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Dulaglutide (LY2189265)

Catalog No.GC31520

Dulaglutide (LY2189265) Chemical Structure

Dulaglutide (LY-2189265) is a novel, long-acting glucagon-like peptide 1 (GLP-1) analog for the treatment of type 2 diabetes mellitus (T2DM).

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Sample solution is provided at 25 µL, 10mM.

Product Documents

Quality Control & SDS

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Protocol

Cell experiment [1]:

Cell lines

HepG2 cells

Preparation Method

HepG2 cells were pretreated with 400 μM PA for 24 hours, followed by treatment with or without 100 nM Dulaglutide (LY2189265) for 24 hours.

Reaction Conditions

100 nM Dulaglutide (LY2189265) for 24 hours.

Applications

Dulaglutide (LY2189265) significantly decreased hepatic lipid accumulation and reduced the expression of genes associated with lipid droplet binding proteins, de novo lipogenesis, and TG synthesis in PA-treated HepG2 cells. Dulaglutide (LY2189265) also increased the expression of proteins associated with lipolysis and fatty acid oxidation and FAM3A in PA-treated cells.

Animal experiment [2]:

Animal models

Young (4 months) and old (24 months) C57BL/6J male mice

Preparation Method

The mice were subcutaneously administered 600 μg/kg/week Dulaglutide (LY2189265) for 4 weeks. Body weight and food intake were assessed daily. The mice were weighed and humanely sacrificed after 4 weeks of treatment.

Dosage form

600 μg/kg/week Dulaglutide (LY2189265) for 4 weeks

Applications

Dulaglutide (LY2189265) administration attenuated muscle wasting and restored muscle strength by reducing inflammation through the OPA-1-TLR-9 signaling pathway in the tibialis anterior (TA) and quadriceps (QD) muscles of aged mice.

References:

[1]. Lee J, Hong SW, et,al. Dulaglutide Ameliorates Palmitic Acid-Induced Hepatic Steatosis by Activating FAM3A Signaling Pathway. Endocrinol Metab (Seoul). 2022 Feb;37(1):74-83. doi: 10.3803/EnM.2021.1293. Epub 2022 Feb 9. PMID: 35144334; PMCID: PMC8901965.

[2]. Khin PP, Hong Y, et,al. Dulaglutide improves muscle function by attenuating inflammation through OPA-1-TLR-9 signaling in aged mice. Aging (Albany NY). 2021 Sep 19;13(18):21962-21974. doi: 10.18632/aging.203546. Epub 2021 Sep 19. PMID: 34537761; PMCID: PMC8507261.

Background

Dulaglutide (LY-2189265) is a novel, long-acting glucagon-like peptide 1 (GLP-1) analog for the treatment of type 2 diabetes mellitus (T2DM) [1].

Dulaglutide (LY2189265) significantly decreased hepatic lipid accumulation and reduced the expression of genes associated with lipid droplet binding proteins, de novo lipogenesis, and TG synthesis in PA-treated HepG2 cells. Dulaglutide (LY2189265) also increased the expression of proteins associated with lipolysis and fatty acid oxidation and FAM3A in PA-treated cells[8].Dulaglutide (LY2189265) significantly promoted microglia to phagocytose and get rid of the Aβ plague. Additionally, Dulaglutide (LY2189265) treatment inhibited the production of pro-inflammatory factors, including tumor necrosis factor (TNF)-α, interleukin -1β, and IL-6, whereas increased the load of anti-inflammatory molecules such as IL-10 affected by Aβ1-42 exposure[9].

Dulaglutide (LY2189265) administration attenuated muscle wasting and restored muscle strength by reducing inflammation through the OPA-1-TLR-9 signaling pathway in the tibialis anterior (TA) and quadriceps (QD) muscles of aged mice[3]. Dulaglutide (LY2189265) may reduce the hyperandrogenemia of PCOS rats by regulating the content of serum SHBG and the expression of 3βHSD, CYP19α1, and StAR related genes and proteins, thereby inhibiting the excessive development of small follicles and the formation of cystic follicles in the ovaries of PCOS rats, thereby improving polycystic ovary in PCOS rats[4]. Dulaglutide (LY2189265) improves learning and memory ability in 9-week-old male wild-type C57/BL6 mice (AD mice)[2].

