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Integrating liver endpoints in clinical trials of cardiovascular and kidney disease

Nature Medicine volume 30, pages 2423–2431 (2024) Cite this article

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Abstract

The intersection of cardiovascular disease, metabolic disorders and chronic kidney disease represents a complex clinical picture challenging healthcare systems worldwide. Metabolic-dysfunction-associated steatotic liver disease (MASLD) often manifests sequentially or concomitantly with these diseases, and may share underlying mechanisms and risk factors. Growing evidence suggests that new therapies could have benefits across these diseases, but trial sponsors and investigators tend to be reluctant to include patients with comorbidities—particularly liver diseases—in clinical trials. In this Perspective, we call for inclusion of patients with MASLD and measurement of liver outcomes in cardio–kidney–metabolic trials, when data suggest mechanistically plausible benefits and liver and cardiovascular safety. We discuss the implications of this new paradigm for clinical trial design and considerations for regulatory approval. Finally, we outline the challenges to implementing such an approach and provide recommendations for future clinical trial conduct.

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Fig. 1: Conceptual diagram for CKM syndrome from the American Heart Association.
The alternative text for this image may have been generated using AI.
Fig. 2: The intersection of CVD, metabolic disorders and CKD provides support for designing cross-organ clinical trials.
The alternative text for this image may have been generated using AI.
Fig. 3: Cardio–metabolic–renal interconnections and therapeutic options.
The alternative text for this image may have been generated using AI.

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Acknowledgements

This article was generated from discussions at the second annual MOSAIC (Metabolic multi-Organ Science Accelerating Innovation in Clinical Trials) meeting held in October 2023 (https://mosaic-nash.tmacademy.org/). MOSAIC is a strategic workshop for high-level dialog between clinical trialists, industry representatives, regulatory authorities and patients. We thank P. Lavigne and S. Portelance for medical writing and editing services (funded by the MOSAIC group). The views expressed in this article are the personal views of the author(s) and may not be understood or quoted as being made on behalf of or reflecting the position of the regulatory agency/agencies or organizations with which the author(s) is/are employed/affiliated. MOSAIC meetings are supported by unrestricted educational grants from 89Bio, AstraZeneca, Boehringer Ingelheim, Echosens, Gilead, Inventive, Kowa, Madrigal Pharmaceuticals, Merck, Novo Nordisk, Northsea Therapeutics and Olink, with no allocation for speakers’ fees.

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Authors and Affiliations

  1. Université de Lorraine, Inserm Clinical Investigation Center at Institut Lorrain du Coeur et des Vaisseaux, University Hospital of Nancy, Nancy, France

    Faiez Zannad

  2. Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA, USA

    Arun J. Sanyal

  3. Baylor Scott and White Research Institute, Dallas, TX, USA

    Javed Butler

  4. University of Mississippi, Jackson, MS, USA

    Javed Butler

  5. Forum for Collaborative Research, Washington DC; University of California Berkeley School of Public Health, Berkeley, CA, USA

    Veronica Miller

  6. Visiting Professor of Hepatology Radcliffe Department of Medicine, University of Oxford, Oxford, UK

    Stephen A. Harrison

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  1. Faiez Zannad
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  2. Arun J. Sanyal
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  5. Stephen A. Harrison
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Contributions

All co-authors contributed to conceptualization of the MOSAIC meeting, including the aims and selection of the topics. F.Z. drafted the initial manuscript; all authors critically revised the manuscript, gave final approval, and agreed to be accountable for all aspects of work ensuring integrity and accuracy.

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Correspondence to Faiez Zannad.

