Semaglutide in MASH with F2-F3 fibrosis: a holistic perspective on the ESSENCE phase 3 trial

Abstract

Metabolic dysfunction-associated steatohepatitis (MASH) with significant fibrosis (F2-F3) is a critical stage of metabolic dysfunction-associated steatotic liver disease (MASLD), during which intervention may avert transition to cirrhosis, hepatocellular carcinoma, and liver-related death. The phase 3 ESSENCE trial (NCT04822181) evaluated once-weekly subcutaneous semaglutide 2.4 mg vs. placebo over 240 weeks in adults with biopsy-confirmed MASH and F2-F3 fibrosis. A prespecified interim histologic assessment was performed at week 72 among the first 800 randomized participants. Semaglutide increased MASH resolution without worsening fibrosis and significantly increased the proportion of individuals achieving ≥ 1-stage fibrosis improvement compared with placebo, with a clinically meaningful number needed to treat. These histologic effects coincided with substantial weight reduction (~10%-11% vs. ~2% with placebo) and broad improvements in cardiometabolic risk profiles, including glycemia, blood pressure, lipid levels, and inflammatory biomarkers. Favorable shifts were also observed in non-invasive assessments, including the enhanced liver fibrosis score, vibration-controlled transient elastography, N-terminal type III Collagen Propeptide (PRO-C3), FibroScan-AST (FAST) score, and aminotransferases. Safety outcomes were consistent with the established semaglutide profile in type 2 diabetes and obesity. Here, we critically appraise ESSENCE from clinical and translational perspectives and consider the relative contributions of weight loss vs. potential weight-independent mechanisms. Semaglutide was also situated among emerging latestage therapies, including resmetirom, a thyroid hormone receptor β agonist with demonstrated antifibrotic and antisteatohepatitic activity. Finally, we outline the implications of adopting semaglutide as a disease-modifying agent in MASH with F2-F3 fibrosis, note the study limitations and remaining questions, and argue that combinatorial approaches targeting complementary metabolic and hepatocentric pathways may define the next phase of MASLD management.

Keywords

GLP-1 receptor agonists / weight loss / liver fibrosis / phase 3 clinical trial / metabolic syndrome / non-invasive tests

References

[1] Dulai PS,Patel J.Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: systematic review and meta-analysis.Hepatology2017;65:1557-65 PMCID:5397356

[2] Younossi ZM,Abdelatif D,Henry L.Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes.Hepatology2016;64:73-84

[3] Do A,Mehal WZ.Therapeutic landscape of metabolic dysfunction-associated steatohepatitis (MASH).Nat Rev Drug Discov2025;24:171-89

[4] Yabut JM.Glucagon-like peptide-1 receptor-based therapeutics for metabolic liver disease.Endocr Rev2023;44:14-32

[5] Banerjee M,Pal S.Histological efficacy of anti-diabetic agents in MASH and the mediating role of weight loss: a network meta-analysis.Diabetes Obes Metab2026;28:287-95

[6] Schattenberg JM,Kliers I.Proteomic signatures reflect effects of semaglutide treatment for MASH.JHEP Rep2025;7:101521 PMCID:PMC12447996

[7] Sanyal AJ, Newsome PN, Kliers I, et al.; ESSENCE Study Group. Phase 3 trial of semaglutide in metabolic dysfunction-associated steatohepatitis. N Engl J Med. 2025;392:2089-99. PMCID:12341575

[8] Newsome PN, Buchholtz K, Cusi K, et al.; NN9931-4296 Investigators. A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis. N Engl J Med. 2021;384:1113-24.

[9] Sanyal AJ, Friedman SL, McCullough AJ, Dimick-Santos L; American Association for the Study of Liver Diseases, United States Food and Drug Administration. Challenges and opportunities in drug and biomarker development for nonalcoholic steatohepatitis: findings and recommendations from an American Association for the Study of Liver Diseases-U.S. Food and Drug Administration Joint Workshop. Hepatology. 2015;61:1392-405. PMCID:4900161

[10] Wilding JPH, Batterham RL, Calanna S, et al.; STEP 1 Study Group. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med. 2021;384:989-1002. PMCID:12058953

[11] Vilar-Gomez E,Calzadilla-Bertot L.Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis.Gastroenterology2015;149:367-78.e5 PMCID:9904363

[12] Marso SP, Bain SC, Consoli A, et al.; SUSTAIN-6 Investigators. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375:1834-44. PMCID:11543192

[13] Newsome PN,Deeks JJ.FibroScan-AST (FAST) score for the non-invasive identification of patients with non-alcoholic steatohepatitis with significant activity and fibrosis: a prospective derivation and global validation study.Lancet Gastroenterol Hepatol2020;5:362-73 PMCID:7066580

[14] Rosenberg WM, Voelker M, Thiel R, et al.; European Liver Fibrosis Group. Serum markers detect the presence of liver fibrosis: a cohort study. Gastroenterology. 2004;127:1704-13.

[15] Petta S,Targher G.Focus on semaglutide 2.4 mg/week for the treatment of metabolic dysfunction-associated steatohepatitis.Liver Int2025;45:e70407 PMCID:12558666

[16] Loomba R, Abdelmalek MF, Armstrong MJ, et al.; 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;8:511-22. PMCID:10792518

[17] Jara M,Kjær MS.Modulation of metabolic, inflammatory and fibrotic pathways by semaglutide in metabolic dysfunction-associated steatohepatitis.Nat Med2025;31:3128-40 PMCID:PMC12443624

[18] Xiao T,Wang Y,Zhang C.Benchmarking large language models for cell typing in single-cell RNA-Seq.Brief Bioinform2025;26:bbaf677 PMCID:PMC12704438

[19] Maretty L,Simonsen L.Proteomic changes upon treatment with semaglutide in individuals with obesity.Nat Med2025;31:267-77 PMCID:PMC11750704

[20] Harrison SA, Bedossa P, Guy CD, et al.; MAESTRO-NASH Investigators. A phase 3, randomized, controlled trial of resmetirom in NASH with liver fibrosis. N Engl J Med. 2024;390:497-509.

[21] Harrison SA,Guy CD.Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial.Lancet2019;394:2012-24

[22] Zhou XD,Byrne CD.Combination therapies for metabolic dysfunction-associated steatohepatitis: challenges and opportunities.Gut2026;75:815-25

[23] Pirola CJ.Panomics in metabolic dysfunction-associated steatotic liver disease: unravelling the drivers of disease heterogeneity.Clin Mol Hepatol2026;32:156-69 PMCID:PMC12835749

[24] Pirola CJ,Sookoian S.The proteomics of MASLD progression: insights from functional analysis to drive the development of new therapeutic solutions.Aliment Pharmacol Ther2025;61:614-27