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1kits（10Vials）
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▎Tirzepatide Structure
Source: PubChem | Sequence: Tyr-{Aib}-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Ile-{Aib}-Leu-Asp-Lys-Ile-Ala-Gln-{diacid-C20-gamma-Glu-(AEEA)2-Lys}-Ala-Phe-Val-Gln-Trp-Leu-Ile-Ala-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 Molecular Formula: C225H348N48O68 Molecular Weight: 4813 g/mol CAS Number: 2023788-19-2 PubChem CID: 163285897 Synonyms: Zepbound; Mounjaro |
▎Tirzepatide Research
What is the research background of Tirzepatide?
Tirzepatide is a synthetic polypeptide drug. Its development stems from a profound understanding of the limitations of existing GLP-1 receptor agonists in the treatment of type 2 diabetes mellitus (T2DM) and obesity. Although GLP-1 receptor agonists have shown excellent performance in blood glucose control and weight loss, scientists have found that their activation of the GIP receptor is relatively weak, which limits the therapeutic effect of the drugs. Therefore, the research and development team has been committed to developing a new type of drug that can activate both the GIPR and GLP-1R simultaneously, aiming to achieve more comprehensive and effective blood glucose control and weight management [1].
During the research and development process, scientists have conducted a large number of basic research studies and clinical trials. In the preclinical research stage, the pharmacodynamic properties of Tirzepatide were thoroughly evaluated through animal experiments, verifying its potential in blood glucose control and weight loss. The results showed that it could significantly reduce the blood glucose level in animal models and demonstrated excellent performance in weight management, laying the foundation for subsequent clinical trials.
Subsequently, the clinical trial stage included Phase I, II, and III trials. The Phase I trial mainly evaluated the safety, tolerability, and pharmacokinetic properties of the drug. The results indicated that Tirzepatide had good safety and tolerability. The Phase II trial further explored the efficacy and safety of different doses of Tirzepatide in patients with T2DM, preliminarily determining its effective dose range. The most crucial Phase III clinical trials, such as the SURPASS series of studies, involved a large number of patients with T2DM. The results showed that Tirzepatide was significantly superior to existing GLP-1 receptor agonists, such as semaglutide, in reducing blood glucose and weight, providing strong evidence for the marketing application of Tirzepatide [1].
What is the mechanism of action of Tirzepatide?
Tirzepatide lowers blood glucose through multiple mechanisms working together. When activating the GLP-1 receptor, Tirzepatide binds to the GLP-1 receptor on pancreatic β-cells, mimicking the action of natural GLP-1. GLP-1 is a hormone produced in the intestine and is crucial for maintaining glucose homeostasis. It can promote insulin synthesis, secretion, and glucose sensing, reduce glucagon secretion to promote satiety, and suppress appetite.
This activation can promote insulin secretion. Insulin is the main hypoglycemic hormone in the body, which can increase the uptake and utilization of glucose by cells, thereby reducing blood glucose levels. In patients with T2DM, insulin secretion is insufficient or cells' sensitivity to insulin decreases, leading to elevated blood glucose. By activating the GLP-1 receptor, Tirzepatide increases insulin secretion, which helps to improve blood glucose control.
At the same time, the activation of the GLP-1 receptor also inhibits the release of glucagon. Glucagon usually promotes glycogenolysis and gluconeogenesis during fasting, increasing blood glucose production. By inhibiting the action of glucagon, Tirzepatide further reduces the source of blood glucose, contributing to blood glucose control [2].
When activating the GIP receptor, Tirzepatide acts on the GIP receptor simultaneously. After activation, it can enhance insulin sensitivity and secretion. The GIP receptor is mainly present in tissues such as pancreatic β-cells. After activation, through the transmission of intracellular signaling pathways, insulin secretion is increased, and the cell's responsiveness to insulin is improved, thus more effectively reducing blood glucose.
Tirzepatide is a first-in-class dual glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide (GIP) analog, approved for the treatment of adult patients with T2DM as an adjunct to diet and exercise. Tirzepatide is a synthetic chemical structure based on the GIP sequence, composed of a 39-amino acid peptide. It increases insulin secretion, reduces glucagon release in a glucose-dependent manner, lowers fasting and postprandial blood glucose levels, promotes satiety, reduces body weight, and delays gastric emptying. This dual receptor agonist effect makes Tirzepatide more effective than single GLP-1 receptor agonists in promoting insulin secretion and inhibiting glucagon release [2].
