Updating the MASH pharmacotherapy landscape: a network meta-analysis incorporating SGLT2 inhibitors and emerging combination therapies
Abstract
Background: Multiple 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.
Methods: We 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.
Results: We 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…
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