DETEMIR: ROLE IN TYPE 1 DIABETES

DETEMIR：在 1 型糖尿病中的作用

• 批准号: 8166689
• 负责人: RUBINA A HEPTULLA
• 金额: $ 1.56万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-01 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8166689
• 关键词: Adherence; Affect; Blood Glucose; Child; Childhood; Computer Retrieval of Information on Scientific Projects Database; Data; Dose; Drug Kinetics; Euglycemic Clamping; Funding; Genetic Engineering; Glucose; Glucose Clamp; Glycosylated hemoglobin A; Gold; Grant; Hypoglycemia; Injection of therapeutic agent; Institution; Insulin; Insulin-Dependent Diabetes Mellitus; Long-Acting Insulin; Long-Term Effects; Manufacturer Name; Normal Pressure Hydrocephalus; Patients; Pharmacodynamics; Physiological; Plasma; Population; Population Study; Protocols documentation; Randomized; Recruitment Activity; Regimen; Reporting; Research; Research Personnel; Resources; Role; Source; Syringes; System; Time; United States National Institutes of Health; Variant; analog; arm; clinical practice; clinically significant; glargine; glucose monitor; glycemic control; healthy volunteer; improved; insulin detemir; treatment planning

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Optimal treatment of type 1 diabetes mellitus (T1DM) should focus on physiologic insulin replacement. Insulin glargine is used as a long acting insulin (LAI) analog. Glargine is superior to NPH in decreasing nocturnal hypoglycemia and improving glycemic control. Glargine, as per manufacturer, must be given separate from rapid acting insulin (RAI), resulting in undesired multiple insulin injections. This is especially problematic in pediatric T1DM. In pediatric patients, glargine action is less than 24 hrs. We have previously demonstrated that mixing glargine with RAI, and given twice daily compared to separately given injections of RAI and glargine does not adversely affect glucose excursions. Furthermore, we demonstrated that 3 months of twice-daily glargine mixed with RAI results in a 30% improvement in HbA1C as compared to standard therapy of NPH and RAI. Detemir is a new long-acting insulin analog. In this proposal, we aim to study the efficacy of detemir in pediatric T1DM, and compare it to the gold standard of using glargine. Since there is no data regarding mixing insulin, in this protocol, detemir will be mixed with RAI in the same syringe, and be compared with giving them as separate injections twice-daily. 1. Insulin detemir mixed with RAI analog given twice daily will have equivalent effects on lowering blood glucose vs. giving insulin detemir and RAI as separate injections twice daily, in the treatment of pediatric T1DM. 2. Glucose excursions will be similar with the use of either detemir or glargine when either of the two is given mixed with RAI as a twice-daily injection. Insulin glargine was the first long-acting insulin analog to be produced by recombinant DNA technology [2,3]. Early pharmacokinetic (pK) studies with insulin glargine in healthy volunteers reported a duration of action of up to 30 h [4]. However, the duration was significantly shorter with mean plasma glucose levels in euglycemic clamp studies rising 16 h after glargine administration with the mean duration of action for the entire study population being 20.5 h [5]. There are limited pK data available in the pediatric population and clinical practice suggests that glargine lasts for a much shorter period of time in some patients with T1DM [6]. Despite the benefits of intensive insulin management, the use of long-acting analogs