of 6.0 months. CONCLUSIONS: In this study, the GLP-1 receptor agonist-SGLT-2 inhibitor combination was associated with a lower risk of major adverse liver and cardiovascular outcomes compared with either agent alone among patients with MASLD and T2D.