Glucagon-like peptide-1 receptor agonist

Glucagon-like peptide-1 receptor agonists, also known as GLP-1 receptor agonists (GLP-1-RA) or incretin mimetics, are agonists of the GLP-1 receptor. This class of medications is used for the treatment of type 2 diabetes[1][2] Some drugs are also approved for obesity. One of their advantages over older insulin secretagogues, such as sulfonylureas or meglitinides, is that they have a lower risk of causing hypoglycemia.[3] 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.[4]

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.[5]

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.[6] 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.[7]

Preclinical research has suggested the possibility that the drugs may increase the risk of pancreatitis and pancreatic cancer.[8] Analyses of human trials have not found an increased risk of pancreatitis but are insufficiently powered to rule out an effect on pancreatic cancer.[9][10][11]

Studies in rodents have shown GLP1 mediated thyroid c-cell hyperplasia.[12]

A 2020 Cochrane systematic review did not find enough evidence of reduction of all-cause mortality, serious adverse events, cardiovascular mortality, non-fatal myocardial infarction, non-fatal stroke, end-stage renal disease nor health-related quality of life when comparing metformin monotherapy to Glucagon-like peptide 1 analogues in the treatment of type 2 diabetes.[13]

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[14]
  • lixisenatide (Lyxumia in Europe, Adlyxin in the United States, manufactured by Sanofi), approved in 2016[15]
  • albiglutide (Tanzeum, manufactured by GSK), approved in 2014[16]
  • dulaglutide (Trulicity, manufactured by Eli Lilly), approved in 2014[17]
  • semaglutide (Ozempic and Rybelsus for diabetes, Wegovy for obesity, manufactured by Novo Nordisk), approved in 2017[18]
  • tirzepatide (Mounjaro, manufactured by Eli Lilly), approved in 2022[19]

Under investigation

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.[21]

References
  1. Baggio LL (2008). "Glucagon-like Peptide-1 Analogs Other Than Exenatide". Medscape Diabetes & Endocrinology.
  2. Ali ES, Hua J, Wilson CH, Tallis GA, Zhou FH, Rychkov GY, Barritt GJ (September 2016). "The glucagon-like peptide-1 analogue exendin-4 reverses impaired intracellular Ca(2+) signalling in steatotic hepatocytes". Biochimica et Biophysica Acta. 1863 (9): 2135–2146. doi:10.1016/j.bbamcr.2016.05.006. PMID 27178543.
  3. "Standards of medical care in diabetes--2012". Diabetes Care. 35 Suppl 1: S11–S63. January 2012. doi:10.2337/dc12-s011. PMC 3632172. PMID 22187469.
  4. Das A, Geetha KM, Hazarika I (29 August 2019). "Contemporary Updates on the Physiology of Glucagon like Peptide-1 and Its Agonist to Treat Type 2 Diabetes Mellitus". International Journal of Peptide Research and Therapeutics. 26 (3): 1211–1221. doi:10.1007/s10989-019-09927-y. S2CID 202854512.
  5. Draznin B, Aroda VR, Bakris G, Benson G, Brown FM, Freeman R, et al. (January 2022). "9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes-2022". Diabetes Care. 45 (Suppl 1): S125–S143. doi:10.2337/dc22-S009. PMID 34964831.
  6. Sattar N, Lee MM, Kristensen SL, Branch KR, Del Prato S, Khurmi NS, et al. (October 2021). "Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of randomised trials". The Lancet. Diabetes & Endocrinology. 9 (10): 653–662. doi:10.1016/s2213-8587(21)00203-5. PMID 34425083.
  7. Zheng SL, Roddick AJ, Aghar-Jaffar R, Shun-Shin MJ, Francis D, Oliver N, Meeran K (April 2018). "Association Between Use of Sodium-Glucose Cotransporter 2 Inhibitors, Glucagon-like Peptide 1 Agonists, and Dipeptidyl Peptidase 4 Inhibitors With All-Cause Mortality in Patients With Type 2 Diabetes: A Systematic Review and Meta-analysis". Jama. 319 (15): 1580–1591. doi:10.1001/jama.2018.3024. hdl:10044/1/60316. PMC 5933330. PMID 29677303.
  8. Pinto LC, Falcetta MR, Rados DV, Leitão CB, Gross JL (February 2019). "Glucagon-like peptide-1 receptor agonists and pancreatic cancer: a meta-analysis with trial sequential analysis". Scientific Reports. 9 (1): 2375. doi:10.1038/s41598-019-38956-2. PMID 30787365.
  9. Forsmark CE (2016). "Incretins, Diabetes, Pancreatitis and Pancreatic Cancer: What the GI specialist needs to know". Pancreatology. 16 (1): 10–13. doi:10.1016/j.pan.2015.11.009. PMID 26795258.
  10. Nreu B, Dicembrini I, Tinti F, Mannucci E, Monami M (July 2020). "Pancreatitis and pancreatic cancer in patients with type 2 diabetes treated with glucagon-like peptide-1 receptor agonists: an updated meta-analysis of randomized controlled trials". Minerva Endocrinologica. doi:10.23736/S0391-1977.20.03219-8. PMID 32720500.
  11. Boniol M, Franchi M, Bota M, Leclercq A, Guillaume J, van Damme N, et al. (February 2018). "Incretin-Based Therapies and the Short-term Risk of Pancreatic Cancer: Results From Two Retrospective Cohort Studies". Diabetes Care. 41 (2): 286–292. doi:10.2337/dc17-0280. PMID 29146599. S2CID 207368560.
  12. Bjerre Knudsen L, Madsen LW, Andersen S, Almholt K, de Boer AS, Drucker DJ, et al. (April 2010). "Glucagon-like Peptide-1 receptor agonists activate rodent thyroid C-cells causing calcitonin release and C-cell proliferation". Endocrinology. 151 (4): 1473–1486. doi:10.1210/en.2009-1272. PMID 20203154.
  13. Gnesin F, Thuesen AC, Kähler LK, Madsbad S, Hemmingsen B, et al. (Cochrane Metabolic and Endocrine Disorders Group) (June 2020). "Metformin monotherapy for adults with type 2 diabetes mellitus". The Cochrane Database of Systematic Reviews. 6 (6): CD012906. doi:10.1002/14651858.CD012906.pub2. PMC 7386876. PMID 32501595.
  14. "FDA Approves New Treatment for Type 2 Diabetes". Food and Drug Administration.
  15. "FDA approves Adlyxin to treat type 2 diabetes". Food and Drug Administration. 2019-09-10.
  16. "FDA Approves Weekly Injectable Diabetes Drug: Albiglutide".
  17. "FDA Approves Weekly Injectable Diabetes Drug: Dulaglutide". Food and Drug Administration.
  18. Longer Acting GLP-1 Receptor Agonists and the Potential for Improved Cardiovascular Outcomes. 2013
  19. Frías JP, Davies MJ, Rosenstock J, Pérez Manghi FC, Fernández Landó L, Bergman BK, et al. (August 2021). "Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes". The New England Journal of Medicine. 385 (6): 503–515. doi:10.1056/NEJMoa2107519. PMID 34170647. S2CID 235635529.
  20. Gerstein HC, Sattar N, Rosenstock J, Ramasundarahettige C, Pratley R, Lopes RD, et al. (September 2021). "Cardiovascular and Renal Outcomes with Efpeglenatide in Type 2 Diabetes". The New England Journal of Medicine. 385 (10): 896–907. doi:10.1056/NEJMoa2108269. PMID 34215025. S2CID 235723092.
  21. "GLP-1 Receptor Agonists vs. DPP-4 Inhibitors for Type 2 Diabetes".
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