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

Abstract

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.

Keywords: FGF21; GLP-1; metabolic and insulin-sensitizing agents; metabolic-dysfunction-associated steatohepatitis; network meta-analysis; randomized controlled trial; translation to patients.