Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2023 Jun;8(6):511-522.
doi: 10.1016/S2468-1253(23)00068-7. Epub 2023 Mar 16.

Semaglutide 2·4 mg once weekly in patients with non-alcoholic steatohepatitis-related cirrhosis: a randomised, placebo-controlled phase 2 trial

Rohit Loomba  1 , Manal F Abdelmalek  2 , Matthew J Armstrong  3 , Maximilian Jara  4 , Mette Skalshøi Kjær  4 , Niels Krarup  4 , Eric Lawitz  5 , Vlad Ratziu  6 , Arun J Sanyal  7 , Jörn M Schattenberg  8 , Philip N Newsome  3 ; NN9931-4492 investigators
Affiliations
Clinical Trial

Semaglutide 2·4 mg once weekly in patients with non-alcoholic steatohepatitis-related cirrhosis: a randomised, placebo-controlled phase 2 trial

Rohit Loomba et al. Lancet Gastroenterol Hepatol. 2023 Jun.

Abstract

Background: Patients with non-alcoholic steatohepatitis (NASH)-related cirrhosis are at high risk of liver-related and all-cause morbidity and mortality. We investigated the efficacy and safety of the glucagon-like peptide-1 analogue semaglutide in patients with NASH and compensated cirrhosis.

Methods: This double-blind, placebo-controlled phase 2 trial enrolled patients from 38 centres in Europe and the USA. Adults with biopsy-confirmed NASH-related cirrhosis and body-mass index (BMI) of 27 kg/m2 or more were randomly assigned (2:1) to receive either once-weekly subcutaneous semaglutide 2·4 mg or visually matching placebo. Patients were randomly allocated via an interactive web response system, stratified by presence or absence of type 2 diabetes. Patients, investigators, and those assessing outcomes were masked to treatment assignment. The primary endpoint was the proportion of patients with an improvement in liver fibrosis of one stage or more without worsening of NASH after 48 weeks, assessed by biopsy in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study drug. The trial is closed and completed, and registered with ClinicalTrials.gov, number NCT03987451.

Findings: 71 patients were enrolled between June 18, 2019, and April 22, 2021; 49 (69%) patients were female and 22 (31%) were male. Patients had a mean age of 59·5 years (SD 8·0) and mean BMI of 34·9 kg/m2 (SD 5·9); 53 (75%) patients had diabetes. 47 patients were randomly assigned to the semaglutide group and 24 to the placebo group. After 48 weeks, there was no statistically significant difference between the two groups in the proportion of patients with an improvement in liver fibrosis of one stage or more without worsening of NASH (five [11%] of 47 patients in the semaglutide group vs seven [29%] of 24 in the placebo group; odds ratio 0·28 [95% CI 0·06-1·24; p=0·087). There was also no significant difference between groups in the proportion of patients who achieved NASH resolution (p=0·29). Similar proportions of patients in each group reported adverse events (42 [89%] patients in the semaglutide group vs 19 [79%] in the placebo group) and serious adverse events (six [13%] vs two [8%]). The most common adverse events were nausea (21 [45%] vs four [17%]), diarrhoea (nine [19%] vs two [8%]), and vomiting (eight [17%] vs none). Hepatic and renal function remained stable. There were no decompensating events or deaths.

Interpretation: In patients with NASH and compensated cirrhosis, semaglutide did not significantly improve fibrosis or achievement of NASH resolution versus placebo. No new safety concerns were raised.

