Combination pharmacotherapy for MASH: Potential synergistic approaches

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent and severe liver disease globally, encompassing a spectrum from isolated steatosis to metabolic dysfunction-associated steatohepatitis (MASH), the progressive inflammatory form that can lead to fibrosis, cirrhosis, and hepatocellular carcinoma. The multifaceted pathogenesis of MASH, particularly in the setting of obesity and type 2 diabetes mellitus (T2DM), has resulted in the exploration of pharmaca that target metabolic, inflammatory, and fibrotic processes. Until quite recently, demonstrating efficacy in phase 3 trials with single agents has been challenging. Multiple combination trials have been conducted, often requiring complex multi-arm designs, but demonstrating limited additive benefit over monotherapy. The recent conditional approval of two monotherapies targeting metabolic pathways, the thyroid hormone receptor beta agonist (THRβ) resmetirom and the glucagon-like peptide 1 receptor agonist (GLP1 RA) semaglutide, is kickstarting the therapeutic armamentarium for MASH. Other promising monotherapies may follow in the near future, in particular fibroblast growth factor 21 (FGF21) analogues and pan-peroxisome proliferator-activated receptor (pan-PPAR) agonist lanifibranor. As a result, the position of combination therapy in MASH may shift toward add-on strategies evaluated in clinical practice rather than pharma-driven trial settings. The four monotherapy classes mentioned may be applied in combination, as is already occurring with resmetirom and semaglutide. In this review, we break down the rationale for the various combinations. In addition, we highlight the unmet need for effective antifibrotic therapies and discuss future directions for combination therapy in MASH. Based on the available data, we provide recommendations for the most promising combination strategies.