Tirzepatide can also delay gastric emptying and increase satiety. It can delay gastric emptying, prolonging the residence time of food in the stomach and slowing down the absorption rate of nutrients, thereby avoiding a sharp rise in postprandial blood glucose. In non-clinical and clinical studies, the effect of Tirzepatide on gastric emptying is comparable to that of GLP-1 receptor agonists. In diet-induced obese mice, the degree of gastric emptying delay by Tirzepatide is similar to that of semaglutide, but these acute inhibitory effects disappear after 2 weeks of treatment.
In participants with and without T2DM, once-weekly Tirzepatide (≥5 mg and ≥4.5 mg, respectively) delayed gastric emptying after a single dose. In healthy participants, the effect was attenuated after multiple doses of Tirzepatide or dulaglutide (Urva S, 2020). At the same time, it can also act on the central nervous system, increasing satiety, reducing appetite, and food intake. By controlling dietary intake, it indirectly helps to control blood glucose levels, especially suitable for the obesity problem often accompanied by patients with T2DM, and helps to improve insulin resistance and the overall metabolic status [2].
Tirzepatide has been found to increase the level of adiponectin, an adipocytokine related to insulin sensitivity. An increase in adiponectin levels helps to improve insulin sensitivity, making cells more responsive to insulin, thus more effectively taking up and utilizing glucose and reducing blood glucose[2]. In addition, Tirzepatide can also improve the lipid profile and has a potential protective effect on cardiovascular health. Tirzepatide has been proven to be able to improve blood pressure, reduce low-density lipoprotein (LDL) cholesterol and triglycerides [3], further supporting its comprehensive benefits in blood glucose management.
Source: PubMed[5]
Related research
Efficacy on weight management in patients with obesity and type 2 diabetes mellitus
Numerous clinical studies have confirmed the significant efficacy of Tirzepatide in the management of body weight in patients with obesity and T2DM. In a study named "SURMOUNT-2", which was a Phase 3, double-blind, randomized, placebo-controlled trial conducted in seven countries. Adults (aged ≥18 years) with a body mass index (BMI) of 27 kg/m² or higher and a glycated hemoglobin (HbA₁c) level of 7 - 10% were randomly assigned to receive once-weekly subcutaneous injections of Tirzepatide (10 mg or 15 mg) or placebo for 72 weeks.
The results showed that at week 72, the percentage of weight loss in the Tirzepatide 10 mg and 15 mg groups was -12.8% and -14.7%, respectively, compared with -3.2% in the placebo group. The estimated treatment differences of Tirzepatide 10 mg and 15 mg compared with the placebo were -9.6 percentage points and -11.6 percentage points, respectively, both of which were statistically significant (p < 0.0001). In addition, a greater proportion of patients receiving Tirzepatide treatment reached the threshold of a weight loss of 5% or more (79 - 83% vs 32%)[4].
In the "SURMOUNT-2" study, the baseline average weight was 100.7 kg, the BMI was 36.1 kg/m², and the HbA₁c was 8.02%. After 72 weeks of treatment, Tirzepatide not only significantly reduced body weight but also had a positive effect on blood glucose control [4].
Improvement effect on diabetes-related neuropathy
ome studies have pointed out that GLP1-RAs can reduce the risk of dementia in patients with T2DM by improving memory, learning, and overcoming cognitive impairment. As a dual GIP-RA/GLP-1RA, Tirzepatide was studied in the neuroblastoma cell line (SHSY5Y) for its effects on markers of neuronal growth (CREB and BDNF), apoptosis (BAX/Bcl2 ratio), differentiation (pAkt, MAP2, GAP43, and AGBL4), and insulin resistance (GLUT1, GLUT4, GLUT3, and SORBS1).
