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This 26-wk observational study in children and adolescents with type 1 diabetes (T1D) in Sweden investigated the safety and efficacy of insulin detemir (IDet) in newly diagnosed (ND) patients and those with established diabetes (ED) switching to IDet. A total of 159 patients initiated IDet as part of basal–bolus therapy, 59 in the ND stratum (mean age 9.7 yr) and 97 in the ED stratum (mean age 12.5 yr). The primary outcome measure was the incidence of severe adverse drug reactions; just one major hypoglycemic event occurred in a patient in the ND stratum during the study and one patient was withdrawn due to injection-site reactions. All other events were classified as mild. In the ED stratum, there was a reduction in hypoglycemic events in the 4 wk prior to study end from baseline (mean reduction of 2.46 events, not significant) and a significant reduction in nocturnal hypoglycemia (mean reduction of 2.24 events, p = 0.0078). Glycemic control improved in the ND stratum as expected and, in the ED stratum, there was no significant change in HbA1c from baseline (mean reduction of −0.45%). At study end, mean daily IDet doses were 0.39 U/kg (ND) and 0.54 U/kg (ED). Weight increased by 5.7 and 2.0 kg in the ND and ED strata, respectively, and was within the normal limits for growing children. IDet provided good glycemic control and was well tolerated, with a reduced risk of nocturnal hypoglycemia in a heterogeneous cohort of children and adolescents with T1D.
Basal–bolus insulin therapy is the gold-standard treatment in patients with type 1 diabetes (T1D). Insulin is required to achieve glycemic control and to delay the onset of diabetic complications resulting from prolonged hyperglycemia . Patients with intensive insulin treatment reaching lower glycemic targets had a reduced risk of retinopathy and nephropathy [2, 3], and decreasing HbA1c has also been associated with reduced diabetic complications in nonselected patient populations [4, 5]. However, intensive insulin therapy may be associated with an increase in adverse effects, particularly hypoglycemia and weight gain [2, 6]. Hypoglycemia is more common in children than adults, and often requires third-party assistance [3, 7]. The consequences of hypoglycemia are more pronounced in the pediatric population compared with adults, and may have severe consequences, as reviewed by Bjørgaas . Several studies have suggested that severe hypoglycemia may result in long-term brain abnormalities in children, such as excitotoxic damage, seizures, and cognitive decline [8-11]; as a result, physicians may be reluctant to increase insulin dose to reach optimal HbA1c targets . A patient's fear of hypoglycemia, and especially a parent's fear of hypoglycemia in their child, can also lead to reduced treatment adherence .
Several other factors lead to challenges in achieving glycemic control in children. Firstly, younger children are largely dependent on carers to administer their insulin. Secondly, children and adolescents have changing routines and varied eating patterns, which can make adhering to insulin treatment regimens cumbersome. Thirdly, weight gain can be problematic with insulin therapy, particularly in adolescent females, who are prone to adiposity . Fourthly, psychosocial problems, such as broken homes and difficulties in understanding the complicated treatment regimens, may contribute to a lack of adherence.
In Sweden, the majority of patients with T1D follow a basal–bolus insulin regimen, whereby a long-acting basal insulin is injected once or twice daily and a fast-acting bolus insulin is injected prior to meals, with up to 40% of Swedish pediatric patients using insulin pumps for administration . An ideal basal insulin for children and adolescents would provide a physiological, flexible, and predictable profile, with a low risk of hypoglycemia. Insulin detemir (IDet) is a long-acting basal insulin analog that has been tested in many patients as part of a basal–bolus regimen in randomized, controlled clinical trials and demonstrated a beneficial safety:efficacy ratio, with more predictable glycemic control, and less hypoglycemia and weight gain (in adults) compared with neutral protamine Hagedorn (NPH) insulin [16-19]. Similarly, good glycemic control and a low risk of hypoglycemia have been reported from two randomized, controlled clinical trials carried out in children [20, 21].
Results seen in randomized, controlled trials with IDet have been supported by those from observational studies. Observational studies are a valuable tool for investigating the efficacy and safety of therapeutics in a routine clinical setting. The PREDICTIVE (Predictable Results and Experience in Diabetes through Intensification and Control to Target: An International Variability Evaluation) study evaluated the safety and efficacy of IDet in clinical practice in over 40 000 adults globally (>25 countries) with T1D or type 2 diabetes (T2D) [22-24]. Previously published results from cohorts of the PREDICTIVE study have shown that switching to IDet reduced major and nocturnal hypoglycemia and improved HbA1c in adult patients with T1D [23, 24].
This analysis describes data from the Swedish pediatric and adolescent cohort of the PREDICTIVE study. In the main part, PREDICTIVE explored the effect of switching from NPH insulin or insulin glargine to IDet. In this current cohort, both recently diagnosed insulin-naïve patients and those with established diabetes (ED) who were switching basal insulin were included. The main objective was to evaluate the incidence of serious adverse drug reactions (SADRs), including major hypoglycemic events, following initiation of IDet in children and adolescents with T1D.
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This observational study in a diverse cohort of 159 children and adolescents (age range 0–18 yr) with T1D shows that IDet was well tolerated in both insulin-naïve children and those switching to IDet from another basal insulin. IDet provided good glycemic control, a reduced risk of nocturnal confirmed hypoglycemia, and no inappropriate weight gain. The main outcome measure here was the incidence of SADRs; only one event that was classified as serious occurred during the study, so no statistical analysis could be performed. The low frequency of SADRs in this study might indicate that IDet is well tolerated in young patients, which is supported by findings from another PREDICTIVE youth cohort in which there were no SADRs . It has been shown that fear of severe hypoglycemia is particularly apparent among parents of children with diabetes ; therefore, the low rate of hypoglycemia with IDet in children is particularly relevant.
