Tirzepatide: Dual GIP and GLP-1 Receptor Agonist Research

Tirzepatide is a dual agonist at the glucose-dependent insulinotropic polypeptide (GIP) receptor and the glucagon-like peptide-1 (GLP-1) receptor. It is an active subject of published metabolic research, and has been studied in relation to glucose regulation, body weight endpoints and obstructive sleep apnea.

The summary below describes findings reported in the published literature. Tirzepatide is supplied for laboratory research use only and is not approved for human or veterinary use. No conclusions can be drawn regarding safety or efficacy in humans.

Structurally, tirzepatide is a linear 39-amino-acid peptide linked to a C20 fatty diacid moiety via a linker coupled to the lysine-20 residue. Comparative studies report that the dual-agonist approach produces a greater combined effect on insulin and glucagonostatic responses than a GLP-1 agonist such as semaglutide alone.

Mechanism of Action of Tirzepatide Peptide

In a glucose-dependent manner, tirzepatide acts to increase first- and second-phase insulin production and to lower systemic glucagon levels. Studies have also reported delayed gastric emptying, lower fasting and post-prandial blood glucose concentrations, reduced food intake, and reductions in body weight in study populations with type 2 diabetes.

GLP-1 receptors (GLP-1R) are expressed in several tissues, including pancreatic beta-cells and the gastrointestinal tract. GLP-1R signalling has been linked to the pathophysiology of type 2 diabetes mellitus, as it increases glucose-stimulated insulin secretion, delays gastric transit, lowers plasma glucagon and reduces body weight by activating anorexigenic pathways in the brain.

GLP-1 and GIP are both peptide hormones involved in glucose homeostasis, prompting pancreatic beta-cells to secrete insulin in response to glucose. GIP is the primary incretin hormone responsible for the insulinotropic effects triggered by food intake.

The precise mechanism of action of tirzepatide has not been fully defined. Dual agonism at GIP and GLP-1R may account for the glycaemic and body weight effects reported for the compound. Studies show that combining GIP with a GLP-1R agonist produces a greater rise in insulin responsiveness and greater suppression of glucagon secretion than either hormone alone.

Tirzepatide binds both GIP and GLP-1R with strong affinity. In vitro testing reports GIP receptor binding affinity comparable to native GIP, and GLP-1R affinity approximately five times lower than natural GLP-1. Acting at either the GIP receptor (GIPR) or GLP-1R, tirzepatide produces potent activation of the GLP-1R signalling pathway, stimulating glucose-dependent insulin release.

Further research is required to determine the role GIPR agonism plays in the compound's mechanism, as preclinical and clinical evidence on the contribution of GIPR agonism to glycemic and weight endpoints is not consistent.

Research Evidence

A study led by researchers at Weill Cornell Medicine, NewYork-Presbyterian, Yale School of Medicine and other institutions reported that tirzepatide reduced the incidence of diabetes among participants with prediabetes by more than 90% over three years compared with placebo.

Tirzepatide belongs to a class of compounds that mimic nutrient-stimulated hormones. These act at least in part by activating one or more receptors, including GLP-1 and GIP receptors on cells in the brain, pancreas and other tissues. Because tirzepatide activates both GLP-1 and GIP, published comparisons report greater reductions in body weight and fewer adverse events than compounds acting on GLP-1 alone. Reported effects include increased satiety signalling, reduced food intake and increased insulin production with corresponding reductions in blood glucose.

Trial participants with obesity who received tirzepatide over 72 weeks recorded a significant mean reduction in glycated hemoglobin (A1c), a standard measure of glucose control. The SURMOUNT-1 trial reported that participants recorded mean reductions of between 15% and 22.5% of initial body weight, depending on dose. A subsequent analysis focused on 1,032 participants who had obesity and prediabetes at baseline, prediabetes being characterised by A1c levels above normal but below the diabetes threshold.

At 176 weeks, ten participants in the tirzepatide arm had developed diabetes, a reduction in risk of approximately 93% relative to placebo. At the same timepoint, participants in the tirzepatide arm recorded normal A1c levels, compared with 59% of the placebo arm.

