Chemistry:Semaglutide

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Short description: Chemical compound (anti-diabetic medication)
Semaglutide
Semaglutide.svg
Clinical data
Trade namesOzempic, Rybelsus, others
AHFS/Drugs.comMonograph
MedlinePlusa618008
Pregnancy
category
  • AU: D
Routes of
administration		Subcutaneous, by mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability89%
MetabolismProteolysis
Elimination half-life1 week
Duration of action63.6 h
ExcretionUrine and faeces
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
Chemical and physical data
FormulaC187H291N45O59
Molar mass4113.641 g·mol−1
3D model (JSmol)

Semaglutide, sold under the brand names Ozempic and Rybelsus, is an anti-diabetic medication used for the treatment of type 2 diabetes.[3][4]

Semaglutide acts like human glucagon-like peptide-1 (GLP-1) such that it increases insulin secretion, thereby increasing sugar metabolism. It is distributed as a metered subcutaneous injection in a prefilled pen or as an oral form. One of its advantages over other antidiabetic drugs is that it has a long duration of action, thus, only once-a-week injection is sufficient.[5]

An injection version (Ozempic) was approved for medical use in the United States in December 2017,[6] and in the European Union,[1] Canada,[7] and Japan in 2018. A version which is taken by mouth (Rybelsus) was approved for medical use in the United States in September 2019,[8] and in the European Union in April 2020.[2] It is the first glucagon-like peptide receptor protein treatment approved for use in the United States that does not need to be injected.[9] It was developed by Novo Nordisk.

Side effects including nausea, vomiting, diarrhea, abdominal pain, and constipation may occur.[10]

Medical uses

Semaglutide is prepared for subcutaneous injection and is available in prefilled pen. It is recommended for once-weekly injection.[11]

Adverse effects

Side effects including nausea, vomiting, diarrhea, abdominal pain, and constipation may occur.[10] In people with heart problems, it can cause damage to the back of the eye (retinopathy).[12] Side effects include medullary thyroid cancer, kidney problems, diabetic retinopathy, allergic reactions, low blood sugar, and pancreatitis.[9]

Mechanism of action

Semaglutide is a glucagon-like peptide-1 receptor agonist. It increases the production of insulin, a hormone that lowers the blood sugar level.[13] It also appears to enhance growth of β cells in the pancreas, which are the sites of insulin production.[14] On the other hand it inhibits glucagon, which is a hormone that increases blood sugar. It additionally reduces food intake by lowering appetite and slows down digestion in the stomach.[12] In this way it works in body fat reduction.[11]

Structure

Semaglutide is chemically similar to human glucagon-like peptide-1 (GLP-1), with 94% similarity. The only differences are two amino acid substitutions at positions 8 and 34, where alanine and lysine are replaced by 2-aminoisobutyric acid and arginine respectively.[15] Amino acid substitution at position 8 prevents chemical breakdown by an enzyme dipeptidyl peptidase-4. In addition, lysine at position 26 is in its derivative form (acylated with stearic diacid). Acylation with a spacer and C-18 fatty diacid chain increases the drug binding to blood protein (albumin), which enables longer presence in the blood circulation.[16] Its half-life in the blood is about 7 days (165–184 hours), therefore, once-weekly injection is enough.[5][14]

History

Semaglutide was developed in 2012,[17] by a team of researchers at Novo Nordisk as a longer-acting alternative to liraglutide.[18] It was given the brand name Ozempic. Clinical trials were started in 2015, and phase III was completed in 2016.[19][full citation needed]

Researchers at the University of Leeds and Novo Nordisk reported in 2017, that it can also be used for the treatment of obesity.[20] It reduces hunger, food craving and body fat.[21] A Phase 3 Randomized Controlled Trial found that once-weekly injection of 2.4 mg of the drug resulted in an average change of −14.9% body weight at 68 weeks compared to −2.4% for the placebo.[22]

The US FDA New Drug Application (NDA) was filed in December 2016, and in October 2017, the FDA Advisory Committee voted 16–0 in favor.[23] Approval was announced in December 2017.[6] It can be used as both injection-type or oral-type drug.[24] The marketing authorization in the European Union was granted in February 2018.[1][25] The Japanese Ministry of Health, Labour and Welfare announced approval on 23 March 2018.[26] Health Canada issued approval on 4 January 2018.[7]

Semaglutide was approved for medical use in Australia in August 2019.[27]

