---
type: source
title: "Phase 3 Trial of Semaglutide in Metabolic Dysfunction-Associated Steatohepatitis (MASH)"
author: "New England Journal of Medicine"
url: https://www.nejm.org/doi/10.1056/NEJMoa2413258
date: 2025-05-01
domain: health
secondary_domains: []
format: paper
status: enrichment
priority: medium
tags: [glp-1, semaglutide, MASH, NASH, liver-disease, organ-protection]
processed_by: vida
processed_date: 2026-03-16
enrichments_applied: ["glp-1-multi-organ-protection-creates-compounding-value-across-kidney-cardiovascular-and-metabolic-endpoints.md", "GLP-1 receptor agonists are the largest therapeutic category launch in pharmaceutical history but their chronic use model makes the net cost impact inflationary through 2035.md"]
extraction_model: "anthropic/claude-sonnet-4.5"
---

## Content

Phase 3 trial of semaglutide 2.4mg in patients with MASH and moderate or advanced liver fibrosis.

**Key findings:**
- Resolution of steatohepatitis without worsening fibrosis: 62.9% semaglutide vs. 34.3% placebo
- GLP-1 RAs improve fibrosis stage without worsening MASH (meta-analysis data)
- Hepatoprotective effects are multifactorial: glycemic control + insulin resistance + weight loss + direct liver effects
- Some liver benefits appear at least partly independent of weight loss

**Meta-analysis context (2025):**
- GLP-1 RAs significantly increase histologic resolution of MASH
- Decreased liver fat deposition, improved hepatocellular ballooning, reduced lobular inflammation
- Associated with reduced risk of major CV events, clinically significant portal hypertension, and all-cause mortality in MASLD/MASH patients

## Agent Notes
**Why this matters:** MASH/NASH is projected to become the leading cause of liver transplantation. If GLP-1s can resolve steatohepatitis and slow fibrosis, this prevents enormously expensive late-stage liver disease. Combined with CV and kidney protection, GLP-1s are emerging as multi-organ protective agents, not just weight loss drugs.
**What surprised me:** The 62.9% resolution rate is very high — nearly 2x placebo. And some benefits are independent of weight loss, suggesting a direct hepatoprotective mechanism. This adds a third organ-protection pathway (heart, kidney, liver) to the multi-indication economic case.
**What I expected but didn't find:** No cost-effectiveness analysis specific to MASH indication. The Value in Health Medicare study showed only $28M MASH savings — surprisingly small given the clinical magnitude, likely because MASH progression to transplant takes decades.
**KB connections:** Strengthens the multi-indication benefit thesis that the existing GLP-1 claim doesn't fully capture. The combined CV + kidney + liver protection may justify chronic use even if weight management alone doesn't.
**Extraction hints:** Potential claim: "GLP-1 agonists protect three major organ systems simultaneously — cardiovascular, renal, and hepatic — through mechanisms partially independent of weight loss, making them the first drug class to address the metabolic syndrome as a unified disease."
**Context:** NEJM publication — highest evidence tier. Resmetirom (Rezdiffra) was approved for MASH in March 2024, so GLP-1s now compete with a dedicated MASH therapy. Head-to-head data unclear.

## Curator Notes (structured handoff for extractor)
PRIMARY CONNECTION: [[GLP-1 receptor agonists are the largest therapeutic category launch in pharmaceutical history but their chronic use model makes the net cost impact inflationary through 2035]]
WHY ARCHIVED: Third organ-protection pathway (after CV and kidney) strengthens the case that GLP-1s should be evaluated as multi-organ protective agents, not just weight loss drugs
EXTRACTION HINT: The multi-organ protection thesis may justify reframing the existing GLP-1 claim from a weight-loss-economics frame to a metabolic-disease-prevention frame


## Key Facts
- Semaglutide 2.4mg achieved 62.9% resolution of steatohepatitis without worsening fibrosis vs 34.3% placebo in Phase 3 trial
- Resmetirom (Rezdiffra) was approved for MASH in March 2024, creating a dedicated MASH therapy competitor
- MASH/NASH is projected to become the leading cause of liver transplantation
- Meta-analysis shows GLP-1 RAs reduce risk of major CV events, clinically significant portal hypertension, and all-cause mortality in MASLD/MASH patients
