Comparative efficacy of phase 2–3 therapies for non-cirrhotic metabolic dysfunction-associated steatohepatitis: An updated network meta-analysis

Background: Metabolic-dysfunction-associated steatohepatitis has a rapidly expanding phase 2–3 drug pipeline, yet comparative evidence across mechanisms remains limited, and most trials are placebo controlled. Methods: We performed a systematic review and frequentist network meta-analysis of phase 2–3 randomized trials in adults with non-cirrhotic disease. Primary endpoints were (1) resolution of steatohepatitis without worsening of fibrosis, (2) at least one-stage improvement in fibrosis without worsening of steatohepatitis (both biopsy based), and (3) at least a 30% relative reduction in liver fat measured by magnetic resonance imaging-derived proton density fat fraction. Interventions were compared across mechanistic groups and ranked using network estimates. Findings: Sixty-four trials (12,787 participants) were included. Therapies targeting metabolic dysfunction and insulin sensitivity showed the most consistent benefits versus placebo (odds ratios 2.5–7.1) and the lowest failure rates across biopsy and imaging endpoints, whereas anti-inflammatory and anti-fibrotic agents showed more variable biopsy responses. Fibroblast growth factor 21 analogs and incretin-based multi-agonists ranked among the leading classes. Despite favorable relative effects, absolute non-response remained substantial: 35%–70% of treated participants did not meet prespecified biopsy endpoints, and biopsy placebo response rates were 11%–18%. Conclusions: By benchmarking cross-class performance in a predominantly placebo-anchored network, these findings support metabolic therapies as a rational foundation for combination regimens spanning complementary mechanisms and highlight the need for more durable approaches to achieve clinically meaningful biopsy outcomes. Funding: This work received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.