Clinical trial design, biomarkers and end points in metabolic and alcohol-related liver disease

Luis Antonio Diaz^{1

2}, Maja Thiele^{3

4}, Alexandre Louvet^{5

6}, Brian P Lee^{7

8}, Veeral Ajmera¹, Federica Tavaglione¹, Cynthia L Hsu¹, Daniel Q Huang^{9

10}, Elisa Pose¹¹, Ramon Bataller¹¹, Craig McClain^{12

13}, Jessica Mellinger¹⁴, Monica Tincopa¹, Mack C Mitchell¹⁵, Vlad Ratziu^{16

17

18

19}, Mary E Rinella²⁰, Shiv K Sarin²¹, Vijay H Shah²², Gyongyi Szabo²³, Vincent Wai-Sun Wong²⁴, Meena B Bansal²⁵, Lorenzo Leggio^{26

27}, Patrick S Kamath²², Aleksander Krag^{3

4}, Arun J Sanyal²⁸, Marco Arrese², Juan Pablo Arab^{2

28}, Quentin M Anstee^{29

30}, Philippe Mathurin^{5

6}, Rohit Loomba³¹

Affiliations

¹ MASLD Research Center, Division of Gastroenterology and Hepatology, University of California San Diego, San Diego, CA, USA.
² Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
³ Center for Liver Research, Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark.
⁴ Institute of Clinical Research, University of Southern Denmark, Odense, Denmark.
⁵ Service des maladies de l'appareil digestif, University Hospital of Lille, Lille, France.
⁶ Unité INSERM INFINITE, Lille, France.
⁷ Division of Gastroenterology and Liver Disecases, University of Southern California Keck School of Medicine, Los Angeles, CA, USA.
⁸ Institute for Addiction Science, University of Southern California, Los Angeles, CA, USA.
⁹ Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
¹⁰ Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore, Singapore.
¹¹ Liver Unit, Hospital Clinic and Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
¹² Department of Medicine, University of Louisville, Louisville, KY, USA.
¹³ Robley Rex Louisville Veterans Affairs Medical Center, Louisville, KY, USA.
¹⁴ Department of Internal Medicine, Division of Gastroenterology & Hepatology, Henry Ford Health-Michigan State University, Detroit, MI, USA.
¹⁵ Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
¹⁶ Sorbonne Université, Paris, France.
¹⁷ ICAN (Institute of Cardiometabolism and Nutrition), Paris, France.
¹⁸ Assistance Publique-Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Paris, France.
¹⁹ INSERM UMRS 1138 CRC, Paris, France.
²⁰ Pritzker School of Medicine, University of Chicago, Chicago, IL, USA.
²¹ Department of Hepatology and Liver Transplantation, Institute of Liver & Biliary Sciences, New Delhi, India.
²² Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA.
²³ Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
²⁴ Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong, China.
²⁵ Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²⁶ Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA.
²⁷ National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Baltimore, MD, USA.
²⁸ Division of Gastroenterology, Hepatology, and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
²⁹ Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
³⁰ NIHR Newcastle Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
³¹ MASLD Research Center, Division of Gastroenterology and Hepatology, University of California San Diego, San Diego, CA, USA. roloomba@health.ucsd.edu.

PMID: 41006824
DOI: 10.1038/s41575-025-01120-5

Review

Clinical trial design, biomarkers and end points in metabolic and alcohol-related liver disease

Luis Antonio Diaz et al. Nat Rev Gastroenterol Hepatol. 2025 Dec.

. 2025 Dec;22(12):866-884.

doi: 10.1038/s41575-025-01120-5. Epub 2025 Sep 26.