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Competing interests

F.Z.: consulting fees from Applied Therapeutics, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Boston Scientific, Cardior Pharmaceuticals, Cereno Scientific, Cellprothera, CVRx, Merck, Novartis, Pfizer and Servier and is the co-founder of cardiorenal and the founder of CVCT. A.J.S.: institutional research grants from Conatus, Gilead, Mallinckrodt, Boehringer Ingelheim, Novartis, Bristol Myers Squibb, Merck, Lilly, Novo Nordisk, Fractyl Health, Madrigal, Inventiva Pharma and Covance; research grants or contracts from Gilead, Mallinckrodt, Salix, Novartis, Galectin, Bristol Myers Squibb and Sequana Medical; royalties or licenses from Elsevier and UpToDate; consulting fees from Genfit, Gilead, Mallinckrodt, Pfizer, Salix, Boehringer Ingelheim, Novartis, Bristol Myers Squibb, Merck, HemoShear Therapeutics, Lilly, Novo Nordisk, Terns, Albireo Pharma, Jansen, Poxel, 89bio, Siemens, NGM Bio, Amgen, Regeneron, Genentech, Alnylam, Roche, Madrigal, Inventiva Pharma, Covance, ProSciento, HistoIndex and Path AI; an unpaid consultancy for Intercept, Sequana, Fractyl Health and AstraZeneca; a leadership role on board of Sanyal Bio (president, unpaid); stock or stock options from Sanyal Bio, Genfit, Exhalenz Bioscience, HemoShear Therapeutics, Durect, Indalo Therapeutics, NorthSea Therapeutics, Tiziana Life Sciences and Rivus Pharmaceuticals; receipt of equipment, materials or drugs from Contaus Pharmaceuticals, Immuron and Echosens-Sandhill; ongoing research collaborations (no direct funding) with Echosens-Sandhill, Owl Pharma, Second Genome, and Siemens; and employment with Sanyal Bio. J.B.: consulting fees from 3ivelabs, Abbott, Amgen, American Regent, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardiac Dimension, Cardior, CVRx, Cytokinetics, Edwards Life Sciences, Element, Faraday, G3 Pharmaceutical, Imbria, Impulse Dynamics, Innolife, Inventiva, Ionis, Janssen, LivaNova, Lexicon, Medtronic, Merck, Novartis, Novo Nordisk, Otsuka, Occlutech, PharmaCosmos, Roche, Sanofi, Secretome, Sequana, Tricog and Vifor; and payment or honoraria for lectures, presentations or speakers bureaus from Novartis, Boehringer Ingelheim-Lilly, AstraZeneca and Impulse Dynamics. V.M.: received institutional research grants from 89bio, Akero Therapeutics Inc., Albireo Pharma Inc., Aligos Therapeutics, Alimentiv, AlloVir, Altimmune Inc., AMRA Medical AB, Arrowhead Pharmaceuticals, Assembly Biosciences, BioMarin Pharmaceutical Inc., ChemomAb Ltd., Covance Inc., Cymabay Therapeutics, DDL Diagnostic Laboratory, Dynavax Technologies, E-Scopics, EA Pharma Co. LTD, Echosens, Eiger BioPharmaceuticals, Eli Lilly & Company, ENYO Pharma SA, Galectin Therapeutics, Gilead Sciences Inc., GlaxoSmithKline PLC, HepQuant, High Tide Therapeutics, Histolndex, Icare USA, Immunocore, Intercept Pharmaceuticals, Inventiva Pharma, Janssen, LabCorp, LG Chem Life Sciences, Andos Therapeutics Inc., Merck & Company, Inc., NorthSea Therapeutics, Novartis Pharma AG, Novo Nordisk, Oncoustics, Pharmanest, Pliant Therapeutics, Qiagen Sciences, Regeneron Pharmaceuticals, VBI Vaccines Inc., Vir Biotechnology Inc. and Virion Therapeutics LLC. S.A.H.: grants or contracts from Akero, Altimmune, Axcella, Bristol Myers Squibb, Corcept, CymaBay Therapeutics, Enyo, Galectin, Genentech, Genfit, Gilead, GlaxoSmithKline, Hepion, Hightide, Immuron, Intercept, Inventiva, Ionis, Madrigal, NGM Bio, Novartis, Novo Nordisk, NorthSea Therapeutics, Pfizer, Poxel, Sagimet Biosciences, Terns and Viking; consulting fees from Akero, Aligos, Altimmune, Arrowhead, Boxer Capital, Chronwell, Echosens, Foresite Labs, Galectin, Galecto, Gilead, GlaxoSmithKline, Hepagene, Hepion, Hepta Bio, HistoIndex, Humana, Intercept, Ionis, Inventiva, Madrigal, Medpace, Merck, NeuroBo Pharmaceuticals, NorthSea Therapeutics, Novo Nordisk, Perspectum, Pfizer, Sonic Incytes, Sagimet Biosciences, Terns and Viking; and stock or stock options from Akero, Altimmune, Axcella, Bristol Myers Squibb, Corcept, CymaBay Therapeutics, Enyo, Galectin, Genentech, Genfit, Gilead, GlaxoSmithKline, Hepion, Hightide, Immuron, Intercept, Inventiva, Ionis, Madrigal, NGM Bio, Novartis, Novo Nordisk, NorthSea Therapeutics, Pfizer, Poxel, Sagimet Biosciences, Terns and Viking.

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Zannad, F., Sanyal, A.J., Butler, J. et al. Integrating liver endpoints in clinical trials of cardiovascular and kidney disease. Nat Med 30, 2423–2431 (2024). https://doi.org/10.1038/s41591-024-03223-z

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