Tirzepatide
(Synonyms: 新型双重GIP\GLP-1,LY3298176) 目录号 : GC34840
Tirzepatide是一种双重胰高血糖素样肽-1 (GLP-1)和葡萄糖依赖性胰岛素性多肽(GIP)受体激动剂，是2型糖尿病(T2DM)的前瞻性治疗药物。
Cas No.:2023788-19-2
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
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Cell experiment [1]: |
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Cell lines |
SHSY5Y human neuroblastoma cell line |
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Preparation method |
The cells were exposed to normal (NG) and high glucose (HG) for 7 days. Both NG and HG cells, after reaching 70–80% of confluence, were treated with Tirzepatide at concentration of 0.2 μM. |
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Reaction Conditions |
0.2 μM Tirzepatide;7days |
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Applications |
Tirzepatide increases the growth markers expression in neuronal cells exposed to HG. |
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Animal experiment [2]: |
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Animal models |
C57BL/6 mice |
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Preparation method |
Obese insulin-resistant mice were dosed once daily for 14 days with vehicle or tirzepatide. |
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Dosage form |
3-10 nmol/kg;14days; s.c |
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Applications |
Chronic treatment with tirzepatide enhanced insulin tolerance in obese mice. |
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References: [1]. Fontanella RA, Ghosh P, et, al. Tirzepatide prevents neurodegeneration through multiple molecular pathways. J Transl Med. 2024 Jan 29;22(1):114. doi: 10.1186/s12967-024-04927-z. PMID: 38287296; PMCID: PMC10823712. [2].Samms RJ, Christe ME,et,al. GIPR agonism mediates weight-independent insulin sensitization by tirzepatide in obese mice. J Clin Invest. 2021 Jun 15;131(12):e146353. doi: 10.1172/JCI146353. PMID: 34003802; PMCID: PMC8203452. |
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Tirzepatide, a dual glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, is a prospective therapy for type 2 diabetes mellitus (T2DM) [1-3].
Tizepatide(0.2 μM;7days) can ameliorate high glucose-induced neurodegeneration and overcome neuronal insulin resistance[4].
Tirzepatide (10 nmol/kg;14days; s.c) remarkably reduces LPS-mediated inflammatory responses by inhibiting the cardiac protein levels of TNF-α, IL-6, and IL-1B in mice[5]. Chronic treatment with tirzepatide(3-10 nmol/kg;14days; s.c) enhanced insulin tolerance in obese mice[6]. Tirzepatide had anti-allergic inflammatory effects for the aeroallergen-induced model in obese asthma[7]. Tirzepatide improves beta-cell function and insulin sensitivity in type 2 diabetes[8].
References:
[1]. Willard FS, Douros JD, et,al. Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist. JCI Insight. 2020 Sep 3;5(17):e140532. doi: 10.1172/jci.insight.140532. PMID: 32730231; PMCID: PMC7526454.
[2]. Coskun T, Sloop KW, 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 Dec;18:3-14. doi: 10.1016/j.molmet.2018.09.009. Epub 2018 Oct 3. PMID: 30473097; PMCID: PMC6308032.
[3]. Forzano I, Varzideh F, et,al. Tirzepatide: A Systematic Update. Int J Mol Sci. 2022 Nov 23;23(23):14631. doi: 10.3390/ijms232314631. PMID: 36498958; PMCID: PMC9741068.
[4]. Fontanella RA, Ghosh P, et, al. Tirzepatide prevents neurodegeneration through multiple molecular pathways. J Transl Med. 2024 Jan 29;22(1):114. doi: 10.1186/s12967-024-04927-z. PMID: 38287296; PMCID: PMC10823712.
[5]. Liu Q, Zhu J, et,al. Tirzepatide attenuates lipopolysaccharide-induced left ventricular remodeling and dysfunction by inhibiting the TLR4/NF-kB/NLRP3 pathway. Int Immunopharmacol. 2023 Jul;120:110311. doi: 10.1016/j.intimp.2023.110311. Epub 2023 May 15. PMID: 37196559.
[6]. Samms RJ, Christe ME, et,al. GIPR agonism mediates weight-independent insulin sensitization by tirzepatide in obese mice. J Clin Invest. 2021 Jun 15;131(12):e146353. doi: 10.1172/JCI146353. PMID: 34003802; PMCID: PMC8203452.
