Is Automated Insulin Delivery System Therapy Safe and Effective in Children Under Seven Years Old?

Nihal Gül Uslu; Deniz Özalp Kızılay; Günay Demir; Yasemin Atik Altınok; Şükran Darcan; Samim Özen; Damla Gökşen

doi:10.4274/jcrpe.galenos.2024.2024-11-2

Abstract

Objective

To evaluate the off-label use of the MiniMed™ 780G system in children under seven years old, as clinical outcomes in this age group are less well-established, despite the improvements in glycemic control seen with MiniMed™ 780G therapy.

Methods

Children under seven years old with type 1 diabetes using MiniMed™ 780G pump therapy were compared with children of similar age and gender using MiniMed™ 640G insulin pump therapy and multiple-dose insulin therapy with continuous glucose monitoring systems (CGMs). CGM metrics, total daily insulin (TDI) dose, and hemoglobin A1c (HbA1c) levels were evaluated retrospectively at baseline and at the 3^rd, 6^th, and 12^th months.

Results

At the initiation of MiniMed™ 780G therapy, the mean age was 5.25±1.22 years (range: 2.8-6.8 years), and the mean TDI was 10.12±4.34 U/day (range: 4.5-17.0 U/day). The glucose management indicator and HbA1c remained lower in the MiniMed™ 780G group at the 3^rd, 6^th, and 12^th months compared to baseline (p=0.009 and p<0.001, respectively). In the MiniMed™ 780G group, time above range (TAR) was significantly lower at the 3^rd, 6^th, and 12^th months (p=0.018, p=0.017 and p=0.04, respectively) while time in range (TIR) was higher at the 3^rd, and 12^th months (p=0.026 and p=0.019, respectively) compared to other groups. The coefficient of variation (CV) of the sensor glucose and HbA1c were lower at the 12^th month (p=0.008 and p=0.015, respectively) compared to both other groups. No instances of ketoacidosis or severe hypoglycemic events were observed in any of the children during the follow-up period.

Conclusion

The absence of significantly higher levels of hypoglycemia compared to other groups at any time point, along with a significant decrease in TAR across all time points, a significant increase in TIR at the 3^rd and 12^th months, and a significant decrease in HbA1c and CV suggests that the MiniMed™ 780G system is both safe and effective for children under seven years old.

Keywords:

Automated delivery system, diabetes, diabetes mellitus, endocrinology, predictive low glucose suspension

What is already known on this topic?

The evidence, experience and knowledge about the use of automated insulin delivery systems in patients under seven years of age are currently inadequate.

What this study adds?

The present study demonstrated for the first time that the MinimedTM 780G may be used in patients with type 1 diabetes mellitus under seven years of age by comparing the Minimed^TM 780G with the Minimed^TM 640G and multiple daily dose therapy.

Introduction

The incidence of type 1 diabetes (T1D) continues to rise, with 18% of new diagnoses occurring in children aged nine and younger (1). Treatment of T1D in young children is challenging since they often experience marked day-to-day and within-day variability in glucose levels and high variability in insulin requirements compared with older children with T1D (2). Current glycemic goals issued by the American Diabetes Association and the International Society of Pediatric and Adolescent Diabetes (ISPAD) recommend that young children maintain a hemoglobin A1c (HbA1c) level <7.0% when possible but without risk of severe hypoglycemia (3). However, recent data from the SWEET study found that 69% of children with T1D under six years old have HbA1c higher than 7%, suggesting this age group would benefit from increased attention and interventions to support diabetes management (4). Diabetes management is complicated by rapid physical and neurological development, difficulty verbalizing thoughts and feelings, frequent and unpredictable physical activity, picky eating, and behavioral challenges and fears (5). The fear of nighttime hypoglycemia is common, and only a minority of young children’s hypoglycemia appears to be recognized with self-monitoring blood glucose (BG) measurements (6). Apart from hypoglycemia, a 6-year longitudinal study suggested that gray and white matter volumes and cognitive scores are affected by hyperglycemia in early-onset T1D (7).

