Semaglutide
Structure of Semaglutide
Clinical data
Pronunciation/sɛmˈæɡlʊtaɪd/ sem-AG-luu-tyde or /ˌsɛməˈɡluːtaɪd/ SEM-ə-GLOO-tyde
Trade namesOzempic, Rybelsus, Wegovy, others
AHFS/Drugs.comMonograph
MedlinePlusa618008
License data
Pregnancy
category
Routes of
administration		Subcutaneous, oral
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability89%
MetabolismProteolysis
Elimination half-life7 days
Duration of action63.6 h
ExcretionUrine and feces
Identifiers
  • 18-[[(1R)-4-[2-[2-[2-[2-[2-[2-[[(5S)-5-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S,3R)-2-[[2-[[(2S)-2-[[2-[[(2S)-2-amino-3-(1H-imidazol-5-yl)propanoyl]amino]-2-methylpropanoyl]amino]-4-carboxybutanoyl]amino]acetyl]amino]-3-hydroxybutanoyl]amino]-3-phenylpropanoyl]amino]-3-hydroxybutanoyl]amino]-3-hydroxypropanoyl]amino]-3-carboxypropanoyl]amino]-3-methylbutanoyl]amino]-3-hydroxypropanoyl]amino]-3-hydroxypropanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-methylpentanoyl]amino]-4-carboxybutanoyl]amino]acetyl]amino]-5-oxopentanoyl]amino]propanoyl]amino]propanoyl]amino]-6-[[(2S)-1-[[(2S)-1-[[(2S,3S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-5-carbamimidamido-1-[[2-[[(2S)-5-carbamimidamido-1-(carboxymethylamino)-1-oxopentan-2-yl]amino]-2-oxoethyl]amino]-1-oxopentan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-6-oxohexyl]amino]-2-oxoethoxy]ethoxy]ethylamino]-2-oxoethoxy]ethoxy]ethylamino]-1-carboxy-4-oxobutyl]amino]-18-oxooctadecanoic acid
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ECHA InfoCard100.219.541
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 is an antidiabetic medication used for the treatment of type 2 diabetes and an anti-obesity medication used for long-term weight management.[18][19][20] A once-a-week regimen was trialed in a 12-week study by Novo Nordisk in 2012, and it was approved for use in the US in 2017. It is a peptide similar to the hormone glucagon-like peptide-1 (GLP-1), modified with a side chain.[21][22] It can be administered by subcutaneous injection or taken orally.[23][12][13][14] It is sold under the brand names Ozempic (injectable)[12] and Rybelsus (pill)[13] for diabetes, and under the brand name Wegovy for weight loss.[14]

Semaglutide is a glucagon-like peptide-1 receptor agonist.[12][13][14] The most common side effects include nausea, vomiting, diarrhea, abdominal pain, and constipation.[12][15][16][17][24]

In 2020, semaglutide was the 129th most commonly prescribed medication in the United States, with more than 4 million prescriptions.[25][26]

Medical uses

An Ozempic pen sold in China

Semaglutide is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.[12][13]

The higher-dose formulation of semaglutide is 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 who are overweight (initial BMI ≥ 27 kg/m2) and have at least one weight-related comorbidity.[14][17][27] Oral semaglutide is marketed in three strengths: 3 mg, 7 mg and 14 mg. The subcutaneous injection of semaglutide is available in four strengths: 0.25 mg, 0.5 mg, 1 mg, 1.7 mg, 2 mg, and 2.4 mg.[14]

Eating disorders

Semaglutide and similar drugs, such as dulaglutide and liraglutide, have been used to treat binge eating disorder (BED), as they can successfully minimize obsessive thoughts about food and binging urges.[28][29][30][31] Some users of these drugs have reported significant reduction in what is colloquially known as "food noise" – constant, unstoppable thoughts about eating despite not being physically hungry – which can be a factor of BED.[32][33] As of January 2024, more research is needed.[34]

Adverse effects

Possible side effects include nausea, diarrhea, vomiting, constipation, abdominal pain, headache, fatigue, indigestion/heartburn, dizziness, abdominal distension, belching, hypoglycemia (low blood glucose) in people with type 2 diabetes, flatulence, gastroenteritis, and gastroesophageal reflux disease (GERD).[14] It can also cause pancreatitis, gastroparesis, and bowel obstruction.[35]

The US FDA label for semaglutide contains a boxed warning for thyroid C-cell tumors in rodents.[12][13][14][24] It is unknown whether semaglutide causes thyroid C-cell tumors, including medullary thyroid carcinoma, in humans.[12][13][14][24][36]

