Dulaglutide (LY-2189265) for the treatment of type 2 diabetes

Scheen, André

doi:10.1586/17512433.2016.1141046

Cited by 21 publications

(22 citation statements)

References 61 publications

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“…The second strategy exploits the structure of native GLP-1, with a few amino acid alterations that protect the molecule from being degraded by DPP-IV (taspoglutide; Dong et al, 2011). The third strategy is to slow down absorption and to reduce renal elimination by fusion with larger carrier molecules such as albumin (albiglutide; Tomkin, 2009;Trujillo and Nuffer, 2014) or Fc fragments of immunoglobulin G (dulaglutide; Scheen, 2016) or by attachment of a fatty-acid side-chain that allows reversible binding to albumin [liraglutide (Vilsboll, 2009) and semaglutide (Lau et al, 2015)]. Besides this, the incorporation of the molecules in injectable microspheres (exenatide once-weekly) is a viable strategy to extend drug duration.…”

Section: Glp-1 Analogues and T2dmmentioning

confidence: 99%

Incretin-based therapy for type 2 diabetes mellitus is promising for treating neurodegenerative diseases

Hölscher

2016

Reviews in the Neurosciences

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AbstractIncretin hormones include glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Due to their promising action on insulinotropic secretion and improving insulin resistance (IR), incretin-based therapies have become a new class of antidiabetic agents for the treatment of type 2 diabetes mellitus (T2DM). Recently, the links between neurodegenerative diseases and T2DM have been identified in a number of studies, which suggested that shared mechanisms, such as insulin dysregulation or IR, may underlie these conditions. Therefore, the effects of incretins in neurodegenerative diseases have been extensively investigated. Protease-resistant long-lasting GLP-1 mimetics such as lixisenatide, liraglutide, and exenatide not only have demonstrated promising effects for treating neurodegenerative diseases in preclinical studies but also have shown first positive results in Alzheimer’s disease (AD) and Parkinson’s disease (PD) patients in clinical trials. Furthermore, the effects of other related incretin-based therapies such as GIP agonists, dipeptidyl peptidase-IV (DPP-IV) inhibitors, oxyntomodulin (OXM), dual GLP-1/GIP, and triple GLP-1/GIP/glucagon receptor agonists on neurodegenerative diseases have been tested in preclinical studies. Incretin-based therapies are a promising approach for treating neurodegenerative diseases.

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Section: Glp-1 Analogues and T2dmmentioning

confidence: 99%

Incretin-based therapy for type 2 diabetes mellitus is promising for treating neurodegenerative diseases

Hölscher

2016

Reviews in the Neurosciences

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“…E2HSA is a genetic fusion protein consisting of two tandem exendin-4 molecules that are covalently bonded to recombinant human serum albumin via a peptide linker, such as to decrease degradation and glomerular filtration [6]. This modification has been also adopted for use in other analogs, including two approved drugs, albiglutide and dulaglutide [7, 8]. Our previous studies demonstrated that E2HSA retained biological activity of exendin-4 in vitro, displayed prolonged hypoglycemic action and improved β-cell function in both normal ICR and spontaneous diabetic db/db mice [9].…”

Section: Introductionmentioning

confidence: 99%

The albumin-exendin-4 recombinant protein E2HSA improves glycemic control and β-cell function in spontaneous diabetic KKAy mice

