ESPEYB20 8. Type 1 Diabetes Clinical Trials – New Treatments (2 abstracts)
8.2. Closed-loop therapy and preservation of C-peptide secretion in type 1 diabetes
Boughton CK , Allen JM , Ware J , Wilinska ME , Hartnell S , Thankamony A , Randell T , Ghatak A , Besser REJ , Elleri D , Trevelyan N , Campbell FM , Sibayan J , Calhoun P , Bailey R , Dunseath G , Hovorka R & CLOuD Consortium
N Engl J Med 2022;387(10):882–893.PMID: 36069870
Brief summary: In this multicenter, open-label, parallel-group, randomized trial, 97 adolescents (aged 10–16.9 years) were randomized within 21 days after the diagnosis of type 1 diabetes (T1D) to receive either hybrid closed-loop therapy or standard insulin therapy (control) for 24 months. Although closed-loop therapy was associated with better glycemic outcomes, there were no differences in C-peptide between the two groups.
The Closed Loop from Onset in Type 1 Diabetes (CLOuD) trial addressed the important question whether sustained best-possible glucose control with hybrid closed-loop therapy can preserve residual β-cell function in young people with new-onset T1D. Although the efficacy and safety of several closed-loop insulin delivery systems has been widely proven both in adult and pediatric populations, including very young children [1,2], there are no data on the effect on β-cell function and glycemic outcomes following an early implementation soon after diagnosis.
This trial enrolled adolescents soon after diagnosis and followed up to 24 months to assess residual β-cell function, as measured by stimulated C-peptide during a mixed meal tolerance test. It could not show any benefit of an early implementation of the closed-loop system on C-peptide levels. Indeed, the area under the curve for the meal-stimulated C-peptide level at 12 months was similar in the two groups, as was the decline in C-peptide secretion over the 24-month trial period. Glycemic control was superior in the closed-loop than control group, as indicated by lower HbA1c and a higher proportion of time in the target glucose. It is important to note that the mean HbA1c at 12 months was 52 mmol/mol (6.9%), which is above the UK recommended target (48 mmol/mol, 6.5%), raising the question whether achieving even better glycemic targets is needed to slow the decline in residual β-cell function. This trial was performed in several centres in the UK and Europe. Of interest, similar results were reported by a more recent trial performed in the USA in 113 youth (7–17 years old) newly diagnosed with T1D using a different closed loop system (3). Again, there was no difference in C-peptide between the closed-loop system vs. standard therapy, but closed-loop system led to better glycemic targets.
Overall, these findings indicate the value of early implementation of closed loop systems to achieve good glycemic targets, which are linked to better long-term outcomes. However, the findings do not support the so-called ‘glucotoxicity hypothesis’, which posits that hyperglycemia plays a key role in the loss of residual β-cell function post-T1D diagnosis.
References: 1. Nwokolo M, Hovorka R. The Artificial Pancreas and Type 1 Diabetes. J Clin Endocrinol Metab. 2023;108(7):1614–1623. 2. Wadwa RP, Reed ZW, Buckingham BA, et al. Trial of hybrid closed-loop control in young children with type 1 diabetes. N Engl J Med. 2023;388(11):991–1001. 3. McVean J, Forlenza GP, Beck RW, et al. Effect of tight glycemic control on pancreatic beta cell function in newly diagnosed pediatric type 1 diabetes: A randomized clinical trial. JAMA. 2023; 329(12):980–989.
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ESPE Yearbook of Paediatric Endocrinology
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