Tirzepatide: the dual GIP/GLP-1 agonist and what the research shows

Tirzepatide is a synthetic peptide of 39 amino acids built to activate two receptors at once: the receptor for glucose-dependent insulinotropic polypeptide (GIP) and the receptor for glucagon-like peptide-1 (GLP-1). Both hormones are incretins — signals released by the gut after a meal that influence insulin secretion, appetite and energy use. Earlier drugs in this field targeted GLP-1 alone; tirzepatide was the first dual agonist to complete large clinical programmes.

Structure

The backbone is based on the GIP sequence, modified so that it also binds the GLP-1 receptor. A C20 fatty-diacid side chain lets it bind albumin in the blood, which slows its clearance and gives it a long half-life of about five days. Its molecular formula is C225H348N48O68, with a molecular weight of about 4,813 g/mol.

Mechanism

In laboratory studies tirzepatide activates the GIP receptor with an affinity close to that of native GIP, and the GLP-1 receptor more weakly than native GLP-1 — an imbalance that is part of its design. At the GLP-1 receptor it also shows a signalling bias, favouring cAMP generation over β-arrestin recruitment, which has been linked to reduced receptor internalisation.

What the clinical programmes found

The SURPASS trials studied tirzepatide in type 2 diabetes, including a head-to-head comparison with semaglutide; SURMOUNT-1 studied adults with obesity. Both reported changes in glycaemic and body-weight endpoints; the most common adverse events were gastrointestinal.

These results led to regulatory approval of tirzepatide as a prescription medicine for type 2 diabetes and for weight management. Those approved products are not what research suppliers sell: research-grade tirzepatide is supplied for laboratory work only.

Between semaglutide and retatrutide

Tirzepatide is often discussed as the middle step in a series: semaglutide acts on GLP-1 alone, tirzepatide on GIP and GLP-1, and retatrutide on GIP, GLP-1 and the glucagon receptor. Comparing the three is one of the clearest ways to study how each receptor contributes to metabolic effects.

This article summarises published research for laboratory context. It is not guidance for use in humans or animals, and research-grade tirzepatide is not sold for that purpose.

1. 1.Coskun T, et al. LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus. Molecular Metabolism, 2018.
2. 2.Frías JP, et al. Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes (SURPASS-2). New England Journal of Medicine, 2021.
3. 3.Jastreboff AM, et al. Tirzepatide Once Weekly for the Treatment of Obesity (SURMOUNT-1). New England Journal of Medicine, 2022.