Funding: Novo Nordisk A/S.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests RL, MFA, MJA, EL, VR, AJS, JMS, and PNN were investigators in the trial and received grants from the study sponsor paid to their institutions to conduct the study. RL is co-founder of LipoNexus Inc, and a consultant to Aardvark Therapeutics, Altimmune, Anylam/Regeneron, Amgen, Arrowhead Pharmaceuticals, AstraZeneca, Bristol Myers Squibb, CohBar, Eli Lilly, Galmed, Gilead, Glympse bio, Hightide, Inipharma, Intercept, Inventiva, Ionis, Janssen, Madrigal, Metacrine, NGM Biopharmaceuticals, Novartis, Novo Nordisk, Merck, Pfizer, Sagimet, Theratechnologies, 89bio, Terns Pharmaceuticals, and Viking Therapeutics. In addition, his institutions have received research grants from Arrowhead Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Galectin Therapeutics, Galmed Pharmaceuticals, Gilead, Hanmi, Intercept, Inventiva, Ionis, Janssen, Madrigal Pharmaceuticals, Merck, NGM Biopharmaceuticals, Novo Nordisk, Pfizer, Sonic Incytes, and Terns Pharmaceuticals. MFA has received research/grant support from Allergan, Boeringher Ingelheim, BMS, Celgene, Durect, Enanta, Enyo, Galmed, Genentech, Gilead, Hanmi, Intercept, Inventiva, Madrigal, Novo Nordisk, Poxel, TARGET Pharma, and Viking; has acted as a consultant for Hanmi, NGM, BMS, 89bio, Madrigal, Intercept, Merck, Inventiva, Novo Nordisk, Sonic Incytes, and Theratechnologies; has served as a speaker for Clinical Care Options, Medscape, Fishawack LLC, and Terra Firma; has received royalties from UptoDate; and holds stock in Pfizer. MJA has received consultation fees, speaker fees, and research grants from Novo Nordisk and speaker fees and consultation fees from Norgine. JS has acted as a consultant for Apollo Endoscopy, Bristol Myers Squibb, Boehringer Ingelheim, Echosens, Genfit, Gilead Sciences, Intercept Pharmaceuticals, Madrigal, Merck, Nordic Bioscience, Novartis, Pfizer, Roche, Sanofi, and Siemens Healthcare GmbH; received research funding from Boehringer Ingelheim, Gilead Sciences, and Siemens Healthcare GmbH; and received speaker honorarium from Falk Foundation and Madrigal. MJ, MSK, and NK are employees of Novo Nordisk A/S; MSK and MJ are shareholders in Novo Nordisk A/S. EL has received research/grant support from 89bio, AbbVie, Akero Therapeutics, Allergan, Alnylam Pharmaceuticals, Amgen, Ascelia Pharma, Assemblybio, AstraZeneca, Axcella Health, Biocryst Pharmaceuticals, Bird Rock Bio, Boehringer Ingelheim, Bristol Myers Squibb, Conatus Pharmaceuticals, Cymabay Therapeutics, CytoDyn, DSM, Durect Corporation, Eli Lilly and Company, Enanta Pharmaceuticals, Enyo Pharma, Exalenz Bioscience, Galectin Therapeutics, Galmed Pharmaceuticals, Genfit, Genentech, Gilead Sciences, GlaxoSmithKline, Hanmi Pharmaceuticals, Hightide Biopharma, Intercept Pharmaceuticals, Inventiva, Janssen Pharmaceuticals, Laboratory for Advanced Medicine, Loxo Oncology, Madrigal Pharmaceuticals, Merck & Co, Metacrine, NGM Biopharmaceuticals, Northsea Therapeutics, Novartis, Novo Nordisk, Pfizer, Poxel, Roche, Sagimet Biosciences, Synlogic Therapeutics, Terns Pharmaceuticals, Viking Therapeutics, and Zydus Pharmaceuticals; has acted as a consultant for Akero, Boehringer Ingelheim, BMS, Intercept, Novo Nordisk, Metacrine, Sagimet, and Terns; and has received speaker honorarium from Gilead Sciences, AbbVie, and Intercept. AJS is President of Sanyal Biotechnology and has stock options in Exhalenz, Genfit, Hemoshear, Durect, Indalo, Northsea, Tiziana, and Rivus. He has served as a consultant to Genfit, Gilead, Malinckrodt, Pfizer, Salix, Boehringer Ingelheim, Novartis, Bristol Myers Squibb, Merck, Hemoshear, Lilly, Novo Nordisk, Terns, Albireo, Janssen, Poxel, 89bio, Siemens, AstraZeneca, NGM Bio, Amgen, Regeneron, Genentech, Alnylam, Roche, Madrigal, Inventiva, Covance, Prosciento, Histoindex, and PathAI. His institution has received grant support from Gilead, Malinckrodt, Boehringer Ingelheim, Novartis, Bristol Myers Squibb, Merck, Lilly, Novo Nordisk, Fractyl, Madrigal, and Inventiva. He has received royalties from Elsevier and UptoDate. PNN has received grants from Novo Nordisk and Boehringer Ingelheim; and has acted as a consultant on behalf of the University of Birmingham for Novo Nordisk, Boehringer Ingelheim, Gilead, Intercept Pharmaceuticals, Pfizer, and Poxel Pharmaceuticals. VR has acted as a consultant for Boehringer Ingelheim, Novo Nordisk, Poxel, Enyo, Madrigal, Terns, Intercept, NGM Bio, and Pfizer; and received research grants from Gilead Sciences and Intercept Pharmaceuticals.

