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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以出现在其他 CRISP 条目中 列出的机构是。 中心，不一定是研究者的机构。 根据制造商的说法，1 型糖尿病 (T1DM) 的最佳治疗应侧重于生理性胰岛素替代。甘精胰岛素作为长效胰岛素 (LAI) 类似物，在减少夜间低血糖和改善血糖控制方面优于 NPH。 ，必须与速效胰岛素 (RAI) 分开注射，导致不必要的多次胰岛素注射，这在儿科 T1DM 中尤其成问题。对于患者，我们之前已经证明，与单独注射 RAI 和甘精胰岛素相比，将甘精胰岛素与 RAI 混合并每天注射两次不会对血糖波动产生不利影响。此外，我们还证明了 3 个月的两次注射。与 NPH 和 RAI 的标准疗法相比，每日甘精胰岛素与 RAI 混合可使 HbA1C 改善 30%。在本提案中，我们的目的是研究地特胰岛素在儿科 T1DM 中的疗效，并将其与使用甘精胰岛素的金标准进行比较，因为没有混合胰岛素的数据，因此在本方案中，地特胰岛素将与 RAI 混合。注射器，并与每天两次单独注射进行比较。 1. 在治疗儿童 T1DM 时，每天两次地特胰岛素与 RAI 类似物混合，与每天两次单独注射地特胰岛素和 RAI 相比，在降低血糖方面具有同等效果。 2. 当将两者中的任何一种与 RAI 混合每日两次注射时，使用地特胰岛素或甘精胰岛素时，血糖波动将相似。 具体目标 1. 确定在同一注射器中混合地特胰岛素和 RAI 对葡萄糖浓度的影响，并将其与单独注射的地特胰岛素进行比较。 2. 确定每天两次注射地特胰岛素与每天两次注射甘精胰岛素相比，血糖波动是否有所不同。 1 型糖尿病 (T1DM) 的治疗目标是实现接近正常的血糖控制，从而预防和/或延迟长期并发症的发生 [1]。通过使用胰岛素泵或使用模仿胰岛素基础曲线的长效胰岛素类似物和速效胰岛素（RAI）类似物（例如赖脯胰岛素和门冬胰岛素）来调节与膳食相关的胰岛素。甘精胰岛素和最近开发的地特胰岛素是用于治疗 T1DM 的新型基础胰岛素类似物。 甘精胰岛素是第一个通过重组 DNA 技术生产的长效胰岛素类似物 [2,3]，早期的甘精胰岛素在健康志愿者中的药代动力学 (pK) 研究报告其作用持续时间长达 30 小时 [4]。正常血糖钳夹研究中，服用甘精胰岛素 16 小时后，平均血糖水平上升，持续时间显着缩短，整个研究人群的平均作用持续时间为 20.5 小时[5]. 儿科人群中可用的 pK 数据有限，临床实践表明甘精胰岛素在一些 T1DM 患者中的持续时间要短得多 [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]和对治疗计划的依从性有关，这是因为与标准治疗相比，维持血糖正常所需的注射次数增加。为了克服这一障碍，我们阻碍了虽然当甘精胰岛素与短效类似物混合时可能存在一些 pK 变化，但它可能不会显着影响药效学 (pD) 曲线。为了证明这一点，我们招募了接受治疗的受试者。一次每天服用甘精胰岛素并使用连续血糖监测系统 (CGMS) 获得 3 天的血糖曲线，然后将受试者随机分为每天两次与 RAI 类似物混合的甘精胰岛素或每天两次与 CGMS 分开的甘精胰岛素。在每个治疗计划后获得，并且当甘精胰岛素与 RAI 混合给药或单独给药时，没有检测到血糖浓度的差异 [8]。不进行评估，因为受试者仅接受该方案 10 天。 目前正在进行的试验 2 正在检查甘精胰岛素与 RAI 混合并每日两次给药的长期血糖影响，并将其与每日两次 NPH 的效果进行比较（参见初步数据）。招募 T1DM 受试者，并在 3 个月时随机接受 NPH 和 RAI 混合疗法，每日两次给药方案与甘精胰岛素和 RAI 混合疗法，每日两次给药方案。