Tirzepatide
Tirzepatide is a dual GIP/GLP-1 receptor agonist approved for type 2 diabetes and obesity, featuring a C20 fatty diacid linker for albumin binding and once-weekly dosing.
Chemical Identity
| Property | Value |
|---|---|
| Chemical Formula | C225H348N48O68S |
| Molecular Weight | 4813.53 g/mol |
| CAS Number | 2023788-19-2 |
| IUPAC Name | Modified GIP(1-29) analog |
| Peptide Class | Dual GIP/GLP-1 Receptor Agonist |
| Sequence Homology | GIP(1-29) with GLP-1 sequence elements |
Structure
Tirzepatide is a 39-amino acid linear peptide derived from the native gastric inhibitory polypeptide (GIP) sequence with incorporation of GLP-1 receptor-active elements. Key modifications include:
- Aib at position 2: Provides resistance to DPP-4 cleavage, extending enzymatic stability.
- C-terminal extension: A 20-carbon fatty diacid (icosanedioic acid) connected via a miniPEG linker to Lys20, enabling strong albumin binding for half-life extension.
- Sequence substitutions: Selective amino acid changes at positions that enhance GLP-1 receptor cross-reactivity while maintaining potent GIP receptor activation.
Dual Receptor Pharmacology
Tirzepatide is the first-in-class dual GIP/GLP-1 receptor agonist approved for clinical use:
- GIP receptor: Potent agonist with native GIP-like efficacy. GIP signaling enhances insulin secretion in a glucose-dependent manner and may improve adipose tissue function.
- GLP-1 receptor: Partial agonist activity contributing to insulin secretion, glucagon suppression, delayed gastric emptying, and central satiety signaling.
- Synergistic effects: The combination of GIP and GLP-1 receptor activation produces greater glycemic control and weight loss than either pathway alone.
Clinical Applications
Tirzepatide received FDA approval as Mounjaro for type 2 diabetes (2022) and as Zepbound for obesity (2023). In the SURPASS clinical trial program, tirzepatide demonstrated HbA1c reductions of up to 2.58% and weight loss of up to 12.4 kg at the highest dose (15 mg weekly). The SURMOUNT trials showed mean weight loss of 15-21% in adults with obesity.
Pharmacokinetics
- Half-life: Approximately 5 days (118 hours), supporting once-weekly subcutaneous administration
- Tmax: 8-72 hours post-injection
- Metabolism: Proteolytic degradation; not CYP-mediated
- Albumin binding: The C-20 fatty diacid moiety enables extensive non-covalent albumin binding
Safety and Side Effects
The most common adverse effects are gastrointestinal: nausea (12-18%), diarrhea (12-17%), decreased appetite (5-11%), and vomiting (5-9%). These are generally mild to moderate and dose-dependent. Tirzepatide carries a boxed warning regarding thyroid C-cell tumors observed in rodent studies, consistent with the GLP-1 receptor agonist class.
References
- Frías, J.P., et al. (2021). Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. New England Journal of Medicine, 385, 503-515.
- Jastreboff, A.M., et al. (2022). Tirzepatide once weekly for the treatment of obesity. New England Journal of Medicine, 387, 205-216.
Test Your Knowledge
Reinforce what you learned about Tirzepatide with interactive quizzes on Wikipept.
Take a Quiz on Wikipept