BACKGROUND & AIMS: The comparative effectiveness of antidiabetic therapies on hepatic outcomes in patients with type 2 diabetes mellitus (T2DM) is not well established.
METHODS: We conducted a retrospective new-user cohort study emulating a target trial using electronic health records from the Mass General Brigham health system (USA) between January 2012 and June 2024. Adults with T2DM who newly initiated sodium-glucose cotransporter-2 inhibitors (SGLT2is), glucagon-like peptide-1 receptor agonists (GLP-1RAs), dipeptidyl peptidase-4 inhibitors (DPP4is), or sulfonylureas were included. Propensity scores were estimated using prespecified clinical and high-dimensional covariates, and overlap weighting was applied to achieve covariate balance.
RESULTS: Among 38,524 eligible patients, 12,344 initiated GLP-1RAs, 5,233 SGLT2is, 3,717 DPP4is, and 17,230 sulfonylureas. Over a median follow-up of 3.1 years, 1,743 hepatic decompensation events occurred. In the intention-to-treat analysis, GLP-1RAs (hazard ratio [HR] 0.58, 95% CI 0.38-0.88) and SGLT2is (HR 0.65, 95% CI 0.43-0.98) were associated with significantly lower risk compared with sulfonylureas. Pairwise analyses also showed reduced risk with GLP-1RAs (HR 0.59, 95% CI 0.39-0.89) and SGLT2is (HR 0.66, 95% CI 0.43-1.00) compared with DPP4is, with no significant difference between GLP-1RAs and SGLT2is. In the per-protocol analysis (1,151 events), GLP-1RAs (HR 0.43, 95% CI 0.22-0.82) remained strongly protective, while SGLT2is showed a trend toward reduced risk (HR 0.61, 95% CI 0.33-1.12). Sensitivity analyses excluding early events or using alternative weighting approaches produced consistent results.
CONCLUSION: In patients with T2DM, initiation of GLP-1RAs or SGLT2is was associated with substantially lower risk of hepatic decompensation compared with sulfonylureas and DPP4is. These findings support their preferential use in clinical practice.
IMPACT AND IMPLICATIONS: This study provides robust real-world evidence on the comparative effectiveness of four major antidiabetic drug classes in reducing hepatic decompensation among patients with type 2 diabetes mellitus. Our findings suggest that glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors are associated with substantially lower risk of hepatic decompensation compared with sulfonylureas and dipeptidyl peptidase-4 inhibitors, supporting their preferential use in patients with coexisting diabetes and liver disease risk. These results are particularly relevant for clinicians managing patients with type 2 diabetes who may have unrecognized metabolic dysfunction-associated steatotic liver disease or other chronic liver diseases. In practice, these findings can help guide therapeutic decision-making by integrating liver-related outcomes into antidiabetic drug selection. However, future prospective studies are needed to validate these findings and clarify the mechanisms underlying the observed benefits.