Diabetes technology, insulin pumps, and continuous glucose monitoring systems (CGMs) are evolving tools for diabetes management, and the use of such technologies in young children has increased markedly in recent years (8). Recent data from the T1D exchange indicate that CGM use in children under 6 years old has increased by 45% from 2016 to 2022 (9), and insulin pump use nearly doubled, with the highest use rates in the youngest patients (10). Hybrid closed-loop systems, which automatically adjust insulin delivery according to glucose levels aside from mealtime boluses, are relatively novel in young children. There are results from observational and randomized studies for MiniMed™ 780G systems in children over seven years old suggesting that an algorithm that automatically doses basal insulin based on sensor glucose (SG) levels improved time in range (TIR) without increasing or even decreasing the time spent below range (TBR) (11, 12, 13). Use of the MiniMed™ 780G improved glycemic control safely in a 12-week study period in toddlers and preschoolers, while simultaneously diminishing parental diabetes distress (14). In another study involving 11 patients aged between 2 and 6 years, the use of MiniMed™ 780G for 6 months resulted in an increase in TIR without any risk of hypoglycemia (15).

This is the first safety study comparing the off-label use of MiniMed™ 780G in children aged 2-7 years, diagnosed with T1D for at least one year and comparing with in patients using MiniMed™ 640G pump or multiple daily insulin (MDI) therapy plus CGM and comparing outcomes quarterly over a period of one year.

Methods

This retrospective, non-randomised study reviewed children between 2 and 7 years of age diagnosed with T1D for at least one year and who were on MiniMed™ 780G insulin pump, MiniMed™ 640G insulin pump or MDI + CGM therapy at least 12 months. HbA1c, insulin dose and CGM metrics of all the patients were downloaded from patient charts and Medtronic Carelink Personal Software, Libreview, and Dexcom Clarity Diabetes Management Software reports retrospectively. Clinicians and diabetes nurses monitored the safety of the treatment on a weekly basis (via phone call and WhatsApp), and pump settings [target glucose, insulin carbohydrate ratio, active insulin time (AIT)] were adjusted as required in the first month of pump initiation and monthly thereafter.

In our T1D clinic, all patients receive standardized training. T1D patients who start on MiniMed™ 780G or MiniMed™ 640G pump therapy receive complete carbohydrate counting training standardised according to ISPAD guidelines (16, 17). In patients under 7 years of age the MiniMed™ 780G insulin pump is initially used in manual mode for 2 weeks followed by auto mode. The target BG is set to 100 mg/dL, and the active insulin time to 3 hours initially.

In MiniMed™ 640G insulin pump therapy, target BG is set to 100 mg/dL, low glucose suspend to 60 mg/dL, low and high alarm to 60 mg/dL and 180 mg/dL, and active insulin time to 3 hours at the beginning.

MDI+CGM patients receive the standardised education for CGM including the use of arrows, alarm settings and target glucose levels according to the CGMs consensus (18).

Outcomes measured included CGMs metrics according to the international recommendations (19). Safety endpoints included serious adverse events, such as severe hypoglycemia and diabetic ketoacidosis. Clinical and glycemic data are reported using descriptive statistics, expressed as mean (standard deviation) and/or median (interquartile range).

Ethical committee approval was obtained from the Ethics Committee of the Ege University (decision date: 24-5.1T/24, date: 23.05.2024). The study was conducted in accordance with the Helsinki Declaration, which was revised in October 2013. Informed consent was obtained from all parents or caregivers of children recruited in the study.

Statistical Analysis

Statistical Package for the Social Sciences statistics for Windows, version 28.0. was used for statistical analysis (IBM Inc., Armonk, NY, USA). A normality test was performed for the distribution. Shapiro-Wilk test was used in groups that included 30 or fewer children; otherwise, Kolmogorov-Smirnov test was used to determine distribution. One-way ANOVA test was used to compare MiniMed™ 780G, MiniMed™ 640G, and MDI+CGMs therapy groups in normally distributed variables. Kruskal-Wallis test was used to compare three groups’ variables which were not distributed normally. Wilcoxon test was used in variables that were not distributed normally to compare pre-treatment (baseline) variables with the same at 3, 6 and 12 months. These were TAR, TIR, TBR, HbA1c, and other variables in the same group, and a paired t-test was used as a parametric equivalent. A p<0.05 was accepted as statistically significant.

Results

Thirty-three children with T1D, eleven using the MiniMed™ 780G insulin pump, eleven MiniMed™ 640G insulin pump, and eleven using MDI+CGMs, were retrospectively analyzed. Among the 33 participants, 14 (42%) were female, the mean age was 98±1.39 (2-6,8) years at the time of CGMs/pump initiation, and the duration of diabetes was 3.51±1.54 years.

