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Orforglipron-Diabetes
This information is provided in response to your request. Resources may contain information about doses, uses, formulations and populations different from product labeling.
What is the mechanism of action of orforglipron?
Orforglipron binds to the same receptor site as native GLP -1. Preclinical data suggest this binding results in biased agonism which favors G-protein stimulatory signaling linked to physiological responses over receptor downregulation via β-arrestin.
Orforglipron Mechanism of Action
What is Glucagon-like Peptide-1?
Glucagon-like peptide-1 (GLP-1) is an incretin hormone released from specialized gut cells in response to the absorption of oral glucose.1
Glucagon-like peptide-1 acts on its receptors in the pancreas to stimulate insulin release and suppress glucagon secretion, in the stomach to delay gastric emptying, and in the hypothalamus to decrease appetite and increase satiety.2,3
These effects help
- keep blood glucose levels within acceptable ranges after nutrient intake, and
- people to stop eating when they feel satiated.1
In people living with type 2 diabetes (T2D) or obesity, GLP-1 has a diminished effect compared to those without these conditions.4
How Does Orforglipron Work?
Orforglipron is a chemically synthesized, nonpeptide GLP-1 receptor agonist designed for daily oral administration.5-7
Orforglipron is an investigational molecule and is not currently approved in any countries or geographies.8
Orforglipron binds to the same receptor site as native GLP-1.6
In preclinical studies, orforglipron was found to be a partial agonist of the GLP-1 receptor. Orforglipron activates the G protein coupled receptor and exhibits biased agonism favoring cyclic adenosine monophosphate (cAMP) accumulation versus β-arrestin recruitment.6
There is no evidence linking preclinical receptor pharmacology results of biased agonism towards cAMP accumulation with clinical efficacy in humans.
See Orforglipron: Mechanism of Action for a video illustrating the mechanism of action of orforglipron.
References
1Nauck MA, Meier JJ. Incretin hormones: their role in health and disease. Diabetes Obes Metab. 2018;20(suppl 1):5-21. https://doi.org/10.1111/dom.13129
2Samms RJ, Coghlan MP, Sloop KW. How may GIP enhance the therapeutic efficacy of GLP-1? Trends Endocrinol Metab. 2020;31(6):410-421. https://doi.org/10.1016/j.tem.2020.02.006
3Holst JJ. Incretin hormones and the satiation signal. Int J Obes (Lond). 2013;37(9):1161-1168. https://doi.org/10.1038/ijo.2012.208
4Holst JJ. GLP-1 physiology in obesity and development of incretin-based drugs for chronic weight management. Nat Metab. 2024;6(10):1866-1885. https://doi.org/10.1038/s42255-024-01113-9
5Pratt E, Ma X, Liu R, et al. Orforglipron (LY3502970), a novel, oral non-peptide glucagon-like peptide-1 receptor agonist: a phase 1b, multicentre, blinded, placebo-controlled, randomized, multiple-ascending-dose study in people with type 2 diabetes. Diabetes Obes Metab. 2023;25(9):2642-2649. https://doi.org/10.1111/dom.15150
6Kawai T, Sun B, Yoshino H, et al. Structural basis for GLP-1 receptor activation by LY3502970, an orally active nonpeptide agonist. Proc Natl Acad Sci U S A. 2020;117(47):29959-29967. https://doi.org/10.1073/pnas.2014879117
7Wharton S, Blevins T, Connery L, et al; GZGI Investigators. Daily oral GLP-1 receptor agonist orforglipron for adults with obesity. N Engl J Med. 2023;389(10):877-888. https://doi.org/10.1056/NEJMoa2302392
8Medicines in development. Eli Lilly and Company. Clinical Development Pipeline website. Accessed February 6, 2025. https://www.lilly.com/pipeline
Date of Last Review: March 20, 2025