Semaglutide

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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
  • 910463-68-2
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ECHA InfoCard100.219.541 Edit this at Wikidata
Chemical and physical data
FormulaC187H291N45O59
Molar mass4113.641 g·mol−1
3D model (JSmol)
  • CCC(C)C(C(=O)NC(C)C(=O)NC(CC1=CNC2=CC=CC=C21)C(=O)NC(CC(C)C)C(=O)NC(C(C)C)C(=O)NC(CCCNC(=N)N)C(=O)NCC(=O)NC(CCCNC(=N)N)C(=O)NCC(=O)O)NC(=O)C(CC3=CC=CC=C3)NC(=O)C(CCC(=O)O)NC(=O)C(CCCCNC(=O)COCCOCCNC(=O)COCCOCCNC(=O)CCC(C(=O)O)NC(=O)CCCCCCCCCCCCCCCCC(=O)O)NC(=O)C(C)NC(=O)C(C)NC(=O)C(CCC(=O)N)NC(=O)CNC(=O)C(CCC(=O)O)NC(=O)C(CC(C)C)NC(=O)C(CC4=CC=C(C=C4)O)NC(=O)C(CO)NC(=O)C(CO)NC(=O)C(C(C)C)NC(=O)C(CC(=O)O)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C(CC5=CC=CC=C5)NC(=O)C(C(C)O)NC(=O)CNC(=O)C(CCC(=O)O)NC(=O)C(C)(C)NC(=O)C(CC6=CN=CN6)N
  • InChI=1S/C187H291N45O59/c1-18-105(10)154(180(282)208-108(13)159(261)216-133(86-114-89-200-119-50-40-39-49-117(114)119)170(272)218-129(82-102(4)5)171(273)228-152(103(6)7)178(280)215-121(53-44-72-199-186(192)193)162(264)201-91-141(242)209-120(52-43-71-198-185(190)191)161(263)204-94-151(257)258)230-172(274)131(83-111-45-33-31-34-46-111)219-167(269)126(64-69-149(253)254)214-166(268)122(51-41-42-70-195-144(245)98-290-79-78-289-76-74-197-145(246)99-291-80-77-288-75-73-196-139(240)66-61-127(183(285)286)211-140(241)54-37-29-27-25-23-21-19-20-22-24-26-28-30-38-55-146(247)248)212-158(260)107(12)206-157(259)106(11)207-165(267)125(60-65-138(189)239)210-142(243)92-202-163(265)123(62-67-147(249)250)213-168(270)128(81-101(2)3)217-169(271)130(85-113-56-58-116(238)59-57-113)220-175(277)135(95-233)223-177(279)137(97-235)224-179(281)153(104(8)9)229-174(276)134(88-150(255)256)221-176(278)136(96-234)225-182(284)156(110(15)237)231-173(275)132(84-112-47-35-32-36-48-112)222-181(283)155(109(14)236)227-143(244)93-203-164(266)124(63-68-148(251)252)226-184(287)187(16,17)232-160(262)118(188)87-115-90-194-100-205-115/h31-36,39-40,45-50,56-59,89-90,100-110,118,120-137,152-156,200,233-238H,18-30,37-38,41-44,51-55,60-88,91-99,188H2,1-17H3,(H2,189,239)(H,194,205)(H,195,245)(H,196,240)(H,197,246)(H,201,264)(H,202,265)(H,203,266)(H,204,263)(H,206,259)(H,207,267)(H,208,282)(H,209,242)(H,210,243)(H,211,241)(H,212,260)(H,213,270)(H,214,268)(H,215,280)(H,216,261)(H,217,271)(H,218,272)(H,219,269)(H,220,277)(H,221,278)(H,222,283)(H,223,279)(H,224,281)(H,225,284)(H,226,287)(H,227,244)(H,228,273)(H,229,276)(H,230,274)(H,231,275)(H,232,262)(H,247,248)(H,249,250)(H,251,252)(H,253,254)(H,255,256)(H,257,258)(H,285,286)(H4,190,191,198)(H4,192,193,199)/t105-,106-,107-,108-,109+,110+,118-,120-,121-,122-,123-,124-,125-,126-,127+,128-,129-,130-,131-,132-,133-,134-,135-,136-,137-,152-,153-,154-,155-,156-/m0/s1
  • Key:DLSWIYLPEUIQAV-CCUURXOWSA-N checkY[pubchem]

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[edit]

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

Adverse effects[edit]

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[edit]

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[edit]

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[edit]

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[edit]

  1. ^ a b c "Ozempic EPAR". European Medicines Agency (EMA). Retrieved 26 September 2020.
  2. ^ a b "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. ^ a b 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. ^ a b "Ozempic (semaglutide) Injection". U.S. Food and Drug Administration (FDA). 16 January 2018. Retrieved 26 September 2020.
  7. ^ a b "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. ^ a b "FDA approves first oral GLP-1 treatment for type 2 diabetes" (Press release). FDA. 20 September 2019. Retrieved 20 September 2019.
  10. ^ a b "Selected Important Safety Information". www.ozempicpro.com. Novo Nordisk A/S. Retrieved 2 April 2019.
  11. ^ a b 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. ^ a b 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.
  13. ^ 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.
  14. ^ a b 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.
  15. ^ 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.
  16. ^ 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.
  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. ^ Kalra S, Gupta Y (July 2015). "Once-weekly glucagon-like peptide 1 receptor agonists". The Journal of the Pakistan Medical Association. 65 (7): 796–8. 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. ^ 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.
  21. ^ "Drug can dramatically reduce weight of people with obesity". ScienceDaily. 23 October 2017. Retrieved 24 October 2017.
  22. ^ Wilding, John P.H.; Batterham, Rachel L.; Calanna, Salvatore; Davies, Melanie; Van Gaal, Luc F.; Lingvay, Ildiko; McGowan, Barbara M.; Rosenstock, Julio; Tran, Marie T.D.; Wadden, Thomas A.; Wharton, Sean; Yokote, Koutaro; Zeuthen, Niels; Kushner, Robert F. (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. 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.

External links[edit]