is associated with poor compliance [7] and adherence to treatment plans. This is due to the increased number of injections that are required to maintain euglycemia as compared to standard therapy of NPH as a basal injection. To overcome this obstacle we hypothesized that although there may be some pK variation when insulin glargine is mixed with short acting analogs it may not affect pharmacodynamic (pD) profile significantly. To prove this, we recruited subjects who were on once a day insulin glargine and used continuous glucose monitoring system (CGMS) to obtain 3 days glucose profiles. Subjects were then randomized to either receiving insulin glargine twice a day mixed with RAI analogs or insulin glargine given twice a day separate from the RAI analogs. CGMS was obtained after each of these treatment plans and no difference in glucose concentrations were detected when insulin glargine was given mixed or given separately from the RAI [8]. However, the long-term effects of mixing on glycemic control could not be evaluated because subjects were on this regimen for only 10 days. In trial 2, currently in progress, long-term glycemic effects of mixing insulin glargine with RAI and administering it as a twice-daily dose and comparing its effect to twice-a-day NPH is being examined (See preliminary data). New onset T1DM subjects were recruited and at 3 months were randomized to either receiving NPH and RAI mixed and given as a twice a day regimen vs. insulin glargine and RAI mixed and given as a twice a day regimen. At the end of 3 months, we found that subjects on twice daily glargine mixed with had a significantly better hemoglobin A1c (HbA1c) (NPH vs. glargine 7.5% Vs 6.3%) as compared to the NPH arm (p<0.03). These studies suggest that some pK variation when insulin glargine is mixed with RAI (discussions with Sanofi-Aventis) may not be of clinical significance. Furthermore, the ability to mix insulins results in fewer injections, which increases compliance in all T1DM subjects but makes an immense difference in children with T1DM.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 1型糖尿病（T1DM）的最佳治疗应集中于生理胰岛素替代。胰岛素甘蓝用作长作用胰岛素（LAI）类似物。谷氨酸在降低夜间低血糖和改善血糖控制方面优于NPH。根据制造商，必须给予甘醇蛋白与快速作用胰岛素（RAI）分开，导致不需要的多重胰岛素注射。这在小儿T1DM中尤其有问题。在小儿患者中，甘醇甘藻症的作用小于24小时。我们以前已经证明，将甘胶与RAI混合，并且与单独注射RAI和Glargine相比，每天两次都不会对葡萄糖偏移产生不利影响。此外，与NPH和RAI的标准疗法相比，我们证明了每天两次与RAI混合的3个月的HBA1C提高了30％。 detemir是一种新的长效胰岛素类似物。在此提案中，我们旨在研究detemir在小儿T1DM中的疗效，并将其与使用谷氨酸的黄金标准进行比较。由于没有有关混合胰岛素的数据，因此在该协议中，将与RAI混合在同一注射器中，并与每天两次给出单独的注射。 1。胰岛素detemir与RAI类似物混合，每天两次将胰岛素对降低血糖与给予胰岛素detemir和RAI的作用等效，每天两次作为单独的注射，以治疗儿科T1DM。 2。葡萄糖偏移将与使用detemir或glargine相似，而两者中的任何一个将两次注射都与RAI混合在一起。 胰岛素谷氨酸是重组DNA技术产生的第一个长效胰岛素类似物[2,3]。在健康志愿者中，早期的药代动力学（PK）研究报告的持续时间高达30 h [4]。然而，在glargine施用后16小时的电子糖夹研究中，平均血浆葡萄糖水平的持续时间显着短，整个研究人群的平均作用持续时间为20.5 h [5] [5]。小儿人群中可用的PK数据有限，临床实践表明，在某些T1DM患者中，glargine持续时间短得多[6]。 尽管强化胰岛素管理有好处，但长效类似物的使用与依从性差[7]和遵守治疗计划有关。这是由于与NPH作为基础注射的标准治疗相比，要维持葡萄糖的注射量增加。为了克服这一障碍，我们假设，尽管当胰岛素甘ggin与短作用类似物混合时可能会有一些PK变化，但它可能不会显着影响药效学（PD）谱。为了证明这一点，我们招募了每天每天胰岛素glargine的受试者，并使用连续的葡萄糖监测系统（CGM）获得3天的葡萄糖谱。然后将受试者随机分配给每天两次与RAI类似物混合，或每天两次与RAI类似物分开两次。在每个治疗计划中，获得CGM，并且当胰岛素与RAI分开混合或分别给出胰岛素时，葡萄糖浓度没有差异[8]。但是，由于受试者仅在该方案上仅10天，因此无法评估混合对血糖控制的长期影响。 在目前正在进行的试验2中，将胰岛素与RAI混合并以每天两次剂量和将其作用与每天两次NPH进行比较的长期血糖作用正在检查（请参阅初步数据）。招募了新的发病T1DM受试者，并在3个月后随机分配NPH和RAI混合，并以每天两次疗法和胰岛素谷氨酸和RAI混合，并将其混合为每天两次。在3个月结束时，我们发现与NPH ARM相比，与NPH ARM相比，与NPH ARM相比，与NPH的受试者混合了血红蛋白A1C（HBA1C）（NPH对7.5％vs 6.3％）的情况明显更好（NPH与6.3％）（p <0.03）。这些研究表明，当胰岛素谷氨酸与RAI混合时（与Sanofi-Aventis的讨论）时，某些PK变化可能不是临床意义。此外，混合胰岛素的能力导致注射量较少，这增加了所有T1DM受试者的依从性，但在T1DM儿童中产生了巨大差异。