Authors

Affiliations

¹ MASLD Research Center, Division of Gastroenterology and Hepatology, University of California San Diego, San Diego, CA, USA.
² Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
³ Center for Liver Research, Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark.
⁴ Institute of Clinical Research, University of Southern Denmark, Odense, Denmark.
⁵ Service des maladies de l'appareil digestif, University Hospital of Lille, Lille, France.
⁶ Unité INSERM INFINITE, Lille, France.
⁷ Division of Gastroenterology and Liver Disecases, University of Southern California Keck School of Medicine, Los Angeles, CA, USA.
⁸ Institute for Addiction Science, University of Southern California, Los Angeles, CA, USA.
⁹ Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
¹⁰ Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore, Singapore.
¹¹ Liver Unit, Hospital Clinic and Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
¹² Department of Medicine, University of Louisville, Louisville, KY, USA.
¹³ Robley Rex Louisville Veterans Affairs Medical Center, Louisville, KY, USA.
¹⁴ Department of Internal Medicine, Division of Gastroenterology & Hepatology, Henry Ford Health-Michigan State University, Detroit, MI, USA.
¹⁵ Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
¹⁶ Sorbonne Université, Paris, France.
¹⁷ ICAN (Institute of Cardiometabolism and Nutrition), Paris, France.
¹⁸ Assistance Publique-Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Paris, France.
¹⁹ INSERM UMRS 1138 CRC, Paris, France.
²⁰ Pritzker School of Medicine, University of Chicago, Chicago, IL, USA.
²¹ Department of Hepatology and Liver Transplantation, Institute of Liver & Biliary Sciences, New Delhi, India.
²² Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA.
²³ Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
²⁴ Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong, China.
²⁵ Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²⁶ Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA.
²⁷ National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Baltimore, MD, USA.
²⁸ Division of Gastroenterology, Hepatology, and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
²⁹ Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
³⁰ NIHR Newcastle Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
³¹ MASLD Research Center, Division of Gastroenterology and Hepatology, University of California San Diego, San Diego, CA, USA. roloomba@health.ucsd.edu.

PMID: 41006824
DOI: 10.1038/s41575-025-01120-5

Abstract

Metabolic and alcohol-related liver disease (MetALD) is a newly defined entity within the spectrum of steatotic liver disease, characterized by the interplay of cardiometabolic risk factors and alcohol consumption. The evolving epidemiology and complex pathophysiology of MetALD present unique challenges and opportunities for clinical trial design. Inclusion criteria should require simultaneous evidence of metabolic dysfunction (at least two cardiometabolic features) and verified quantifiable alcohol exposure recorded over the preceding 3-6 months. Traditional histological end points are limited by invasiveness, sampling error and interpretative variability. Thus, imaging modalities, serum-based fibrosis biomarkers and quantitative measures of alcohol intake are gaining relevance as non-invasive, reproducible and patient-centric end points aiming to improve trial feasibility. Furthermore, incorporating alcohol biomarkers, stratifying patients by metabolic risk factor burden, and using adaptive designs of trials might enhance the precision and generalizability of MetALD clinical trials. Although uncertainties remain regarding optimal patient selection criteria, event rates and the dynamic interplay between metabolic dysfunction and alcohol intake, ongoing research efforts aim to refine diagnostic criteria, standardize methodologies and validate novel end points. These advances will ultimately accelerate drug development, improve trial efficiency and foster interventions to treat MetALD.