After subcutaneous injection, Dulaglutide (LY2189265) was slowly absorbed and tmax at steady state ranged from 24 to 72 h (median = 48 h) [5,6]. The absolute bioavailability was 47% and the half-life was estimated at 4.7 days. Steady state was achieved between 2 and 4 weeks of dosing and the accumulation ratio was approximately 1.56[7].

References:
[1]:Jimenez-Solem E, Rasmussen MH, et,al. Dulaglutide, a long-acting GLP-1 analog fused with an Fc antibody fragment for the potential treatment of type 2 diabetes. Curr Opin Mol Ther. 2010 Dec;12(6):790-7. PMID: 21154170.
[2]: Jiang Guo-Jing, ZHOU Mei, et,al. Protective effects of dura glycopeptide on learning and memory loss and synaptic degeneration in AD mice [J]. Medical theory & practice,2021,34(14):2365-2368.
[3]: Khin PP, Hong Y, et,al. Dulaglutide improves muscle function by attenuating inflammation through OPA-1-TLR-9 signaling in aged mice. Aging (Albany NY). 2021 Sep 19;13(18):21962-21974. doi: 10.18632/aging.203546. Epub 2021 Sep 19. PMID: 34537761; PMCID: PMC8507261.
[4]: Wu LM, Wang YX, et,al. Dulaglutide, a long-acting GLP-1 receptor agonist, can improve hyperandrogenemia and ovarian function in DHEA-induced PCOS rats. Peptides. 2021 Nov;145:170624. doi: 10.1016/j.peptides.2021.170624. Epub 2021 Aug 8. PMID: 34375684.
[5]: Barrington P, Chien JY, et,al. A 5-week study of the pharmacokinetics and pharmacodynamics of LY2189265, a novel, long-acting glucagon-like peptide-1 analogue, in patients with type 2 diabetes. Diabetes Obes Metab. 2011 May;13(5):426-33. doi: 10.1111/j.1463-1326.2011.01364.x. Epub 2011 Jan 19. PMID: 21251178.
[6]: Barrington P, Chien JY, et,al. LY2189265, a long-acting glucagon-like peptide-1 analogue, showed a dose-dependent effect on insulin secretion in healthy subjects. Diabetes Obes Metab. 2011 May;13(5):434-8. doi: 10.1111/j.1463-1326.2011.01365.x. Epub 2011 Jan 19. PMID: 21251179.
[7]: Scheen AJ. Dulaglutide (LY-2189265) for the treatment of type 2 diabetes. Expert Rev Clin Pharmacol. 2016;9(3):385-99. doi: 10.1586/17512433.2016.1141046. Epub 2016 Feb 6. PMID: 26761217.
[8]: Lee J, Hong SW, et,al. Dulaglutide Ameliorates Palmitic Acid-Induced Hepatic Steatosis by Activating FAM3A Signaling Pathway. Endocrinol Metab (Seoul). 2022 Feb;37(1):74-83. doi: 10.3803/EnM.2021.1293. Epub 2022 Feb 9. PMID: 35144334; PMCID: PMC8901965.
[9]: Wang Y, Han B. Dulaglutide Alleviates Alzheimer's Disease by Regulating Microglial Polarization and Neurogenic Activity. Comb Chem High Throughput Screen. 2022 Jul 26. doi: 10.2174/1386207325666220726163514. Epub ahead of print. PMID: 35894460.

Chemical Properties

Cas No. 923950-08-7 SDF
Synonyms HGEGTFTSDVSSYLEEQAAKEFIAWLVKGGG
Chemical Name N/A
Canonical SMILES N/A
Formula C149H221N37O49 M.Wt 3314.62
Solubility > 40mg/mL in water Storage Store at -20°C
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
Shipping Condition Evaluation sample solution : ship with blue ice
All other available size: ship with RT , or blue ice upon request

