Type 2 diabetes mellitus (T2DM) substantially increases the burden of chronic liver disease, although the comparative hepatic effects of glucose-lowering therapies remain incompletely characterized. A network meta-analysis published in Diabetes Care evaluated associations between major glucose-lowering drug classes and major adverse liver outcomes (MALOs) in adults with T2DM.
The analysis searched PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials through August 2025 and included observational studies evaluating liver-related outcomes across antihyperglycemic drug classes. A 3-level Bayesian network meta-analysis with study- and database-level random effects was performed.
Overall, 46 observational studies involving 7,124,845 participants were included. Outcomes included hepatocellular carcinoma incidence, cirrhosis, hepatic decompensation events, hepatic encephalopathy, variceal bleeding, and liver-related mortality.
Findings
- Thiazolidinediones were least associated with hepatocellular carcinoma incidence and showed significantly lower risk compared with dipeptidyl peptidase 4 (DPP-4) inhibitors (hazard ratio [HR] 0.50), glucagon-like peptide 1 receptor agonists (GLP-1RAs) (HR 0.72), insulin (HR 0.20), and sulfonylureas (HR 0.69).
- GLP-1RAs were associated with the lowest risk of hepatic decompensation outcomes compared with all other drug classes (HRs 0.16-0.91; all statistically significant).
- Sodium-glucose cotransporter 2 (SGLT2) inhibitors were least associated with cirrhosis, including lower risk versus DPP-4 inhibitors (HR 0.66) and GLP-1RAs (HR 0.66).
- GLP-1RAs were least associated with variceal bleeding and hepatic encephalopathy.
- SGLT2 inhibitors were least associated with liver-related mortality.
Associations between glucose-lowering drug classes and liver-related outcomes varied substantially across therapies in adults with T2DM. The findings support further randomized trials to determine whether the observed associations reflect true drug-specific hepatic effects.
