Semaglutide

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Semaglutide
Semaglutide.svg
Names
Trade namesOzempic, Rybelsus, others
Clinical data
Drug classGLP-1 agonist[1]
Pregnancy
category
Routes of
use
Subcutaneous, by mouth[1]
Duration of action63.6 h
Typical dose0.25 to 1 mg SC per week[1]
External links
AHFS/Drugs.comMonograph
MedlinePlusa618008
Legal
Legal status
Pharmacokinetics
Bioavailability89%
MetabolismProteolysis
Elimination half-life1 week
ExcretionUrine and faeces
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 among others, is an medication used to treat type 2 diabetes.[1] It is less preferred to metformin, though they may be used together.[1][5] It improves blood sugar control, decreases the risk of heart disease, and decreases the risk of kidney problems.[1] It is used by mouth or by injection under the skin.[1]

Common side effects including nausea, vomiting, diarrhea, abdominal pain, and constipation.[1] Serious side effects may include diabetic ketoacidosis, low blood sugar, and pancreatitis.[5] There are concerns that use during pregnancy may harm the baby and use when breastfeeding is not recommended.[1] It works like human glucagon-like peptide-1 (GLP-1) and increases insulin release, decreases glucagon release, and slows stomach emptying.[5]

Semaglutide was approved for medical use in the United States in 2017.[1] It was developed by Novo Nordisk.[1] It was the first GLP-1 that can be taken by mouth.[6] In the United Kingdom 2 mg for injection costs the NHS about £73 as of 2020.[5] This amount in the United States costs about 850 USD as of 2021.[7]

Medical uses

Semaglutide is used to treat type 2 diabetes.[1]

It is prepared for subcutaneous injection and is available in prefilled pen. It is recommended for once-weekly injection.[8]

Dosage

By mouth, the typical initial dose is 3 mg once per day for the first month.[1] This may than be increased to 7 mg daily and 14 mg daily.[1] Once people are at 14 mg by mouth once a day they may be switched to 0.25 mg once per week for 4 weeks, which is than increased to 0.5 and potentially 1 mg per week.[1] It may also be started as 0.25 mg SC once per week.[5]

Side effects

Side effects including nausea, vomiting, diarrhea, abdominal pain, and constipation may occur. In people with heart problems, it can cause damage to the back of the eye (retinopathy).[9] Side effects include medullary thyroid cancer, kidney problems, diabetic retinopathy, allergic reactions, low blood sugar, and pancreatitis.[6]

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.[10] It also appears to enhance growth of β cells in the pancreas, which are the sites of insulin production.[11] 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.[9] In this way it works in body fat reduction.[8]

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.[12] 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.[13] Its half-life in the blood is about 7 days (165–184 hours), therefore, once-weekly injection is enough.[11]

History

Semaglutide was developed in 2012,[14] by a team of researchers at Novo Nordisk as a longer-acting alternative to liraglutide.[15] It was given the brand name Ozempic. Clinical trials were started in 2015, and phase III was completed in 2016.[16][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.[17] It reduces hunger, food craving and body fat.[18] 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.[19]

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.[20] Approval was announced in December 2017 for the injectable version.[21] It can be used as both injection-type or oral-type drug.[22] The marketing authorization in the European Union was granted in February 2018.[3][23] The Japanese Ministry of Health, Labour and Welfare announced approval on 23 March 2018.[24] Health Canada issued approval on 4 January 2018.[25] Semaglutide was approved for medical use in Australia in August 2019.[26]

A version which is taken by mouth (Rybelsus) was approved for medical use in the United States in September 2019,[27] and in the European Union in April 2020.[4]

References

  1. 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 "Semaglutide Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. Retrieved 2 April 2021. CS1 maint: discouraged parameter (link)
  2. "Semaglutide Use During Pregnancy". Drugs.com. Retrieved 16 April 2021. CS1 maint: discouraged parameter (link)
  3. 3.0 3.1 "Ozempic EPAR". European Medicines Agency (EMA). Retrieved 26 September 2020.
  4. 4.0 4.1 "Rybelsus EPAR". European Medicines Agency (EMA). 29 January 2020. Retrieved 26 September 2020.
  5. 5.0 5.1 5.2 5.3 5.4 BNF (80 ed.). BMJ Group and the Pharmaceutical Press. September 2020 – March 2021. p. 738. ISBN 978-0-85711-369-6.CS1 maint: date format (link)
  6. 6.0 6.1 "FDA approves first oral GLP-1 treatment for type 2 diabetes" (Press release). FDA. 20 September 2019. Retrieved 20 September 2019.
  7. "Ozempic Prices, Coupons & Savings Tips". GoodRx. Retrieved 16 April 2021. CS1 maint: discouraged parameter (link)
  8. 8.0 8.1 Dhillon S (February 2018). "Semaglutide: First Global Approval". Drugs. 78 (2): 275–284. doi:10.1007/s40265-018-0871-0. PMID 29363040. S2CID 46851453.
  9. 9.0 9.1 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.
  10. 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.
  11. 11.0 11.1 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.
  12. 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.
  13. 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.
  14. "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.
  15. 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.
  16. 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
  17. 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.
  18. "Drug can dramatically reduce weight of people with obesity". ScienceDaily. 23 October 2017. Retrieved 24 October 2017.
  19. 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.
  20. "Development Status and FDA Approval Process for semaglutide". Drugs.com. 2017. Retrieved 24 October 2017.
  21. "Ozempic (semaglutide) Injection". U.S. Food and Drug Administration (FDA). 16 January 2018. Retrieved 26 September 2020.
  22. 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.
  23. "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.
  24. "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.
  25. "Regulatory Decision Summary – Ozempic". Health Canada. Retrieved 2 April 2019.
  26. "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.
  27. "Drug Approval Package: Rybelsus". U.S. Food and Drug Administration (FDA). 10 June 2020. Retrieved 26 September 2020.

External links

External sites:
Identifiers: