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Semaglutide

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Semaglutide
Structure of Semaglutide
Experimentally determined structure of semaglutide while complexed with the GLP-1 receptor. PDB: 7KI0​
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 Edit this at Wikidata
Chemical and physical data
FormulaC187H291N45O59
Molar mass4113.641 g·mol−1
  • 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.[19][20][21] It is a peptide similar to the hormone glucagon-like peptide-1 (GLP-1), modified with a side chain.[22][23] It can be administered by subcutaneous injection or taken orally.[24][13][14][15] It is sold under the brand names Ozempic[13] and Rybelsus[14] for diabetes, and under the brand name Wegovy for weight loss.[15]

Semaglutide is a glucagon-like peptide-1 receptor agonist.[13][14][15] The most common side effects include nausea, vomiting, diarrhea, abdominal pain, and constipation.[13][16][17][18][25]

It was approved for medical use in the US in 2017.[13][26] In 2022, it was the 48th most commonly prescribed medication in the United States, with more than 13 million prescriptions.[27][28]

Medical uses

[edit]

Semaglutide is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.[13][14]

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.[15][18][29]

In March 2024, the US Food and Drug Administration (FDA) expanded the indication for semaglutide (Wegovy), in combination with a reduced calorie diet and increased physical activity, to reduce the risk of cardiovascular death, heart attack, and stroke in obese or overweight adults with cardiovascular disease.[30]

Side effects

[edit]

Possible adverse 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).[15] It has in the past been suspected to cause pancreatitis, and can cause gastroparesis, and bowel obstruction.[31]Among people who were prescribed a GLP-1, 0.1% were diagnosed with gastroparesis at least six months later, which equates to a 52% increased risk of being diagnosed with gastroparesis while on a GLP-1 medication.[32] A 2019 meta-analysis did not indicate a significantly elevated risk of acute pancreatitis.[33]According to the FDA’s Adverse Events Reporting System (FAERS), more than 150 patients taking Ozempic reported ileus or intestinal obstructions after taking the medication.[34]

The US FDA label for semaglutide contains a boxed warning for thyroid C-cell tumors in rodents.[13][14][15][25] It is unknown whether semaglutide causes thyroid C-cell tumors, including medullary thyroid carcinoma, in humans.[13][14][15][25][35]

Contraindications

[edit]

Data from rodent studies of GLP-1-mediated thyroid C-cell hyperplasia[36] indicates that use is contraindicated in people with a personal or family history of medullary thyroid carcinoma or with multiple endocrine neoplasia type 2.[14][13]

Mechanism of action

[edit]
GLP-1 regulates digestion and blood sugar. The small intestine releases GLP-1 when food is eaten. It reduces hunger, signals fullness, stimulates insulin, and inhibits glucagon, maintaining glucose levels.

Semaglutide is a glucagon-like peptide-1 receptor agonist.[13][14][15] The drug decreases blood sugar levels. The decrease is theorized to be caused by the mimicking of the incretin glucagon-like peptide-1 (GLP-1).[37] It also appears to enhance growth of pancreatic beta cells, which are responsible for insulin production and release.[23][38] 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,[22] helping reduce body weight.[39][40]

Structure and pharmacology

[edit]
Schematic representation of the structures of semaglutide and liraglutide, compared to GLP-1

Semaglutide is chemically similar to human GLP-1.[41] The first six amino acids of GLP-1 are missing.[41] 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.[41] The substitution of the alanine prevents chemical breakdown by dipeptidyl peptidase-4.[42] The lysine at GLP position 26 (semaglutide position 20) has a long chain attached, ending with a chain of 18 carbon atoms and a carboxyl group.[42] This increases the drug's binding to blood protein (albumin), which enables longer presence in the blood circulation.[42]

Semaglutide's half-life in the blood is about seven days (165–184 hours).[23][43]

History

[edit]

