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'''GLP1 poly-agonist peptides''' are a class of drugs that activate multiple [[peptide hormone]] receptors including the [[glucagon-like peptide-1 receptor|glucagon-like peptide-1 (GLP-1) receptor]]. These drugs are developed for the same indications as [[GLP-1 receptor agonist]]s—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 receptor]]s.
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==GLP-1 and GIP receptor dual agonists==
[[Tirzepatide]], a dual agonist of GLP-1 and [[GIP receptor]]s, 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.
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==GLP-1 and glucagon receptor dual agonists==
{{see also|Glucagon receptor agonist}}
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 acid]]s and the production of [[ketones]]. Unlike currently approved [[weight loss drug]]s, 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.
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==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.
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==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.
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GLP-1 and [[amylin receptor]] agonist conjugates have also been tested in preclinical trials.
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==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.
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==See also==
*[[Cagrilintide/semaglutide]]
*[[Insulin icodec/semaglutide]]
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{{二次利用|date=8 December 2023}}
[[Category:GLP-1 receptor agonists]]
[[Category:Peptide therapeutics]]
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