Products
The first agent in the GLP-1 receptor agonist group to be approved was exenatide (Byetta) in the United States in 2005 and in many countries and the EU in 2006. In the meantime, several other drugs have been registered (see below). These drugs are also known as incretin mimetics. They are commercially available as injectable solutions and are usually administered by patients using a prefilled pen.
Structure and properties
The agents are analogs of GLP-1 (glucagon-like peptide-1). 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. The GLP-1 receptor agonists are chemically modified to have a longer half-life and are suitable for therapeutic administration. For example, they are resistant to DPP-4 or bind to albumin. Galenic methods are also used. Regarding nomenclature, it should be noted that the German name is written without -e at the end of the active ingredient name. Thus, for example, the correct name is exenatide and not exenatide. The use of English active ingredient names is not common in German. The active ingredients with the suffix -enatid (i.e., exenatide, lixisenatide) are derived from an ingredient in the venom of the Gila crustacean. The active ingredients with the suffix -glutide are derivatives of GLP-1. Example liraglutide:
Effects
GLP-1 receptor agonists (ATC A10BJ) have blood glucose-lowering and antidiabetic 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. Liraglutide is additionally approved for the treatment of overweight and obesity (Saxenda).
Dosage
According to the SmPC. GLP-1 receptor agonists are usually injected subcutaneously, in the abdomen, thigh, or upper arm. Some drugs must be administered daily; for others, once-weekly administration is sufficient (e.g., albiglutide, dulaglutide). GLP-1 receptor agonists can be combined with other antidiabetic drugs, for example, metformin, sulfonylureas, and insulins. In 2019, tablets containing semaglutide were approved for the first time in the United States for the treatment of type 2 diabetes (Rybelsus). It is the first GLP-1 receptor agonist that can be administered orally.
Agents
Daily administration (short-acting GLP-1 RA):
- Exenatide (Byetta, twice daily).
- Liraglutide (Victoza, Saxenda)
- Lixisenatide (Lyxumia)
- Semaglutide oral (Rybelsus)
Weekly administration (long-acting GLP-1 RA):
- Albiglutide (Eperzan).
- Dulaglutide (Trulicity)
- Exenatide (Bydureon)
- Semaglutide subcutaneous (Ozempic)
GLP-1 receptor agonists are also combined with insulins fixed, see under IDegLira (Xultophy) and IGlarLixi (Suliqua). Development of taspoglutide was halted in 2010 because of adverse effects.
Contraindications
The drugs are contraindicated in the presence of hypersensitivity. Full precautions can be found in the drug label.
Interactions
GLP-1 receptor agonists slow gastric emptying and thus may affect the absorption and pharmacokinetics of other agents. In particular, the maximum plasma concentration may be reached later.
Adverse effects
The most common adverse effects include gastrointestinal disturbances such as nausea, vomiting, diarrhea, and abdominal pain, as well as injection site reactions. Hypoglycemia may occur when combined with sulfonylureas and insulins. GLP-1 receptor agonists may slightly increase heart rate and rarely cause cardiac arrhythmias. Inflammation of the pancreas (pancreatitis) is a serious and rare side effect. Typical symptoms are persistent, severe abdominal pain. Patients should be aware of these.
