GLP1 poly-agonist peptides[1] are a class of drugs that activate multiplepeptide hormone receptors including theglucagon-like peptide-1 (GLP-1) receptor. These drugs are developed for the same indications asGLP-1 receptor agonists—especially obesity, type 2 diabetes, and non-alcoholic fatty liver disease. They are expected to provide superior efficacy with fewer adverse effects compared to GLP-1 mono-agonists, which are dose-limited by gastrointestinal disturbances.[2] The effectiveness of multi-receptor agonists could possibly equal or exceed that ofbariatric surgery. The first such drug to receive approval istirzepatide, a dual agonist of GLP-1 andGIP receptors.[1]
Tirzepatide, a dual agonist of GLP-1 andGIP receptors, is approved for type 2 diabetes and obesity. With an average 20 percent weight loss at a high dosage, it appears to be more effective than GLP-1 mono agonists although there have been no head to head trials as of 2023.[1][3]
Glucagon is a hormone that generally opposes the action ofinsulin.[4] It increases blood glucose by stimulating the production of glucose in the liver viaglycogenolysis (breakdown ofglycogen) andgluconeogenesis (production of glucose from non-carbohydrate sources).[5] Glucagon also increases the breakdown of lipids andamino acids and the production ofketones.[6][7] Unlike currently approvedweight loss drugs, glucagon receptor agonists increaseenergy expenditure.[8] Combination GLP-1/glucagon receptor agonists provide the thermogenic benefits of glucagon activation while almost eliminating hyperglycemia induced by glucagon receptor activation. Several such drugs have reached human trials for obesity, diabetes, and non-alcoholic fatty liver disease but adverse effects have hampered development. The most advanced of these drugs ismazdutide which is in a phase III trial as of 2023.[5]
Following the discovery of GLP-1/GIP and GLP-1/glucagon dual agonists, it was hoped that a triple agonist would provide additive or synergistic metabolic benefits.[9] A clinical trial of the triple agonistretatrutide found an average −24.2 percent weight reduction in the highest dosage group after 24 weeks.[10]
Attaching other hormones such asestrogen,thyroid hormone (T3), anddexamethasone to GLP-1 or glucagon restrict the activity of the attached hormone to cells that express GLP-1 or glucagon.[9]
GLP-1 andamylin receptor agonist conjugates have also been tested in preclinical trials.[9]
In 2023, researchers disclosed the discovery of multiple peptides that activated the GLP-1 receptor,neuropeptide Y receptor Y1, andneuropeptide Y receptor Y2. Since neuropeptide Y receptors were a previous anti-obesity target, it is hoped that the combination might be more efficacious than GLP-1 receptor agonists.[11]
^Jastreboff, Ania M.; Kaplan, Lee M.; Frías, Juan P.; Wu, Qiwei; Du, Yu; Gurbuz, Sirel; Coskun, Tamer; Haupt, Axel; Milicevic, Zvonko; Hartman, Mark L. (2023). "Triple–Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial".New England Journal of Medicine.389 (6):514–526.doi:10.1056/NEJMoa2301972.PMID37366315.S2CID259260926.
