Due to the central roles exerted by the three metabolically related peptide hormone receptors (GIPR, GLP-1R and GCGR) in the management of T2DM and obesity, the concept of combinatorial agonism or polypharmacology to synergize metabolic actions and maximize therapeutic benefits has been explored in the past decade with remarkable preclinical and clinical achievements. This evidence concerns the gene GLP1R and Obesity.