Semaglutide
Semaglutide, sold under the brand names Wegovy and Ozempic among others, is an antidiabetic medication used for the treatment of type 2 diabetes and long-term weight management.Semaglutide is a GLP-1 receptor agonist, meaning that it mimics the action of the human incretin glucagon-like peptide-1 (GLP-1), thereby increasing insulin secretion and increasing blood sugar disposal and improving glycemic control.
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.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. It was approved for medical use in the European Union in January 2022.

Medical uses
Semaglutide is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.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. 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.

Adverse effects
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.

Contraindications
Due to data from rodents studies of GLP1 mediated thyroid C-cell hyperplasia, their use is contraindicated in patients with a personal or family history of medullary thyroid carcinoma and in patients with multiple endocrine neoplasia syndrome type 2.

Mechanism of action
Semaglutide is a glucagon-like peptide-1 receptor agonist. By mimicking the action of the incretin GLP-1, it increases the production of insulin, a hormone that lowers the blood sugar level. It appears to enhance growth of pancreatic beta cells, which are responsible for insulin production and release. It also inhibits the production of glucagon, which is a 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, helping to reduce body fat. Its half-life in the blood is about seven days (165–184 hours).

Structure
Semaglutide is chemically similar to human 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 drugs binding to blood protein (albumin), which enables longer presence in the blood circulation.

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

2022 shortages
As a result of an increase in prescriptions for weight loss in non-diabetic patients, a shortage of Semaglutide/Ozempic was reported in Australia in 2022. This shortage resulted in many people with type 2 diabetes being unable to access the drug. In May 2022, the Australian Therapeutic Goods Administration, along with Novo Nordisk, sent out guidelines to all health professionals, reminding them that people with type 2 diabetes need to be prioritised in terms of supply. An update to the guidelines was released in August 2022.Shortages were also reported contemporaneously in the United States In the same month, rival Eli Lilly stated in its quarterly investors call that it was working "around the clock" to ensure adequate supply of its rival GLP-1 agonist tirzepatide (Mounjaro).

Research
Semaglutide was found to be inferior to tirzepatide in a 2021 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 including a small number of patients found that semaglutide may be effective in lowering liver enzymes (transaminitis) and improving certain radiologically observed features of metabolic-dysfunction–associated fatty-liver disease (MAFLD).

References
External links
"Semaglutide". Drug Information Portal. U.S. National Library of Medicine.
"Semaglutide". MedlinePlus.