<scp>GLP</scp> ‐ <scp>1RA</scp> and Liver Fibrosis Progression in <scp>MASLD</scp> and Type 2 Diabetes: Target Trial Emulation Using Propensity Score Matching

BACKGROUND AND AIMS: GLP-1 receptor agonists (GLP-1RA) are widely used in type 2 diabetes mellitus (T2DM) and may confer hepatoprotective effects in metabolic dysfunction-associated steatotic liver disease (MASLD). Their impact on liver fibrosis progression in real-world clinical settings remains unclear. This study evaluated the link between GLP-1RA use and liver fibrosis progression in T2DM patients with early-stage MASLD. METHODS: We conducted a retrospective cohort study emulating a target trial using electronic health records from the Mass General Brigham (MGB) system between 2010 and 2023. Adults with MASLD and T2DM who initiated GLP-1RA or dipeptidyl peptidase-4 inhibitor (DPP-4i) therapy and had baseline Fibrosis-4 (FIB-4) scores < 2.67 were included. Propensity score matching (1:1) was applied to balance baseline covariates between groups. The primary outcome was progression to high-risk FIB-4 (> 2.67), confirmed by two consecutive values ≥ 90 days apart within a one-year period. The secondary outcome was a composite of cirrhosis, hepatic decompensation, hepatocellular carcinoma, or liver transplantation. RESULTS: A total of 2238 matched pairs were analysed. GLP-1RA use was associated with a lower risk of fibrosis progression compared to DPP-4i (incidence rate 3.25 vs. 4.29 per 100 person-years; HR 0.75, 95% CI 0.65-0.87). Results were consistent in per-protocol (HR 0.80) and landmark sensitivity analyses. The risk reduction was also observed across subgroups, including those with low baseline FIB-4, BMI < 30, and users of statins, aspirin or metformin. No significant difference was found in secondary liver-related outcomes (HR 0.98, 95% CI 0.72-1.34). CONCLUSION: GLP-1RA use significantly reduced the risk of liver fibrosis progression in patients with MASLD and T2DM, supporting its potential role in early disease modification.