Tirzepatide (revision 9)

Tirzepatide is a 39-residue synthetic peptide that activates both the receptor for Glucose-dependent insulinotropic polypeptide and the GLP-1 receptor, making it the first dual incretin agonist to reach the market. Its backbone is derived from GIP rather than from GLP-1, and it is described in the literature as GIP-biased, with greater potency at the GIP receptor than at the GLP-1 receptor.^[1]

Half-life extension follows the same logic as semaglutide: α-aminoisobutyric acid at positions 2 and 13 confers protease resistance, and a C-20 fatty diacid at Lys20 confers albumin binding. The resulting half-life of about five days supports weekly administration.^[1]

In SURMOUNT-1, 15 mg weekly produced a mean weight change of −20.9% against −3.1% for placebo at 72 weeks in participants with obesity and without diabetes.^[2] As with every compound covered here, tirzepatide sold as a research chemical is not the approved medicine and carries none of its assurances; see Research use only.

Tirzepatide was built from the GIP sequence rather than from GLP-1, which is the reverse of the intuitive approach and reflects the finding that a GIP backbone tolerates the substitutions needed for GLP-1 activity better than the converse.^[1]

Reported potency at the GIP receptor approaches that of native GIP, while potency at the GLP-1 receptor is roughly an order of magnitude below that of native GLP-1. The molecule is therefore not a balanced dual agonist, and the term "GIP-biased" is used in that sense. It also shows signalling bias at the GLP-1 receptor, favouring cAMP accumulation over β-arrestin recruitment; whether this contributes to the clinical effect is unresolved. See Receptor bias.

Why dual agonism outperforms GLP-1 monotherapy is not settled. Proposed contributions include GIP action on adipose tissue, central GIP-receptor effects on nausea that permit higher effective exposure, and restored beta-cell GIP responsiveness under ambient GLP-1 signalling. The trials were not designed to separate these, and cross-trial comparison of tirzepatide with semaglutide is confounded by differences in population and escalation.^[3]