Glucagon-like peptide-1/glucose-dependent insulinotropic polypeptide receptor co-agonists for cardioprotection, type 2 diabetes and obesity: a review of mechanisms and clinical data

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are approved for the management of type 2 diabetes (T2D) and obesity, and some are recommended for cardiorenal risk reduction in T2D. To enhance the benefits with GLP-RA mono-agonist therapy, GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor co-agonists are in development to capitalize on the synergism of GLP-1 and GIP agonism. We review the mechanisms of action and clinical data for GLP-1/GIP receptor co-agonists in T2D and obesity and their potential role in cardiovascular protection.Tirzepatide, a first-in-class unimolecular GLP-1/GIP receptor co-agonist, is approved for T2D and is awaiting approval for obesity management. Phase 3 trials in T2D cohorts revealed significant reductions in glycemia and body weight and superiority compared with GLP-1R mono-agonism with semaglutide. Tirzepatide has demonstrated significant body weight reductions in individuals with obesity but not diabetes. It enhances lipid metabolism, reduces blood pressure, and lowers liver fat content. Pooled phase 2/3 data showed cardiovascular safety in T2D while a post hoc analysis suggested tirzepatide slows the decline of kidney function in T2D.GLP-1/GIP receptor co-agonists are a novel addition to the diabetes and obesity armamentarium. The cardiorenal-metabolic benefits position them as promising multiprong tools for metabolically complex individuals with chronic vascular complications.