Semaglutide
Semaglutide.svg
Clinical data
Trade namesOzempic, Rybelsus, Wegovy, others
AHFS/Drugs.comMonograph
MedlinePlusa618008
License data
Pregnancy
category
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 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 name Ozempic among others, is an antidiabetic medication used for the treatment of type 2 diabetes and long-term weight management.[15][16][17]

Semaglutide acts like human glucagon-like peptide-1 (GLP-1) in 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, so a once-a-week injection is sufficient.[18]

An injectable version (Ozempic) was approved for medical use in the United States in December 2017,[19] and in the European Union,[12] Canada,[20] and Japan in 2018. A version which is taken by mouth (Rybelsus) was approved for medical use in the United States in September 2019,[21] and in the European Union in April 2020.[13] It is the first glucagon-like peptide receptor protein treatment approved for use in the United States that does not need to be injected.[22] It was developed by Novo Nordisk. Side effects include nausea, vomiting, diarrhea, abdominal pain, and constipation.[9]

In June 2021, the US Food and Drug Administration (FDA) approved semaglutide injection sold under the brand name Wegovy for long-term weight management in adults.[11][17]

Medical uses

Semaglutide is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.[9][10]

Semaglutide may be administered in combination with other antidiabetic drugs; dose of concomitant insulin or sulfonylurea may need to be reduced.[23]

Semaglutide (Wegovy) is also indicated as an adjunct to diet and exercise for long-term weight management in adults with obesity (initial body mass index (BMI) ≥ 30 kg/m2) or overweight (initial BMI ≥ 27 kg/m2) with at least one weight-related comorbidity.[11][14][17]

Adverse effects

Side effects include nausea, vomiting, diarrhea, abdominal pain, and constipation.[9] In people with heart problems, it can cause damage to the retina of the eye (retinopathy).[24] Other, less common side effects include kidney problems, allergic reactions, low blood sugar, and pancreatitis.[22]

Contraindications

It is contraindicated in patients with a personal or family history of medullary thyroid carcinoma and in patients with multiple endocrine neoplasia syndrome type 2.[10][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.[25] It also appears to enhance growth of β cells in the pancreas, which are the sites of insulin production.[26] It also 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.[24] In this way it reduces body fat.[27]

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.[28] Amino-acid substitution at position 8 prevents chemical breakdown by 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.[29] Its half-life in the blood is about 7 days (165–184 hours); therefore, once-weekly injection is enough.[18][26]

History

Semaglutide was developed in 2012,[30] by a team of researchers at Novo Nordisk as a longer-acting alternative to liraglutide as a once-weekly diabetes therapy.[31] It was given the brand name Ozempic. Clinical trials were started on 6 January 2016, and completed on 19 May 2017.[32]

Researchers at the University of Leeds and Novo Nordisk reported in 2017, that it can also be used for the treatment of obesity.[33] It reduces hunger, food craving and body fat.[34] 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.[35]

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.[36] Approval was announced in December 2017.[19] It can be administered by injection or orally.[37] Marketing authorization in the European Union was granted in February 2018.[12][38] The Japanese Ministry of Health, Labour and Welfare announced approval on 23 March 2018.[39] Health Canada issued approval on 4 January 2018.[20]

Semaglutide was approved for medical use in Australia in August 2019 for "the treatment of adults with insufficiently controlled type 2 diabetes mellitus as an adjunct to diet and exercise; and as monotherapy when metformin is not tolerated or contraindicated."[1][3]

Society and culture

Legal status

In November 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Wegovy, intended for the treatment of people with obesity or who are overweight in the presence of other related conditions.[40] The applicant for this medicinal product is Novo Nordisk A/S.[40] Wegovy was approved for medical use in the European Union in January 2022.[14]

Research

Semaglutide was found to be inferior to tirzepatide, in a study of tirzepatide (LY3298176) vs semaglutide once weekly as add-on therapy to metformin in participants with type 2 diabetes (SURPASS-2), in both endpoints of reduction in A1C and body weight, with a roughly similar safety profile.[41][42]

