If you wish to report an adverse event or product complaint, please call 1-800-LILLYRX (1-800-545-5979)
Mounjaro ® (tirzepatide) injection
2.5 mg/5 mg/7.5 mg/10 mg/12.5 mg/15 mg
This information is provided in response to your request. Resources may contain information about doses, uses, formulations and populations different from product labeling. See Prescribing Information above, if applicable.
What is Mounjaro® (tirzepatide) and how does it exert its actions through GIP and GLP-1 receptors?
Tirzepatide is a once-weekly injectable medicine for the treatment of type 2 diabetes. It is a single molecule that binds and activates both the GIP and GLP-1 receptors.
See important safety information, including boxed warning, in the attached prescribing information.
What is Tirzepatide?
Molecular Description
Tirzepatide is an amino acid sequence with a C20 fatty diacid that enables albumin binding and prolongs the half-life. Tirzepatide selectively binds to and activates both the GIP and GLP-1 receptors, the targets for native GIP and GLP-1.1 Preclinical studies support that it binds at the GLP-1 receptor with slightly lower affinity compared to endogenous GLP-1; however, it binds at the GIP receptor with equal affinity to endogenous GIP.2,3
Tirzepatide is based on the GIP sequence and contains
- aminoisobutyric acid, Aib) in positions 2 and 13
- a C-terminal amide, and
- Lys residue at position 20 that is attached to a 1,20-eicosanedioic acid via a linker (Tirzepatide Chemical Structure).1,3
The molecular weight of tirzepatide is 4813.53 Da, and the empirical formula is C225H348N48O68. The elimination half-life is approximately 5 days, enabling once-weekly dosing.1
Preclinical Studies
The contribution of agonism at the GLP-1 and GIP receptors by tirzepatide was evaluated in preclinical studies in isolated human pancreatic cells and animal models.2-4
In isolated human islets, GLP-1 receptor antagonism alone led to variable results between donors and did not significantly reduce tirzepatide-stimulated insulin secretion. However, antagonizing the GIP receptor consistently reduced insulin secretion across all 8 sets of human islets.4 When both GIP and GLP-1 receptors were antagonized, the insulinotropic effect was similar to that of GIP receptor antagonism (Effect of Tirzepatide on Insulin Secretion During GLP-1 and GIP Receptor Antagonism in Isolated Human Islets).4
Tirzepatide demonstrated activity at both the GIP and GLP-1 receptors in isolated human islets; however, the relative effect at each receptor varied between donors.4
Figure 2 description: In isolated human islets, glucagon-like peptide-1 (GLP-1) receptor antagonism alone led to variable results between donors and failed to significantly reduce tirzepatide-stimulated insulin secretion. However, antagonizing the glucose-dependent insulinotropic polypeptide (GIP) receptor consistently reduced insulin secretion across all 8 sets of human islets. When both receptors were antagonized, the insulinotropic effect was similar to that of GIP receptor antagonism.
Abbreviations: Ant = antagonist; AUC = area under the curve; GIP = glucose-dependent insulinotropic polypeptide; GIPR = glucose-dependent insulinotropic polypeptide receptor; GLP-1= glucagon-like peptide-1; GLP-1R = glucagon-like peptide-1 receptor.
In animal studies, tirzepatide lowered high blood sugar in the absence of GLP-1 receptor. Tirzepatide administration in obese insulin-resistant mice lacking the GLP-1 receptor also resulted in improved glycemic control. This indicates that tirzepatide, acting through the GIP receptor, is sufficient for glycemic control.2
A long-acting, selective GIP receptor agonist was sufficient to reduce hyperglycemia when given to mice lacking the GLP-1 receptor in a glucose challenge test.2
Tirzepatide can also lower high blood sugar in the absence of GIP receptor as shown in GIP receptor null mice.3
Taken together, these data support that tirzepatide has activity at both the GLP-1 and GIP receptors, which together contribute to improved glycemic control. These preclinical observations are not currently possible to confirm in humans given the available pharmacological tools.2
Enclosed Prescribing Information
References
The published references below are available by contacting 1-800-LillyRx (1-800-545-5979).
1Mounjaro [package insert]. Indianapolis, IN: Eli Lilly and Company; 2024.
2Samms RJ, Christe ME, Collins KAL, et al. GIPR agonism mediates weight-independent insulin sensitization by tirzepatide in obese mice. J Clin Invest. 2021;131(12):e146353. https://doi.org/10.1172/JCI146353
3Coskun 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: from discovery to clinical proof of concept. Mol Metab. 2018;18:3-14. https://doi.org/10.1016/j.molmet.2018.09.009
4El K, Douros JD, Willard FS, et al. The incretin co-agonist tirzepatide requires GIPR for hormone secretion from human islets. Nat Metab. 2023;5(6):945-954. https://doi.org/10.1038/s42255-023-00811-0
5Data on file, Eli Lilly and Company and/or one of its subsidiaries.
Date of Last Review: November 06, 2024