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Research Update

GLP-1 receptor agonists in the treatment of type 2 diabetes - state-of-the-art

Mol Metab2021 Apr;46:101102.PMID: 33068776DOI: 10.1016/j.molmet.2020.101102

Background: GLP-1 receptor agonists (GLP-1 RAs) with exenatide b.i.d. first approved to treat type 2 diabetes in 2005 have been further developed to yield effective compounds/preparations that have overcome the original problem of rapid elimination (short half-life), initially necessitating short intervals between injections (twice daily for exenatide b.i.d.).
Scope of review: To summarize current knowledge about GLP-1 receptor agonist.
Major conclusions: At present, GLP-1 RAs are injected twice daily (exenatide b.i.d.), once daily (lixisenatide and liraglutide), or once weekly (exenatide once weekly, dulaglutide, albiglutide, and semaglutide). A daily oral preparation of semaglutide, which has demonstrated clinical effectiveness close to the once-weekly subcutaneous preparation, was recently approved. All GLP-1 RAs share common mechanisms of action: augmentation of hyperglycemia-induced insulin secretion, suppression of glucagon secretion at hyper- or euglycemia, deceleration of gastric emptying preventing large post-meal glycemic increments, and a reduction in calorie intake and body weight. Short-acting agents (exenatide b.i.d., lixisenatide) have reduced effectiveness on overnight and fasting plasma glucose, but maintain their effect on gastric emptying during long-term treatment. Long-acting GLP-1 RAs (liraglutide, once-weekly exenatide, dulaglutide, albiglutide, and semaglutide) have more profound effects on overnight and fasting plasma glucose and HbA1c, both on a background of oral glucose-lowering agents and in combination with basal insulin. Effects on gastric emptying decrease over time (tachyphylaxis). Given a similar, if not superior, effectiveness for HbA1c reduction with additional weight reduction and no intrinsic risk of hypoglycemic episodes, GLP-1RAs are recommended as the preferred first injectable glucose-lowering therapy for type 2 diabetes, even before insulin treatment. However, GLP-1 RAs can be combined with (basal) insulin in either free- or fixed-dose preparations. More recently developed agents, in particular semaglutide, are characterized by greater efficacy with respect to lowering plasma glucose as well as body weight. Since 2016, several cardiovascular (CV) outcome studies have shown that GLP-1 RAs can effectively prevent CV events such as acute myocardial infarction or stroke and associated mortality. Therefore, guidelines particularly recommend treatment with GLP-1 RAs in patients with pre-existing atherosclerotic vascular disease (for example, previous CV events). The evidence of similar effects in lower-risk subjects is not quite as strong. Since sodium/glucose cotransporter-2 (SGLT-2) inhibitor treatment reduces CV events as well (with the effect mainly driven by a reduction in heart failure complications), the individual risk of ischemic or heart failure complications should guide the choice of treatment. GLP-1 RAs may also help prevent renal complications of type 2 diabetes. Other active research areas in the field of GLP-1 RAs are the definition of subgroups within the type 2 diabetes population who particularly benefit from treatment with GLP-1 RAs. These include pharmacogenomic approaches and the characterization of non-responders. Novel indications for GLP-1 RAs outside type 2 diabetes, such as type 1 diabetes, neurodegenerative diseases, and psoriasis, are being explored. Thus, within 15 years of their initial introduction, GLP-1 RAs have become a well-established class of glucose-lowering agents that has the potential for further development and growing impact for treating type 2 diabetes and potentially other diseases.

Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial

Lancet2019 Jul 13;394(10193):121-130.PMID: 31189511DOI: 10.1016/S0140-6736(19)31149-3

Background: Three different glucagon-like peptide-1 (GLP-1) receptor agonists reduce cardiovascular outcomes in people with type 2 diabetes at high cardiovascular risk with high glycated haemoglobin A1c (HbA1c) concentrations. We assessed the effect of the GLP-1 receptor agonist dulaglutide on major adverse cardiovascular events when added to the existing antihyperglycaemic regimens of individuals with type 2 diabetes with and without previous cardiovascular disease and a wide range of glycaemic control.
Methods: This multicentre, randomised, double-blind, placebo-controlled trial was done at 371 sites in 24 countries. Men and women aged at least 50 years with type 2 diabetes who had either a previous cardiovascular event or cardiovascular risk factors were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (1·5 mg) or placebo. Randomisation was done by a computer-generated random code with stratification by site. All investigators and participants were masked to treatment assignment. Participants were followed up at least every 6 months for incident cardiovascular and other serious clinical outcomes. The primary outcome was the first occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes (including unknown causes), which was assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01394952.
Findings: Between Aug 18, 2011, and Aug 14, 2013, 9901 participants (mean age 66·2 years [SD 6·5], median HbA1c 7·2% [IQR 6·6-8·1], 4589 [46·3%] women) were enrolled and randomly assigned to receive dulaglutide (n=4949) or placebo (n=4952). During a median follow-up of 5·4 years (IQR 5·1-5·9), the primary composite outcome occurred in 594 (12·0%) participants at an incidence rate of 2·4 per 100 person-years in the dulaglutide group and in 663 (13·4%) participants at an incidence rate of 2·7 per 100 person-years in the placebo group (hazard ratio [HR] 0·88, 95% CI 0·79-0·99; p=0·026). All-cause mortality did not differ between groups (536 [10·8%] in the dulaglutide group vs 592 [12·0%] in the placebo group; HR 0·90, 95% CI 0·80-1·01; p=0·067). 2347 (47·4%) participants assigned to dulaglutide reported a gastrointestinal adverse event during follow-up compared with 1687 (34·1%) participants assigned to placebo (p<0·0001).
Interpretation: Dulaglutide could be considered for the management of glycaemic control in middle-aged and older people with type 2 diabetes with either previous cardiovascular disease or cardiovascular risk factors.
Funding: Eli Lilly and Company.