The results for the first time emphasized the role of Tirzepatide in activating the pAkt/CREB/BDNF pathway and downstream signaling cascades, as well as its neuroprotective efficacy. It also indicated that Tirzepatide was able to counteract the effects related to hyperglycemia and insulin resistance at the neuronal level. Therefore, Tirzepatide can improve the neurodegeneration caused by hyperglycemia and overcome neuronal insulin resistance, providing new insights for the improvement of diabetes-related neuropathy [5].
Research progress in the treatment of type 2 diabetes mellitus
Some studies have pointed out that as a new type of hypoglycemic drug, Tirzepatide has become the first dual GIP/GLP-1R agonist approved for the treatment of diabetes in the United States. It has been confirmed to have significant effects on lowering blood glucose and reducing body weight in multiple large-scale clinical trials, and there is evidence indicating that it also has great potential in cardiovascular protection.
In addition, the concept of synthetic peptides has opened up many unknown possibilities for Tirzepatide. Ongoing trials (NCT04166773) and evidence suggest that it appears to be a promising drug in fields such as non-alcoholic fatty liver disease (NAFLD), renal protection, and neuroprotection [6].
Long-term effects of tirzepatide on cardiovascular health
Tirzepatide may reduce the risk of cardiovascular diseases by promoting weight loss. A study examined the impact of Tirzepatide on obesity and cardiovascular disease events in American adults (Wong N D, 2024). The study found that among American adults eligible for Tirzepatide treatment, after treatment with 15 mg of Tirzepatide, it was estimated that 70.6% and 56.7% of adults had a weight loss of ≥15% and ≥20%, respectively, which meant a 58.8% reduction in the number of obese people.
Among those without cardiovascular diseases, the estimated 10-year cardiovascular disease risk decreased from 10.1% "before treatment" to 7.7% "after treatment", reflecting an absolute risk reduction of 2.4% and a relative risk reduction of 23.6%, which means that 2 million cardiovascular disease events could be prevented within 10 years.
In conclusion ，Tirzepatide is a novel dual agonist of GIP and GLP-1 receptors, which is of great significance in the treatment of T2DM and obesity. It can more effectively promote insulin secretion, inhibit glucagon secretion, precisely regulate blood glucose, reduce the risk of complications, improve the function of pancreatic β-cells, and delay the progression of diabetes. It also has a protective effect on the cardiovascular system.
In the treatment of obesity, it can effectively reduce food intake, decrease appetite, increase satiety, help obese patients lose weight, and reduce the risk of obesity-related complications. It can also improve insulin resistance and lipid metabolism. In addition, it has shown potential in the treatment of metabolic disorder-related diseases such as non-alcoholic steatohepatitis, sleep apnea syndrome, and heart failure. It can improve multiple metabolic indicators simultaneously, providing a more comprehensive treatment plan.
Its once-weekly injection regimen is convenient to use and can improve patients' treatment compliance.
About The Author
The above-mentioned materials are all researched, edited and compiled by Cocer Peptides.
Scientific Journal Author
Dr. William T. Garvey is a distinguished scholar and researcher affiliated with multiple prestigious institutions, including the University of Alabama at Birmingham, Aston University, and the Birmingham Veterans Affairs Medical Center. His academic background and professional experience span a wide range of disciplines within the medical and scientific fields. Dr. Garvey has made significant contributions to the fields of endocrinology and metabolism, nutrition and dietetics, biochemistry and molecular biology, as well as general and internal medicine, with a particular focus on the cardiovascular system and cardiology. His work has been widely recognized and honored, notably being named a Highly Cited Researcher in the Cross-Field category for both 2023 and 2024, reflecting the substantial impact and influence of his research on the broader scientific community.
Dr. Garvey's research interests and expertise extend to various aspects of metabolic diseases and their management. He has been actively involved in studying diabetes mellitus, obesity, and their associated complications, aiming to uncover novel therapeutic strategies and improve patient outcomes. His work encompasses basic scientific research, clinical trials, and translational studies, bridging the gap between laboratory findings and real-world medical applications. Through his extensive research, Dr. Garvey has contributed to a deeper understanding of the underlying mechanisms of metabolic disorders and has helped shape clinical guidelines and treatment protocols in the field of endocrinology and metabolism. Dr. William T. Garvey is listed in the reference of citation [4].
