DETEMIR: ROLE IN TYPE 1 DIABETES

DETEMIR：在 1 型糖尿病中的作用

• 批准号: 7950637
• 负责人: RUBINA A HEPTULLA
• 金额: $ 0.86万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7950637
• 关键词: Acylation; Adherence; Adolescent; Adult; Affect; Affinity; Albumins; Amino Acids; Area Under Curve; Binding; Blood Glucose; Child; Childhood; Clinical Research; Computer Retrieval of Information on Scientific Projects Database; Data; Diabetes Mellitus; Dose; Double-Blind Method; Drug Kinetics; Euglycemic Clamping; Fatty Acids; Funding; Genetic Engineering; Glucose; Glucose Clamp; Glycosylated hemoglobin A; Goals; Gold; Grant; Human; Hypoglycemia; Infusion procedures; Injection of therapeutic agent; Institution; Insulin; Insulin Infusion Systems; Insulin, Aspart, Human; Insulin, Lispro, Human; Insulin-Dependent Diabetes Mellitus; Isophane Insulin; Long-Acting Insulin; Long-Term Effects; Lysine; Manufacturer Name; Marketing; Metabolic; Myristic Acids; Normal Pressure Hydrocephalus; Pain; Paper; Patients; Pharmacodynamics; Physiological; Plasma; Population; Population Study; Positioning Attribute; Preparation; Property; Protocols documentation; Publishing; Randomized; Randomized Controlled Trials; Recruitment Activity; Reporting; Research; Research Personnel; Resources; Risk; Role; Safety; Sample Size; Sampling; Solutions; Source; Syringes; System; Time; Treatment Protocols; United States National Institutes of Health; Upper arm; Variant; absorption; age group; analog; basal insulin; clinical practice; clinically significant; glargine; glucose monitor; glycemic control; healthy volunteer; improved; insulin detemir; novel; prevent; standard care; 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. SPECIFIC AIMS 1. To determine the effects on glucose concentration of mixing detemir with RAI in the same syringe and comparing them to insulin detemir administered as a separate injection. 2. To determine if glucose excursions differ with twice-daily injections of detemir compared to giving glargine twice a day. The goal of treatment in the management of type 1 diabetes mellitus (T1DM) is achieving near normal glycemic control. This prevents and/or delays the onset of long-term complications [1]. This goal is achieved by delivering insulin in a physiologic manner by using an insulin pump or with the use of a long-acting insulin analog that mimics basal insulin profile and rapid-acting insulin (RAI) analog such as lispro and aspart for meal related glucose excursions. Insulin glargine and more recently detemir are new basal insulin analogs developed to treat T1DM. 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. Insulin detemir recently received FDA approval for use in type 1 and 2 diabetes. Insulin detemir [LysB29(N¿- tetradecanoyl) des(B30) human insulin] is the first of a new class of long-acting soluble insulin analogs. Its prolonged duration of action is attributable to a combination of increased self-association (hexamer stabilization and hexamer- hexamer interaction) and albumin binding due to acylation of the amino acid lysine in position B29 with a 14C fatty acid (myristic acid). Insulin detemir binds to albumin with high affinity