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Tirzepatide is indicated to improve blood sugar control in adults with type 2 diabetes, as an addition to diet and exercise.
Tirzepatide is also indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management.
Tirzepatide has demonstrated significant benefits in obese patients with a common type of heart failure, preserved ejection fraction (HFpEF) in a Phase 3 trial. Over two years, tirzepatide reduced the risk of major complications, including urgent heart failure visits, hospitalizations, increased diuretic treatment, and cardiovascular-related deaths, by 38% compared to placebo. This makes tirzepatide the second GLP-1 drug to show positive results in this area, following semaglutide, to date.
Contraindications
Tirzepatide is contraindicated for use in people with a personal or family history of medullary thyroid cancer or for use in people with multiple endocrine neoplasia syndrome type 2.
Pharmacology
Tirzepatide is an analogue of gastric inhibitory polypeptide (GIP), a human 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.
Mechanism of action
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 reported that tirzepatide mimics the actions of natural GIP at the GIP receptor.[33] At the GLP-1 receptor, though, 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 been reported 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 Wochen, at the 10 mg dosage.
