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Description

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 which 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 to reduce body fat. It reduces hunger, food craving and body fat.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 4 million prescriptions.

Semaglutide is an antidiabetic medication used for the treatment of type 2 diabetes and an anti-obesity medication used for long-term weight management.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.It is sold under the brand names Ozempic and Rybelsus for diabetes, and under the brand name Wegovy for weight loss.

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

It was approved for medical use in the US in 2017.In 2021, it was the 90th most commonly prescribed medication in the United States, with more than 8 million prescriptions.

Medical uses

Semaglutide is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 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.Oral Semaglutide is marketed in three strengths 3mg, 7mg and 14 mg. The subcutaneous injection of Semaglutide is available in four strengths 0.25mg, 0.5mg, 1mg and 2mg.

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.

Eating disorders

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. 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.

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

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

Contraindications

Data from rodent studies of GLP-1-mediated thyroid C-cell hyperplasia[37] 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 GLP-1 analogue with 94% sequence homology to human GLP-1. Semaglutide acts as a GLP-1 receptor agonist that selectively binds to and activates the GLP-1 receptor, the target for native GLP-1.GLP-1 is a physiological hormone that has multiple actions on glucose,mediated by the GLP-1 receptors.The principal mechanism of protraction resulting in the long half-life of semaglutide is albumin binding, which results in decreased renal clearance and protection from metabolic degradation. Furthermore, semaglutide is stabilized against degradation by the DPP-4 enzyme.Semaglutide reduces blood glucose through a mechanism where it stimulates insulin secretion and lowers glucagon secretion, both in a glucose-dependent manner. Thus, when blood glucose is high, insulin secretion is stimulated and glucagon secretion is inhibited.The mechanism of blood glucose lowering also involves a minor delay in gastric emptying in the early postprandial phase.

Semaglutide is a glucagon-like peptide-1 receptor agonist.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). 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

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

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).

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.

On September 20, 2019, the FDA officially approved the marketing application for Sommarutide, which is used in combination with diet and exercise to improve blood sugar control in patients with type 2 diabetes.

Sommarutide is a human GLP-1 analogue with high albumin affinity and a long half-life. It can be administered once a week to stimulate insulin secretion and inhibit glucagon secretion in a glucose-dependent manner.

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.

In March 2023, a Novo Nordisk official said that patients using semaglutide to lose weight can regain their original weight within 5 years of stopping treatment.

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

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.

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

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. 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.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). 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.

References

• [1]. Marso SP, et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2016 Nov 10;375(19):1834-1844. [Content Brief]
• [2]. Zhang L, et al. Neuroprotective effects of the novel GLP-1 long acting analogue semaglutide in the MPTP Parkinson’s disease mouse model. Neuropeptides. 2018 Oct;71:70-80. [Content Brief]
• [3]. Dhillon S, et al. Semaglutide: First Global Approval. Drugs. 2018 Feb;78(2):275-284. [Content Brief]