Network meta-analysis ranks FGF21 analogs and SGLT2 inhibitors highest for MASH fibrosisNew analysis shows SGLT2 inhibitors may help liver scarring improve in adults with fatty liver disease

BackgroundMultiple pharmacological agents targeting distinct pathways (e.g., GLP-1, FGF21, THR-β) show promise for metabolic dysfunction-associated steatohepatitis (MASH). However, while recent meta-analyses have established the efficacy of GLP-1 RAs and FGF21 analogs, they largely predate critical histological trials on SGLT2 inhibitors, leaving the comparative position of this highly accessible oral therapy undefined. We aimed to systematically rank the efficacy and tolerability of distinct pharmacological mechanisms for MASH and characterize their benefit–risk profiles through cluster analysis.MethodsWe searched PubMed, Embase, Web of Science, Scopus, and Cochrane Library for Phase II/III randomized controlled trials (RCTs) involving adults with biopsy-proven MASH. The primary outcome was fibrosis improvement (≥1 stage reduction without MASH worsening). Secondary outcomes included MASH resolution and safety (discontinuation due to adverse events). A frequentist network meta-analysis (NMA) was performed.ResultsWe included 34 studies from 33 unique publications. For fibrosis improvement, FGF21 analogs (RR 2.22, 95% CI 1.40-3.54) and SGLT2 inhibitors (RR 2.27, 95% CI 1.22-4.17) ranked highest. Notably, SGLT2 inhibitors numerically outperformed the FDA-approved THR-β agonist (RR 1.61) and GLP-1 RAs (RR 1.51, 95% CI 1.09-2.10). For MASH resolution, GLP-1/GIP dual agonists (RR 5.21) and FGF21 analogs (RR 3.52) showed the highest efficacy, while SGLT2 inhibitors also yielded significant benefits (RR 2.92, 95% CI 1.18-7.26). In the two-dimensional cluster analysis evaluating the balance between fibrosis efficacy and tolerability, SGLT2 inhibitors numerically occupied the “Optimal Zone,” though this finding is based on limited histological data. Sensitivity analyses excluding small-scale studies confirmed the robustness of these rankings.ConclusionFGF21 analogs (RR 2.22, 95% CI 1.40-3.54) demonstrated the most robust evidence for fibrosis improvement. Preliminary evidence from a single pivotal trial suggests SGLT2 inhibitors (RR 2.27, 95% CI 1.22-4.17) may represent a promising oral option, though this requires confirmation in adequately powered Phase 3 trials. Further adequately powered Phase 3 trials are warranted to validate the magnitude of these histological benefits.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD420261292638.