Fibroblast Growth Factor 21 Analogues Improve Fibrosis in Metabolic Dysfunction-Associated Steatohepatitis: An Updated Systematic Review and Meta-Analysis.

Background: Metabolic dysfunction-associated steatohepatitis (MASH) (formerly nonalcoholic steatohepatitis, MASH) is a growing cause of liver morbidity worldwide. Although therapeutic options for MASH fibrosis have expanded, including the approval of resmetirom for noncirrhotic MASH with F2-F3 fibrosis, additional therapies with antifibrotic efficacy remain needed. Fibroblast growth Factor 21 (FGF21) is a liver-derived hormone that regulates lipid metabolism, insulin sensitivity, and energy balance, and long-acting FGF21 analogues have shown promise in Phase 2 trials. We performed a systematic review and meta-analysis to quantify the efficacy and safety of FGF21 analogues in improving liver fibrosis in MASH. Methods: We searched PubMed, Scopus, and the Cochrane Library (through February 2026) for randomized controlled trials (RCTs) comparing an FGF21 analogue versus placebo in adults with biopsy-confirmed MASH. Primary outcomes were ≥ 1-stage histological fibrosis improvement without MASH worsening. Secondary outcomes included changes in hepatic fat, liver enzymes, and key metabolic parameters. Data were pooled using random-effects models, calculating pooled risk ratios (RRs) or standardized mean differences (SMDs) with 95% confidence intervals (CI). Results: We identified 10 RCTs (total: 1113 patients with F1-F4 fibrosis) meeting inclusion criteria. FGF21 analogue treatment significantly increased the likelihood of achieving ≥ 1-stage fibrosis improvement (RR: 2.25, CI: 1.25-4.03) compared with placebo. FGF21 analogues also produced larger reductions in hepatic fat content, liver stiffness, and fibrosis biomarkers than placebo. The incidence of serious adverse events was similar between groups. The most reported treatment-related side effects were gastrointestinal, especially nausea and diarrhea, and local injection reactions; these were generally mild and did not significantly limit therapy. Conclusions: FGF21 analogue therapy is associated with significantly greater histological fibrosis improvement in patients with MASH and appears to be well tolerated. These findings suggest that FGF21 analogues may become a valuable pharmacotherapy for MASH, but confirmatory larger trials and long-term data are needed.