Figures

Figure 1:
Figure 1:
Trial profile
Figure 2:
Figure 2:. Improvement in liver fibrosis and no worsening of NASH (A) and resolution of NASH (B) at 48 weeks
p-values are two-sided and taken from a Cochran–Mantel–Haenszel test stratified by baseline diabetes status. Patients with missing outcomes were imputed as non-responders. NASH=non-alcoholic steatohepatitis. OR=odds ratio.
Figure 3:
Figure 3:. Change in imaging parameters and liver enzymes from baseline to week 48
Liver stiffness assessed by MRE (A), liver steatosis assessed by MRI-PDFF (B), ALT (C), and AST (D). Number of observations per treatment group and visit is presented in the lower part of each plot. Error bars show the SE of the mean for observed values. ALT=alanine aminotransferase. ANCOVA=analysis of covariance. AST=aspartate aminotransferase. ETR=estimated treatment ratio. MRE=magnetic resonance elastography. MRI-PDFF=MRI proton density fat fraction. *ETRs with 95% CI and two-sided p-values were calculated using the same ANCOVA analysis. Missing data were imputed from the observed data in the placebo group using the same ANCOVA model but without treatment as factor.
Figure 4:
Figure 4:. Change in (A) bodyweight and (B) HbA1c (in patients with type 2 diabetes) from baseline to week 48
Number of observations per treatment group and visit is presented in the lower part of each plot. Error bars show the SE of the mean for observed values. ANCOVA=analysis of covariance. ETD=estimated treatment difference. *ETDs with 95% CI and two-sided p-values were calculated using the same ANCOVA analysis. Missing data were imputed from the observed data in the placebo group using the same ANCOVA model but without treatment as factor.
See this image and copyright information in PMC

Comment in

References

    1. Taylor RS, Taylor RJ, Bayliss S, et al. Association between fibrosis stage and outcomes of patients with nonalcoholic fatty liver disease: a systematic review and meta-analysis. Gastroenterology 2020; 158: 1611–25. - PubMed
    1. Sanyal AJ, Van Natta ML, Clark J, et al. Prospective study of outcomes in adults with nonalcoholic fatty liver disease. N Engl J Med 2021; 385: 1559–69. - PMC - PubMed
    1. Mantovani A, Csermely A, Petracca G, et al. Non-alcoholic fatty liver disease and risk of fatal and non-fatal cardiovascular events: an updated systematic review and meta-analysis. Lancet Gastroenterol Hepatol 2021; 6: 903–13. - PubMed
    1. Ng CH, Lim WH, Lim GEH, et al. Mortality outcomes by fibrosis stage in nonalcoholic fatty liver disease: a systematic review and meta-analysis. Clin Gastroenterol Hepatol 2022; published online May 2. 10.1016/j.cgh.2022.04.014. - DOI - PMC - PubMed
    1. Estes C, Razavi H, Loomba R, Younossi Z, Sanyal AJ. Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. Hepatology 2018; 67: 123–33. - PMC - PubMed

Publication types

Associated data