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

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.