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.
Gray market sellers offer unauthorized products claimed to be GLP-1 agonists online. This practice is illegal in the United States, but some buyers turn to unauthorized retailers due to being denied insurance coverage and not being able to afford the name brand drug.
Health effects
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.
A meta-analysis including 13 cardiovascular outcome trials found that SGLT-2 inhibitors reduce the risk for three-point MACE, especially in subjects with an estimated glomerular filtration rate (eGFR) below 60 mL/min, whereas GLP-1 receptor agonists were more beneficial in persons with higher eGFR. Likewise, the risk reduction due to SGLT-2 inhibitors was larger in populations with a higher proportion of albuminuria, but this relationship was not observed for GLP-1 receptor agonists. This suggests differential use of the two substance classes in patients with preserved and reduced renal function or with and without diabetic nephropathy, respectively.
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.
GLP-1 agonists are being studied for the treatment of non-alcoholic fatty liver disease. They are at least as effective as the medications in current use, pioglitazone and Vitamin E, and significantly reduce steatosis, ballooning necrosis, lobular inflammation, and fibrosis according to a 2023 systematic review. Semaglutide is in a Phase III study for this disease as of 2023.
Links between GLP-1 agonists and risk of self-harm or suicidal thoughts (which have previously been an issue with other weight loss drugs such as rimonabant) have been controversial, with clinical studies showing no evidence of risk, but subsequent post-marketing surveillance showing some possible risks, which will be investigated further.
Approved
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
Under investigation
taspoglutide, phase III halted Sept 2010
efpeglenatide
danuglipron
lotiglipron
orforglipron
retatrutide (LY3437943), also a GIP and GCGR agonist
GSBR-1290
Mechanism
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.
References