and is demonstrated to have a protracted metabolic action with a slow onset of action and less peak as compared to that observed with NPH [9]. Insulin detemir is a clear neutral solution and its absorption is not dependent on resuspension like NPH or on the formation and dissolution of microprecipitates like glargine. These properties result in a more uniform absorption and a significant more predictable glucose-lowering effect than both NPH and glargine [10]. Although, these properties would suggest that detemir could be mixed with insulin aspart, currently detemir is being marketed as separate injections citing pK variations. Like glargine, there is lack of information of the mixture of glargine with RAI and its effect on glucose excursions, which is what would be clinically important and aid in decreasing the number of insulin injections/day. To study the inter-subject pK and pD effect of insulin detemir as compared to NPH and glargine, a randomized double- blinded study was undertaken. In 54 adults under the hyperinsulinemic euglycemic clamp conditions, 24 hr period post-dosing of basal insulin preparations were studied. The glucose infusion rate (GIR) area under the curve (AUC) (0-12 h) 27% (detemir) vs. 59% (NPH) vs. 46% (glargine) was noted. Furthermore, insulin detemir had Cmax 18 vs. 24 vs. 34%; Insulin (INS) AUC (0- ¿) 14 vs. 28 vs. 33%[11]. These results indicate a lower within-subject variability of insulin detemir and may result in a lowering of the day-to-day fluctuations seen with other basal insulins. Most of the studies reported non-superiority of detemir as compared to standard care of NPH [12-14]. In a more recent study, the STEADINESS study group reported in a sample of 408 T1DM subjects that when subjects received detemir in a randomized control study the HbA1c was improved by 0.18% [15]. A 26-week study using insulin detemir as compared to NPH demonstrated that HbA1c's were comparable. However, there was a lower risk of hypoglycemia by 22% with the use of detemir as compared to NPH [13] and nocturnal blood glucose concentrations were less variable and more "smooth". Although these studies suggest that detemir may have slight advantage over NPH, there are no studies to date comparing detemir to insulin glargine. To truly study efficacy of long acting insulin analog detemir, it is now important to compare it to insulin glargine since insulin glargine has been used for a more extended period of time. Although insulin detemir has a neutral pH, no studies on the mixing of detemir with RAI are published. Danne et al reported the pK effects of insulin detemir as compared to insulin NPH in children with T1DM in two age groups: 6-12 years and 13-17 years. These subjects were also compared to adults with T1DM. Data is reported on 10 children, 10 adolescents and 9 adults. No statistical differences were observed between the insulins or between age groups. However, the data was fraught with missing values and a very small sample size. The t ¿ for insulin detemir was shorter in children (302 min) and adolescents (301 min) as compared to adults. Interestingly, no effects on glucose were reported in this