[7]. Toki S, Zhang J, et,al. Dual GIPR and GLP-1R agonist tirzepatide inhibits aeroallergen-induced allergic airway inflammation in mouse model of obese asthma. Clin Exp Allergy. 2023 Feb;53(2):216-221. doi: 10.1111/cea.14252. Epub 2022 Nov 15. PMID: 36377605; PMCID: PMC10163938.
[8]. Thomas MK, Nikooienejad A, et,al. Dual GIP and GLP-1 Receptor Agonist Tirzepatide Improves Beta-cell Function and Insulin Sensitivity in Type 2 Diabetes. J Clin Endocrinol Metab. 2021 Jan 23;106(2):388-396. doi: 10.1210/clinem/dgaa863. PMID: 33236115; PMCID: PMC7823251.
Tirzepatide是一种双重胰高血糖素样肽-1 (GLP-1)和葡萄糖依赖性胰岛素性多肽(GIP)受体激动剂，是2型糖尿病(T2DM)的前瞻性治疗药物[1-3]。
Tirzepatide (0.2 μM;7d)可改善高糖诱导的神经变性，克服神经元胰岛素抵抗[4]。
Tirzepatide(10 nmol/kg;14days; s.c)通过抑制小鼠心肌蛋白TNF-α、IL-6和IL-1B水平显著降低LPS介导的炎症反应[5]。Tirzepatide(3-10 nmol/kg;14days; s.c)慢性治疗可增强肥胖小鼠的胰岛素耐量[6]。Tirzepatide对空气变应原诱导的肥胖哮喘模型具有抗变应性炎症作用[7]。Tirzepatide改善2型糖尿病的β细胞功能和胰岛素敏感性[8]。
| Cas No. | 2023788-19-2 | SDF | |
| 别名 | 新型双重GIP\GLP-1,LY3298176 | ||
| 分子式 | C225H348N48O68 | 分子量 | 4813.45 |
| 溶解度 | Soluble in DMSO | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 0.2078 mL | 1.0388 mL | 2.0775 mL |
| 5 mM | 0.0416 mL | 0.2078 mL | 0.4155 mL |
| 10 mM | 0.0208 mL | 0.1039 mL | 0.2078 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes
N Engl J Med 2021 Aug 5;385(6):503-515.PMID:34170647DOI:10.1056/NEJMoa2107519.
Background: Tirzepatide is a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 (GLP-1) receptor agonist that is under development for the treatment of type 2 diabetes. The efficacy and safety of once-weekly Tirzepatide as compared with semaglutide, a selective GLP-1 receptor agonist, are unknown. Methods: In an open-label, 40-week, phase 3 trial, we randomly assigned 1879 patients, in a 1:1:1:1 ratio, to receive Tirzepatide at a dose of 5 mg, 10 mg, or 15 mg or semaglutide at a dose of 1 mg. At baseline, the mean glycated hemoglobin level was 8.28%, the mean age 56.6 years, and the mean weight 93.7 kg. The primary end point was the change in the glycated hemoglobin level from baseline to 40 weeks. Results: The estimated mean change from baseline in the glycated hemoglobin level was -2.01 percentage points, -2.24 percentage points, and -2.30 percentage points with 5 mg, 10 mg, and 15 mg of Tirzepatide, respectively, and -1.86 percentage points with semaglutide; the estimated differences between the 5-mg, 10-mg, and 15-mg Tirzepatide groups and the semaglutide group were -0.15 percentage points (95% confidence interval [CI], -0.28 to -0.03; P = 0.02), -0.39 percentage points (95% CI, -0.51 to -0.26; P<0.001), and -0.45 percentage points (95% CI, -0.57 to -0.32; P<0.001), respectively. Tirzepatide at all doses was noninferior and superior to semaglutide. Reductions in body weight were greater with Tirzepatide than with semaglutide (least-squares mean estimated treatment difference, -1.9 kg, -3.6 kg, and -5.5 kg, respectively; P<0.001 for all comparisons). The most common adverse events were gastrointestinal and were primarily mild to moderate in severity in the Tirzepatide and semaglutide groups (nausea, 17 to 22% and 18%; diarrhea, 13 to 16% and 12%; and vomiting, 6 to 10% and 8%, respectively). Of the patients who received Tirzepatide, hypoglycemia (blood glucose level, <54 mg per deciliter) was reported in 0.6% (5-mg group), 0.2% (10-mg group), and 1.7% (15-mg group); hypoglycemia was reported in 0.4% of those who received semaglutide. Serious adverse events were reported in 5 to 7% of the patients who received Tirzepatide and in 3% of those who received semaglutide. Conclusions: In patients with type 2 diabetes, Tirzepatide was noninferior and superior to semaglutide with respect to the mean change in the glycated hemoglobin level from baseline to 40 weeks. (Funded by Eli Lilly; SURPASS-2 ClinicalTrials.gov number, NCT03987919.).
