PMID-36934740 — Loomba: Semaglutide in MASH-related Cirrhosis (Phase 2, Lancet Gastro Hepatol 2023)

[DRAFT — authored 2026-04-19. Citation verified against PubMed/Lancet Gastroenterology & Hepatology 2026-04-19.]

Citation

Loomba R, Abdelmalek MF, Armstrong MJ, Jara M, Kjær MS, Krarup N, Lawitz E, Ratziu V, Sanyal AJ, Schattenberg JM, Newsome PN; NN9931-4492 Investigators. Semaglutide 2·4 mg once weekly in patients with non-alcoholic steatohepatitis-related cirrhosis: a randomised, placebo-controlled, phase 2 trial. Lancet Gastroenterol Hepatol. 2023;8(6):511-522. doi: 10.1016/S2468-1253(23)00068-7. PMID: 36934740.

External URL: PubMed

Study Design

Design: Phase 2 double-blind, placebo-controlled, randomized trial
Setting: 38 centers in Europe and USA
Population: Adults with biopsy-proven MASH-related compensated cirrhosis (F4 fibrosis)
Intervention: Semaglutide 2.4 mg weekly SC vs placebo, 48 weeks
Primary endpoint: Proportion achieving improvement in liver fibrosis without worsening of MASH at 48 weeks

Key Findings

Primary endpoint

Primary endpoint NOT met: No statistically significant difference between semaglutide and placebo in fibrosis improvement without worsening of MASH in the cirrhosis population

Secondary findings

Weight loss: Substantial with semaglutide, consistent with class expectations
Metabolic improvements: HbA1c, blood pressure, lipid improvements
ALT / AST: Improvements consistent with other MASH trials
No new safety signals in the cirrhosis population specifically

Clinical Relevance

Loomba 2023 is an important negative trial that demonstrates a key biological distinction:

MASH-cirrhosis biology differs from pre-cirrhotic MASH. Semaglutide 2.4 mg achieves fibrosis improvement in F2/F3 MASH (ESSENCE, PMID: 40305708: 36.8% fibrosis improvement) but NOT in F4 compensated cirrhosis.
Cirrhosis is less reversible — fibrosis regression is possible in F2/F3 but may be precluded once architectural remodeling and portal hypertension have developed.
Clinical implication: Semaglutide MASH approval (FDA August 2025) is for F2/F3 fibrosis — it does NOT extend to compensated or decompensated cirrhosis. Appropriate patient selection is essential.
Metabolic benefits still accrue in cirrhosis patients — weight loss and cardiometabolic benefits persist even without fibrosis improvement.

Linked Peptides

Semaglutide

Related Lessons

Lesson 5.2 — Semaglutide Deep Dive (MASH section — cirrhosis caveat; pair with ESSENCE for F2/F3 vs F4 framing)
Lesson 5.4 — MASH pipeline

Related Studies

PMID-40305708 – ESSENCE Sanyal Newsome Semaglutide MASH Phase 3 — positive Phase 3 in F2/F3 population
PMID-39412509 – ESSENCE Design Baseline Characteristics — ESSENCE design
PMID-38856224 – Sanyal Tirzepatide MASH Phase 2 SYNERGY-NASH — tirz Phase 2 MASH (also F2/F3 population)

PMID-36934740 – Loomba Semaglutide MASH Cirrhosis Phase 2