In the 1970s, Jens Juul Holst and Joel Habener began research on the GLP-1 hormone, initially in relation to duodenal ulcer disease.[44] They were examining hormones secreted during eating, and testing them on pig pancreases, leading to the discovery of GLP-1's significant potency in 1988. Their work, which later contributed significantly to diabetes and obesity treatments, earned them and Daniel J. Drucker the 2021 Warren Alpert Foundation Prize.[44] Research continued and in 1993 Michael Nauck managed to infuse GLP-1 into people with type 2 diabetes, stimulating insulin while inhibiting glucagon and bringing blood glucose to normal levels. However, treating diabetes patients with GLP-1 hormones resulted in significant side effects, leading researchers financed by Novo Nordisk to start looking to develop a suitable compound for therapeutic use.[44]

In 1998 a team of researchers at Novo Nordisk led by the scientist Lotte Bjerre Knudsen developed liraglutide, a glucagon-like peptide-1 receptor agonist that could be used to treat diabetes.[45]

Clinical trials and early approvals for diabetes

[edit]

In June 2008, a phase II clinical trial began studying semaglutide, a once-weekly diabetes therapy as a longer-acting alternative to liraglutide.[46][47] It was given the brand name Ozempic. Clinical trials started in January 2016 and ended in May 2017.[19][48]

The US Food and Drug Administration (FDA) approved semaglutide based on evidence from seven clinical trials of 4087 participants with type 2 diabetes.[25] The trials were conducted at 536 sites in 33 countries, including Canada, Mexico, Russia, Ukraine, Turkey, India, South Africa, Japan, Hong Kong, multiple European countries, Argentina, and the United States.[25] In two of these trials (NCT #02054897 and NCT #02305381), participants were randomly assigned to receive either semaglutide or placebo injection weekly.[25] Neither the participant nor the health care provider knew which treatment was being given until after the trials were completed.[25] Treatment was given for 30 weeks.[25] 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.[25] Treatment was given for 30 weeks or 56 weeks.[25]

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.[25]

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.[25] This trial was conducted in 20 countries: multiple European countries, Russia, Turkey, Brazil, Israel, Malaysia, Brazil, Mexico, Thailand, Taiwan, Canada, and the United States.[25] The participants were randomly assigned to receive semaglutide or placebo.[25] Neither the participant nor the health care provider knew which treatment was being given.[25] 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.[25]

Trials for obesity

[edit]

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]

In March 2023, a Novo Nordisk official said, based on a randomized, double-blind study (NCT #03548935) funded by the company, that patients using semaglutide to lose weight regained two-thirds of their original weight loss one year (52 weeks) after discontinuing use of the drug. After two years (120 weeks), the patients retained roughly one-third of their original weight loss (5.6% of the original 17.3% loss).[54][55]

For cardiovascular health

[edit]

In March 2024, the FDA expanded the indication for semaglutide (Wegovy) to reduce the risk of cardiovascular death, heart attack and stroke in adults with cardiovascular disease and either obesity or overweight.[30] The efficacy and safety for this new indication were studied in a multi-national, multi-center, placebo-controlled double-blind trial that randomly assigned over 17,600 participants to receive either semaglutide (Wegovy) or placebo.[30] Participants in both groups also received standard-of-care medical treatment (e.g., management of blood pressure and cholesterol) and healthy lifestyle counseling (including diet and physical activity).[30] Semaglutide (Wegovy) significantly reduced the risk of major adverse cardiovascular events (cardiovascular death, heart attack and stroke), which occurred in 6.5% of participants who received semaglutide (Wegovy) compared to 8% of participants who received placebo.[30]

Novo Nordisk reported that its oral drug, Rybelsus (semaglutide), significantly reduced the risk of cardiovascular events by 14% in a late-stage trial.[56] This included reductions in cardiovascular death, non-fatal heart attacks and strokes, compared to a placebo. The trial involved 9,650 patients with type 2 diabetes and either established cardiovascular disease or chronic kidney disease, using the drug alongside standard care.[57]

Benefits beyond metabolic and cardiovascular

[edit]

A 2024 study published in Alzheimer’s & Dementia suggests that semaglutide may help reduce the risk of Alzheimer’s disease.[58] Researchers analyzed three years of electronic medical records from over 1 million patients with Type 2 diabetes who had not been previously diagnosed with Alzheimer’s and had at least one additional cardiometabolic risk factor.[59] The study found that, compared to seven other anti-diabetic drugs, semaglutide was particularly effective in lowering the risk of Alzheimer’s, as well as other GLP-1 medications.[60]

