From pathophysiology to therapy: dual and triple agonists as a new frontier in metabolic dysfunction-associated steatotic liver disease

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as the most prevalent chronic liver condition worldwide, reflecting the growing global burden of obesity and type 2 diabetes (T2D). The complex pathophysiology of MASLD, characterized by insulin resistance (IR), lipotoxicity, and chronic low-grade inflammation, necessitates therapeutic strategies that address systemic metabolic dysfunction rather than isolated hepatic markers. Current evidence highlights the synergistic potential of targeting multiple incretin and metabolic pathways. Dual agonists, most notably Tirzepatide (a GIP and GLP-1 receptor agonist), have demonstrated profound efficacy in clinical trials (SURPASS and SURMOUNT programs), achieving significant reductions in hemoglobin A1c, body weight, and liver fat content. Furthermore, dual GLP-1/glucagon receptor agonists like Survodutide and Cotadutide offer complementary benefits by enhancing energy expenditure and modulating hepatic lipid metabolism. The development of triple agonists, such as Retatrutide (targeting GIP, GLP-1, and glucagon receptors), represents a further escalation in potency, showing unprecedented results in liver fat reduction and weight loss. The integration of these multi-target agents, together with emerging pathways involving amylin analogues and pan-PPAR agonists like Chiglitazar, marks a paradigm shift toward holistic cardiometabolic management. These therapies not only target the resolution of metabolic dysfunction-associated steatohepatitis and fibrosis but also address the interconnected risks of cardiovascular and renal complications. This review aims to explore the evolving landscape of pharmacological interventions, focusing on the emergence of dual and triple receptor agonists as a transformative frontier in metabolic dysfunction and MASLD therapy.