Targeting the cardiohepatic-metabolic axis: GLP-1-based and incretin multi-agonist therapies in MASH

Metabolic dysfunction-associated steatohepatitis (MASH) has emerged as a leading cause of chronic liver disease worldwide and is increasingly recognized as a systemic metabolic-inflammatory disorder closely linked to cardiovascular risk. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and emerging incretin-based multi-receptor agonists have demonstrated substantial therapeutic potential in this context. Mechanistically, these agents exert integrated effects across the cardiohepatic-metabolic axis. They reduce metabolic burden through appetite suppression and increased energy expenditure, improve hepatic steatosis and inflammation by modulating pathways such as AMP-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR) and NLRP3 inflammasome signalling and may confer cardiovascular protection through effects on endothelial function and autonomic regulation. Clinically, evidence from large-scale trials supports distinct benefits across hepatic, heart failure and cardiovascular outcomes. The ESSENCE trial demonstrated MASH resolution and improvements in liver histology, STEP-HFpEF showed clinically meaningful benefits in patients with obesity-related HFpEF, and SELECT demonstrated a significant reduction in major adverse cardiovascular events in patients with overweight or obesity and established cardiovascular disease. Importantly, these cardiovascular outcome data should not be interpreted as direct evidence of cardiovascular benefit specifically in patients with biopsy-confirmed MASH. The relative contributions of weight loss, glycemic improvement and other pharmacological effects remain incompletely defined. Despite these advances, important challenges remain, including uncertainties regarding long-term outcomes, reliance on surrogate endpoints and incomplete understanding of direct vs. indirect mechanisms of action. Overall, GLP-1-based and incretin multi-agonist therapies represent a promising integrative strategy targeting the cardiohepatic-metabolic axis, supporting an emerging therapeutic paradigm for the integrated management of MASH and its associated cardiometabolic complications.