State-of-the-art perspective: Advances in incretin-based therapy targeting progression of diabetes and cardiovascular-kidney-metabolic syndrome

The incretin system is targeted in the treatment of type 2 diabetes mellitus (T2DM) and cardiovascular-kidney-metabolic (CKM) conditions. Increasingly, incretin hormones (i.e., gut peptides that enhance glucose-stimulated insulin secretion) reduce blood glucose levels, consequently alleviating CKM syndrome. Specifically, glucagon-like peptide 1 (GLP-1) demonstrated glucose-lowering effects, delayed gastric emptying, decreased glucagon secretion, and weight loss. An investigational medication, retatrutide, interacts as a tri-agonist with glucose-dependent insulinotropic polypeptide (GIP), GLP-1, and the glucagon receptor. Contemporary data indicate that early intervention, targeting not only the GLP-1 receptor but also the GIP and glucagon receptors, are forthcoming therapeutics affecting T2DM in earlier phases and CKM outcomes, demonstrating the advances in tri-agonists versus only GLP-1. Notably, endogenous levels of gut incretin hormones shift as pre-diabetes progresses to diabetes or regresses to normoglycemia. The present perspective provides a review of incretin therapy and its prospects in hindering the progression of T2DM and CKM syndrome.