The EU label for IDet has recently been updated to include an indication for treatment of children aged 2 yrs and above. Owing to the observational nature of this study, 12 of the included patients were under the age of 6 yr at the start of this study (nine and three patients in the ND and ED strata, respectively) and are in line with a previous study  illustrating that IDet is a suitable basal insulin for young children (aged 2 yrs and upwards).
After 26 wk, patients in the ND stratum had improved glycemic control; an improvement of this magnitude can be expected in ND patients with T1D. Small but nonsignificant decreases in HbA1c and FPG were observed in the ED stratum from baseline, suggesting that IDet provided similar glycemic control to other basal insulins. No statistical analysis was conducted between the ND and ED groups, as they are not comparable. The results of this study were in accordance with the Turkish PREDICTIVE youth cohort of 101 patients aged 6–17 yr, in which switching to IDet significantly improved HbA1c (−0.7%, compared to a nonsignificant reduction of −0.45% in the ED stratum in this study) . The lack of significance in this study may be due to the smaller cohort of patients switching from another basal insulin to IDet. The American Diabetes Association recommends HbA1c targets of between 7.5 and 8.5% for children under 6 yr of age, of ≤8% for children aged 6–12 yr, and of <7.5% for adolescents (aged 13–19 yr) , and the ISPAD guidelines recommend a target of <7.5% in children and adolescents . Therefore, the end-of-study HbA1c of 6.8% for the ND stratum (mean age of 9.7 yr) and 7.7% for the ED stratum (with a mean age 12.5 yr) indicates that many children reached these targets (46.3% patients in the ED stratum with HbA1c <7.5% at end of study). Results from the adult PREDICTIVE cohorts demonstrated improved glycemic control following a switch to IDet, but these studies included much larger numbers of patients [23, 24]. Randomized, controlled trials have shown both comparable  and superior  glycemic control with IDet compared with NPH insulin.
Mean basal insulin doses significantly increased from baseline to end of study in the ED stratum. This may, in part, be because physicians cited ‘to improve glycemic control’ as a major reason for initiating IDet therapy. Alternatively, it could be because many patients switched from once-daily insulin glargine to twice-daily IDet, and higher doses of basal insulin are sometimes observed with twice-daily compared with once-daily basal insulin dosing . The increase in insulin dose during the study was coupled with a numerically lower HbA1c at the end of study. A previous controlled trial in children showed that end-of-trial doses of IDet were similar to NPH insulin, as were end-of-trial HbA1c levels [21, 30]. Additionally, higher basal doses may have been required because patients underestimated their bolus doses.
Importantly, switching basal insulin to IDet resulted in a numerical reduction in overall and day-time hypoglycemic events, and significantly fewer nocturnal hypoglycemic events. In the Turkish PREDICTIVE youth study, both overall and nocturnal hypoglycemia were significantly reduced from baseline after 12 wk' treatment with IDet. A reduction in nocturnal hypoglycemia in children treated with IDet compared to NPH has also been shown in controlled trials [20, 21], which are more reliable. The data in this study are also in agreement with the results from the adult PREDICTIVE cohort [23, 24]. Hypoglycemia is often reported as the major limiting factor in achieving good glycemic control in diabetes . The reduction in incidence of hypoglycemia, in particular nocturnal hypoglycemia, seen here, and in other studies with IDet, suggests that more aggressive titration of insulin dose may be possible to achieve better glycemic control and reduce the development of future macro- and microvascular complications. However, it should be noted that, as some of the patients in this study switched to IDet to reduce hypoglycemia, it is possible that any change of treatment may have caused a reduction in hypoglycemia, or that natural fluctuations in the disease course may have resulted in an observed decrease in hypoglycemia.
In addition to hypoglycemia, inappropriate weight gain following treatment with insulin is a major barrier to achieving glycemic control in teenagers and adults with T1D. Results from randomized, controlled trials have shown that IDet results in less weight gain than NPH insulin [16, 19], and this has also been reported in children [20, 21]. In this study, BMI was classified as within 3 SD of the reference population mean , suggesting that IDet did not cause inappropriate weight gain in children and adolescents. The moderate increase in BMI in the ED stratum was expected, as the BMI of a growing child increases by approximately this amount with increasing age  and the BMI-SD score did not increase during this study. The weight increase observed in the ND stratum was also expected, because children typically lose weight prior to diagnosis with T1D.
Observational studies provide an important and necessary supplement to controlled trials, contributing valuable information on the use, safety, and efficacy of therapies in clinical practice. However, observational studies rely on patient recall for the reporting of hypoglycemic events, so it must be acknowledged that this recall may not be completely accurate. Owing to the low patient numbers in this cohort, it is possible that the frequency of some adverse events may have been missed or under-represented. Furthermore, any change of regimen may have positive effects on metabolic control due to an increased interest in self-management by the patients and their carers. Moreover, it is possible that some of the improvements observed are due to a bias in patient selection. As this was an observational study, there was no control group, making it difficult to ascertain whether the outcomes were directly related to the study medication. However, as there are relatively few controlled trials examining the effects of IDet in children and adolescents [20, 21, 30], this observational study provides important data on its efficacy and safety in young patients in clinical practice.