From Single Agents to Synergy: Redefining Therapeutic Strategies in MASLD.

The recent approvals of resmetirom and semaglutide have marked a pivotal advance in the management of metabolic dysfunction-associated steatotic liver disease (MASLD). Nevertheless, the modest fibrosis responses observed with current monotherapies and the persistence of substantial residual disease burden highlight the need for more comprehensive therapeutic strategies. Given the multifactorial pathogenesis of MASLD, combination therapy has emerged as a promising approach to simultaneously target metabolic dysfunction, hepatic steatosis, inflammation, and fibrogenesis. In this opinion article, we discuss the biological rationale for combination treatment and critically appraise the evidence from randomized clinical trials evaluating multidrug approaches in MASLD. While several studies have demonstrated encouraging improvements in hepatic and metabolic outcomes, others have failed to achieve their primary endpoints, underscoring that mechanistic complementarity does not necessarily translate into clinical synergy. We further review ongoing trials, including studies in advanced fibrosis and compensated cirrhosis, that are expected to shape the next phase of therapeutic development. Finally, we address key challenges related to patient selection, disease heterogeneity, treatment duration, safety, cost-effectiveness, and regulatory approval. We propose that the future of combination therapy in MASLD will likely rely on precision-medicine approaches that align therapeutic mechanisms with individual disease biology and stage.