Review maps evolving gut-pancreatic peptide therapies from mono- to multi-agonists for T2D, obesity, MASLD, MASH

Type 2 diabetes (T2D), obesity, metabolic dysfunction-associated steatotic liver disease (MASLD), and metabolic dysfunction-associated steatohepatitis (MASH) are rapidly escalating global health crises. Traditional therapies like insulin and metformin have limitations, driving the urgent need for novel pharmacotherapies. Gut-pancreatic peptides, particularly glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs), have revolutionized treatment due to their multifaceted metabolic benefits. This success has spurred interest in other peptides like glucose-dependent insulinotropic polypeptide (GIP), glucagon, amylin, and peptide YY (PYY), which offer distinct pharmacological advantages and therapeutic promise for these complex metabolic disorders. This review addresses the evolving landscape of these non-insulin, peptide-based therapies.

This comprehensive review synthesizes current knowledge on non-insulin gut-pancreatic peptide signalling-based therapies. It systematically examines both clinically approved and investigational compounds, focusing on their mechanisms of action, therapeutic efficacy, and limitations. The authors critically narrate their development status and positioning within the treatment landscape for T2D, obesity, and associated liver disease (MASLD/MASH). Furthermore, the review delineates emerging avenues in novel peptide-based pharmacotherapy development, offering insights into future potential and acquainting the reader with developments in non-insulin gut-pancreatic peptide signalling-based therapies for metabolic disorders.

The review highlights the "watershed moment" of GLP-1 receptor agonists (GLP-1RAs), which have fundamentally reshaped T2D and obesity treatment due to their multifaceted metabolic benefits. It details the distinct pharmacological benefits and therapeutic promise of other gut-pancreatic peptides such as glucose-dependent insulinotropic polypeptide (GIP), glucagon, amylin, and peptide YY (PYY). The authors emphasize the emerging therapeutic convergence between T2D, obesity, and associated liver disease (MASLD/MASH), driven by these peptide-based therapies. The review critically narrates the mechanisms of action, therapeutic efficacy, limitations, current development status, and positioning of these non-insulin gut-pancreatic peptide signalling-based therapies in the treatment landscape. It also delineates emerging avenues in novel peptide-based pharmacotherapy development, offering insights into their future potential. The shift from mono- to multi-agonist approaches is a key theme, aiming for enhanced efficacy across multiple metabolic targets.