References

  1. ^ a b c "AusPAR: Semaglutide". Therapeutic Goods Administration (TGA). 2 December 2020. Retrieved 23 February 2022.
  2. ^ a b "Rybelsus". Therapeutic Goods Administration (TGA). 22 February 2022. Retrieved 23 February 2022.
  3. ^ a b "Summary for ARTG Entry:315107 Ozempic 1 mg semaglutide (rys) 1.34 mg/mL solution for injection pre-filled pen". Therapeutic Goods Administration (TGA). Retrieved 6 June 2021.
  4. ^ "Summary for ARTG Entry:346198 Rybelsus semaglutide 3 mg tablet blister pack". Therapeutic Goods Administration (TGA). Retrieved 23 February 2022.
  5. ^ https://pdf.hres.ca/dpd_pm/00058023.PDF[bare URL PDF]
  6. ^ https://pdf.hres.ca/dpd_pm/00055582.PDF[bare URL PDF]
  7. ^ "Ozempic 0.25 mg solution for injection in pre-filled pen - Summary of Product Characteristics (SmPC)". (emc). 9 April 2021. Retrieved 6 June 2021.
  8. ^ "Rybelsus - Summary of Product Characteristics (SmPC)". (emc). 25 November 2020. Retrieved 6 June 2021.
  9. ^ a b c d e "Ozempic- semaglutide injection, solution". DailyMed. Retrieved 5 June 2021.
  10. ^ a b c "Rybelsus- oral semaglutide tablet". DailyMed. Retrieved 5 June 2021.
  11. ^ a b c "Wegovy- semaglutide injection, solution". DailyMed. 4 June 2021. Retrieved 11 March 2022.
  12. ^ a b c "Ozempic EPAR". European Medicines Agency (EMA). Retrieved 26 September 2020.
  13. ^ a b "Rybelsus EPAR". European Medicines Agency (EMA). 29 January 2020. Retrieved 26 September 2020.
  14. ^ a b c "Wegovy EPAR". European Medicines Agency (EMA). 11 November 2021. Retrieved 11 March 2022.
  15. ^ "Semaglutide Approval Status". drugs.com.
  16. ^ "Ozempic (semaglutide) approved in the US". Novo Nordisk (Press release). 5 December 2017. Retrieved 5 June 2021.
  17. ^ a b c "FDA Approves New Drug Treatment for Chronic Weight Management, First Since 2014". U.S. Food and Drug Administration (FDA) (Press release). 4 June 2021. Retrieved 5 June 2021.
  18. ^ 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.
  19. ^ a b "Drug Approval Package: Ozempic (semaglutide) Injection". U.S. Food and Drug Administration (FDA). 16 January 2018. Retrieved 26 September 2020.
  20. ^ a b "Regulatory Decision Summary – Ozempic". Health Canada. 23 October 2014. Retrieved 2 April 2019.
  21. ^ "Drug Approval Package: Rybelsus". U.S. Food and Drug Administration (FDA). 10 June 2020. Retrieved 26 September 2020.
  22. ^ a b "FDA approves first oral GLP-1 treatment for type 2 diabetes" (Press release). FDA. 20 September 2019. Retrieved 20 September 2019.
  23. ^ "SEMAGLUTIDE". British National Formulary (BNF). National Institute for Health and Care Excellence (NICE). Retrieved 25 March 2022.
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  25. ^ 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.
  26. ^ 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.
  27. ^ Dhillon S (February 2018). "Semaglutide: First Global Approval". Drugs. 78 (2): 275–284. doi:10.1007/s40265-018-0871-0. PMID 29363040. S2CID 46851453.
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  29. ^ 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.
  30. ^ "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.
  31. ^ 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.
  32. ^ 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
  33. ^ 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.
  34. ^ "Drug can dramatically reduce weight of people with obesity". ScienceDaily. 23 October 2017. Retrieved 24 October 2017.
  35. ^ Wilding JP, Batterham RL, Calanna S, Davies M, Van Gaal LF, Lingvay I, et al. (March 2021). "Once-Weekly Semaglutide in Adults with Overweight or Obesity". New England Journal of Medicine. 384 (11): 989–1002. doi:10.1056/NEJMoa2032183. ISSN 0028-4793. PMID 33567185. S2CID 231883214.
  36. ^ "Development Status and FDA Approval Process for semaglutide". Drugs.com. 2017. Retrieved 24 October 2017.
  37. ^ 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.
  38. ^ "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 19 August 2018 – via GlobeNewswire.
  39. ^ "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.
  40. ^ a b "Wegovy : Pending EC decision". European Medicines Agency. 11 November 2021. Retrieved 13 November 2021. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  41. ^ Frías, Juan P.; Davies, Melanie J.; Rosenstock, Julio; Pérez Manghi, Federico C.; Fernández Landó, Laura; Bergman, Brandon K.; Liu, Bing; Cui, Xuewei; Brown, Katelyn; SURPASS-2 Investigators (25 June 2021). "Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes". New England Journal of Medicine. 385 (6): 503–515. doi:10.1056/NEJMoa2107519. PMID 34170647. S2CID 235635529. Retrieved 30 June 2021.
  42. ^ "'Stunning' Twincretin Beats Semaglutide in Type 2 Diabetes". Medscape Medical News > Conference News > ADA 2021. 27 June 2021. Retrieved 30 June 2021.