Tirzepatide Once Weekly for the Treatment of Obesity
N Engl J Med 2022 Jul 21;387(3):205-216.PMID:35658024DOI:10.1056/NEJMoa2206038.
Background: Obesity is a chronic disease that results in substantial global morbidity and mortality. The efficacy and safety of Tirzepatide, a novel glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, in people with obesity are not known. Methods: In this phase 3 double-blind, randomized, controlled trial, we assigned 2539 adults with a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) of 30 or more, or 27 or more and at least one weight-related complication, excluding diabetes, in a 1:1:1:1 ratio to receive once-weekly, subcutaneous Tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 72 weeks, including a 20-week dose-escalation period. Coprimary end points were the percentage change in weight from baseline and a weight reduction of 5% or more. The treatment-regimen estimand assessed effects regardless of treatment discontinuation in the intention-to-treat population. Results: At baseline, the mean body weight was 104.8 kg, the mean BMI was 38.0, and 94.5% of participants had a BMI of 30 or higher. The mean percentage change in weight at week 72 was -15.0% (95% confidence interval [CI], -15.9 to -14.2) with 5-mg weekly doses of Tirzepatide, -19.5% (95% CI, -20.4 to -18.5) with 10-mg doses, and -20.9% (95% CI, -21.8 to -19.9) with 15-mg doses and -3.1% (95% CI, -4.3 to -1.9) with placebo (P<0.001 for all comparisons with placebo). The percentage of participants who had weight reduction of 5% or more was 85% (95% CI, 82 to 89), 89% (95% CI, 86 to 92), and 91% (95% CI, 88 to 94) with 5 mg, 10 mg, and 15 mg of Tirzepatide, respectively, and 35% (95% CI, 30 to 39) with placebo; 50% (95% CI, 46 to 54) and 57% (95% CI, 53 to 61) of participants in the 10-mg and 15-mg groups had a reduction in body weight of 20% or more, as compared with 3% (95% CI, 1 to 5) in the placebo group (P<0.001 for all comparisons with placebo). Improvements in all prespecified cardiometabolic measures were observed with Tirzepatide. The most common adverse events with Tirzepatide were gastrointestinal, and most were mild to moderate in severity, occurring primarily during dose escalation. Adverse events caused treatment discontinuation in 4.3%, 7.1%, 6.2%, and 2.6% of participants receiving 5-mg, 10-mg, and 15-mg Tirzepatide doses and placebo, respectively. Conclusions: In this 72-week trial in participants with obesity, 5 mg, 10 mg, or 15 mg of Tirzepatide once weekly provided substantial and sustained reductions in body weight. (Supported by Eli Lilly; SURMOUNT-1 ClinicalTrials.gov number, NCT04184622.).
Tirzepatide: First Approval
Drugs 2022 Jul;82(11):1213-1220.PMID:35830001DOI:10.1007/s40265-022-01746-8.
Tirzepatide (Mounjaro™) is a single molecule that combines dual agonism of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors. Native GIP and GLP-1 are incretin hormones that stimulate insulin secretion and decrease glucagon secretion. GIP also plays a role in nutrient and energy metabolism, while GLP-1 also delays gastric emptying, supresses appetite and improves satiety. Eli Lilly is developing Tirzepatide for the treatment of type 2 diabetes mellitus (T2DM), obesity, cardiovascular disorders in T2DM, heart failure, non-alcoholic steatohepatitis, obstructive sleep apnoea and for reducing mortality/morbidity in obesity. In May 2022, Tirzepatide received its first approval in the USA to improve glycaemic control in adults with T2DM, as an adjunct to diet and exercise. Tirzepatide is in phase III development for heart failure, obesity and cardiovascular disorders in T2DM, and in phase II development for non-alcoholic steatohepatitis. This article summarizes the milestones in the development of Tirzepatide leading to this first approval for T2DM.
