GLP1 poly-agonist peptides

GLP1 poly-agonist peptides are a class of drugs that activate multiple peptide hormone receptors including the glucagon-like peptide-1 (GLP-1) receptor. These drugs are developed for the same indications as GLP-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. The effectiveness of multi-receptor agonists could possibly equal or exceed that of bariatric surgery. The first such drug to receive approval is tirzepatide, a dual agonist of GLP-1 and GIP receptors.

GLP-1 and GIP receptor dual agonists
Tirzepatide, a dual agonist of GLP-1 and GIP 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.

GLP-1 and glucagon receptor dual agonists
Glucagon is a hormone that generally opposes the action of insulin. It increases blood glucose by stimulating the production of glucose in the liver via glycogenolysis (breakdown of glycogen) and gluconeogenesis (production of glucose from non-carbohydrate sources). Glucagon also increases the breakdown of lipids and amino acids and the production of ketones. Unlike currently approved weight loss drugs, glucagon receptor agonists increase energy expenditure. 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 is mazdutide which is in a phase III trial as of 2023.

GLP-1, GIP, and glucagon receptor triple agonists
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. A clinical trial of the triple agonist retatrutide found an average −24.2 percent weight reduction in the highest dosage group after 24 weeks.

Conjugates
Attaching other hormones such as estrogen, thyroid hormone (T3), and dexamethasone to GLP-1 or glucagon restrict the activity of the attached hormone to cells that express GLP-1 or glucagon.

GLP-1 and amylin receptor agonist conjugates have also been tested in preclinical trials.

GLP-1 and neuropeptide Y multi-agonists
In 2023, researchers disclosed the discovery of multiple peptides that activated the GLP-1 receptor, neuropeptide Y receptor Y1, and neuropeptide 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.