The ground-breaking development of the incretin agonists by manipulation of the incretin system, including the gut hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), as well as the pancreatic hormone glucagon, has led to the emergence of promising pharmacotherapy for metabolic health. The GLP-1 receptor agonists (GLP-1RAs), namely liraglutide, dulaglutide, albiglutide, exenatide, and semaglutide, have been found to have beneficial effects on glycated hemoglobin, weight, lipid profile, and liver fat and thereby improving cardiometabolic health. Other drugs of the same group in development include Orforglipron, which has a high weight loss efficacy (-15% weight reduction). Long-acting GLP-1RAs in trials are Ecnoglutide, Efpeglenatide, TG103, and Visepegenatide. Many of these have cardiovascular benefits in terms of reduction in MACE (Non-fatal MI, Non-fatal stroke, and mortality). Tirzepatide is a dual GIP/GLP-1RA, the first drug of the group to be approved for diabetes and obesity with remarkably lower gastrointestinal side effects compared to GLP-1 monoagonists. The dual GLP-1/glucagon co-agonists cause tremendous weight loss due to the synergistic action. Most drugs in this class are long-acting and developed for once-weekly administration. The revolutionary triple agonists at the GLP-1, GIP, and Glucagon receptors have demonstrated the highest achievable weight loss with pharmacotherapy. Retatrutide and Efocipegtrutide belong to this novel group of drugs. The newer drugs in the broad category of incretin co-agonists include the GLP-1/amylin receptor agonist like CagriSema and Amycretin, oral GLP-1 agonists other than semaglutide, and the peptide YY/GLP-1 receptor dual agonists. The profound biochemical and weight loss outcomes associated with incretin co-/poly-agonists are expected to translate into outstanding cardiometabolic benefits, the theme of this evidence review.