paper. Furthermore, NPH and insulin detemir demonstrated temporary decline in concentrations between 2- 4 and 4-6 h after injection, respectively. This is the only published study of the use of insulin detemir in pediatric patients with T1DM [16]. In summary, there is a paucity of data on the use of detemir in pediatric T1DM. Furthermore, intensive insulin management using long acting analogs is difficult to achieve because of the number of insulin injections required. These studies aim to improve glycemic control, increase adherence to intensive insulin management by simplifying regimens and decreasing the number of injections and thus pain. Furthermore we would like to study novel compounds that are brought to market that could benefit children but there is lack of safety and efficacy data for this population.

该副本是使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，这是调查员的机构。 1型糖尿病（T1DM）的最佳治疗应集中在生理胰岛素上。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，我们旨在研究小儿T1DM的detemir效率，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。 具体目标 1。为了确定对同一注射器中混合葡萄糖混合葡萄糖浓度的影响，并将其与单独注射的胰岛素detemir进行比较。 2。确定葡萄糖偏移是否与每天两次注射的葡萄糖相比，与每天两次给出甘针碱相比。 治疗1型糖尿病（T1DM）的治疗的目标是接近正常的血糖控制。这可以防止和/或延迟长期并发症的发作[1]。通过使用胰岛素泵或使用长效胰岛素类似物来模仿基本胰岛素概况和快速作用胰岛素（RAI）类似物（例如Lispro和Aspart）进行相关的葡萄糖散发，通过使用胰岛素泵和使用长效胰岛素类似物来实现这一目标。 Grargine和最近的Detemir是用于治疗T1DM的新基本胰岛素类似物。 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作为基本注射的标准治疗相比，要维持葡萄糖的注射次数增加。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房（PD）的特征。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，混合胰岛素的能力会导致更少的注射，这增加了所有T1DM受试者的依从性，但在T1DM儿童中产生了巨大的差异。 胰岛素Detemir最近获得了FDA批准，用于1型和2型糖尿病。胰岛素detemir [lysb29（n¿-tetradecanoyl）des（b30）人类胰岛素]是一类新的长效可溶性胰岛素类似物中的第一类。它的延长作用持续时间归因于增加的自我关联（己酯稳定和己酰胺 - 己酰胺相互作用）和白蛋白结合的组合，这是由于氨基酸赖氨酸与14c脂肪酸（Myristic Acid）位置的氨基酸赖氨酸酰化所致。胰岛素detemir与高亲和力与白蛋白结合，并且与NPH观察到的相比，作用缓慢，作用较慢，峰值较小，峰值较小[9]。胰岛素detemir是一种清晰的中性溶液，其损失并不取决于像NPH这样的重悬，或像谷氨酸那样的微量重质物的形成和溶解。与NPH和Grargine相比，这些特性导致更均匀的滥用和更明显的降糖作用[10]。尽管这些特性表明可以将detemir与胰岛素阿斯帕特混合，但目前以PK变化为单独的注射剂，目前正在销售Detemir。像甘晶石线一样，缺乏谷氨酸与RAI的混合物及其对葡萄糖偏移的影响的信息，这在临床上很重要，有助于减少胰岛素注射的数量/天。 为了研究胰岛素detemir的受试者间PK和PD效应，与NPH和Grargine相比，进行了一项随机的双盲研究。在高胰岛素血糖夹板条件下的54名成年人中，研究了基本胰岛素制剂后24小时的剂量。注意到曲线下的葡萄糖输注率（GIR）面积（AUC）（0-12 h）27％（detemir）vs. 59％（NPH）vs. 46％（谷氨酸）。此外，胰岛素detemir的CMAX为18 vs. 24 vs. 34％；胰岛素（INS）AUC（0-¿）14 vs. 28 vs. 33％[11]。这些结果表明胰岛素替代的受试者内部变异性较低，可能导致其他基本胰岛素看到的日常波动降低。与NPH的标准护理相比，大多数研究都报告了detemir的过时[12-14]。 在最近的一项研究中，稳定研究小组在408个T1DM受试者的样本中报道了，当受试者在随机对照研究中接受detemir时，HBA1C提高了0.18％[15]。与NPH相比，使用胰岛素替代的26周研究表明，HBA1C是可比的。然而，与NPH相比，使用Detemir的低血糖风险较低[13]，而夜间血糖浓度的变化较小，更“光滑”。尽管这些研究表明，detemir可能比NPH具有略有优势，但迄今为止，尚无研究与胰岛素甘醇蛋白进行比较。为了真正研究长作用胰岛素类似物detemir的效率，现在将其与胰岛素甘醇蛋白进行比较非常重要，因为胰岛素甘醇蛋白已被使用了更长的时间。尽管胰岛素detemir具有中性pH值，但未发表关于detemir与RAI的混合的研究。 Danne等人报道了两个年龄组的T1DM儿童的胰岛素NPH与胰岛素NPH相比：6-12岁零13-17岁。这些受试者也与具有T1DM的成年人进行了比较。报告了10名儿童，10名青少年和9名成人的数据。胰岛素或年龄组之间未观察到统计差异。但是，数据以缺失的值和很小的样本量为其。与成年人相比，儿童（302分钟）和青少年（301分钟）的胰岛素detemir剂量较短。有趣的是，本文未报告对葡萄糖的影响。此外，注射后2-4至4-6 h之间的浓度暂时下降，NPH和胰岛素detemir暂时下降。这是唯一关于在T1DM儿科患者中使用胰岛素detemir的唯一发表的研究[16]。 总而言之，关于在小儿T1DM中使用detemir的数据很少。此外，由于需要大量的胰岛素注射，因此很难实现使用长作用类似物的密集胰岛素管理。这些研究旨在改善血糖控制，通过简化方案并减少注射次数并因此疼痛来增加对密集型胰岛素管理的依从性。此外，我们想研究将可能使儿童受益的新颖化合物，但对于该人群缺乏安全性和效率数据。