Efficacy and Mechanism Evaluation (May 2024)
The effect of closed-loop glucose control on C-peptide secretion in youth with newly diagnosed type 1 diabetes: the CLOuD RCT
Abstract
Background We assessed whether a sustained period of intensive glucose control with hybrid closed-loop for 12 months following diagnosis of type 1 diabetes in children and adolescents can preserve C-peptide secretion compared to standard insulin therapy. Methods In an open-label, multicentre, randomised, parallel trial, youth aged 10–16.9 years were randomised within 21 days of type 1 diabetes diagnosis to hybrid closed-loop or standard insulin therapy (control). Primary end point was the difference in mixed-meal C-peptide area under the curve 12 months post diagnosis. Key secondary end points included time spent in target glucose range, glycated haemoglobin and time spent below target glucose range at 12 months. Analysis was by intention to treat. The Closed Loop from Onset in Type 1 Diabetes consortium secured external funding for participants to continue on beyond 12 months, but the funding by National Institute for Health and Care Research and the results reported here refer only to the 12 months follow-up. Results We randomised 97 participants (mean ± standard deviation age 12 ± 2 years), 51 to closed-loop and 46 to control therapy. There was no difference in C-peptide area under the curve at 12 months between groups [geometric mean (interquartile range) closed-loop (n = 46): 0.35 pmol/ml (0.16, 0.49) vs. control (n = 37): 0.46 pmol/ml (0.22, 0.69); mean adjusted difference –0.06 (95% confidence interval –0.14 to 0.03); p = 0.19]. The proportion of time in target range 3.9–10.0 mmol/l based on 14-day masked LibrePro (Abbott Diabetes Care, Maidenhead, UK) sensor glucose data at 12 months was 10 percentage points (95% confidence interval 2 to 17) higher in the closed-loop group (64 ± 14%) compared to control group (54 ± 23%). Arithmetic mean glycated haemoglobin A1c was lower in the closed-loop group by 4 mmol/mol (0.4%) [95% confidence interval 0 to 8 mmol/mol (0.0% to 0.7%)] at 12 months. The mean difference in time spent 10.0 mmol/l was 11 percentage points (95% CI 3 to 19 percentage points) lower in the CL group compared to the control group at 12 months. Glucose variability measured by standard deviation (SD) was similar between CL and control groups, while coefficient of variation of glucose was 4 percentage points higher in the CL group at 12 months (95% CI 1 to 8 percentage points). The primary end point was similar in a per-protocol analysis using data from randomised participants in the CL group with at least 60% CL use and those in the control group who did not start insulin pump therapy. Total daily insulin dose was similar between treatment groups, but there was a greater proportion of basal insulin (mean ± SD closed-loop 0.52 ± 0.31 U/kg/day, control 0.37 ± 0.26 U/kg/day) to bolus insulin (mean ± SD closed-loop 0.44 ± 0.22 U/kg/day, control 0.46 ± 0.23 U/kg/day) in the CL group at 12 months. Blood pressure, lipid profile and BMI percentile were similar between treatment groups. In the CL group, median CL use was 66% (IQR 44–80) over the 12-month period. In the control group, 10% of participants (n = 4) were using insulin pump therapy and 57% (n = 21) were using a flash or real-time continuous glucose sensor at 12 months post diagnosis. Three severe hypoglycaemic events occurred in the CL group (two participants), and one in the control group; one DKA occurred in the CL group and none in the control group. The number of other AEs (CL group 34, control group 37) and SAEs (CL group 2, control group 4) was similar between groups. Responses to the Pediatric Quality of Life Inventory (PedsQL), hypoglycaemia fear survey (HFS), problem areas in diabetes (PAID) and Strengths and Difficulties Questionnaires (SDQs) were similar between treatment groups in both children and parents at 12 months. Scores for the INSPIRE (INsulin Dosing Systems: Perceptions, Ideas, Reflections and Expectations) questionnaire were high in children, teenagers and parents, suggesting positive expectancies regarding automated insulin delivery in this population. In-depth interviews of 18 youths and 21 parents with ≥ 12 months’ experience of using CL technology were undertaken. Interviews explored the impact of using CL systems on diabetes management practices and everyday family life. As reported by Lawton et al. Participants reported very few disruptions to their lives when using a closed-loop system. Reports of family conflict were minimal as the closed-loop enabled dietary flexibility and glucose levels to be checked effortlessly. Adolescents described doing ‘normal’ activities without worrying about high or low glucose, and parents reported allowing them to do so unsupervised because the closed-loop would regulate their glucose and keep them safe. Some adolescents expressed concerns about the visibility of components and, to avoid stigma, described curtailing activities such as swimming. Participants described how the closed-loop enabled adolescents to be in control of, or create distance from, their diabetes. Lawton J, Kimbell B, Rankin D, Ashcroft NL, Varghese L, Allen JM, et al.; CLOuD Consortium. Health professionals’ views about who would benefit from using a closed-loop system: a qualitative study. Diabet Med: J Br Diabet Assoc 2020;37(6):1030–7. Interviews of multidisciplinary healthcare professionals (n = 22) providing support to trial participants explored the benefits, issues and