Hou

Liu

et al. 2017

BMC Pharmacol Toxicol

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BackgroundE2HSA is a genetic fusion protein that consists of two tandem exendin-4 molecules that are covalently bonded to recombinant human serum albumin via a peptide linker. Previous studies have demonstrated that E2HSA significantly decreased blood glucose levels, improved β-cell function and promoted β-cell proliferation in diabetic db/dB mice. This study aimed to evaluate the benefits of E2HSA on glucose and lipid metabolism in a spontaneous diabetes animal model, KKAy mice.MethodsE2HSA was acutely administered at doses of 1, 3 and 9 mg/kg by subcutaneous injection in diabetic KKAy mice with exendin-4 (2 μg/kg) as a positive reference, and then the non-fasting blood glucose and food intake levels were dynamically monitored. In addition, different doses of E2HSA were injected once daily, as well as with exendin-4 twice daily, for 7 weeks to evaluate the effect on glucose and lipid metabolism, as well as the body weight, food and water intake.ResultsSingle injection of E2HSA decreased non-fasting blood glucose and food intake levels in a dose-dependent manner for 4 days and 2 days, respectively. Repeated injections with E2HSA significantly decreased variations in blood glucose levels with a reduction of HbA1c levels by 1.6% at a 9 mg/kg dose, simultaneously increased fasting blood insulin levels, inhibited fasting blood glucagon levels, improved the impaired oral glucose tolerance and enhanced glucose infusion rate, which is the gold standard for evaluating β-cell function. Moreover, repeated injections with E2HSA also ameliorated the dyslipidemia and reduced body weight, food and water intake in diabetic KKAy mice.ConclusionsE2HSA significantly reduced blood glucose levels over a prolonged duration, enhanced β-cell function, and ameliorated dyslipidemia and obesity in diabetic KKAy mice. Thus, E2HSA may be a new candidate for the treatment of type 2 diabetes.Electronic supplementary materialThe online version of this article (doi:10.1186/s40360-017-0143-8) contains supplementary material, which is available to authorized users.

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“…Glucagon-like peptide-1 (GLP-1) receptor agonists, including exenatide, liraglutide, dulaglutide, and lixisenatide are efficacious for the treatment of type 2 diabetes [ 9 – 13 ]. In addition to having glycemic efficacy, this class of drugs has other advantages such as the promotion of satiety and weight loss [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

Lixisenatide improves glycemic outcomes of Japanese patients with type 2 diabetes: a meta-analysis

Seino¹,

Onishi

Naito

et al. 2016

Diabetol Metab Syndr

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BackgroundThe GetGoal-L-Asia and -S trials were multi-center trials conducted in 4 and 16 countries, respectively including Japan that evaluated the efficacy and safety of lixisenatide add-on treatment vs. placebo among patients with type 2 diabetes. The aims of this study were to determine the efficacy and safety of lixisenatide add-on treatment among Japanese patient groups.MethodsAll Japanese intent-to-treat patients with baseline and endpoint HbA1c measurements were included in the meta-analyses. Subgroup analyses were carried out for patients with low (<8 %) and high (≥8 %) baseline HbA1c levels, low (<25 kg/m2) and high (≥25 kg/m2) baseline body mass index (BMI), short (<10 years) and long (≥10 years) durations of diabetes, and for those <65 and ≥65 years of age.ResultsThe overall study population of Japanese type 2 diabetes patients included 143 patients (mean age: 59.0 years; 35 % female) treated with lixisenatide and 136 patients treated with placebo (mean age: 57.8 years; 32 % female). Among the subgroups, lixisenatide treatment vs. placebo was associated with greater change in HbA1c (Low HbA1c −0.80 %, p < 0.0001; High HbA1c −1.19 %, p < 0.0001; low BMI −0.88 %, p < 0.0001; high BMI −1.28 %, p < 0.0001; short diabetes duration −1.28 %, p < 0.0001; long diabetes duration −0.93 %, p < 0.0001; <65 years: −1.00 %, p < 0.0001; ≥65 years −1.24 %, p < 0.0001). Additionally, among the subgroups, lixisenatide treatment vs. placebo was associated with greater change in post-prandial glucose.ConclusionsFor Japanese type 2 diabetes patients lixisenatide may be an efficacious and safe add-on therapy leading to improved glycemic outcomes.GetGoal-L-Asia NCT01169779GetGoal-S NCT00713830

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Dulaglutide (LY-2189265) for the treatment of type 2 diabetes

Cited by 21 publications

References 61 publications

Incretin-based therapy for type 2 diabetes mellitus is promising for treating neurodegenerative diseases

Incretin-based therapy for type 2 diabetes mellitus is promising for treating neurodegenerative diseases

The albumin-exendin-4 recombinant protein E2HSA improves glycemic control and β-cell function in spontaneous diabetic KKAy mice

Lixisenatide improves glycemic outcomes of Japanese patients with type 2 diabetes: a meta-analysis

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