Therapeutic Signals Without Histologic Certainty: FGF Analogues in Compensated MASH Cirrhosis—A Systematic Review and Meta‐Analysis

Background and Aims Compensated MASH cirrhosis is an advanced disease with no current approved pharmacologic therapy. FGF analogues have shown biological activity, but individual trials have not established histologic efficacy. We aim to evaluate their effects across histologic and non‐invasive outcomes in this population. Methods PubMed, Embase, CENTRAL and ClinicalTrials.gov were searched from inception through 8 July 2026 for RCTs comparing FGF analogues with placebo in adults with compensated (F4) MASH cirrhosis. The primary outcome was at least 1‐stage fibrosis improvement without MASH worsening. Secondary outcomes included Pro‐C3, Enhanced Liver Fibrosis (ELF) score and liver stiffness. MASH resolution and safety were exploratory. Random‐effects meta‐analyses were performed. RoB 2 and GRADE assessments were conducted. Results Five RCTs involving 589 participants were included. FGF analogues did not significantly improve fibrosis by at least one stage without worsening of MASH (RR, 1.32; 95% CI, 0.89–1.97). In post hoc exploratory analyses, FGF21 analogues increased MASH resolution alone (RR, 3.17; 95% CI, 1.49–6.73), whereas resolution without worsening of fibrosis remained inconclusive (RR, 1.75; 95% CI, 0.95–3.23). Treatment reduced ELF score (MD, −0.52; 95% CI, −0.79 to −0.25), Pro‐C3 (MD, −26.49 percentage points; 95% CI, −40.47 to −12.51) and liver stiffness (MD, −2.30 kPa; 95% CI, −3.90 to −0.71). Serious adverse events were not significantly increased, but adverse‐event‐related discontinuation was more frequent (RR, 3.44; 95% CI, 1.13–10.43). FGF19 findings derive from a single trial (aldafermin). Conclusions FGF analogues did not significantly improve the primary fibrosis endpoint, but improved MASH resolution and non‐invasive fibrosis measures, supporting continued evaluation of FGF analogues in Phase 3 trials with longer follow‐up.