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

  1. ↑ "List of Incretin mimetics". Drugs.com. Archived from the original on 12 May 2023. Retrieved 23 July 2023.
  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.
  5. 1 2 3 4 5 American Diabetes Association Professional Practice Committee (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. S2CID 245538347.
  6. ↑ Young, Clipper F.; Moussa, Marianne; Shubrook, Jay H. (1 August 2020). "Diabetic Gastroparesis: A Review". Diabetes Spectrum. 33 (3): 290–297. doi:10.2337/ds19-0062.
  7. ↑ Jankovic, Saša (28 June 2023). "Government declares 'national shortage' of GLP-1 receptor agonists for type 2 diabetes until 2024". The Pharmaceutical Journal. Archived from the original on 20 July 2023. Retrieved 23 July 2023.
  8. ↑ Cruz, Jace (11 July 2023). "Global Shortage of Diabetes Medicine 'Ozempic' Could Persist for a Longer Time, Experts Claim". Retrieved 23 July 2023.
  9. ↑ 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" (PDF). The Lancet Diabetes & Endocrinology (Article). 9 (10): 653–662. doi:10.1016/s2213-8587(21)00203-5. PMID 34425083. S2CID 237281403. Archived (PDF) from the original on 2023-05-22. Retrieved 2023-07-11.
  10. ↑ 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 (Original investigation). 319 (15): 1580–1591. doi:10.1001/jama.2018.3024. hdl:10044/1/60316. PMC 5933330. PMID 29677303 – via JAMA Network.
  11. 1 2 Sohn, M; Dietrich, JW; Nauck, MA; Lim, S (28 June 2023). "Characteristics predicting the efficacy of SGLT-2 inhibitors versus GLP-1 receptor agonists on major adverse cardiovascular events in type 2 diabetes mellitus: a meta-analysis study". Cardiovascular Diabetology. 22 (1): 153. doi:10.1186/s12933-023-01877-6. PMC 10303335. PMID 37381019. {{cite journal}}: Check |pmc= value (help)
  12. 1 2 3 Pinto LC, Falcetta MR, Rados DV, Leitão CB, Gross JL (20 February 2019). "Glucagon-like peptide-1 receptor agonists and pancreatic cancer: a meta-analysis with trial sequential analysis". Scientific Reports (Article). 9 (1): 2375. Bibcode:2019NatSR...9.2375P. doi:10.1038/s41598-019-38956-2. PMC 6382780. PMID 30787365.
  13. 1 2 Forsmark CE (2016). "Incretins, Diabetes, Pancreatitis and Pancreatic Cancer: What the GI specialist needs to know". Pancreatology (Review article). 16 (1): 10–13. doi:10.1016/j.pan.2015.11.009. eISSN 1424-3911. PMID 26795258.
  14. 1 2 Nreu B, Dicembrini I, Tinti F, Mannucci E, Monami M (June 2023). "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. 48 (2): 206–213. doi:10.23736/S0391-1977.20.03219-8. eISSN 2724-6116. PMID 32720500. S2CID 220839863. Archived from the original on 2023-06-02. Retrieved 2023-07-11.
  15. 1 2 Boniol M, Franchi M, Bota M, Leclercq A, Guillaume J, van Damme N, Corrao G, Autier P, Boyle P (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. hdl:10281/184291. PMID 29146599. S2CID 207368560.
  16. ↑ Bjerre Knudsen L, Madsen LW, Andersen S, Almholt K, de Boer AS, Drucker DJ, et al. (1 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. S2CID 20934882.
  17. ↑ Gamble JM, Chibrikov E, Midodzi WK, Twells LK, Majumdar SR (October 2018). "Examining the risk of depression or self-harm associated with incretin-based therapies used to manage hyperglycaemia in patients with type 2 diabetes: a cohort study using the UK Clinical Practice Research Datalink". BMJ Open. 8 (10): e023830. doi:10.1136/bmjopen-2018-023830. PMC 6194463. PMID 30297350.
  18. ↑ Roberts M (10 July 2023). "Weight-loss jabs investigated for suicide risk". BBC News. Archived from the original on 10 July 2023. Retrieved 11 July 2023.
  19. ↑ "FDA Approves New Treatment for Type 2 Diabetes" (Press release). Food and Drug Administration. 25 January 2010. Archived from the original on 28 January 2010.
  20. ↑ Busko, Marlene (15 April 2014). "FDA Approves Weekly Injectable Diabetes Drug: Albiglutide". Medscape (News, FDA Approvals). Archived from the original on 27 December 2022. Retrieved 11 July 2023.
  21. ↑ "FDA approves Trulicity to treat type 2 diabetes" (Press release). Food and Drug Administration. 18 September 2014. Archived from the original on 18 September 2014.
  22. ↑ "FDA approves Adlyxin to treat type 2 diabetes" (Press release). Food and Drug Administration. 28 July 2016. Archived from the original on 2 June 2023. Retrieved 11 July 2023.
  23. ↑ Tibble CA, Cavaiola TS, Henry RR (10 January 2014). "Longer acting GLP-1 receptor agonists and the potential for improved cardiovascular outcomes: a review of current literature". Expert Review of Endocrinology & Metabolism. Taylor & Francis. 8 (3): 247–259. doi:10.1586/eem.13.20. eISSN 1744-8417. ISSN 1744-6651. PMID 30780817. S2CID 73313508. Archived from the original on 18 February 2023. Retrieved 11 July 2023.
  24. ↑ 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.
  25. ↑ "GLP-1 Receptor Agonists vs. DPP-4 Inhibitors for Type 2 Diabetes". Archived from the original on 2022-12-27. Retrieved 2023-07-11.
  26. ↑ 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. eISSN 1573-3904. S2CID 202854512. Archived from the original on 2 June 2023. Retrieved 11 July 2023 – via SpringerLink.
  27. ↑ Erin-Yazicioglu CY, Yigit A, Dogruoz RE, Yapici-Eser H (2021-01-18). "Can GLP-1 Be a Target for Reward System Related Disorders? A Qualitative Synthesis and Systematic Review Analysis of Studies on Palatable Food, Drugs of Abuse, and Alcohol". Frontiers in Behavioral Neuroscience. 14: 614884. doi:10.3389/fnbeh.2020.614884. ISSN 1662-5153. PMC 7848227. PMID 33536884.
  28. ↑ Baggio LL, Drucker DJ (2008). "Glucagon-like Peptide-1 Analogs Other Than Exenatide". Medscape Diabetes & Endocrinology. Archived from the original on 24 July 2023. Retrieved 1 June 2023.
  29. ↑ 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" (PDF). The New England Journal of Medicine. 385 (10): 896–907. doi:10.1056/NEJMoa2108269. PMID 34215025. S2CID 235723092. Archived (PDF) from the original on 2023-07-24. Retrieved 2023-07-11.
  30. ↑ "Pfizer's diabetes drug results in similar weight loss levels as Novo's Ozempic". Reuters. 2023-05-22. Archived from the original on 2023-05-29. Retrieved 2023-05-29.
  31. ↑ Jastreboff AM, Kaplan LM, Frías JP, Wu Q, Du Y, Gurbuz S, Coskun T, Haupt A, Milicevic Z, Hartman ML (June 2023). "Retatrutide Phase 2 Obesity Trial Investigators. Triple-Hormone-Receptor Agonist Retatrutide for Obesity - A Phase 2 Trial". The New England Journal of Medicine. doi:10.1056/NEJMoa2301972. PMID 37366315. Archived from the original on 2023-07-14. Retrieved 2023-07-11.
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