Mellitus Disease Burden and Clinical Landscape
Despite years of research, the aetiology of Type 1 Diabetes Mellitus (T1DM) remains elusive. In South East Asia, the burden of T1DM is set to increase, with China and India estimated to contribute 38 million and 51 million to the global burden of diabetes by the year 20251.
T1DM is the most common type of diabetes in children and youth (from 0 to 19 years old)2 and makes up a large portion of cases diagnosed later in adulthood. Management of T1DM in children, especially younger children (below the age of 6)3, requires much consideration compared to adults, youths or older children. This is due to children’s unpredictable physical movements and physical growth4, accompanied by a diminished ability to recognize and deploy treatment for hypoglycaemia3. Consequently, many younger children fail to maintain glycaemic targets.
Current Treatment Guidelines
Children with T1DM depend on insulin for survival and use multiple daily injections each day. Treatment plans aim to achieve as close to physiological insulin replacement as possible and optimal glycaemic control5, making self-monitoring of blood glucose crucial. Frequent monitoring of blood glucose helps determine insulin requirements throughout the day, decreasing fluctuations in blood glucose levels and potential complications.
The current standard employs on-demand blood glucose monitoring or continuous glucose monitoring (CGM), subsequently adjusting insulin doses throughout the day. Comparatively, the hybrid closed-loop system (also known as the artificial pancreas or automated insulin) combines a predictive algorithm with user control. These systems mainly rely on three algorithms, namely model predictive control (MPC), proportional-integral-derivative (PID), and fuzzy logic. These three algorithms work hand in hand to predict and decide the amount of insulin administered, mimicking the thought processes of diabetes clinicians6. However, the user still interacts with the pump and CGM to input the timing and carbohydrate content of meals, to account for the corrective bolus doses. Currently, only two hybrid closed-loop systems are approved in the US, for use in children with T1DM aged 6 or less4. Though real-world data on uptake is not available, it is reported that more hybrid systems are soon to emerge in the market in addition to those approved. In Europe, the DBLG1 (Diabeloop, Grenoble, France) has already received the CE mark for use in adults with T1DM, while the Omnipod Horizon (Insulet, Billerica, Massachusetts, USA) and insulin-only iLet (Beta Bionics, Boston, Massachusetts, USA) are currently undergoing clinical trials6. In Asia, hybrid closed-loop systems are not extensively used or studied.
Efficacy and safety
The New England Journal of Medicine (NEJM) recently studied the effects of using a hybrid closed-loop system on children with T1DM3.
The study was a multi-centre, unblinded, parallel-group and randomized study that recruited 102 children between 2 to 6 years old. They were randomized in a 2:1 ratio to the hybrid closed-loop control system of insulin or to standard care that included either an insulin pump or multiple daily injections plus a continuous glucose monitor. 68 children were randomized to the closed-loop group, and 34 children to the standard care group.
At the end of the 13-week trial, the closed-loop group demonstrated an increase in the mean (±SD) percentage of time that the glucose level was within the target range, from 56.7±18.0% at baseline to 69.3±11.1%. The standard care group saw an increase from 54.9±14.7% to 55.9±12.6%. Thus, the study concluded that the closed-loop group spent approximately 3 hours more each day within a range of their glycaemic target, as compared to the standard care group.
The most significant difference between the groups was during night time (10 p.m. and 5:59 a.m.), where the closed-loop group spent 18% more time being in the range of their glycaemic target.
The closed-loop system also performed better on the percentage of time that the glucose level was above 250 mg per decilitre (dL) and glycated haemoglobin levels. No significant between-group difference was found in the percentage of time that the glucose level was below 70 mg/dL.
In other literature, Ware et al.7 studied 74 children from 2.3 to 7.9 years and found that the percentage of time that glucose level was the target range was 8.7 percentage points higher for the closed-loop system as compared to the group that used a sensor-augmented pump (without automation). Another study by Forlenza et al.8 on children at least 2 but younger than 7 years of age also reported an 8.1 percentage point increase, and Sherr et al.9 studied children aged 2.0 to 5.9 years reporting an 11 percentage point increase in the time that the glucose level was in range for children in the closed-loop system.
In the NEJM study, two cases of severe hypoglycaemia were observed in the closed-loop group and one case in the standard care group. One case of diabetic ketoacidosis occurred in the closed-loop group.