Contraindications

Data from rodent studies of GLP-1-mediated thyroid C-cell hyperplasia[37] indicates that use is contraindicated in people with a personal or family history of medullary thyroid carcinoma or with multiple endocrine neoplasia type 2.[13][12]

Mechanism of action

Semaglutide is a glucagon-like peptide-1 receptor agonist.[12][13][14] By mimicking the action of the incretin glucagon-like peptide-1 (GLP-1), it somehow lowers blood sugar level.[38] It also appears to enhance growth of pancreatic beta cells, which are responsible for insulin production and release.[22][39] Additionally, it inhibits the production of glucagon, the hormone that increases glycogenolysis (release of stored carbohydrate from the liver) and gluconeogenesis (synthesis of new glucose). It reduces food intake by lowering appetite and slowing down digestion in the stomach,[21] helping reduce body fat.[40][41]

Structure and pharmacology

Schematic representation of the structures of Semaglutid and Liraglutide, compared to GLP-1

Semaglutide is chemically similar to human GLP-1.[42] The first six amino acids of GLP-1 are missing.[42] Substitutions are made at GLP positions 8 and 34 (semaglutide positions 2 and 28), where alanine and lysine are replaced by 2-aminoisobutyric acid and arginine, respectively.[42] The substitution of the alanine prevents chemical breakdown by dipeptidyl peptidase-4.[43] The lysine at GLP position 26 (semaglutide position 20) has a long chain attached, ending with a chain of 17 carbon atoms and a carboxyl group.[43] This increases the drug's binding to blood protein (albumin), which enables longer presence in the blood circulation.[43]

Semaglutide's half-life in the blood is about seven days (165–184 hours).[22][44] It can be administered by subcutaneous injection or taken orally (by mouth).[12][13][14]

History

In June 2008, a phase II clinical trial began studying semaglutide.[45]

In 2012, a team of researchers at Novo Nordisk developed semaglutide[46] for a once-weekly diabetes therapy as a longer-acting alternative to liraglutide.[47] It was given the brand name Ozempic. Clinical trials started in January 2016 and ended in May 2017.[18][48]

In March 2021, in a phase III randomized, double-blind, trial, 1,961 adults with a body mass index of 30 or greater were assigned in a 2:1 ratio to a treatment with once-weekly subcutaneous semaglutide or placebo, plus lifestyle intervention. The trials occurred at 129 sites in 16 countries in Asia, Europe, North America, and South America. The mean percentage change in body weight at week 68 was −14.9% in the semaglutide group vs −2.4% with placebo, for an estimated treatment difference of −12.4 percentage points (95% CI, −13.4 to −11.5).[49][50][51][52]

A 2022 review of anti-obesity treatments found that semaglutide as well as tirzepatide (which has an overlapping mechanism of action) were more promising than previous anti-obesity drugs, although less effective than bariatric surgery.[53]

The US Food and Drug Administration (FDA) approved semaglutide based on evidence from seven clinical trials of 4087 participants with type 2 diabetes.[24] The trials were conducted at 536 sites in 33 countries, including Canada, Mexico, Russian Federation, Ukraine, Turkey, India, South Africa, Japan, Hong Kong, multiple European countries, Argentina, and the United States.[24] In two of these trials (NCT #02054897 and NCT#02305381), participants were randomly assigned to receive either semaglutide or placebo injection weekly.[24] Neither the participant nor the health care provider knew which treatment was being given until after the trials were completed.[24] Treatment was given for 30 weeks.[24] In the other five trials (NCT #01930188, 01885208, 02128932, 02207374, 02254291), participants were randomly assigned to receive either semaglutide or another antidiabetic medication, and the participant and provider knew which medication was being given in four trials.[24] Treatment was given for 30 weeks or 56 weeks.[24]

In each trial, HbA1c was measured from the start of the trial to the end of the trial and compared between the semaglutide group and the other groups.[24]

The FDA also considered data from one separate trial (NCT #01720446) of 3297 participants with type 2 diabetes who were at high risk for cardiovascular events.[24] This trial was conducted in 20 countries in Europe, Russian Federation, Turkey, Brazil, Israel, Malaysia, Brazil, Mexico, Thailand, Taiwan, Canada, and the United States.[24] The participants were randomly assigned to receive semaglutide or placebo.[24] Neither the participant nor the health care provider knew which treatment was being given.[24] Treatment was given for 104 weeks (2 years), and the occurrence of cardiovascular events, including heart attacks, strokes and hospitalization due to unstable angina (near heart attack) were recorded and compared in the two groups of participants.[24]

