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Tirzepatide is a new dual-receptor channel agonist for glucagon-like peptide-1 receptor (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP, also known as gastric inhibitory peptide). Administer once a week. Both GLP-1 and GIP are incretins, polypeptides secreted by the human gastrointestinal mucosa. The former can bind to receptors on pancreatic islet cells and stimulate insulin secretion, thus producing a hypoglycemic effect and delaying gastric excretion. Empty and suppress appetite, thereby controlling weight; while the latter has the functions of inhibiting gastric acid and pepsin secretion, stimulating insulin release, inhibiting gastric motility and emptying, and can supplement the GLP-1 receptor agonist effect. Tirzepatide combines two insulinotropic effects into a single molecule and represents a new class of drugs for the treatment of type 2 diabetes.

Function

The addition of GIP which anatagonizes the central effects of GLP-1 to cause nausea is designed to improve tolerability and also allow for more aggressive dosing with increased systemic exposure. A recent post-hoc analysis showed significantly decreased NASH-related biomarkers and increased adiponectin in patients with T2DM

The weight-reducing actions of the GIPR-GLP1R co-agonist tirzepatide.Considerable interest is focused on the mechanisms of action of tirzepatide, a highly effective GIPR-GLP1R co-agonist that produces superior reductions in HbA1c and body weight, relative to that achieved with 1 mg once weekly of semaglutide in people with T2D. The GIPR is expressed in multiple regions of the mouse and human brain, in subsets of neurons and glial cells, with some hypothalamic and hindbrain cells exhibiting co-expression of the GIPR and GLP1R. Chemogenetic activation of GIPR + cells in the mouse hypothalamus acutely reduced food intake; however, co-administration of exendin-4 did not produce an additive reduction of food intake when compared to either intervention alone.

Therapy with tirzepatide, 5-15 mg once weekly produces 8-12% body weight reduction in people with T2D, prompting ongoing development of tirzepatide as a weight loss agent for people with overweight or obesity. The importance of GIP for the weight loss properties of tirzepatide in humans is uncertain; however, tirzepatide failed to reduce body weight in Glp1r−/- mice, implicating a dominant role for the GLP1R in the weight loss observed with this agent. Glucose-dependent insulinotropic polypeptide (GIP) has been shown to reduce the extent of aversive responses induced by GLP-1 in mice and rats and decrease nausea and vomiting in the shrew.

Application

Tirzepatide has a similar sequence to semaglutide. The lys side chain in the sequence is modified with PEG, which is a functional group of phospholipids and can increase the solubility of the sequence. The main physiological function of Tirzepatide is a dual agonist of insulin nutritional bridge (GIP) and glucagon-like peptide-1 (GLP-1) in diabetes. It is being developed for the treatment of type 2 diabetes and has entered the clinical stage.

Company Profile

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