PMID-40305708 — ESSENCE: Semaglutide Phase 3 in MASH (NEJM 2025)

[DRAFT — authored 2026-04-19. Citation verified against PubMed/NEJM 2026-04-19.]

Citation

Sanyal AJ, Newsome PN, Kliers I, Østergaard LH, Long MT, Kjær MS, Cali AMG, Bugianesi E, Rinella ME, Roden M, Ratziu V; ESSENCE Study Group. Phase 3 Trial of Semaglutide in Metabolic Dysfunction-Associated Steatohepatitis. N Engl J Med. 2025;392:2089-2099. doi: 10.1056/NEJMoa2413258. PMID: 40305708. NCT04822181.

External URL: PubMed

Study Design

Design: Two-part Phase 3 randomized, multicenter, double-blind, placebo-controlled trial
Planned total duration: 240 weeks (follow-up biopsy at week 240)
Part 1 (this publication): 72-week primary analysis
N (interim Part 1 analysis): 800 participants (1,197 enrolled total)
Population: Adults with biopsy-proven MASH with liver fibrosis stage F2 or F3
Randomization: 2:1 to once-weekly subcutaneous semaglutide 2.4 mg vs placebo
Dual primary endpoints: (1) Resolution of steatohepatitis without worsening of fibrosis; (2) Reduction in liver fibrosis without worsening of steatohepatitis
Key secondary: Combined endpoint (both primary outcomes achieved); body weight change; cardiometabolic parameters

Key Findings

Primary endpoints at week 72

Outcome	Semaglutide	Placebo	Estimated difference
Resolution of MASH without worsening fibrosis	62.9%	34.3%	+28.6 pp (95% CI 20.5 to 36.7, P<0.001)
Reduction in liver fibrosis without worsening MASH	36.8%	22.4%	+14.4 pp (95% CI 7.0 to 21.9, P<0.001)

Combined endpoint

Both outcomes achieved in 32.7% semaglutide vs 16.1% placebo (estimated difference +16.5 pp; P<0.001)

Body weight

Semaglutide: −10.5% at week 72
Placebo: −2.0%
Treatment difference: −8.5 pp (95% CI −9.6 to −7.4, P<0.001)

Safety

GI adverse events more common in semaglutide group as expected
No new safety concerns in a liver-disease population
No signals of drug-induced liver injury
Reinforces favorable safety profile in MASH context

Clinical Relevance

ESSENCE is the pivotal Phase 3 trial establishing semaglutide 2.4 mg weekly as a disease-modifying therapy for MASH with F2/F3 fibrosis. Core points:

FDA approval August 15, 2025 — semaglutide became the second FDA-approved therapy for MASH, after resmetirom (March 2024). This is a landmark expansion of the Wegovy indication into hepatology.
Effect size exceeds resmetirom — 62.9% MASH resolution in ESSENCE compares favorably with ~30% MASH resolution in MAESTRO-NASH (resmetirom pivotal trial). Cross-trial comparison caveats apply.
Both primary endpoints met — robust evidence supporting both steatohepatitis resolution AND fibrosis improvement as independent clinical outcomes.
Ongoing Part 2: 240-week follow-up with end-of-treatment liver biopsy will evaluate long-term outcomes including progression to cirrhosis, liver-related events, and mortality.
Contrasts with Loomba 2023 Phase 2 in cirrhosis (PMID-36934740 – Loomba Semaglutide MASH Cirrhosis Phase 2) where primary endpoint was NOT met — MASH-cirrhosis biology may differ from pre-cirrhotic MASH biology.

Linked Peptides

Semaglutide

Related Lessons

Lesson 5.2 — Semaglutide Deep Dive (MASH section — FDA-approved indication)
Lesson 5.4 — MASH class-level comparison

Related Studies

PMID-39412509 – ESSENCE Design Baseline Characteristics — design / baseline companion
PMID-36934740 – Loomba Semaglutide MASH Cirrhosis Phase 2 — cirrhosis-population negative contrast
PMID-38856224 – Sanyal Tirzepatide MASH Phase 2 SYNERGY-NASH — tirzepatide Phase 2 MASH companion

PMID-40305708 – ESSENCE Sanyal Newsome Semaglutide MASH Phase 3