Tirzepatide

Overview

Tirzepatide is a synthetic peptide that mimics two related gut hormones at once: glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). Where earlier agents act on a single incretin receptor, tirzepatide engages two: a dual agonist.

It is a 39-amino-acid peptide built around the GIP sequence, with Aib at positions 2 and 13 against degradation and a C20 diacid on a lysine that binds albumin; the half-life is about five days (weekly dosing).

Tirzepatide is the compound behind approved medicines (Mounjaro, Zepbound). That regulatory status is a fact about the respective authorities. At Peptalis, strictly research use only: in-vitro, not for human or animal use.

Mechanism of action

Tirzepatide activates both the GLP-1 and the GIP receptor. It is an imbalanced agonist leaning more toward the GIP receptor.

Dual incretin activation

• Through the GLP-1 route tirzepatide enhances glucose-dependent insulin release, suppresses glucagon and reduces appetite.
• On top of that comes the GIP route, which also influences the insulin response and energy metabolism.

Imbalanced / biased signalling

• Receptor pharmacology describes tirzepatide as an imbalanced agonist with somewhat biased signalling at the GLP-1 receptor (Willard 2020).
• Exactly how that imbalance contributes to clinical outcomes is an open question.

Research findings

• Preclinical: identified (LY3298176) as a single molecule combining GIP and GLP-1 receptor agonism (Coskun 2018)
• SURPASS-2 (n=1,879, T2D): HbA1c −2.01 to −2.30 points (tirzepatide) vs −1.86 (semaglutide 1 mg) (Frías 2021)
• SURMOUNT-1 (n=2,539, obesity): mean weight change −20.9% at 15 mg vs −3.1% placebo over 72 weeks (Jastreboff 2022)

Preclinical evidence

• In development, tirzepatide (LY3298176) was identified as one molecule activating both incretin receptors and improving glucose control and body weight in animal models (Coskun 2018).
• Receptor pharmacology characterized the imbalanced/biased signalling profile (Willard 2020).

Human studies

• SURPASS-2 (Frías 2021): 1,879 people with type 2 diabetes; tirzepatide 5/10/15 mg per week compared directly with semaglutide 1 mg; HbA1c reduction −2.01 to −2.30 vs −1.86 points, with greater weight loss in the tirzepatide groups.
• SURMOUNT-1 (Jastreboff 2022): 2,539 adults with obesity without diabetes; at 15 mg per week mean weight change −20.9% vs −3.1% placebo over 72 weeks.

Research context

This profile describes what has been done and found in research. Regulatory and clinical facts are facts about the respective trials and authorities, not claims about a Peptalis product; the compound is for in-vitro laboratory research only (RUO).

Open questions

• Longer-term outcomes and behaviour after discontinuation are still being mapped.
• How much of the effect is attributable to the GIP component and what the imbalance means functionally is still open.
• The comparison with the triple agonist retatrutide currently relies on indirect data.

Research outlook

Tirzepatide is a well-characterized model system for multi-receptor incretin pharmacology and biased agonism.

The GIP component opens a mechanistic avenue that deserves further study.

Scientific interest

First dual incretin agonist (GLP-1/GIP), the middle rung of the incretin ladder.

Imbalanced/biased signalling, a distinctive receptor-pharmacology profile.

The only new agent tested directly head-to-head against a predecessor (semaglutide).

Specifications

References

1. Stimulation of insulin secretion by gastric inhibitory polypeptide in man. · Dupre J, et al · J Clin Endocrinol Metab · 1973
2. Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. · Nauck MA, et al · J Clin Invest · 1993
3. Inhibition of gastric inhibitory polypeptide signaling prevents obesity. · Miyawaki K, et al · Nat Med · 2002
4. Glucose-dependent insulinotropic polypeptide: a bifunctional glucose-dependent regulator of glucagon and insulin secretion in humans. · Christensen M, et al · Diabetes · 2011
5. Unimolecular dual incretins maximize metabolic benefits in rodents, monkeys, and humans. · Finan B, et al · Sci Transl Med · 2013
6. 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 · Coskun T, et al. · Mol Metab · 2018
7. Anti-obesity effects of GIPR antagonists alone and in combination with GLP-1R agonists in preclinical models. · Killion EA, et al · Sci Transl Med · 2018
8. Optimized GIP analogs promote body weight lowering in mice through GIPR agonism not antagonism. · Mroz PA, et al · Mol Metab · 2019
9. Glucose-Dependent Insulinotropic Polypeptide Receptor-Expressing Cells in the Hypothalamus Regulate Food Intake. · Adriaenssens AE, et al · Cell Metab · 2019
10. Effects of combined GIP and GLP-1 infusion on energy intake, appetite and energy expenditure in overweight/obese individuals: a randomised, crossover study. · Bergmann NC, et al · Diabetologia · 2019
11. Chronic glucose-dependent insulinotropic polypeptide receptor (GIPR) agonism desensitizes adipocyte GIPR activity mimicking functional GIPR antagonism. · Killion EA, et al · Nat Commun · 2020
12. Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist · Willard FS, et al. · JCI Insight · 2020
13. GIPR agonism mediates weight-independent insulin sensitization by tirzepatide in obese mice. · Samms RJ, et al · J Clin Invest · 2021
14. The glucose-dependent insulinotropic polypeptide (GIP) regulates body weight and food intake via CNS-GIPR signaling. · Zhang Q, et al · Cell Metab · 2021
15. Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes · Frias JP, et al. · N Engl J Med · 2021
16. Tirzepatide, a dual GIP/GLP-1 receptor co-agonist for the treatment of type 2 diabetes with unmatched effectiveness regrading glycaemic control and body weight reduction. · Nauck MA, D'Alessio DA · Cardiovasc Diabetol · 2022
17. Tirzepatide Once Weekly for the Treatment of Obesity · Jastreboff AM, et al. · N Engl J Med · 2022
18. Effects of subcutaneous tirzepatide versus placebo or semaglutide on pancreatic islet function and insulin sensitivity in adults with type 2 diabetes. · Heise T, et al · Lancet Diabetes Endocrinol · 2022
19. Beyond the pancreas: contrasting cardiometabolic actions of GIP and GLP1. · Hammoud R, Drucker DJ · Nat Rev Endocrinol · 2023
20. Tirzepatide as Compared with Semaglutide for the Treatment of Obesity. · Aronne LJ, et al · N Engl J Med · 2025
21. Cardiovascular Outcomes with Tirzepatide versus Dulaglutide in Type 2 Diabetes. · Nicholls SJ, et al · N Engl J Med · 2025
22. Once-Monthly Maridebart Cafraglutide for the Treatment of Obesity - A Phase 2 Trial. · Jastreboff AM, et al · N Engl J Med · 2025

Availability

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