Department of Information Engineering, University of Padova, Padova, Italy.
Translational Disease Modeling, R&D Digital and Data Sciences, Sanofi-Aventis Deutschland GmbH, Frankfurt am Main, Germany.
Diabetes Technol Ther. 2020 Aug;22(8):553-561. doi: 10.1089/dia.2020.0027. Epub 2020 Mar 25.
Second-generation long-acting insulin glargine 300 U/mL (Gla-300) and degludec 100 U/mL (Deg-100) provide novel basal insulin therapies for the treatment of type 1 diabetes (T1D). Both offer a flatter pharmacokinetic (PK) profile than the previous generation of long-acting insulins, thus improving glycemic control while reducing hypoglycemic events. This work describes an head-to-head comparison of the two basal insulins on 24-h glucose profiles and was used to guide the design of a clinical trial. The Universities of Virginia (UVA)/Padova T1D simulator describes the intra-/interday variability of glucose-insulin dynamics and thus provides a robust bench-test for assessing glucose control for basal insulin therapies. A PK model describing subcutaneous absorption of Deg-100, in addition to the one already available for Gla-300, has been developed based on T1D clinical data and incorporated into the simulator. One hundred T1D subjects received a basal insulin dose (Gla-300 or Deg-100) for 12 weeks (8 weeks uptitration, 4 weeks stable dosing) by morning or evening administration in a basal/bolus regimen. The virtual patients were uptitrated to their individual doses with two different titration rules. The last 2-week simulated continuous glucose monitoring data were used to calculate various outcome metrics for both basal insulin treatments, with primary outcome being the percent time in glucose target (70-140 mg/dL). The simulations show no statistically significant difference for Gla-300 versus Deg-100 in the main endpoints. This work suggests comparable glucose control using either Gla-300 or Deg-100 and was used to guide the design of a clinical trial intended to compare second-generation long-acting insulin analogues.
第二代长效胰岛素甘精胰岛素 300U/mL（Gla-300）和德谷胰岛素 100U/mL（Deg-100）为 1 型糖尿病（T1D）的治疗提供了新型基础胰岛素疗法。这两种胰岛素的药代动力学（PK）特征都比上一代长效胰岛素更为平坦，从而改善血糖控制的同时降低低血糖事件的发生。本研究描述了这两种基础胰岛素在 24 小时血糖谱方面的头对头比较，并用于指导临床试验的设计。弗吉尼亚大学（UVA）/帕多瓦 T1D 模拟器描述了血糖-胰岛素动力学的日内和日间变异性，因此为评估基础胰岛素疗法的血糖控制提供了一个稳健的基准测试。基于 T1D 临床数据开发了一种描述 Deg-100 皮下吸收的 PK 模型，此外，还为 Gla-300 开发了一个现有的模型，并将其纳入模拟器中。100 例 T1D 患者在基础/餐时胰岛素方案中，通过早上或晚上给药，接受为期 12 周（8 周滴定，4 周稳定剂量）的基础胰岛素剂量（Gla-300 或 Deg-100）治疗。虚拟患者根据两种不同的滴定规则滴定至各自的剂量。最后 2 周模拟的连续血糖监测数据用于计算两种基础胰岛素治疗的各种结果指标，主要终点是血糖目标（70-140mg/dL）时间的百分比。模拟结果显示，Gla-300 与 Deg-100 之间在主要终点上没有统计学上的显著差异。这项工作表明，使用 Gla-300 或 Deg-100 均可实现相当的血糖控制，这为旨在比较第二代长效胰岛素类似物的临床试验设计提供了参考。
