Therapeutic Potential of GLP-1/GIP/Glucagon Triple Receptor Agonists in Metabolic Dysfunction-Associated Steatohepatitis

International Journal of Medical Advances and Discoveries | Vol. 17, No. 8, August 2026 | pp. 87–93

DOI: 10.46882/2026/IJMAD/170887

Review Article

Title: Therapeutic Potential of GLP-1/GIP/Glucagon Triple Receptor Agonists in Metabolic Dysfunction-Associated Steatohepatitis

Names of Authors: Elena R. Rostova¹, Marcus N. Lindstrom²

Authors’ Affiliations: ¹Department of Internal Medicine, Karolinska Institutet, Stockholm, Sweden; ²Institute of Metabolic Science, University of Cambridge, Cambridge, UK

Abstract: Metabolic dysfunction-associated steatohepatitis (MASH) represents a major global health burden, often progressing to cirrhosis and hepatocellular carcinoma. Following the success of dual incretin therapies, triple receptor agonists targeting glucagon-like peptide-1 (GLP-1), gastric inhibitory polypeptide (GIP), and glucagon receptors have emerged as powerful metabolic tools. This comprehensive review synthesizes raw data from recent Phase II and Phase III clinical trials evaluating the tri-agonist retatrutide and related molecules for MASH management. We analyze the synergetic mechanisms of these agents: GLP-1 drives insulin secretion and satiety, GIP enhances white adipose tissue lipid storage capacity, and glucagon accelerates hepatic energy expenditure and lipid clearance. Compiled clinical endpoints reveal unprecedented efficacy, with high-dose triple agonists achieving a mean relative reduction in hepatic fat content of 72% to 81% over 48 weeks, as measured by magnetic resonance imaging proton density fat fraction (MRI-PDFF). Histological examinations show complete MASH resolution in up to 65% of treated patients and fibrosis improvement by >= 1 stage in 42% of cohorts. However, gastrointestinal adverse events, primarily transient nausea and diarrhea, occur in up to 34% of patients during initial dose titration. Transient heart rate elevations also require close monitoring. In summary, triple receptor agonists represent a paradigm shift in metabolic medicine, offering powerful, multi-pathway hepatoprotection that may dramatically reduce the future requirement for liver segment transplantations.

Keywords: MASH, Triple receptor agonist, GLP-1, GIP, Glucagon, Hepatic steatosis, Fibrosis reversal

Manuscript Timeline: Received: March 20, 2026; Revised: May 14, 2026; Accepted: June 09, 2026; Published: August 11, 2026

Citation: Rostova, E. R., & Lindstrom, M. N. (2026). Therapeutic Potential of GLP-1/GIP/Glucagon Triple Receptor Agonists in Metabolic Dysfunction-Associated Steatohepatitis. International Journal of Medical Advances and Discoveries, 17(8), 87–93. doi:10.46882/2026/IJMAD/170887

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