我们发现，与 NPH 组相比，每日两次与甘精胰岛素混合的受试者的血红蛋白 A1c (HbA1c) 明显更好（NPH 与甘精胰岛素 7.5% 对比 6.3%）（p<0.03）。甘精胰岛素与 RAI 混合（与赛诺菲安万特讨论）可能不具有临床意义。此外，混合胰岛素的能力可能不具有临床意义。更少的注射次数，这提高了所有 T1DM 受试者的依从性，但对 T1DM 儿童产生了巨大的影响。 地特胰岛素 (Insulin detemir) 最近获得 FDA 批准用于治疗 1 型和 2 型糖尿病。作用的增加归因于自缔合的增加（六聚体稳定和六聚体-六聚体相互作用）和由于酰化而导致的白蛋白结合的组合。 B29 位的氨基酸赖氨酸具有 14C 脂肪酸（肉豆蔻酸），地特胰岛素以高亲和力与白蛋白结合，与 NPH 相比，具有持久的代谢作用，起效缓慢且峰值较少。 [9]. 地特胰岛素是一种澄清的中性溶液，其吸收不依赖于 NPH 等重悬，也不依赖于甘精胰岛素等微沉淀的形成和溶解。与 NPH 和甘精胰岛素相比，这些特性导致更均匀的吸收和显着更可预测的降血糖作用 [10]，尽管这些特性表明地特胰岛素可以与门冬胰岛素混合，但目前地特胰岛素以 pK 为依据作为单独的注射剂进行销售。与甘精胰岛素一样，缺乏关于甘精胰岛素与 RAI 的混合物及其对血糖波动的影响的信息，而这在临床上很重要，有助于减少胰岛素的用量。注射/天。 为了研究地特胰岛素与 NPH 和甘精胰岛素相比的受试者间 pK 和 pD 效应，对 54 名处于高胰岛素正常血糖钳条件下的成年人进行了一项随机双盲研究，在基础胰岛素制剂给药后 24 小时内进行了研究。研究显示，葡萄糖输注率 (GIR) 曲线下面积 (AUC)（0-12 小时）为 27%（地特胰岛素）与 59%。 (NPH) vs. 46% (甘精胰岛素) 此外，地特胰岛素的 Cmax 为 18 vs. 24 vs. 34%；胰岛素 (INS) AUC (0-¿) 14 vs. 28 vs. 33%[11]。这些结果表明地特胰岛素的受试者内变异性较低，并可能导致其他基础胰岛素的日常波动降低。研究报告称，与 NPH 的标准治疗相比，地特胰岛素并不具有优越性 [12-14]。 在最近的一项研究中，STEADINESS 研究小组在 408 名 T1DM 受试者样本中报告称，在一项随机对照研究中，当受试者接受地特胰岛素治疗时，与使用地特胰岛素进行的 26 周研究相比，HbA1c 改善了 0.18% [15]。 NPH 证明 HbA1c 具有可比性，但与使用地特胰岛素相比，低血糖风险降低了 22%。 NPH [13] 和夜间血糖浓度变化较小且更“平稳”，尽管这些研究表明地特胰岛素可能比 NPH 稍有优势，但迄今为止还没有研究比较地特胰岛素与甘精胰岛素的疗效。地特胰岛素类似物，现在将其与甘精胰岛素进行比较很重要，因为甘精胰岛素已使用更长时间，尽管地特胰岛素具有中性 pH 值，但尚无关于其混合的研究。与 RAI 确定并发布。 Danne 等人报告了地特胰岛素与 NPH 胰岛素在两个年龄组（6-12 岁和 13-17 岁）的 T1DM 儿童中的 pK 效果，这些受试者还与 10 名 T1DM 成人患者进行了比较。 ，10 名青少年和 9 名成人，在胰岛素之间或年龄组之间没有观察到统计差异，但是数据充满了缺失值并且样本量非常小。与成人注射后 4-6 小时相比，地特胰岛素在儿童（302 分钟）和青少年（301 分钟）中的作用时间分别较短，这是唯一发表的关于在 T1DM 儿科患者中使用地特胰岛素的研究[16]。 ]。 总之，关于地特胰岛素在儿科 T1DM 中使用的数据很少。此外，由于需要注射胰岛素的次数，因此很难实现使用长效类似物的强化胰岛素管理。这些研究旨在改善血糖控制，提高依从性。通过简化治疗方案和减少注射次数来改善胰岛素管理，从而减少疼痛，我们希望研究上市的新型化合物，这些化合物可以使儿童受益，但缺乏针对该人群的安全性和有效性数据。