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.[1][2] 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]

Some GLP-1 receptor agonists have been used off-label for obesity[6] and impulse control.[7]

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.[8][9][10][11][12]

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.[13] 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.[14]

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.[15] 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.[15]

Preclinical research has suggested the possibility that the drugs may increase the risk of pancreatitis and pancreatic cancer.[16] 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.[16][17][18][19] Although some authors caveat this by claiming the patient pools aren't large enough to fully disprove an association,[17][18][19] other authors claim there is a statistically significant lack of correlation between these drugs and pancreatic cancer.[16]

Studies in rodents have shown GLP1 mediated thyroid c-cell hyperplasia.[20]

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.[21] Semaglutide is in a Phase III study for this disease as of 2023.[22]

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,[23] but subsequent post-marketing surveillance showing some possible risks, which will be investigated further.[24]

Approved

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.[35]

References
  1. Baggio LL, Drucker DJ (2008). "Glucagon-like Peptide-1 Analogs Other Than Exenatide". Medscape Diabetes & Endocrinology. Retrieved 1 June 2023.
  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 (BBA) - Molecular Cell Research. 1863 (9): 2135–2146. doi:10.1016/j.bbamcr.2016.05.006. PMID 27178543.
  3. American Diabetes Association (January 2012). "Standards of medical care in diabetes--2012". Diabetes Care. 35 (Suppl 1): S11–S63. 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. eISSN 1573-3904. S2CID 202854512 – via SpringerLink.
  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. "New drugs could spell an end to the world's obesity epidemic". The Economist. 2 March 2023. Archived from the original on 2 March 2023. Retrieved 1 June 2023.
    Full text available via Archive link.
  7. 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.
  8. "Woman says she got less expensive drug for weight loss after being denied by insurance". ABC News. Retrieved 26 September 2023.
  9. "Safety worries over copycat versions of Ozempic and Wegovy prompt state crackdowns". NBC News. 3 May 2023. Retrieved 26 September 2023.
  10. Jones, C. T. (8 June 2023). "The FDA Warned Ozempic Users. They Don't Give a F-ck". Rolling Stone. Retrieved 26 September 2023.
  11. "Inside the gold rush to sell cheaper imitations of Ozempic". Washington Post. 19 September 2023. Retrieved 26 September 2023.
  12. "The high price of Ozempic is pushing many to unregulated, copycat drugs for weight loss". NBC News. 19 March 2023. Retrieved 26 September 2023.
  13. 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.
  14. 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.
  15. 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.
  16. 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.
  17. 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.
  18. 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.
  19. 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.
  20. 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.
  21. Gu, Yunpeng; Sun, Lei; He, Yining; Yang, Luping; Deng, Chaohua; Zhou, Run; Kong, Tingting; Zhang, Wei; Chen, Yutong; Li, Jie; Shi, Junping (4 March 2023). [10.1080/17474124.2023.2172397 "Comparative efficacy of glucagon-like peptide 1 (GLP-1) receptor agonists, pioglitazone and vitamin E for liver histology among patients with nonalcoholic fatty liver disease: systematic review and pilot network meta-analysis of randomized controlled trials"]. Expert Review of Gastroenterology & Hepatology. 17 (3): 273–282. doi:10.1080/17474124.2023.2172397. {{cite journal}}: Check |url= value (help)
  22. Harrison, Stephen A.; Loomba, Rohit; Dubourg, Julie; Ratziu, Vlad; Noureddin, Mazen (July 2023). "Clinical Trial Landscape in NASH". Clinical Gastroenterology and Hepatology. 21 (8): 2001–2014. doi:10.1016/j.cgh.2023.03.041.
  23. 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.
  24. Roberts M (10 July 2023). "Weight-loss jabs investigated for suicide risk". BBC News.
  25. "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.
  26. Busko, Marlene (15 April 2014). "FDA Approves Weekly Injectable Diabetes Drug: Albiglutide". Medscape (News, FDA Approvals).
  27. "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.
  28. "FDA approves Adlyxin to treat type 2 diabetes" (Press release). Food and Drug Administration. 28 July 2016.
  29. 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.
  30. 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.
  31. Sharma, Dilip; Verma, Suril; Vaidya, Shivani; Kalia, Kiran; Tiwari, Vinod (2018). "Recent updates on GLP-1 agonists: Current advancements & challenges". Biomedicine & Pharmacotherapy. 108. Section 4.4: Efpeglenatide. doi:10.1016/j.biopha.2018.08.088. ISSN 0753-3322.
  32. 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.
  33. "Pfizer's diabetes drug results in similar weight loss levels as Novo's Ozempic". Reuters. 2023-05-22. Retrieved 2023-05-29.
  34. 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.
  35. "GLP-1 Receptor Agonists vs. DPP-4 Inhibitors for Type 2 Diabetes".
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