Semaglutide

Description

Semaglutide(910463-68-2) is an anti-diabetic medication that is sold under brand names such as Ozempic, Wegovy, and Rybelsus. It is used to treat type 2 diabetes and manage chronic weight. The drug functions similar to human glucagon-like peptide-1 (GLP-1) by increasing insulin secretion, which leads to improved 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, thus, only once-a-week injection is sufficient.

Uses

Semaglutide is used to manage type 2 diabetes along with lifestyle changes, such as dietary restrictions and increased physical activity. It also works by slowing the movement of food through the stomach and may decrease appetite and cause weight loss. There have been no published reports of hepatotoxicity attributed to semaglutide therapy.

Definition

ChEBI: Semaglutide is a polypeptide that contains a linear sequence of 31 amino acids joined together by peptide linkages. It is an agonist of glucagon-like peptide-1 receptors (GLP-1 AR) and used for the treatment of type 2 diabetes. It has a role as a hypoglycemic agent, a glucagon-like peptide-1 receptor agonist, an anti-obesity agent, a neuroprotective agent and an appetite depressant. It is a polypeptide and a lipopeptide.

Biological Activity

Semaglutide (Rybelsus, Ozempic, NN9535, OG217SC, NNC 0113-0217), a long-acting glucagon-like peptide 1 (GLP-1) analogue, is a GLP-1 receptor agonist with the potential for the treatment of type 2 diabetes mellitus (T2DM).

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.

Pharmacokinetics

Median t_{max,semaglutide} was 1.5 hours for both water volumes with a range of 0.5-3.0 hours for 50 mL and a range of 0.5-4.0 hours for 240 mL. AUC_0-24h,_semaglutide and C_{max,semaglutide} were approximately 70% higher when dosed with 50 versus 240 mL water[2].

Side effects

Some common side effects of Semaglutide include: nausea, vomiting, diarrhea, abdominal pain, and constipation may occur.
Less common but serious side effects of Semaglutide include: kidney problems, diabetic retinopathy, allergic reactions, low blood sugar, and pancreatitis.
In people with heart problems, it can cause damage to the back of the eye (retinopathy). If you experience any of these serious side effects, contact your healthcare provider immediately.
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in vitro

Semaglutide is selected as the optimal once weekly candidate. Semaglutide has two amino acid substitutions compared to human GLP-1 (Aib8, Arg34) and is derivatized at lysine 26. The GLP-1R affinity of semaglutide (0.38 ± 0.06 nM) is three-fold decreased compared to liraglutide, whereas the albumin affinity is increased.

in vivo

The plasma half-life is 46.1 h in mini-pigs following i.v. administration, and semaglutide has an MRT of 63.6 h after s.c. dosing to mini-pigs.

Metabolism

Intact semaglutide was the primary component circulating in plasma for humans and both nonclinical species, accounting for 69–83% of the total amount of semaglutide-related material, and was metabolised prior to excretion. Recovery of excreted radioactivity was 75.1% in humans, 72.1% in rats and 58.2% in monkeys. Urine and faeces were shown to be important routes of excretion, with urine as the primary route in both humans and animals[1]. Semaglutide was metabolised through proteolytic cleavage of the peptide backbone and sequential beta-oxidation of the fatty acid sidechain, and metabolism was not confined to specific organs. Intact semaglutide in urine accounted for 3.1% of the administered dose in humans and less than 1% in rats; it was not detected in urine in monkeys.

Precautions

The FDA recommends Wegovy for weight loss if you meet one of the following criteria: Have a body mass index (BMI) of 27kg/m2 or greater and at least one weight-related condition, such as high blood pressure, Type 2 diabetes, or high cholesterol; Have a BMI of 30kg/m2 or greater.
Avoid semaglutide if you have: History of medullary thyroid cancer; History of gallbladder disease; History of pancreatitis; Multiple endocrine neoplasia syndrome type 2 (MEN2).

References

[1] A, Lene Jensen , et al. "Absorption, metabolism and excretion of the GLP-1 analogue semaglutide in humans and nonclinical species." European Journal of Pharmaceutical Sciences 104(2017):31-41.
[2] Tine A. B?kdal. “Relationship Between Oral Semaglutide Tablet Erosion and Pharmacokinetics: A Pharmacoscintigraphic Study.” Clinical Pharmacology in Drug Development 10 5 (2021): 453–462.