The mean age at the initiation of the MiniMed™ 780G, MiniMed™ 640G insulin pump was 5.25±1.22 (2.8-6.8) years and 4.1±2.13 (2.0-6.5) years, respectively. In the MDI+CGMs group, the mean age was 5.59±1.19 (3.3-6.7) years.

In the MiniMed™ 780G group, SmartGuard™ usage in all children exceeded 85% after the initial two weeks of use in manual mode, as intended (93.73%, 96.45%, and 87.91% at 3, 6 and 12 months, respectively). The glucose management indicator (GMI) and HbA1c remained significantly lower within this group over time (p=0.01 and p<0.001, respectively); of note, marked decreases were observed within three months after auto-mode was switched on (Table 1).

Initially mean TDI dose was 10.6±4.34 (4.5-17.6) U/day in the MiniMed™ 780G group, 13.9±6.0 (3.5-24.2) in the MiniMed™ 640G group, and 14.8±6.72 (4.5-25.0) in the MDI+CGMs group. In the MiniMed™ 780G group, TAR was lower at the 3^rd, 6^th, and 12^th months (p=0.02, p=0.02 and p=0.04, respectively) while TIR was higher at the 3^rd and 12^th months (p=0.03 and p=0.02, respectively). TIR increased by 8.4% (70% to 75.9%), TAR decreased by 10.4% (23.67% to 21.2%), and TBR decreased by 12.1% (3.3% to 2.9%) in twelve months of MiniMed™ 780G use (Figure 1). The coefficient of variation (CV) of the SG and HbA1c were lower at 12 months (p=0.01 and p=0.02, respectively) (Figure 2). Moreover, average BG was lower at the 6^th and 12^th months (p=0.02 and p=0.01, respectively) compared to the other groups (Table 2). The other MiniMed™ 780G, MiniMed™ 640G, and CGM data are also shown in Table 2.

Discussion

T1D is associated with numerous morbidities that may significantly impact the lives of children. Initiating the most effective therapy as early as possible can mitigate complications (20). The MiniMed™ 780G insulin pump appears to be the most effective therapy for achieving this goal (21). However, there is a notable lack of studies investigating the effectiveness and safety of such devices in children under seven years old. Additionally, glucose control in this age group is challenging due to the variability of insulin requirements (2). This paper aimed to show the effectiveness and reliability of the MiniMed™ 780G insulin pump in children aged 2 to 7 years.

Pulkkinen et al. (14) investigated 35 children aged between 2 to 6 years old receiving MiniMed™ 780G treatment. In their study, TIR showed an 8.3% increase with an 8.6% decrease in TAR during the 12 weeks under MiniMed™ 780G treatment. Similar results were reported in their extended follow-up study, though they focused on time in tight range. TIR increased from 58.3% initially to 66.2% in the sixth month, and these values were sustained during an 18-month follow-up. However, TIR remained below 70% throughout the investigation, with the most significant increase observed in the first three months. They concluded that TIR values below 70% might be attributable to the younger age group and lower baseline TIR values compared to other studies (22). Tornese et al. (23) also investigated MiniMed™ 780G in a similar age group, showing an 8.5% increase in TIR along with a significant decrease in TAR. A further study conducted by Abraham et al. (15) found that TIR increased from 64.1% at baseline to 74.7% in the fifth week. In our study, similar to the aforementioned studies, TIR increased by 6.67% in the third month, which remained consistent throughout the 12 months. It demonstrated statistically significantly higher values than the MiniMed™ 640G and MDI+CGMs groups in the third and sixth months, and this difference persisted during the follow-up period.

TAR and TBR serve as additional indicators of treatment success. Similar to studies conducted by Pulkkinen et al. (22) and Tornese et al. (23), TAR showed a significant decrease during follow-up in our study. Additionally, TAR was significantly lower than in the other treatment groups, except initially. However, TBR did not significantly decrease in MiniMed™ 780G compared to MiniMed™ 640G and MDI+CGMs. Furthermore, no instances of severe hypoglycemia or ketoacidosis were observed in any case. This suggests that the MiniMed™ 780G insulin pump is as safe as the MiniMed™ 640G insulin pump and MDI+CGMs, as indicated by TBR and TAR in this vulnerable age group.

