To our knowledge, this study is the largest and longest randomized clinical trial ever performed in children and adolescents with Type 1 diabetes.
The efficacy results from the trial showed that glycaemic control with insulin detemir plus insulin aspart was non-inferior to treatment with NPH plus insulin aspart, as measured by the primary endpoint HbA1c
after 52 weeks of treatment. The slight increase in HbA1c
seen with insulin detemir and NPH reflects the difficulties in treating children for whom many factors, including social status, diabetes care in school or day care, highly variable lifestyle and (fear of) hypoglycaemia, influence glycaemic control 8
. Additionally, physicians and families are often reluctant to titrate insulin in children as aggressively as in adults, because of the risk of severe hypoglycaemia and its consequences 27
Another finding similar to previously reported results in both children and adults was that of a lower within-subject variation in self-monitored plasma glucose before breakfast with insulin detemir than with NPH 28–30
. The low glucose-lowering variability of an insulin is desirable, as fluctuations in glucose levels have been shown to increase the risk of retinopathy and neuropathy in patients with Type 1 diabetes and may induce higher rates of hypoglycaemia 31
Insulin detemir was associated with a significantly lower risk of 24-h and nocturnal hypoglycaemia. The lower rate of hypoglycaemia with insulin detemir may in part be attributable to its lower within-subject variability compared with NPH. These results support findings from a similar study also examining insulin detemir with insulin aspart with children with Type 1 diabetes 30
. Severe hypoglycaemia is associated with impaired cognitive capabilities in children 8,9
and parents' fear of hypoglycaemia episodes has been shown to impact negatively on adherence to diabetes treatment and thus glycaemic control 32
. Hence, attempting to minimize the occurrence of hypoglycaemia in children is essential, and it is therefore noteworthy that there were fewer severe hypoglycaemic events with insulin detemir than with NPH.
Taken together, the outcomes discussed above suggest a reduction in hypoglycaemia was achieved with insulin detemir vs. NPH without an increase in HbA1c
and, reassuringly, this was seen across all age groups studied 19
Weight gain was also lower for insulin detemir when compared with NPH for all age strata. The decrease in weight sd
score from baseline to end of trial in those children treated with insulin detemir indicated that their weight decreased towards that for the normal reference population. Accurate and detailed growth standards were not available for all 11 participating countries; accordingly, British standards 23
were used. These standards allow very accurate calculation of sd
score as data are available for monthly time intervals and gender. This was not the case for other available population data. Although the derivation of the sd
score for all countries was based on British growth curves, the difference between treatment arms was not influenced by this.
The weight-sparing property of insulin detemir is a phenomenon observed in several other studies in both Type 1 28
and Type 2 diabetes 33
, but the reasons for this remain unclear. The importance of keeping weight gain associated with diabetes therapy low, especially in adolescents, is highlighted by the observation that young people with Type 1 diabetes often use insulin omission as a strategy to manage their weight 34,35
, with a detrimental effect on glycaemic control, and complication risk.
In consequence of the findings of this trial, regulatory approval has been granted by the European Medicines Agency for use of insulin detemir within the European Union, for children aged 2–5 years.
In conclusion, this study confirmed efficacy of insulin detemir by demonstrating non-inferiority of insulin detemir compared with NPH with respect to HbA1c, with an improved safety profile including significantly fewer hypoglycaemic episodes and less undesirable weight gain in children and adolescents aged 2–16 years with Type 1 diabetes. An ideal insulin regimen—particularly for children—should be physiological, flexible and predictable, whilst protecting against hypoglycaemia and inappropriate weight gain. Although here the efficacy and tolerability of insulin detemir was compared with NPH, which is not always used as part of a basal–bolus regimen in the young in clinical practice, the most suitable comparator, insulin glargine, has not yet been approved for use in children under the age of 6 years, and therefore the choice of NPH as a comparator does not detract from the positive outcomes seen with insulin detemir. This study therefore confirms that insulin detemir, coupled with insulin aspart in a basal–bolus insulin regimen, has the key characteristics of an ideal insulin regimen, and that these benefits extend to the very young.