References

  1. ↑ 1.0 1.1 1.2 "Ozempic EPAR". European Medicines Agency (EMA). https://www.ema.europa.eu/en/medicines/human/EPAR/ozempic. 
  2. ↑ 2.0 2.1 "Rybelsus EPAR". 29 January 2020. https://www.ema.europa.eu/en/medicines/human/EPAR/rybelsus. 
  3. ↑ "Semaglutide Approval Status". drugs.com. https://www.drugs.com/history/semaglutide.html. 
  4. ↑ "Novo Nordisk Files for Regulatory Approval of Once-Weekly Semaglutide with the FDA for the Treatment of Type 2 Diabetes" (Press release). Novo Nordisk. December 5, 2016.
  5. ↑ 5.0 5.1 "Semaglutide, a once-weekly human GLP-1 analog, does not reduce the bioavailability of the combined oral contraceptive, ethinylestradiol/levonorgestrel". Journal of Clinical Pharmacology 55 (5): 497–504. May 2015. doi:10.1002/jcph.443. PMID 25475122. 
  6. ↑ 6.0 6.1 "Ozempic (semaglutide) Injection". U.S. Food and Drug Administration (FDA). 16 January 2018. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209637Orig1s000TOC.cfm. 
  7. ↑ 7.0 7.1 "Regulatory Decision Summary – Ozempic". Health Canada. https://hpr-rps.hres.ca/reg-content/regulatory-decision-summary-detail.php?lang=en&linkID=RDS00317. 
  8. ↑ "Drug Approval Package: Rybelsus". U.S. Food and Drug Administration (FDA). 10 June 2020. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/213051Orig1s000TOC.cfm. 
  9. ↑ 9.0 9.1 "FDA approves first oral GLP-1 treatment for type 2 diabetes" (Press release). FDA. 20 September 2019. Retrieved 20 September 2019.
  10. ↑ 10.0 10.1 "Selected Important Safety Information". Novo Nordisk A/S. https://www.ozempicpro.com/about-ozempic/ozempic-overview.html. 
  11. ↑ 11.0 11.1 "Semaglutide: First Global Approval". Drugs 78 (2): 275–284. February 2018. doi:10.1007/s40265-018-0871-0. PMID 29363040. 
  12. ↑ 12.0 12.1 "Sgemaglutide in type 2 diabetes - is it the best glucagon-like peptide 1 receptor agonist (GLP-1R agonist)?". Expert Opinion on Drug Metabolism & Toxicology 14 (3): 371–377. March 2018. doi:10.1080/17425255.2018.1441286. PMID 29439603. https://eprints.qut.edu.au/121664/2/121664.pdf. 
  13. ↑ "Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes". The New England Journal of Medicine 375 (19): 1834–1844. November 2016. doi:10.1056/NEJMoa1607141. PMID 27633186. http://www.nejm.org/doi/pdf/10.1056/NEJMoa1607141. 
  14. ↑ 14.0 14.1 "Semaglutide: Review and Place in Therapy for Adults With Type 2 Diabetes". Canadian Journal of Diabetes 43 (2): 136–145. March 2019. doi:10.1016/j.jcjd.2018.05.008. PMID 30195966. 
  15. ↑ "Discovery of the Once-Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue Semaglutide". Journal of Medicinal Chemistry 58 (18): 7370–80. September 2015. doi:10.1021/acs.jmedchem.5b00726. PMID 26308095. 
  16. ↑ "The human GLP-1 analogs liraglutide and semaglutide: absence of histopathological effects on the pancreas in nonhuman primates". Diabetes 63 (7): 2486–97. July 2014. doi:10.2337/db13-1087. PMID 24608440. http://diabetes.diabetesjournals.org/content/diabetes/63/7/2486.full.pdf. 
  17. ↑ "Abstracts of the 48th EASD (European Association for the Study of Diabetes) Annual Meeting of the European Association for the Study of Diabetes. October 1-5, 2012. Berlin, Germany". Diabetologia 55 Suppl 1 (S1): S7-537. October 2012. doi:10.1007/s00125-012-2688-9. PMID 22918257. 
  18. ↑ "Once-weekly glucagon-like peptide 1 receptor agonists". The Journal of the Pakistan Medical Association 65 (7): 796–8. July 2015. PMID 26160096. 
  19. ↑ Clinical trial number NCT02648204 for "Efficacy and Safety of Semaglutide Versus Dulaglutide as add-on to Metformin in Subjects With Type 2 Diabetes" at ClinicalTrials.gov
  20. ↑ "Effects of once-weekly semaglutide on appetite, energy intake, control of eating, food preference and body weight in subjects with obesity". Diabetes, Obesity & Metabolism 19 (9): 1242–1251. September 2017. doi:10.1111/dom.12932. PMID 28266779. 
  21. ↑ "Drug can dramatically reduce weight of people with obesity". ScienceDaily. 23 October 2017. https://www.sciencedaily.com/releases/2017/10/171023131955.htm. 
  22. ↑ Wilding, John P.H.; Batterham, Rachel L.; Calanna, Salvatore; Davies, Melanie; Van Gaal, Luc F.; Lingvay, Ildiko; McGowan, Barbara M.; Rosenstock, Julio et al. (10 February 2021). "Once-Weekly Semaglutide in Adults with Overweight or Obesity". New England Journal of Medicine: NEJMoa2032183. doi:10.1056/NEJMoa2032183. 
  23. ↑ "Development Status and FDA Approval Process for semaglutide". Drugs.com. 2017. https://www.drugs.com/history/semaglutide.html. 
  24. ↑ "Effect of Oral Semaglutide Compared With Placebo and Subcutaneous Semaglutide on Glycemic Control in Patients With Type 2 Diabetes: A Randomized Clinical Trial". JAMA 318 (15): 1460–1470. October 2017. doi:10.1001/jama.2017.14752. PMID 29049653. 
  25. ↑ "Novo Nordisk A/S: Ozempic (semaglutide) approved in the EU for the treatment of type 2 diabetes" (Press release). Novo Nordisk A/S. 9 February 2018. Retrieved 2018-08-19 – via GlobeNewswire.
  26. ↑ "Ozempic approved in Japan for the treatment of type 2 diabetes" (Press release). Novo Nordisk A/S. 23 March 2018. Retrieved 2 April 2019 – via GlobeNewswire.
  27. ↑ "Summary for ARTG Entry:315107 Ozempic 1 mg semaglutide (rys) 1.34 mg/mL solution for injection pre-filled pen" (PDF). http://www.ebs.tga.gov.au/servlet/xmlmillr6?dbid=ebs/PublicHTML/pdfStore.nsf&docid=348BC43E196DD03DCA2585880030E9AF&agid=(PrintDetailsPublic)&actionid=1. 

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