Semaglutide

Semaglutide, sold under the brand names Ozempic, Wegovy and Rybelsus, is an antidiabetic medication used for the treatment of type 2 diabetes and as anti-obesity medication for long-term weight management, developed by Novo Nordisk in 2012.

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. Side effects include nausea, vomiting, diarrhea, abdominal pain, and constipation.

In December 2017, the injectable version named Ozempic was approved, in September 2019, a version which can be taken by mouth (Rybelsus) was approved, and in June 2021, a higher-dose injection sold under the brand name Wegovy for long-term weight management in adults was approved by the US Food and Drug Administration (FDA).

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 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 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 GLP-1-mediated thyroid C-cell hyperplasia, the use is contraindicated in people 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, the hormone which 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, 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 to reduce body fat. It reduces hunger, food craving and body fat.

Pharmacology

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 drug's binding to blood protein (albumin), which enables longer presence in the blood circulation.

Its half-life in the blood is about seven days (165–184 hours). It can be administered by subcutaneous injection once weekly or once-daily by mouth. No significant difference in the decrease from baseline body weight was observed between groups taking it orally (20 mg and 40-mg) or subcutaneously.

History

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 were started in January 2016, and completed in May 2017.

In 2017, researchers at the University of Leeds and Novo Nordisk reported that it could also be used for the treatment of obesity. In March 2021, a phase 3 randomized controlled trial found that once-weekly injection of 2.4 mg of the drug resulted in an average change of −15% body weight at 68 weeks compared to −2% for the placebo.

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 medical use 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 which can be taken by mouth (Rybelsus) was approved for medical use in the United States, and in the European Union in April 2020.

In June 2021, a higher-dose injection version sold under the brand name Wegovy was approved by the US Food and Drug Administration as 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 to Wegovy. to Novo Nordisk A/S. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged. In January 2022, Wegovy was approved for medical use in the European Union. In the US, Wegovy has a list price of $1,349.02 per month per ''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".

2022 shortages

In May 2022, a shortage of semaglutide/Ozempic was reported in Australia as a result of an increase in prescriptions for weight loss in non-diabetic patients (off label use). This shortage resulted in many people with type 2 diabetes being unable to access the drug, so the Australian Therapeutic Goods Administration, along with Novo Nordisk, sent out guidelines to all health professionals, reminding them that people with type 2 diabetes needed to be prioritised in terms of supply. Updated guidelines were released in August 2022.

In September 2022, shortages were also reported 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

In 2021, semaglutide was found to be inferior to tirzepatide when used once weekly as add-on therapy to metformin in people with type 2 diabetes (SURPASS-2), in both endpoints of reduction in A1C and body weight, with a roughly similar safety profile.

A 2014 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

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Antiobesity drugs
Glucagon-like peptide-1 receptor agonists
Peptide hormones