The trial reported no new safety signals, and the most common gastrointestinal adverse events — nausea and vomiting — decreased in frequency as the trial progressed. Following cessation of administration for 17 weeks, follow-up analysis found that some participants recorded slight increases in body weight and A1c, with some returning to the prediabetes and diabetes ranges.

Areas of Study

As a dual agonist at GLP-1 and GIP receptors, tirzepatide has been studied in trial participants with type 2 diabetes, where published results report improvements in glycemic control and reductions in body weight.

Cardiovascular endpoints are an active research area. Reported mechanisms of interest include improved glycemic control through lower HbA1c, which is associated with reduced hyperglycemia-related vascular damage. High or fluctuating blood glucose can contribute to vascular endothelial dysfunction and atherosclerosis through increased oxidative stress, the production of advanced glycation end products (AGEs) and activation of protein kinase C (PKC).

Research has also examined potential direct effects on vascular endothelial function and blood pressure, alongside indirect effects associated with changes in body weight. Some trials suggest GLP-1 receptor agonists may have direct cardiovascular effects in addition to their effects on glucose and body weight.

In animal models, liraglutide and semaglutide have demonstrated anti-atherosclerotic effects including reduced vascular inflammation, improved endothelial function and plaque stabilisation. Research on tirzepatide in this area remains at an early stage. Liraglutide has also been shown to inhibit atherosclerosis through an AMPK-independent mechanism in a hyperglycemic ApoE knockout mouse model, suggesting GLP-1 receptor agonists may act through multiple pathways, potentially mediated in part by anti-inflammatory and antioxidant GLP-1 receptor signalling.

Future Research Perspectives

Published data from the SURMOUNT and SURPASS programmes report substantial effects on glycemic control and body weight endpoints through combined activation of GLP-1 and GIP receptors. Further work is needed to evaluate cardiovascular effects more comprehensively, and to study specific populations including elderly participants and those with renal impairment.

Research use statement. Tirzepatide supplied by Power Peptides is intended for laboratory research use only and is not approved by the U.S. Food and Drug Administration for human or veterinary use. It is not a drug, food or cosmetic, and must not be used in humans or animals.

References

1. Lisco, G., De Tullio, A., Disoteo, O., De Geronimo, V., Piazzolla, G., De Pergola, G., ... & Triggiani, V. (2022). Basal insulin intensification with GLP-1RA and dual GIP and GLP-1RA in patients with uncontrolled type 2 diabetes mellitus: a rapid review of randomized controlled trials and meta-analysis. Frontiers in Endocrinology , 13 , 920541.

2. Coskun T, Sloop KW, Loghin C, Alsina-Fernandez J, Urva S, Bokvist KB, Cui X, Briere DA, Cabrera O, Roell WC, Kuchibhotla U, Moyers JS, Benson CT, Gimeno RE, D'Alessio DA, Haupt A: 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 Dec;18:3-14. doi: 10.1016/j.molmet.2018.09.009. Epub 2018 Oct 3

3. Eli Lilly and Company Investors News Release: FDA approves Lilly's Mounjaro™ (tirzepatide) injection, the first and only GIP and GLP-1 receptor agonist for the treatment of adults with type 2 diabetes.

4. Frias JP: Tirzepatide: a glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) dual agonist in development for the treatment of type 2 diabetes. Expert Rev Endocrinol Metab. 2020 Nov;15(6):379-394. doi: 10.1080/17446651.2020.1830759. Epub 2020 Oct 8. [Article]

5. Min T, Bain SC: The Role of Tirzepatide, Dual GIP and GLP-1 Receptor Agonist, in the Management of Type 2 Diabetes: The SURPASS Clinical Trials. Diabetes Ther. 2021 Jan;12(1):143-157. doi: 10.1007/s13300-020-00981-0. Epub 2020 Dec 15. [Article]

6. FDA Approved Drug Products: MOUNJARO (tirzepatide) Injection, for subcutaneous use.