Comparative effectiveness of antidiabetic therapies on hepatic decompensation in patients with type 2 diabetes: A...

The comparative effectiveness of antidiabetic therapies on hepatic outcomes in patients with type 2 diabetes mellitus (T2DM) is not well established.

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.

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.

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.

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.