From pathophysiology to therapy: dual and triple agonists as a new frontier in metabolic dysfunction-associated steatotic liver disease
- 1Department of Internal Medicine, National Relevance and High Specialization Hospital Trust (ARNAS Ospedali Civico Di Cristina Benfratelli)
- 2Department of Health Promotion Sciences, Maternal and Infant Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo
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.
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BibTeX
@article{argano2026from,
title = {{From pathophysiology to therapy: dual and triple agonists as a new frontier in metabolic dysfunction-associated steatotic liver disease}},
author = {Christiano Argano and Dalila Maggio and Chiara Pollicino and Virginia Cangialosi and Stefania Biscaglia Manno and Valentina Orlando and Martina Lucia Monti and Arianna Grutta and Alessandra Torres and Salvatore Corrao},
journal = {Frontiers in Pharmacology},
year = {2026},
month = oct,
doi = {10.3389/fphar.2026.1784959},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1784959/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - From pathophysiology to therapy: dual and triple agonists as a new frontier in metabolic dysfunction-associated steatotic liver disease
AU - Christiano Argano
AU - Dalila Maggio
AU - Chiara Pollicino
AU - Virginia Cangialosi
AU - Stefania Biscaglia Manno
AU - Valentina Orlando
AU - Martina Lucia Monti
AU - Arianna Grutta
AU - Alessandra Torres
AU - Salvatore Corrao
PY - 2026
DA - 2026/10/13
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.1784959
UR - https://www.frontiersin.org/articles/10.3389/fphar.2026.1784959/full
AB - 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.
SN - 1663-9812
ER -