Society and culture

In December 2016, the US FDA New Drug Application (NDA) was filed, and in October 2017, the FDA Advisory Committee approved it unanimously.[54]

In December 2017, the injectable version with the brand name Ozempic was approved for use by people with diabetes in the United States,[55][56] and, in January 2018, in Canada.[57]

In February 2018, authorization was granted in the European Union,[15][58] in March 2018 in Japan,[59] and in August 2019 in Australia.[1][3]

In September 2019, a version that can be taken orally (Rybelsus) was approved for medical use in the United States,[60][61] and in the European Union in April 2020.[16]

In June 2021, a higher-dose version for injectable use sold under the brand name Wegovy was approved by the US Food and Drug Administration (FDA) as an anti-obesity medication for long-term weight management in adults.[14] In November 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommended to grant a marketing authorization for Wegovy[62] to Novo Nordisk A/S.[62] In January 2022, Wegovy was approved for medical use in the European Union.[17][63]

In January 2023, the label for Rybelsus was updated to reflect that it can be used as a first-line treatment for adults with type 2 diabetes.[64]

Gray market sellers offer unauthorized products claimed to be semaglutide online. This practice is illegal in the United States, but some buyers turn to unauthorized retailers due to being denied insurance coverage and not being able to afford the name brand drug.[65][66][67][68][69]

In October 2023, Belgium announced it was considering a temporary ban on Ozempic for use as a weight loss medication amid a sharp increase in demand leading to a shortage of the drug, which was expected to last into mid-2024. The government had previously advised medical professionals to prescribe the drug only to diabetics. A similar order had been issued by the government of the United Kingdom earlier that month, additionally prohibiting new prescriptions for type 2 diabetics.[70]

Generics

The patent was scheduled to expire in 2026, but a Chinese court ruled in 2022 that all patents on semaglutide were invalid. Novo Nordisk appealed the ruling.[71]

In Brazil, the Supreme Court refused to extend semaglutide's patent protection, which expires in 2026.[72]

Economics

In the US, Wegovy has a list price of $1,349.02 per month as of 2022 suggesting that because of the high costs many people "who could most benefit from weight loss may be unable to afford such expensive drugs".[73] High costs of Ozempic prompted some insurance companies to investigate and refuse to cover patients with what the companies considered was insufficient evidence to support a diabetes diagnosis, alleging off-label prescribing for weight loss.[74]

In the UK, semaglutide is available on NHS prescription for diabetes at nominal or no cost to patients.[75] It is also available for obesity, limited to treatment for two years.[76]

High demand caused worldwide supply shortages of semaglutide in 2023;[74] new UK prescriptions were not issued during the shortage.

By 2023, Novo Nordisk had become the most valuable corporation in the European Union, worth more than US$500 billion, and accounting for almost all of recent economic growth in Denmark.[77]

Counterfeits

In October 2023, there were reports of counterfeit Ozempic pens being sold in Europe.[78] The pens possibly contained insulin, and led to several people being hospitalised with hypoglycaemia and seizures.[79][80][81] In December 2023, the FDA issued a warning about counterfeit Ozempic in the United States.[82]

Some counterfeits have been found to contain salts of semaglutide including the sodium and the acetate in an attempt to avoid the patent of the base semaglutide product and are not considered safe or effective by the US Food and Drug Administration (FDA).[83]

Research

In 2021, semaglutide was found to be inferior to tirzepatide (sold under the brand name Mounjaro) when used once weekly as add-on therapy to metformin in people with type 2 diabetes, in both endpoints of reduction in glycohemoglobin, A1C, and body weight, with a roughly similar safety profile.[84]

A 2014 meta-analysis found that semaglutide may be effective in lowering liver enzymes (transaminitis) and improving certain radiologically observed features of metabolic dysfunction–associated steatotic liver disease.[85] French national health care insurance system database had previously suggested 1–3 years use of glucagon like peptide-1 receptor agonists like exenatide, liraglutide and dulaglutide may be linked with increased occurrence of thyroid cancer. Semaglutide belongs to the same family of medicine. A meta-analysis involving data from 37 randomized controlled trials and 19 real world studies (46,719 patients) showed that semaglutide use over 18 months was not associated with increased risks of any cancer, supported by a high grade of evidence.[86]

In July 2023, the Icelandic Medicines Agency reported two cases of suicidal thoughts and one case of self-injury of users of the injection, prompting a safety assessment of Ozempic,[87] Wegovy, Saxenda, and similar drugs.[88]

