Research and clinical trial design in patients with metabolic dysfunction and alcohol-associated steatotic liver disease (MetALD): a narrative review

Abstract

This narrative review examines current trial design strategies and highlights the limitations of traditional models in capturing the heterogeneity and dynamic nature of metabolic dysfunction and alcohol-associated liver disease (MetALD). MetALD represents an increasingly prevalent and clinically distinct phenotype that reflects the convergence of metabolic risk factors and alcohol-related liver injury. Designing effective clinical and translational research in MetALD presents unique challenges as its burden continues to rise. Novel frameworks, such as adaptive and enrichment designs, offer improved pathways for patient stratification and intervention testing. The integration of molecular and translational biomarkers to inform diagnosis, prognosis, and therapeutic responsiveness is central to this evolution. This review also addresses critical methodological issues, including the need for harmonized definitions, careful endpoint selection, and real-world applicability of findings. Emerging therapies targeting steatosis, inflammation, fibrosis, gut-liver axis dysfunction, and metabolic pathways are now entering clinical development and require trial designs tailored to the multifaceted biology of MetALD. In this context, the article also discusses the importance of early-phase proof-of-concept studies and innovative approaches for combination therapies. Ethical and operational considerations, such as alcohol use thresholds, stigma, and disparities in access to care, further influence trial feasibility and generalizability. Finally, multidisciplinary collaboration across hepatology, addiction medicine, endocrinology, and trial methodology is essential to advance this field.

Keywords

MASLD / NAFLD / non-alcoholic fatty liver disease / metabolic dysfunction-associated steatotic liver disease / alcohol-related liver disease / alcoholic cirrhosis / cirrhosis

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