Tirzepatide (revision 12)
Old revision·23:56, 29 Oct 2024·RetatrutideRuben
| TirzepatideClinical data | |
|---|---|
A 39-residue GIP-based backbone with Aib at positions 2 and 13 and a C-20 diacid on Lys20. | |
| INN | tirzepatide |
| Class | Dual incretin agonist (GIP/GLP-1) |
| Route | Subcutaneous, weekly |
| First approval | 2022 (type 2 diabetes) |
| Identifiers | |
| CAS Number | 2023788-19-2 |
| Molecular formula | C225H348N48O68 |
| Molar mass | 4,813.45 g·mol⁻¹ |
| Residues | 39 |
| Pharmacokinetics | |
| Half-life | ≈5 days |
| Bioavailability, SC | ≈80% |
| Time to steady state | 4 weeks |
| Compound infobox · conventions | |
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.
Design and receptor pharmacology
[edit]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]
Clinical evidence
[edit]| Trial | Population | Dose | Primary result |
|---|---|---|---|
| SURPASS-2 | T2D, on metformin | 5/10/15 mg | HbA1c −2.01 to −2.30% vs semaglutide −1.86% |
| SURMOUNT-1 | Obesity, no T2D | 5/10/15 mg | −15.0% to −20.9% weight vs −3.1% at 72 wk |
| SURMOUNT-2 | Obesity with T2D | 10/15 mg | −12.8% to −14.7% weight vs −3.2% |
| SURPASS-CVOT | T2D, high CV risk | 5–15 mg | Non-inferior to dulaglutide for MACE |
The SURPASS programme covers the glycaemic indication and the SURMOUNT programme the obesity indication. SURPASS-2 is one of the few head-to-head trials in this field, comparing tirzepatide directly with semaglutide 1 mg — not the 2.4 mg obesity dose, a distinction routinely lost when the trial is cited.[3]
References
- ^ a b c Coskun T, Sloop KW, Loghin C, et al. "LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus." Molecular Metabolism 18:3–14 (2018). DOI:10.1016/j.molmet.2018.09.009. PMID 30473097.
- ^ Jastreboff AM, Aronne LJ, Ahmad NN, et al. "Tirzepatide once weekly for the treatment of obesity." New England Journal of Medicine 387(3):205–216 (2022). DOI:10.1056/NEJMoa2206038. PMID 35658024.
- ^ a b Frías JP, Davies MJ, Rosenstock J, et al. "Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes." New England Journal of Medicine 385(6):503–515 (2021). DOI:10.1056/NEJMoa2107519. PMID 34170647.