Glucagon-like peptide-1 receptor agonist
Glucagon-like peptide-1 receptor agonists, also known as GLP-1 receptor agonists (GLP-1-RA), incretin mimetics, or GLP-1 analogs, are agonists of the GLP-1 receptor. This class of medications is used for the treatment of type 2 diabetes. One of their advantages over older insulin secretagogues, such as sulfonylureas or meglitinides, is that they have a lower risk of causing hypoglycemia. GLP-1 has a short duration of action, so to overcome this limitation several modifications in either the drugs or the formulations are being developed. The 2022 ADA standards of medical care in diabetes include GLP-1-RA as a first line pharmacological therapy for type 2 diabetes, specifically in patients with atherosclerotic cardiovascular disease or obesity.
Some GLP-1 receptor agonists have been used off-label for obesity and impulse control.
A 2021 meta-analysis found a 12% reduction in all-cause mortality when GLP-1 analogs are used in the treatment of type 2 diabetes, as well as significant improvements in cardiovascular and renal outcomes. A JAMA article meta-analysis in 2018 (covering studies concerning GLP-1 agonists, DPP-4 inhibitors, and SGLT2 inhibitors) showed GLP-1 agonists were associated with lower stroke risk than controls.
Preclinical research has suggested the possibility that the drugs may increase the risk of pancreatitis and pancreatic cancer. However, several analyses of human trials have not found an increased risk of pancreatitis or pancreatic cancer but researchers note the follow up duration of the included trials may not be sufficient for the occurrence of carcinogenesis as the mean follow-up was only 1.74 years. Although some authors caveat this by claiming the patient pools aren't large enough to fully disprove an association, other authors claim there is a statistically significant lack of correlation between these drugs and pancreatic cancer.
Studies in rodents have shown GLP1 mediated thyroid c-cell hyperplasia.
- exenatide (brand names Byetta and Bydureon, manufactured by AstraZeneca), approved in 2005/2012
- liraglutide (Victoza for diabetes, Saxenda for obesity, manufactured by Novo Nordisk), approved in 2010
- albiglutide (Tanzeum, manufactured by GSK), approved in 2014
- dulaglutide (Trulicity, manufactured by Eli Lilly), approved in 2014
- lixisenatide (Lyxumia in Europe, Adlyxin in the United States, manufactured by Sanofi), approved in 2016
- semaglutide (Ozempic and Rybelsus for diabetes, Wegovy for obesity, manufactured by Novo Nordisk), approved in 2017
- tirzepatide (Mounjaro, manufactured by Eli Lilly, combined with a GIP analog), approved in 2022
- taspoglutide, phase III halted Sept 2010
These agents work by activating the GLP-1R, rather than inhibiting the breakdown of GLP-1 as do DPP-4 inhibitors, and are generally considered more potent.
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