Dulaglutide: A Review in Type 2 Diabetes

Drugs2020 Feb;80(2):197-208.PMID: 32002850DOI: 10.1007/s40265-020-01260-9

Subcutaneous dulaglutide (Trulicity®) is a once-weekly glucagon-like peptide-1 receptor agonist that is approved in numerous countries as an adjunct to diet and exercise for the treatment of adults with type 2 diabetes (T2D). In the clinical trial and real-world settings, once-weekly subcutaneous dulaglutide, as monotherapy or add-on therapy to other antihyperglycaemic agents (including oral antihyperglycaemic drugs and insulin), was an effective and generally well tolerated treatment in adults with inadequately controlled T2D, including in high-risk patients [e.g. obese and elderly patients, those with stage 3 or 4 chronic kidney disease (CKD) and/or cardiovascular (CV) disease]. In the REWIND CV outcomes trial in patients with T2D with or without CV disease, dulaglutide was associated with a significant reduction in the risk of a major adverse cardiac event (MACE; primary composite outcome comprising CV death, nonfatal myocardial infarction or nonfatal stroke) at a median of 5.4 years' follow-up. Given its durable glycaemic efficacy, beneficial effects on bodyweight and MACE outcomes, low inherent risk of hypoglycaemia and convenient once-weekly regimen, dulaglutide remains an important option in the management of T2D.

Efficacy and Safety of Dulaglutide 3.0 mg and 4.5 mg Versus Dulaglutide 1.5 mg in Metformin-Treated Patients With Type 2 Diabetes in a Randomized Controlled Trial (AWARD-11)

Diabetes Care2021 Mar;44(3):765-773.PMID: 33397768DOI: 10.2337/dc20-1473

Objective: To compare efficacy and safety of dulaglutide at doses of 3.0 and 4.5 mg versus 1.5 mg in patients with type 2 diabetes inadequately controlled with metformin.
Research design and methods: Patients were randomly assigned to once-weekly dulaglutide 1.5 mg, 3.0 mg, or 4.5 mg for 52 weeks. The primary objective was determining superiority of dulaglutide 3.0 mg and/or 4.5 mg over 1.5 mg in HbA1c reduction at 36 weeks. Secondary superiority objectives included change in body weight. Two estimands addressed efficacy objectives: treatment regimen (regardless of treatment discontinuation or rescue medication) and efficacy (on treatment without rescue medication) in all randomly assigned patients.
Results: Mean baseline HbA1c and BMI in randomly assigned patients (N = 1,842) was 8.6% (70 mmol/mol) and 34.2 kg/m2, respectively. At 36 weeks, dulaglutide 4.5 mg provided superior HbA1c reductions compared with 1.5 mg (treatment-regimen estimand: -1.77 vs. -1.54% [-19.4 vs. -16.8 mmol/mol], estimated treatment difference [ETD] -0.24% (-2.6 mmol/mol), P < 0.001; efficacy estimand: -1.87 vs. -1.53% [-20.4 vs. -16.7 mmol/mol], ETD -0.34% (-3.7 mmol/mol), P < 0.001). Dulaglutide 3.0 mg was superior to 1.5 mg for reducing HbA1c, using the efficacy estimand (ETD -0.17% [-1.9 mmol/mol]; P = 0.003) but not the treatment-regimen estimand (ETD -0.10% [-1.1 mmol/mol]; P = 0.096). Dulaglutide 4.5 mg was superior to 1.5 mg for weight loss at 36 weeks for both estimands (treatment regimen: -4.6 vs. -3.0 kg, ETD -1.6 kg, P < 0.001; efficacy: -4.7 vs. -3.1 kg, ETD -1.6 kg, P < 0.001). Common adverse events through 36 weeks included nausea (1.5 mg, 13.4%; 3 mg, 15.6%; 4.5 mg, 16.4%) and vomiting (1.5 mg, 5.6%; 3 mg, 8.3%; 4.5 mg, 9.3%).
Conclusions: In patients with type 2 diabetes inadequately controlled by metformin, escalation from dulaglutide 1.5 mg to 3.0 mg or 4.5 mg provided clinically relevant, dose-related reductions in HbA1c and body weight with a similar safety profile.

Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): a randomised, open-label, phase 3b trial

Lancet Diabetes Endocrinol2018 Apr;6(4):275-286.PMID: 29397376DOI: 10.1016/S2213-8587(18)30024-X

Background: Despite common mechanisms of actions, glucagon-like peptide-1 receptor agonists differ in structure, pharmacokinetic profile, and clinical effects. This head-to-head trial compared semaglutide with dulaglutide in patients with inadequately controlled type 2 diabetes.
Methods: This was an open-label, parallel-group, phase 3b trial done at 194 hospitals, clinical institutions or private practices in 16 countries. Eligible patients were aged 18 years or older and had type 2 diabetes with HbA1c 7·0-10·5% (53·0-91·0 mmol/mol) on metformin monotherapy. Patients were randomly assigned (1:1:1:1) by use of an interactive web-response system to once a week treatment with either semaglutide 0·5 mg, dulaglutide 0·75 mg, semaglutide 1·0 mg, or dulaglutide 1·5 mg subcutaneously. The primary endpoint was change from baseline in percentage HbA1c; the confirmatory secondary endpoint was change in bodyweight, both at week 40. The primary analysis population included all randomly assigned patients exposed to at least one dose of trial product obtained while on treatment and before the onset of rescue medication. The safety population included all randomly assigned patients exposed to at least one dose of trial product obtained while on treatment. The trial was powered for HbA1c non-inferiority (margin 0·4%) and bodyweight superiority. This trial is registered with ClinicalTrials.gov, number NCT02648204.
Findings: Between Jan 6, 2016, and June 22, 2016, 1201 patients were randomly assigned to treatment; of these, 301 were exposed to semaglutide 0·5 mg, 299 to dulaglutide 0·75 mg, 300 to semaglutide 1·0 mg, and 299 to dulaglutide 1·5 mg. 72 (6%) patients withdrew from the trial (22 receiving semaglutide 0·5 mg, 13 receiving dulaglutide 0·75 mg, 21 receiving semaglutide 1·0 mg, and 16 receiving dulaglutide 1·5 mg). From overall baseline mean, mean percentage HbA1c was reduced by 1·5 (SE 0·06) percentage points with semaglutide 0·5 mg versus 1·1 (0·05) percentage points with dulaglutide 0·75 mg (estimated treatment difference [ETD] -0·40 percentage points [95% CI -0·55 to -0·25]; p<0·0001) and by 1·8 (0·06) percentage points with semaglutide 1·0 mg versus 1·4 (0·06) percentage points with dulaglutide 1·5 mg (ETD -0·41 percentage points [-0·57 to -0·25]; p<0·0001). From overall baseline mean, mean bodyweight was reduced by 4·6 kg (SE 0·28) with semaglutide 0·5 mg compared with 2·3 kg (0·27) with dulaglutide 0·75 mg (ETD -2·26 kg [-3·02 to -1·51]; p<0·0001) and by 6·5 kg (0·28) with semaglutide 1·0 mg compared with 3·0 kg (0·27) with dulaglutide 1·5 mg (ETD -3·55 kg [-4·32 to -2·78]; p<0·0001). Gastrointestinal disorders were the most frequently reported adverse event, occurring in 129 (43%) of 301 patients receiving semaglutide 0·5 mg, 133 (44%) of 300 patients receiving semaglutide 1·0 mg, 100 (33%) of 299 patients receiving dulaglutide 0·75 mg, and in 143 (48%) of 299 patients receiving dulaglutide 1·5 mg. Gastrointestinal disorders were also the most common reason for discontinuing treatment with semaglutide and dulaglutide. There were six fatalities: one in each semaglutide group and two in each dulaglutide group.
Interpretation: At low and high doses, semaglutide was superior to dulaglutide in improving glycaemic control and reducing bodyweight, enabling a significantly greater number of patients with type 2 diabetes to achieve clinically meaningful glycaemic targets and weight loss, with a similar safety profile.
Funding: Novo Nordisk.

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