Dual GIP and GLP-1 Receptor Agonist Tirzepatide Improves Beta-cell Function and Insulin Sensitivity in Type 2 Diabetes
J Clin Endocrinol Metab 2021 Jan 23;106(2):388-396.PMID:33236115DOI:10.1210/clinem/dgaa863.
Context: Novel dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist (RA) Tirzepatide demonstrated substantially greater glucose control and weight loss (WL) compared with selective GLP-1RA dulaglutide. Objective: Explore mechanisms of glucose control by Tirzepatide. Design: Post hoc analyses of fasting biomarkers and multiple linear regression analysis. Setting: Forty-seven sites in 4 countries. Patients or other participants: Three hundred and sixteen subjects with type 2 diabetes. Interventions: Tirzepatide (1, 5, 10, 15 mg), dulaglutide (1.5 mg), placebo. Main outcome measures: Analyze biomarkers of beta-cell function and insulin resistance (IR) and evaluate WL contributions to IR improvements at 26 weeks. Results: Homeostatic model assessment (HOMA) 2-B significantly increased with dulaglutide and Tirzepatide 5, 10, and 15 mg compared with placebo (P ≤ .02). Proinsulin/insulin and proinsulin/C-peptide ratios significantly decreased with Tirzepatide 10 and 15 mg compared with placebo and dulaglutide (P ≤ .007). Tirzepatide 10 and 15 mg significantly decreased fasting insulin (P ≤ .033) and Tirzepatide 10 mg significantly decreased HOMA2-IR (P = .004) compared with placebo and dulaglutide. Markers of improved insulin sensitivity (IS) adiponectin, IGFBP-1, and IGFBP-2 significantly increased by 1 or more doses of Tirzepatide (P < .05). To determine whether improvements in IR were directly attributable to WL, multiple linear regression analysis with potential confounding variables age, sex, metformin, triglycerides, and glycated hemoglobin A1c was conducted. WL significantly (P ≤ .028) explained only 13% and 21% of improvement in HOMA2-IR with Tirzepatide 10 and 15 mg, respectively. Conclusions: Tirzepatide improved markers of IS and beta-cell function to a greater extent than dulaglutide. IS effects of Tirzepatide were only partly attributable to WL, suggesting dual receptor agonism confers distinct mechanisms of glycemic control.
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.PMID:33325008DOI:10.1007/s13300-020-00981-0.
Glucagon-like peptide 1 (GLP-1) based therapy is an established treatment option for the management of type 2 diabetes mellitus (T2DM) and is recommended early in the treatment algorithm owing to glycaemic efficacy, weight reduction and favourable cardiovascular outcomes. Glucose-dependent insulinotropic polypeptide (GIP), on the other hand, was thought to have no potential as a glucose-lowering therapy because of observations showing no insulinotropic effect from supraphysiological infusion in people with T2DM. However, emerging evidence has illustrated that co-infusion of GLP-1 and GIP has a synergetic effect, resulting in significantly increased insulin response and glucagonostatic response, compared with separate administration of each hormone. These observations have led to the development of a dual GIP/GLP-1 receptor agonist, known as a 'twincretin'. Tirzepatide is a novel dual GIP/GLP-1 receptor agonist formulated as a synthetic peptide containing 39 amino acids, based on the native GIP sequence. Pre-clinical trials and phase 1 and 2 clinical trials indicate that Tirzepatide has potent glucose lowering and weight loss with adverse effects comparable to those of established GLP-1 receptor agonists. The long-term efficacy, safety and cardiovascular outcomes of Tirzepatide will be investigated in the SURPASS phase 3 clinical trial programme. In this paper, we will review the pre-clinical and phase 1 and 2 trials for Tirzepatide in the management of T2DM and give an overview of the SURPASS clinical trials.