References

  1. 1 2 3 "AusPAR: Semaglutide". Therapeutic Goods Administration (TGA). 2 December 2020. Archived from the original on 24 February 2022. Retrieved 23 February 2022.
  2. 1 2 "Rybelsus APMDS". Therapeutic Goods Administration (TGA). 22 February 2022. Retrieved 23 February 2022.
  3. 1 2 "Summary for ARTG Entry:315107 Ozempic 1 mg semaglutide (rys) 1.34 mg/mL solution for injection pre-filled pen". Therapeutic Goods Administration (TGA). Archived from the original on 24 February 2022. Retrieved 6 June 2021.
  4. ↑ "Summary for ARTG Entry: 346198 Rybelsus semaglutide 3 mg tablet blister pack". Therapeutic Goods Administration (TGA). Archived from the original on 24 February 2022. Retrieved 23 February 2022.
  5. ↑ "Wegovy (Novo Nordisk Pharmaceuticals Pty Ltd)". Therapeutic Goods Administration (TGA). 7 October 2022. Archived from the original on 14 April 2023. Retrieved 7 April 2023.
  6. ↑ Product Monograph Including Patient Medication Information – Ozempic semaglutide injection (PDF) (Report). Novo-Nordisk Canada. 21 August 2020 [Initial approval 4 January 2018]. Archived (PDF) from the original on 7 June 2021. Retrieved 6 June 2021.
  7. ↑ Product Monograph Including Patient Medication Information – Rybelsus semaglutide tablets (PDF) (Report). Novo-Nordisk Canada. 30 March 2020. Archived (PDF) from the original on 14 December 2021. Retrieved 6 June 2021.
  8. ↑ "Regulatory Decision Summary – Rybelsus". Health Canada. 23 October 2014. Archived from the original on 5 June 2022. Retrieved 4 June 2022.
  9. ↑ "Ozempic 0.25 mg solution for injection in pre-filled pen – Summary of Product Characteristics (SmPC)". (emc). 9 April 2021. Archived from the original on 6 June 2021. Retrieved 6 June 2021.
  10. ↑ "Rybelsus – Summary of Product Characteristics (SmPC)". (emc). 25 November 2020. Archived from the original on 6 June 2021. Retrieved 6 June 2021.
  11. ↑ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 October 2023.
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  19. ↑ Phillips A, Clements JN (February 2022). "Clinical review of subcutaneous semaglutide for obesity". Journal of Clinical Pharmacy and Therapeutics. 47 (2): 184–193. doi:10.1111/jcpt.13574. PMID 34964141. S2CID 245538758.
  20. ↑ Amaro A, Sugimoto D, Wharton S (January 2022). "Efficacy and safety of semaglutide for weight management: evidence from the STEP program". Postgraduate Medicine. 134 (sup1): 5–17. doi:10.1080/00325481.2022.2147326. PMID 36691309. S2CID 256192982.
  21. 1 2 Doggrell SA (March 2018). "Semaglutide 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. Archived (PDF) from the original on 5 May 2020. Retrieved 12 December 2019.
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  23. ↑ Hughes S, Neumiller JJ (January 2020). "Oral Semaglutide". Clinical Diabetes. 38 (1): 109–111. doi:10.2337/cd19-0079. PMC 6969659. PMID 31975761.
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  32. ↑ Kuhn C (25 September 2023). "Patients say drugs like Ozempic help with 'food noise.' Here's what that means". PBS. Archived from the original on 13 January 2024. Retrieved 13 January 2024.
  33. ↑ Blum D (21 June 2023). "People on Drugs Like Ozempic Say Their 'Food Noise' Has Disappeared". The New York Times. Archived from the original on 11 January 2024. Retrieved 13 January 2014.
  34. ↑ Richards J, Bang N, Ratliff EL, Paszkowiak MA, Khorgami Z, Khalsa SS, et al. (2023). "Successful treatment of binge eating disorder with the GLP-1 agonist semaglutide: A retrospective cohort study". Obesity Pillars. 7. doi:10.1016/j.obpill.2023.100080. PMC 10661993. PMID 37990682.
  35. ↑ Sodhi M, Rezaeianzadeh R, Kezouh A, Etminan M (October 2023). "Risk of Gastrointestinal Adverse Events Associated With Glucagon-Like Peptide-1 Receptor Agonists for Weight Loss". The Journal of the American Medical Association. 330 (18): 1795–1797. doi:10.1001/jama.2023.19574. PMC 10557026. PMID 37796527.
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