Society and culture

[edit]
[edit]

In December 2016, the US FDA New Drug Application (NDA) was filed, and in October 2017, the FDA Advisory Committee approved it unanimously.[61]

In December 2017, the injectable version with the brand name Ozempic was approved for use by people with diabetes in the United States,[26][62] and, in January 2018, in Canada.[63]

In February 2018, authorization was granted in the European Union,[16][64] in March 2018 in Japan,[65] and in August 2019 in Australia.[1][4]

In September 2019, a version that can be taken orally (Rybelsus) was approved for medical use in the United States,[66][67] and in the European Union in April 2020.[17]

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.[15] 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[68] to Novo Nordisk A/S.[68] In January 2022, Wegovy was approved for medical use in the European Union.[18][69]

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.[70]

Grey market sellers offer unauthorized products claimed to be semaglutide online. This practice is legal in the United States as long as marketed for "research purposes only", but some buyers turn to unauthorized retailers due to being denied insurance coverage and not being able to afford the name brand drug.[71][72][73]

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.[74]

Generics

[edit]

Semaglutide is expected to become patent-free in the United States no earlier than December 2031.[75]

The Chinese patent was scheduled to expire in 2026, but a court ruled in 2022 that all patents on semaglutide were invalid. Novo Nordisk appealed the ruling.[76]

In Brazil, the Supreme Court refused to extend semaglutide's patent protection, which expires in 2026.[77]

Economics

[edit]

"Ozempic, the semaglutide injection used for T2D treatment, has a list price of $936 in the United States and $169 in Japan. Prices were $147 in Canada, $144 in Switzerland, $103 in Germany and Netherlands, $96 in Sweden, $93 in the United Kingdom, and $87 in Australia. France had the lowest price at $83." (21 August 2023; figures refer to a one-month supply)[78][79]

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".[80] 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.[81]

In the UK, semaglutide is available on NHS prescription for diabetes at nominal or no cost to patients.[82] It is also available for obesity, limited to treatment for two years.[83]

High demand caused worldwide supply shortages of semaglutide in 2023;[81] new UK prescriptions were not issued during the shortage.

Novo Nordisk revealed in April 2024 that to meet the enormous demand for semaglutide, it was running its production facilities 24 hours a day, 365 days per year; it had budgeted $6 billion in 2024 to expand its crowded and congested facilities; and it had hired over 10,000 new employees in 2023 alone.[84]

Economic impact on Danish society

By 2023, Novo Nordisk had become the most valuable corporation in the European Union, worth more than US$500 billion, and accounted for almost all recent economic growth in Denmark.[85]

Profits from Novo Nordisk generate returns for the Novo Nordisk Foundation, which holds the controlling stake in Novo Nordisk. The profits results in increased Danish tax revenues and employment. Novo Nordisk added 3,500 jobs in Denmark in 2022, bringing the total in the country to 21,000 employees, out of 59,000 worldwide.[86]

Counterfeits

[edit]

In October 2023, there were reports of counterfeit Ozempic pens being sold in Europe.[87] The pens possibly contained insulin, and led to several people being hospitalised with hypoglycemia and seizures.[88][89][90] In December 2023, the FDA issued a warning about counterfeit Ozempic in the United States.[91]

Compounded versions

[edit]

Some compounded versions 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. These are not evaluated for safety and effectiveness by and thus are considered not shown to be safe or effective by the US Food and Drug Administration (FDA).[92]

Research

[edit]

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.[93] 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.[94]

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,[95] Wegovy, Saxenda, and similar drugs.[96] In January 2024, a preliminary review conducted by the FDA confirmed no evidence had been found to suggest that the medicine causes suicidal thoughts or actions.[97][98]

Semaglutide has shown potential to reduce interest in alcohol consumption among users. Scientists speculate that semaglutide may influence brain regions involved in addiction and appetite regulation, although the exact mechanisms remain under study. Animal research has indicated that drugs similar to semaglutide can reduce alcohol intake.[99]

Eating disorders

[edit]

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.[100][101] 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.[102][103]

References

[edit]
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