challenges arising from introducing and using CL systems to support diabetes self-management. Lawton et al. reported that interviewees described how, compared with other insulin regimens, teaching and supporting individuals to use a closed-loop system could be initially more time-consuming. However, they also noted that after an initial adjustment period, users had less need for initiating contact with the clinical team compared with people using pumps or multiple daily injections. Interviewees highlighted how a lessened need for ad hoc clinical input could result in new challenges; specifically, they had fewer opportunities to reinforce users’ diabetes knowledge and skills and detect potential psychosocial problems. Lawton et al. (2020) We explored health professionals’ views about who would benefit from using a CL system. Interviewees described holding strong assumptions about the types of people who would use the technology effectively prior to the trial. Interviewees described changing their views as a result of observing individuals engaging with the CL system in ways they had not anticipated. This included educated, technologically competent individuals who over-interacted with the system in ways which could compromise glycaemic control. Other individuals, who health professionals assumed would struggle to understand and use the technology, were reported to have benefited from it because they stood back and allowed the system to operate without interference. Interviewees concluded that individual, family and psychological attributes cannot be used as pre-selection criteria and ideally all individuals should be given the chance to try the technology. Conclusions The CLOuD study demonstrates that CL glucose control over a period of 12 months does not slow the decline in C-peptide secretion in children and adolescents with new-onset type 1 diabetes. Mean time in range was 10 percentage points higher and mean HbA1c was 0.4% (4 mmol/mol) lower in the CL group compared with the control group at 12 months, but these end points did not reach the pre-specified significance thresholds and it is possible that a greater improvement in glucose control with attainment of normoglycaemia could prevent the decline in C-peptide secretion. Further work may be needed to definitively rule out a role of glycaemic burden in the decline of C-peptide secretion. Total daily exogenous insulin requirements, a surrogate marker of residual insulin secretion, were similar between groups at all time points after diagnosis. This comparison may be hampered by any between-group differences in glycaemic control. It is likely that factors other than glycaemic control, such as autoimmune response, determine the rate of C-peptide decline following diagnosis of type 1 diabetes. It is possible that other factors act in concert with dysglycaemia on C-peptide secretion. The present study demonstrates that hybrid CL is effective in new-onset type 1 diabetes in youth and can safely accommodate the variability in exogenous insulin requirements which occur with beta-cell recovery post diagnosis. Glycaemic control was sustained over 12 months in the CL group, whereas glycaemic control started to deteriorate in the control group at 6 to 9 months after diagnosis. At 12 months post diagnosis, only 56% of youth in the control group (78% in the CL group) were able to achieve a HbA1c of < 58 mmol/mol (< 7.5%) which is above the current national and international glycaemic targets. This highlights the need for improved therapies to allow youth to achieve recommended glycaemic targets from onset of type 1 diabetes irrespective of the lack of effect on residual C-peptide secretion. Strengths of this study include the multicentre, randomised parallel design and the 1-year study duration. We applied no exclusions at enrolment such as technology propensity or healthcare professional considerations about suitability, minimising selection bias. The study population are representative of the general population of youth newly diagnosed with type 1 diabetes. There were no limitations to diabetes therapies used in the control group, supporting generalisability of the findings. This study had limitations. There was no central measurement of auto-antibodies at diagnosis. There was imbalance in the rate of DKA at diagnosis which is associated with a more rapid decline in C-peptide secretion. The rate was higher in the CL group (33%) than in the control group (24%) but this was adjusted for in the analyses. In conclusion, a sustained period of hybrid CL glucose control following diagnosis of type 1 diabetes in children and adolescents does not appear to prevent the decline in residual C-peptide secretion. Trial registration This trial is registered as Clinicaltrials.gov NCT02871089. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 14/23/09), the Helmsley Trust (2016PG-T1D045 and 2016PG-T1D046), and JDRF (22-2013-266 and 2-RSC-2019-828-M-N), and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 8. See the NIHR Funding and Awards website for further award information. Additional support for the artificial pancreas work was from the NIHR Cambridge Biomedical Research Centre and NIHR Oxford Biomedical Research Centre. Abbott Diabetes Care supplied free glucose monitoring devices, and Dexcom supplied discounted continuous glucose monitoring devices. Medtronic supplied discounted insulin pumps, phone enclosures, continuous glucose monitoring devices, and pump consumables.
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