Tirzepatide is a first-in-class medication that activates both the GLP-1 and GIP receptors, which leads to improved blood sugar control.
Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are hormones involved in blood sugar control.
Mechanism of action
Tirzepatide is an analogue of gastric inhibitory polypeptide (GIP), a hormone that stimulates the release of insulin from the pancreas. Tirzepatide is a linear polypeptide of 39 amino acids that has been chemically modified by lipidation to improve its uptake into cells and its stability to metabolism. It completed phase III trials globally in 2021.
Tirzepatide has a greater affinity to GIP receptors than to GLP-1 receptors, and this dual agonist behavior has been shown to produce greater reductions of hyperglycemia compared to a selective GLP-1 receptor agonist. Signaling studies have shown that this is due to tirzepatide mimicking the actions of natural GIP at the GIP receptor. However, at the GLP-1 receptor, tirzepatide shows bias towards cAMP (a messenger associated with regulation of glycogen, sugar and lipid metabolism) generation, rather than β-arrestin recruitment. This combination of preference towards GIP receptor and distinct signaling properties at GLP-1 suggest this biased agonism increases insulin secretion.
Tirzepatide has also been shown to increase levels of adiponectin, an adipokine involved in the regulation of both glucose and lipid metabolism, with a maximum increase of 26% from baseline after 26 weeks, at the 10 mg dosage.