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AIMS: While randomized controlled trials data on the long-term effect of glucose-lowering drugs (GLDs) on liver-related outcomes are lacking, population-based studies have evaluated the associations of GLDs with liver-related outcomes in individuals with type 2 diabetes (T2D). we aimed to conduct a systematic review of population-based studies evaluating the effects of GLDs on liver-related outcomes in people with T2D.METHODS: PubMed, Web of Science, and Embase databases were systematically searched for population-based studies testing the associations of GLDs with liver-related outcomes in individuals with T2D and no liver disease other than non-alcoholic fatty liver disease (NAFLD) from inception to 23 February 2024. GLDs included SGLT2is, TZDs, insulin, GLP-1 RAs and dipeptidyl peptidase-4 inhibitors (DPP4Is).RESULTS: Ten cohort studies, comprising 1,274,641 participants, met the inclusion criteria. The median follow-up period ranged from 8.9 to 76 months. Of all the GLDs under investigation, SGLT2is were associated with the strongest reduction in NAFLD incidence, cirrhosis, and composite liver-related events compared to other medications. TZDs were associated with a reduced risk of developing NAFLD and cirrhosis but were not significantly associated with a lower incidence of hepatocellular carcinoma. GLP-1 RAs demonstrated a significant association with reduced liver-related mortality.CONCLUSIONS: Observational data from population-based studies suggest that GLDs such as SGLT2is are associated with beneficial long-term liver-related outcomes in T2D patients with NAFLD. Additional studies, including randomized controlled trials with long-term follow-up, are needed to confirm these findings.REGISTRATION NUMBER: PROSPERO CRD442024536872.