PubMed Disclaimer

Conflict of interest statement

Competing interests: M. Thiele received speaker’s fee from Echosens, Madrigal Pharmaceuticals, Takeda and Novo Nordisk; received advisory fees from Boehringer Ingelheim, AstraZeneca, Novo Nordisk and GSK; and is co-founder of Evido. D.Q.H. has served as an advisory board member for Gilead Sciences and Roche. B.P.L. served as a consultant or advisory board member for AltImmune, DURECT, Gilead Sciences, GSK, HepaTx, Ipsen and Novo Nordisk; and received a research grant from Siemens Healthineers. R.B. consults for Boehringer Ingelheim, GSK and Novo Nordisk. J.M. serves as advisory board member for 89bio, Eli Lilly, GSK and Novo Nordisk. M.C.M. serves as an advisory board member for GSK. M.E.R. is scientific adviser or consultant for Akero Therapeutics, Boehringer Ingelheim, Cytodyn, Echosens, GSK, Intercept Pharmaceuticals, Madrigal Pharmaceuticals, NGM Biopharmaceuticals, Novo Nordisk and Sonic Incytes. V.W.-S.W. served as a consultant or advisory board member for AbbVie, AstraZeneca, Boehringer Ingelheim, Echosens, Eli Lilly, Gilead Sciences, Intercept Pharmaceuticals, Inventiva, Merck, Novo Nordisk, Pfizer, Sagimet Biosciences, TARGET PharmaSolutions and Visirna; served as a speaker for Abbott, AbbVie, Echosens, Gilead Sciences, Novo Nordisk and Unilab; has received a research grant from Gilead Sciences; and is a co-founder of Illuminatio Medical Technology. A.K. has served as a speaker for Norgine, Novo Nordisk and Siemens; participated in advisory boards for Boehringer Ingelheim, GSK, Novo Nordisk and Siemens, all outside the submitted work; has received research support from AstraZeneca, Echosense, Nordic Bioscience and Siemens; and is a board member and co-founder of Evido. M.A. consults for AstraZeneca and Inventiva; and has served as a speaker for Siemens. R.L. serves as a consultant to 89bio, Aardvark Therapeutics, Altimmune, Amgen, Anylam/Regeneron, Arrowhead Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb, CohBar, Eli Lilly, Galmed, Gilead Sciences, Glympse Bio, Hightide, Inipharma, Intercept Pharmaceuticals, Inventiva, Ionis, Janssen, Madrigal Pharmaceuticals, Merck, Metacrine, NGM Biopharmaceuticals, Novartis, Novo Nordisk, Pfizer, Sagimet Bioscience, Terns Pharmaceuticals, Theratechnologies and Viking Therapeutics; his institutions received research grants from Arrowhead Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Galectin Therapeutics, Galmed Pharmaceuticals, Gilead Sciences, Hanmi, Intercept Pharmaceuticals, Inventiva, Ionis, Janssen, Madrigal Pharmaceuticals, Merck, NGM Biopharmaceuticals, Novo Nordisk, Pfizer, Sonic Incytes and Terns Pharmaceuticals; and he is a co-founder of LipoNexus. All other authors declare no competing interests.

References

1. Younossi, Z. & Henry, L. Contribution of alcoholic and nonalcoholic fatty liver disease to the burden of liver-related morbidity and mortality. Gastroenterology 150, 1778–1785 (2016). - PubMed - DOI
1. Griswold, M. G. et al. Alcohol use and burden for 195 countries and territories, 1990–2016: a systematic analysis for the global burden of disease study 2016. Lancet 392, 1015–1035 (2018). - DOI
1. Rinella, M. E. et al. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. Hepatology 78, 1966–1986 (2023). - PubMed - DOI
1. Kit Ho, G. J. et al. High global prevalence of steatotic liver disease and associated subtypes: a meta-analysis. Clin. Gastroenterol. Hepatol. https://doi.org/10.1016/j.cgh.2025.02.006 (2025). - DOI
1. GBD 2021 Risk Factors Collaborators Global burden and strength of evidence for 88 risk factors in 204 countries and 811 subnational locations, 1990-2021: a systematic analysis for the global burden of disease study 2021. Lancet 403, 2162–2203 (2024). - DOI

Publication types

Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions

LinkOut - more resources

Full Text Sources
- Nature Publishing Group
Medical
- MedlinePlus Health Information

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Clinical trial design, biomarkers and end points in metabolic and alcohol-related liver disease

Affiliations

Clinical trial design, biomarkers and end points in metabolic and alcohol-related liver disease

Authors

Affiliations

Abstract

Conflict of interest statement

References

Publication types

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Medical