Hepatic events prevention by antihyperglycemic therapies and intervention comparisons in type 2 diabetes: the HEPATIC-T2DM network meta-analysis

Journal article

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.

Authors: Passos, PRC; Motta, R; Oliveira Costa Filho, V; Noronha, MM; Venâncio, RC

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: American Diabetes Association
• Journal: Diabetes Care
• Volume: 49
• Issue: 6
• Pages: 1144–1153
• Place of publication: United States
• Publication date: 2026-04-13
• Acceptance date: 2026-03-15
• DOI: 10.2337/dc26-0336
• EISSN: 1935-5548
• ISSN: 0149-5992
• Pmid: 41973508
• Language: English