Glucagon-like peptide-1 receptor agonist

Glucagon-like peptide-1 receptor agonist
Drug class
Names
Other namesGLP-1 receptor agonists, GLP-1 analogs, incretin mimetics[1][2]
Clinical data
UsesType 2 diabetes, obesity[3]
Side effectsNausea, diarrhea, abdominal pain[4]
SubtypesExenatide, dulaglutide, albiglutide, semaglutide, liraglutide[3]
Biological targetGLP-1 receptor[3]
External links
Drugs.comDrug Classes

Glucagon-like peptide-1 receptor agonists (GLP-1-RA) are a class of medications used to treat type 2 diabetes and obesity.[3] The ADA lists them as a first line medication for people with type 2 diabetes who are at high risk for atherosclerotic cardiovascular disease as of 2022.[5] They are available by injection under the skin and by mouth.[3]

Common side effects include nausea, diarrhea, and abdominal pain.[4] They have a low risk of low blood sugar; though may result in pancreatitis or gastroparesis.[2][3][6] Animal models have raised concerns regarding thyroid C-cell tumors.[5] Use is not recommended in pregnancy.[2] They are activators of the GLP-1 receptor.[3] They work by increasing insulin release and decreasing glucagon in response to high blood sugar; and slowing stomach emptying.[3]

The first GLP-1-RA, exenatide, was approved for medical use in the United States in 2005.[3] As of 2022 they are relatively expensive in the United States, costing about 1,000 USD per month.[5] There are versions that come premixed with long acting insulin.[5] Shortages occurred in 2023 due to increased demand.[7][8]

Medical uses

Diabetes

A 2021 meta-analysis found a 12% reduction in all-cause mortality in the treatment of type 2 diabetes, as well as improvements in cardiovascular and kidney outcomes.[9] GLP-1 agonists are associated with lower stroke risk.[10] 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.[11] 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 people with preserved and reduced kidney function or with and without diabetic nephropathy, respectively.[11]

Obesity

They result in a greater weight loss of about 7 kg, then a control.[4]

Side effects

Preclinical research has suggested the possibility that they may increase the risk of pancreatitis and pancreatic cancer.[12] 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.[12][13][14][15] Although some authors caveat this by claiming the patient pools aren't large enough to fully disprove an association,[13][14][15] other authors claim there is a statistically significant lack of correlation between these drugs and pancreatic cancer.[12]

Studies in rodents have shown GLP1 mediated thyroid c-cell hyperplasia.[16]

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,[17] but subsequent post-marketing surveillance showing some possible risks, which will be investigated further.[18]

Approved

  • exenatide (Byetta and Bydureon, manufactured by AstraZeneca), approved in 2005/2012
  • liraglutide (Victoza for diabetes, Saxenda for obesity, manufactured by Novo Nordisk), approved in 2010[19]
  • albiglutide (Tanzeum, manufactured by GSK), approved in 2014[20]
  • dulaglutide (Trulicity, manufactured by Eli Lilly), approved in 2014[21]
  • lixisenatide (Lyxumia in Europe, Adlyxin in the United States, manufactured by Sanofi), approved in 2016[22]
  • semaglutide (Ozempic and Rybelsus for diabetes, Wegovy for obesity, manufactured by Novo Nordisk), approved in 2017[23]
  • tirzepatide (Mounjaro, manufactured by Eli Lilly, combined with a GIP analog), approved in 2022[24]

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.[25]

GLP-1 has a short duration of action, so to overcome this limitation several modifications were developed.[26]

Research

They are being studied in impulse control disorders, type I diabetes, and psoriasis.[27][3][5]

Under investigation

References

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  2. 1 2 3 Collins, Logan; Costello, Ryan A. (2023). "Glucagon-like Peptide-1 Receptor Agonists". StatPearls. StatPearls Publishing. Archived from the original on 8 March 2023. Retrieved 23 July 2023.
  3. 1 2 3 4 5 6 7 8 9 10 Nauck, MA; Quast, DR; Wefers, J; Meier, JJ (April 2021). "GLP-1 receptor agonists in the treatment of type 2 diabetes - state-of-the-art". Molecular metabolism. 46: 101102. doi:10.1016/j.molmet.2020.101102. PMID 33068776.
  4. 1 2 3 Iqbal, J; Wu, HX; Hu, N; Zhou, YH; Li, L; Xiao, F; Wang, T; Jiang, HL; Xu, SN; Huang, BL; Zhou, HD (June 2022). "Effect of glucagon-like peptide-1 receptor agonists on body weight in adults with obesity without diabetes mellitus-a systematic review and meta-analysis of randomized control trials". Obesity reviews : an official journal of the International Association for the Study of Obesity. 23 (6): e13435. doi:10.1111/obr.13435. PMID 35194917.
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