SGLT-2 Inhibitor use and liver-related and mortality outcomes in patients with type 2 diabetes and compensated cirrhosis

BACKGROUND: Sodium-glucose cotransporter-2 (SGLT-2) inhibitors with pleiotropic effects beyond glycemic control potentially improve clinical outcomes in cirrhosis; however, large-scale human evidence remains limited. We aimed to compare liver outcomes and mortality risk in adults with type 2 diabetes and compensated cirrhosis, who initiated either SGLT-2 inhibitors or dipeptidyl peptidase-4 (DPP-4) inhibitors. METHODS: Using the TriNetX Global Collaborative Network and a target trial emulation framework, we identified adults with compensated cirrhosis and type 2 diabetes initiating an SGLT-2- or DPP-4 inhibitor between 2016 and 2024. Baseline demographics, laboratory information, comorbidities and concomitant medications were matched by propensity scores. The primary outcome was a composite of incident hepatic decompensation, hepatocellular carcinoma and all-cause mortality. We used Cox proportional hazards models to estimate the hazard ratios (HR) with 95% confidence intervals (CI). RESULTS: We included 5,398 patients (mean [SD] age: 63.9 [10.3] years), receiving SGLT-2 inhibitors, matched to 5,398 DPP-4 inhibitor users, with an overall mean follow-up of 49.8 months. Compared to DPP-4 inhibitors, SGLT-2 inhibitors were associated with a lower risk of the primary composite outcome (HR: 0.85, 95% CI: 0.79-0.91), with similar results for all-cause mortality (HR: 0.77, 95% CI: 0.69-0.85) and incident hepatic decompensation (HR: 0.89, 95% CI: 0.82-0.96), but not for hepatocellular carcinoma (HR: 0.96, 95% CI: 0.82-1.14). CONCLUSIONS: Among adults with compensated cirrhosis and type 2 diabetes, SGLT-2 inhibitors were associated with lower risk of all-cause mortality and incident hepatic decompensation, compared to DPP-4 inhibitors. Future clinical trials are warranted to confirm this observation.