Pulkkinen et al. (22) showed that CV didn’t decrease significantly during the follow-up period. In contrast to Pulkkinen et al. (22), Tornese et al. (23) found a significant decrease in CV during their study period. Our study is the first study that compares CV between three different treatment groups. Similar to Pulkkinen et al. (22), CV didn’t change during the follow-up in our research but was significantly lower in the MiniMed™ 780G group compared to the other treatment groups.

Pulkkinen et al. (22) found that HbA1c decreased significantly over 18 months. However, during the follow-up period, they observed a temporary increase in HbA1c between the sixth and twelfth months, which was attributed to the lifting of COVID-19 restrictions, particularly an increase in infections during that period. In our study, HbA1c decreased significantly during the 12-month follow-up in the MiniMed™ 780G group. It was significantly lower in the MiniMed™ 780G group, with the most remarkable change observed in the third month compared to the other treatment modalities. GMI, derived from the term of estimated A1c, had been created to assess more accurately and make more personalized glucose management (24). Tornese et al. (23) investigated the GMI and found that the change in the GMI was insignificant. Seget et al. (25) also published their 2023 study with a significant decrease in the GMI. Unfortunately, numerous studies have indicated that the GMI alone might not be used in this regard. Instead, it is advised to be used with HbA1c value to estimate hypoglycemia risk. An increased gap between HbA1c and GMI is associated with an increased risk of hypoglycemia (25). Moreover, if higher HbA1c values persist despite lower GMI, the risk of diabetes-associated complications will increase (26). Although a larger gap between GMI and HbA1c was observed in the MiniMed™ 780G and MiniMed™ 640G groups initially, it decreased during follow-up in our study. However, in the MDI+CGMs group, this gap persisted over time. HbA1c levels in the MiniMed™ 780G group significantly decreased during follow-up, reaching even lower levels than GMI in the twelfth month. In contrast, in the MiniMed™ 640G group, HbA1c did not differ over time. Considering that lower HbA1c values than GMI and lower HbA1c indicate lower diabetes-associated complications, the MiniMed™ 780G insulin pump is more effective and safe than the MiniMed™ 640G insulin pump and MDI+CGMs in this age group.

The instructions for determining minimum and maximum total daily insulin (TDI) doses are outlined in the MiniMed™ 780G insulin pump manual. The manufacturer has set the minimum TDI at eight daily units (27). In the study by Pulkkinen et al. (22), TDI was a minimum of 8 U/day. In Tornese et al.’s (23) study, the minimum TDI was 6 U initially under manual mode, 6.6 U after auto-mode, and 7.2 U in the 3^rd month. In our study, the minimum TDI was under 8 U (4.5 U), initially in manual mode. It reached 8.2 U in the third month and decreased to 7.7 U in the sixth month.

Study Limitations

Low number of patients; more patients are necessary to make more accurate decisions. Retrospective study design.

Conclusion

In our study, we observed that the MiniMed™ 780G was superior to both the MiniMed™ 640G and MDI+CGMs in terms of metabolic control (achieving HbA1c <7% and TIR >70%) over a one-year follow-up period in children 2-7 years.

Ethics

Ethics Committee Approval: Ethical committee approval was obtained from the Ethics Committee of the Ege University (decision date: 24-5.1T/24, date: 23.05.2024).

Informed Consent: Informed consent was obtained from all parents or caregivers of children recruited in the study.

Authorship Contributions

Surgical and Medical Practices: Nihal Gül Uslu, Deniz Özalp Kızılay, Günay Demir, Yasemin Atik Altınok, Şükran Darcan, Samim Özen, Damla Gökşen, Concept: Deniz Özalp Kızılay, Şükran Darcan, Samim Özen, Damla Gökşen, Design: Nihal Gül Uslu, Şükran Darcan, Samim Özen, Damla Gökşen, Data Collection or Processing: Nihal Gül Uslu, Günay Demir, Yasemin Atik Altınok, Damla Gökşen, Analysis or Interpretation: Nihal Gül Uslu, Damla Gökşen, Literature Search: Nihal Gül Uslu, Damla Gökşen, Writing: Nihal Gül Uslu, Damla Gökşen.

Conflict of Interest: Two authors of this article, Samim Özen, Damla Gökşen, are members of the Editorial Board of the Journal of Clinical Research in Pediatric Endocrinology. However, they were not involved in any stage of the editorial decision of the manuscript. The editors who evaluated this manuscript are from different institutions.

Financial Disclosure: The authors declared that this study received no financial support.

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