|Trade names||Ozempic, Rybelsus, Wegovy, others|
|Subcutaneous injection, orally|
|Elimination half-life||1 week|
|Duration of action||63.6 h|
|Excretion||Urine and faeces|
|Chemical and physical data|
|Molar mass||4113.641 g·mol−1|
|3D model (JSmol)|
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.
An injectable version (Ozempic) was approved for medical use in the United States in December 2017, and in the European Union, Canada, and Japan in 2018. A version which is taken by mouth (Rybelsus) was approved for medical use in the United States in September 2019, and in the European Union in April 2020. It is the first glucagon-like peptide receptor protein treatment approved for use in the United States that does not need to be injected. It was developed by Novo Nordisk. Side effects include nausea, vomiting, diarrhea, abdominal pain, and constipation.
Semaglutide 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.
Side effects include nausea, vomiting, diarrhea, abdominal pain, and constipation. In people with heart problems, it can cause damage to the retina of the eye (retinopathy). Other, less common side effects include kidney problems, allergic reactions, low blood sugar, and pancreatitis.
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. It also appears to enhance growth of β cells in the pancreas, which are the sites of insulin production.  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. In this way it reduces body fat.
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. Amino-acid substitution at position 8 prevents chemical breakdown by dipeptidyl peptidase-4. In addition, the 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's binding to blood protein (albumin), which enables longer presence in the blood circulation. Its half-life in the blood is about 7 days (165–184 hours); therefore, once-weekly injection is enough.
Semaglutide was developed in 2012, by a team of researchers at Novo Nordisk as a longer-acting alternative to liraglutide as a once-weekly diabetes therapy. It was given the brand name Ozempic. Clinical trials were started on 6 January 2016, and completed on 19 May 2017.
Researchers at the University of Leeds and Novo Nordisk reported in 2017, that it can also be used for the treatment of obesity. It reduces hunger, food craving and body fat. 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.
The US FDA New Drug Application (NDA) was filed in December 2016, and in October 2017, the FDA Advisory Committee approved it unanimously. It can be administered by injection or orally. Authorization was granted in February 2018 for the European Union, in March 2018 in Japan, on 4 January 2018 in Canada, and in August 2019 in Australia.
Society and culture
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. The applicant for this medicinal product is Novo Nordisk A/S. Wegovy was approved for medical use in the European Union in January 2022.
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.
A meta-analysis highlights that semaglutide may be effective in lowering liver enzymes (transaminitis) and improve radiologic features in people with metabolic dysfunction associated fatty liver disease.
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