Pharmacological Advances in Incretin-based Polyagonism – What we know and what we don’tt

The prevalence of obesity continues to rise in both the adolescent and adult, in parallel obesity is strongly associated with the increased incidence of type 2 diabetes (T2D), heart failure, certain types of cancer, and all-cause mortality. In relation to obesity, many pharmacological approaches of the past have tried and failed to combat the rising obesity epidemic, particularly due to insufficient efficacy or unacceptable side-effects. But while the history of anti-obesity medication is plagued by failures and disappointments, we have witnessed over the last 10 years substantial progress, particularly in regard to biochemically optimized agonists at the receptor for glucagon-like peptide-1 (GLP-1) and unimolecular co-agonists at the receptors for GLP-1 and the glucose-dependent insulinotropic polypeptide (GIP). Although GIPR:GLP-1R co-agonists are being heralded as premier pharmacological tools for the treatment of obesity and diabetes, uncertainty remains as to why these drugs testify superiority over best-in-class GLP-1R monoagonists. Particularly with regard to GIP, there remains great uncertainty if and how GIP acts on systems metabolism and if the GIP system should be activated or inhibited to improve metabolic outcome in adjunct to GLP-1R agonism. In this review, we summarize recent advances in GLP-1- and GIP-based pharmacology, and discuss recent findings and open questions related to how the GIP system affects systemic energy and glucose metabolism.