Semaglutide

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
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
ECHA InfoCard100.219.541
Chemical and physical data
FormulaC187H291N45O59
Molar mass4113.641 g·mol−1
3D model (JSmol)

Semaglutide acts like human glucagon-like peptide-1 (GLP-1) so that it increases insulin secretion, thereby increasing sugar metabolism. It is distributed as a metered subcutaneous injection in a prefilled pen. 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.[12] In people with heart problems, it can cause damage to the back of the eye (retinopathy).[13] 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.[14] It also appears to enhance growth of β cells in the pancreas, which are the sites of insulin production.[15] 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.[13] In this way it works in body fat reduction.[11]

Structure

In humans 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.[16] 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.[17] Its half-life in the blood is about 7 days (165–184 hours), therefore, once-weekly injection is enough.[5][15]

History

Semaglutide was discovered in 2012,[18] by a team of researchers at Novo Nordisk as a longer-acting alternative to liraglutide.[19] It was given the brand name Ozempic. Clinical trials were started in 2015, and phase III was completed in 2016.[20]

Researchers at the University of Leeds and Novo Nordisk reported in 2017, that it can also be used for the treatment of obesity.[21] It reduces hunger, food craving and body fat.[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. "Ozempic EPAR". European Medicines Agency (EMA). Retrieved 26 September 2020.
  2. "Rybelsus EPAR". European Medicines Agency (EMA). 29 January 2020. Retrieved 26 September 2020.
  3. "Semaglutide Approval Status". drugs.com.
  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. Kapitza C, Nosek L, Jensen L, Hartvig H, Jensen CB, Flint A (May 2015). "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. doi:10.1002/jcph.443. PMC 4418331. PMID 25475122.
  6. "Ozempic (semaglutide) Injection". U.S. Food and Drug Administration (FDA). 16 January 2018. Retrieved 26 September 2020.
  7. "Regulatory Decision Summary – Ozempic". Health Canada. Retrieved 2 April 2019.
  8. "Drug Approval Package: Rybelsus". U.S. Food and Drug Administration (FDA). 10 June 2020. Retrieved 26 September 2020.
  9. "FDA approves first oral GLP-1 treatment for type 2 diabetes" (Press release). FDA. 20 September 2019. Retrieved 20 September 2019.
  10. "Selected Important Safety Information". www.ozempicpro.com. Novo Nordisk A/S. Retrieved 2 April 2019.
  11. Dhillon S (February 2018). "Semaglutide: First Global Approval". Drugs. 78 (2): 275–284. doi:10.1007/s40265-018-0871-0. PMID 29363040. S2CID 46851453.
  12. "Selected Important Safety Information". www.ozempicpro.com. Novo Nordisk A/S. Retrieved 2 April 2019.
  13. Doggrell SA (March 2018). "Sgemaglutide in type 2 diabetes - is it the best glucagon-like peptide 1 receptor agonist (GLP-1R agonist)?" (PDF). Expert Opinion on Drug Metabolism & Toxicology. 14 (3): 371–377. doi:10.1080/17425255.2018.1441286. PMID 29439603. S2CID 3421553.
  14. Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jódar E, Leiter LA, et al. (November 2016). "Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes". The New England Journal of Medicine. 375 (19): 1834–1844. doi:10.1056/NEJMoa1607141. PMID 27633186.
  15. Goldenberg RM, Steen O (March 2019). "Semaglutide: Review and Place in Therapy for Adults With Type 2 Diabetes". Canadian Journal of Diabetes. 43 (2): 136–145. doi:10.1016/j.jcjd.2018.05.008. PMID 30195966.
  16. Lau J, Bloch P, Schäffer L, Pettersson I, Spetzler J, Kofoed J, et al. (September 2015). "Discovery of the Once-Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue Semaglutide". Journal of Medicinal Chemistry. 58 (18): 7370–80. doi:10.1021/acs.jmedchem.5b00726. PMID 26308095.
  17. Gotfredsen CF, Mølck AM, Thorup I, Nyborg NC, Salanti Z, Knudsen LB, Larsen MO (July 2014). "The human GLP-1 analogs liraglutide and semaglutide: absence of histopathological effects on the pancreas in nonhuman primates" (PDF). Diabetes. 63 (7): 2486–97. doi:10.2337/db13-1087. PMID 24608440. S2CID 35102048.
  18. "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.
  19. Kalra S, Gupta Y (July 2015). "Once-weekly glucagon-like peptide 1 receptor agonists". JPMA. The Journal of the Pakistan Medical Association. 65 (7): 796–8. PMID 26160096.
  20. 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
  21. Blundell J, Finlayson G, Axelsen M, Flint A, Gibbons C, Kvist T, Hjerpsted JB (September 2017). "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. doi:10.1111/dom.12932. PMC 5573908. PMID 28266779.
  22. "Drug can dramatically reduce weight of people with obesity". ScienceDaily. 23 October 2017. Retrieved 24 October 2017.
  23. "Development Status and FDA Approval Process for semaglutide". Drugs.com. 2017. Retrieved 24 October 2017.
  24. Davies M, Pieber TR, Hartoft-Nielsen ML, Hansen OK, Jabbour S, Rosenstock J (October 2017). "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. doi:10.1001/jama.2017.14752. PMC 5817971. 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). Therapeutic Goods Administration (TGA). Retrieved 26 September 2020.
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