Semaglutide

Products

Semaglutide was approved in the US and EU in 2017 and in many countries in 2018 as a solution for injection (Ozempic). The agent is structurally and pharmacologically related to liraglutide (Victoza), which, unlike semaglutide, is injected once daily (both Novo Nordisk). In 2019, tablets containing semaglutide were approved for the first time in the United States for the treatment of type 2 diabetes (Rybelsus). Semaglutide is the first GLP-1 receptor agonist that can be administered orally. Rybelsus was approved in many countries in 2020.

Structure and properties

Semaglutide is a long-acting analog of GLP-1 (glucagon-like peptide-1) with a sequence homology of 94%. GLP-1 is a peptide hormone composed of amino acids and produced by enteroendocrine L cells in the digestive tract. Due to degradation by the enzymes dipeptidyl peptidase-4 (DPP-4) and neutral endopeptidase (NEP), it has a half-life in the range of only two minutes. Semaglutide differs from the natural peptide hormone as follows:

  • Alanine at position 8 has been replaced by α-aminoisobutyric acid (a synthetic amino acid, protection from degradation by DPP-4).
  • Binding of a hydrophilic spacer and a C18-difatty acid to lysine at position 26 (albumin binding, prolongation of half-life).
  • Lysine at position 34 was replaced by arginine (to allow the fatty acid to attach to the correct position)

Oral absorption is made possible by the formulation with absorption enhancer salcaprozate sodium (SNAC). However, oral bioavailability is low, ranging from only 0.4% to 1%.

Effects

Semaglutide (ATC A10BJ06) has antidiabetic and antihyperglycemic properties. The effects are due to binding to the GLP-1 receptor, a GPCR (G protein-coupled receptor). This receptor is also activated by the incretin GLP-1. GLP-1 receptor agonists:

  • Glucose-dependently promote insulin secretion from pancreatic beta cells.
  • Decrease glucagon secretion from alpha cells, leading to decreased glucose release by the liver (lowering gluconeogenesis).
  • Increase insulin sensitivity.
  • Slow gastric emptying, reducing the rate at which glucose enters the bloodstream.
  • Increase satiety (central), reduce the feeling of hunger and may contribute to weight loss.

GLP-1 receptor agonists tend to cause less hypoglycemia because their effect does not occur until glucose levels are elevated. The orally available gliptins (see there) inhibit the breakdown of GLP-1, thereby enhancing its effects.

Indications

For the treatment of type 2 diabetes.

Dosage

According to the SmPC. The drug is injected subcutaneously once a week. The tablets are taken once daily with water at least 30 minutes before meals on an empty stomach.

Contraindications

  • Hypersensitivity

For complete precautions, see the drug label.

Adverse effects

The most common possible adverse effects include gastrointestinal disturbances such as nausea, vomiting, diarrhea, abdominal pain, and constipation.