Semaglutide

Semaglutide, sold under the brand names Ozempic, Wegovy and Rybelsus, is an antidiabetic medication used for the treatment of type 2 diabetes and an anti-obesity medication used for long-term weight management. It was developed by Novo Nordisk in 2012. It is a peptide similar to the hormone glucagon-like peptide-1 (GLP-1), modified with a side chain. It can be administered by subcutaneous injection or taken orally.

Semaglutide is a glucagon-like peptide-1 receptor agonist. The most common side effects include nausea, vomiting, diarrhea, abdominal pain, and constipation.

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

Medical uses
Semaglutide is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type2 diabetes.

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.

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 patients with type 2 diabetes, flatulence, gastroenteritis, and gastroesophageal reflux disease (GERD). It can also cause pancreatitis, gastroparesis, and bowel obstruction.

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

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

Structure and pharmacology
Semaglutide is chemically similar to human GLP-1. The first six amino acids of GLP-1 are missing. 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. The substitution of the alanine prevents chemical breakdown by dipeptidyl peptidase-4. 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. This increases the drug's binding to blood protein (albumin), which enables longer presence in the blood circulation.

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

History
In June 2008, a phase II clinical trial began studying semaglutide.

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

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).

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.

Society and culture

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

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

In February 2018, authorization was granted in the European Union, in March 2018 in Japan, and in August 2019 in Australia.

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

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 as an anti-obesity medication for long-term weight management in adults. 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 to Novo Nordisk A/S. In January 2022, Wegovy was approved for medical use in the European Union.

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.

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.

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.

Economics 
In the US, Wegovy has a list price of $1,349.02 per month as of 2022, according to The New York Times, suggesting that because of the high costs many people "who could most benefit from weight loss may be unable to afford such expensive drugs". 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.

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

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

Counterfeits

In October 2023 there were reports of counterfeit Ozempic pens being sold in Europe. The pens possibly contained insulin, and led to several people being hospitalised with hypoglycaemia and seizures. In Germany bogus injection pens with German labels in genuine Ozempic packaging were allegedly supplied by a wholesaler in Austria to Germany and to two British wholesalers. No counterfeits had been sold by retail pharmacies.

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 type2 diabetes (SURPASS-2), in both endpoints of reduction in glycohemoglobin, A1C, and body weight, with a roughly similar safety profile.

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 fatty-liver disease (MAFLD).
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. In a meta-analysis involving data from 37 randomized controlled trials and 19 real world studies (46,719 patients), corresponding author Deep Dutta and others demonstrated that semaglutide use over 18 months was not associated with increased risks of any cancer, supported by a high grade of evidence.

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, Wegovy, Saxenda, and similar drugs.

References

External links 
 

Glucagon-like peptide-1 receptor agonists
Peptide hormones