Impact of SGLT2i and GLP-1RA on liver-related events in patients with MASLD and type 2 diabetes: A network meta-analysis

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Background & Aims: Glucose-lowering drugs (GLDs) including glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) have been broadly evaluated in patients with coexisting metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes (T2D). However, their comparative efficacy in reducing the risk of liver-related events remains unclear. Thus, we aim to simultaneously compare the efficacy of different GLDs for patients with MASLD and T2D. Methods: We searched PubMed, EMBASE, Cochrane Library and Web of Science for observational studies from inception to April 2025. We evaluated the comparative efficacy of six GLDs, including GLP-1RAs, SGLT2is, dipeptidyl peptidase-4 inhibitors, metformin, sulfonylureas, and thiazolidinediones using pairwise meta-analysis and Bayesian network meta-analysis. We assessed overall and individual liver-related events, including the development of cirrhosis, decompensation and hepatocellular carcinoma (HCC), with treatments ranked via SUCRA (surface under the cumulative ranking) scores. Results: Twelve studies involving 737,408 patients with MASLD and diabetes were analyzed. Both GLP-1RAs and SGLT2is, when compared to non-GLP-1RA and non-SGLT2i controls, were significantly associated with reduced risk for overall liver-related events (hazard ratio [HR] 0.79, 95% CI 0.70-0.90, and HR 0.75, 95% CI 0.63-0.88, respectively). Similar results were also observed for HCC and liver decompensation (HRs 0.74-0.81). In individuals with obesity, a greater risk reduction was observed for GLP-1RAs (HR 0.74, 95% CI 0.56-0.99) but not for SGLT2is. GLP-1RAs also outperformed SGLT2is in non-Asian populations (HR 0.91, 95% CI 0.83-0.99). Network meta-analysis identified GLP-1RAs and SGLT2is (SUCRA 90%/80%, respectively) as the most effective for risk reduction, with significantly greater efficacy than other GLDs (HRs 0.75-0.79). Conclusions: GLP-1RAs and SGLT2is were associated with reduced risks of liver-related events in patients with MASLD and T2D. GLP-1RAs showed superior benefit in individuals with obesity and in non-Asian populations, supporting a personalized approach to treatment selection. Impact and implications: The long-term liver-related efficacy of different glucose-lowering drugs (GLDs) in patients with coexisting metabolic dysfunction-associated steatotic liver disease and type 2 diabetes remains unclear, despite a higher lifetime risk of advanced liver disease in this population. We evaluated the comparative efficacy of six GLDs by pairwise meta-analysis and Bayesian network meta-analysis, demonstrating GLP-1RAs and SGLT2is may be among the most effective GLDs for reducing liver-related events, with GLP-1RAs appearing particularly beneficial for patients with obesity. These findings support a personalized approach to treatment selection and underscore the need for future clinical trials to confirm the efficacy of GLDs. INPLASY registration number: INPLASY202530085.

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