Table 1 Trial of Hybrid Closed-Loop Control in Young Children with Type 1 Diabetes Study
| Study Design/
Population |
Intervention/
Comparator |
Efficacy | Safety |
| N = 102
Conducted in paediatric diabetes centres at three universities in the United States over 13 weeks. At baseline, children received a diagnosis of T1DM at least 6 months before enrolment received treatment with insulin for at least 6 months, had a body weight of at least 9.1 kg, and received a total daily insulin dose of at At least 5 units. |
Randomized in a 2:1 ratio to hybrid closed-loop control or standard care. | The primary endpoint (% of the time that the glucose level was in the target range of 70 to 180
mg/dL over 13 week): mean (±SD) percentage of time increased from 56.7±18.0% to 69.3±11.1% for the closed-loop group, better than standard care group (54.9±14.7% to 55.9±12.6%) |
Hypoglycaemia: 2 cases for
closed-loop group, 1 case for standard care group Diabetic ketoacidosis: 1 case in closed loop group |
Evidence on the use of a hybrid closed-loop system in T1DM is growing, especially with the demonstrated benefits. However, its place in therapy in Asia remains to be seen. Factors such as regulatory approval, cost-efficacy, and efficacy for different age groups must be demonstrated. We look forward not only to more evidence but also to the emergence of technology to make T1DM treatment more tailored and efficacious.
References
- Low, L.C.K. (2003). Diabetes in South East Asia. In: Menon, R.K., Sperling, M.A. (eds) Pediatric Diabetes. Springer, Boston, MA.
- Mayer-Davis EJ, Lawrence JM, Dabelea D, Divers J, Isom S, Dolan L, Imperatore G, Linder B, Marcovina S, Pettitt DJ, Pihoker C, Saydah S, Wagenknecht L; SEARCH for Diabetes in Youth Study. Incidence Trends of Type 1 and Type 2 Diabetes among Youths, 2002-2012. N Engl J Med. 2017 Apr 13;376(15):1419-1429. doi: 10.1056/NEJMoa1610187. PMID: 28402773; PMCID: PMC5592722.
- Wadwa RP, Reed ZW, Buckingham BA, DeBoer MD, Ekhlaspour L, Forlenza GP, Schoelwer M, Lum J, Kollman C, Beck RW, Breton MD; PEDAP Trial Study Group. Trial of Hybrid Closed-Loop Control in Young Children with Type 1 Diabetes. N Engl J Med. 2023 Mar 16;388(11):991-1001. doi:10.1056/NEJMoa2210834. PMID: 36920756; PMCID: PMC10082994.
- American Diabetes Association; 13. Children and Adolescents: Standards of Medical Care in Diabetes—2021. Diabetes Care 1 January 2021; 44 (Supplement_1): S180–S199. https://doi.org/10.2337/dc21-S013
- Goh, Su-yen & Ang, S B & Bee, Yong Mong & Chen, YT & Gardner, Daphne & Ho, E & Adaikan, Kala & Lee, Y & Lee, C & Lim, Fong & Lim, Hwee & Lim, Su & Seow, Julie & Soh, Abel & Sum, Chee & Tai, E-Shyong & Thai, Ah & Wong, T-Y & Yap, Fabian. (2014). Ministry of Health Clinical Practice Guidelines: Diabetes Mellitus. Singapore medical journal. 55. 334-47. 10.11622/smedj.2014079.
- Templer S. Closed-Loop Insulin Delivery Systems: Past, Present, and Future Directions. Front Endocrinol (Lausanne). 2022 Jun 6;13:919942. doi: 10.3389/fendo.2022.919942. PMID: 35733769; PMCID: PMC9207329.
- Ware J, Allen JM, Boughton CK, et al. Randomized trial of closed-loop control in very young children with type 1 diabetes. N Engl J Med 2022;386:209-219.
- Forlenza GP, Ekhlaspour L, DiMeglio LA, et al. Glycemic outcomes of children 2–6years of age with type 1 diabetes during the pediatric MiniMed 670G system trial. Pediatr Diabetes 2022;23:324-329.
- Sherr JL, Bode BW, Forlenza GP, et al. Safety and glycemic outcomes with a tubeless automated insulin delivery system in very young children with type 1 diabetes: a single-arm multicenter clinical trial. Diabetes Care 2022;45:1907- 1910.
