Hepatic Events Prevention by Antihyperglycemic Therapies and Intervention Comparisons in Type 2 Diabetes: The HEPATIC-T2DM Network Meta-analysis

BACKGROUND: Type 2 diabetes mellitus (T2DM) amplifies liver disease burden, yet the comparative hepatic effects of antidiabetic drugs remain poorly defined. PURPOSE: To compare associations between antidiabetic drug classes and major adverse liver outcomes (MALOs) in adults with T2DM. DATA SOURCES: PubMed, EMBASE, and Cochrane Central Register of Controlled Trials were searched from December 1946 through 23 August 2025. STUDY SELECTION: Studies enrolling adults with T2DM that evaluated associations between antidiabetic drug classes with regard to MALOs were included. DATA EXTRACTION: Data were extracted on study characteristics, drug exposures, and MALOs. DATA SYNTHESIS: A three-level Bayesian network meta-analysis with study- and database-level random effects was performed. Outcomes are reported as hazard ratios (HRs) and ranked using the surface under the cumulative ranking curve. Forty-six observational studies (N = 7,124,845) were included. Thiazolidinediones were least associated with hepatocellular carcinoma incidence and significantly lower than DPP-4 inhibitors (HR 0.50), GLP-1RAs (HR 0.72), insulin (HR 0.20), and sulfonylureas (HR 0.69). For decompensation (composite), GLP-1RAs were associated with the lowest hazard compared with all other classes (HRs 0.16-0.91; all significant). SGLT2 inhibitors were least associated with cirrhosis (HR 0.66 vs. DPP-4 inhibitors; HR 0.66 vs. GLP-1RAs). GLP-1RAs were least associated with variceal bleeding and hepatic encephalopathy, whereas SGLT2 inhibitors were least associated with liver-related mortality. LIMITATIONS: All included studies were observational, precluding causal inference. CONCLUSIONS: Liver-specific risk reduction is not uniform across antihyperglycemic drug classes. Randomized trials are needed to determine whether these associations reflect true drug effects.