MASLD, MASH, and the CKM Spectrum: A Roadmap for Multiorgan Clinical Trial Design

Faiez Zannad; Muhammad Shahzeb Khan; Nisha Bansal; Michael Böhm; Sven M Francque; Nicolas Girerd; James L Januzzi; Veronica Miller; Marie-Eve Piché; Vlad Ratziu; Bart Staels; Harriette G C Van Spall; Arun J Sanyal; Javed Butler

doi:10.1016/j.jacc.2025.12.015

MASLD, MASH, and the CKM Spectrum: A Roadmap for Multiorgan Clinical Trial Design

J Am Coll Cardiol. 2026 Jan 27:S0735-1097(25)10429-4. doi: 10.1016/j.jacc.2025.12.015. Online ahead of print.

Authors

Affiliations

¹ CHRU Nancy, Centre d'Investigations Cliniques Plurithématique 1433, Université de Lorraine, Nancy, France. Electronic address: f.zannad@chru-nancy.fr.
² Baylor Scott and White Research Institute, Dallas, Texas, USA; Department of Medicine, Baylor School of Medicine, Temple, Texas, USA; Baylor Scott and White, The Heart Hospital Plano, Plano, Texas, USA.
³ Kidney Research Institute, Division of Nephrology University of Washington, Seattle, Washington, USA.
⁴ Universitätsklinikum des Saarlandes, Saarland University, Homburg, Germany.
⁵ Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium.
⁶ CHRU Nancy, Centre d'Investigations Cliniques Plurithématique 1433, Université de Lorraine, Nancy, France.
⁷ Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
⁸ Forum for Collaborative Research, University of California Berkeley School of Public Health, Berkeley, California, USA.
⁹ Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Québec City, Québec, Canada.
¹⁰ Sorbonne Université, Paris, France.
¹¹ Université Lille, INSERM, Institut Pasteur de Lille, Lille, France.
¹² Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
¹³ Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
¹⁴ Baylor Scott and White Research Institute, Dallas, Texas, USA; Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi, USA.

PMID: 41636667
DOI: 10.1016/j.jacc.2025.12.015

Abstract

Cardiovascular, kidney, and metabolic (CKM) diseases and liver disease are not merely linked by shared risk factors, but also frequently coexist as comorbidities with overlapping pathophysiology. Metabolic dysfunction-associated steatotic liver disease (MASLD) is highly prevalent in individuals with CKM disorders, and vice versa. The concomitant presence of these conditions amplifies the risk of both CKM and liver-related outcomes, raising the question of whether the CKM model should formally incorporate liver dysfunction. In this review, we detail the epidemiologic and pathophysiologic evidence that supports that expanded framework, highlighting the shared mechanisms of systemic inflammation, lipotoxicity, and fibrotic remodeling that unite these conditions. We then critically appraise the current landscape of selected heart failure, chronic kidney disease, and MASLD/metabolic dysfunction-associated steatohepatitis (MASH) trials, demonstrating how focus on single disease states with the exclusion of or insufficient data on the others has created knowledge gaps. Building on this, we provide a pragmatic outline for designing integrated multiorgan trials. We outline strategies for enriching trial populations, discuss the evidence and challenges for establishing noninvasive tests as surrogate endpoints to replace liver biopsy, and provide a framework for advanced biomarker and imaging substudies in CKM and MASLD/MASH trials. Finally, we advocate for a transition from isolated studies to patient-centered basket and platform trials that use master protocols to develop holistic therapies for these interconnected diseases.

Keywords: cardiovascular-kidney-liver-metabolic; metabolic dysfunction–associated steatotic liver disease; multiorgan trials; noninvasive tests; surrogate endpoints.

Publication types

Review