OBJECTIVE. To compare by age and glycemic control continuous subcutaneous insulin infusion with multiple daily injections in youth with type 1 diabetes.
METHODS. The files of 279 patients who had type 1 diabetes and switched from multiple daily injections to continuous subcutaneous insulin infusion between 1998 and 2003 were reviewed for glycemic control, body mass index standard deviation score, and adverse events. Patients were divided by age as follows: 23 prepubertal (median age: 5.4; range: 1.6–8.6 years), 127 adolescent (median age: 13.7; range 9–17 years), and 129 young adult (median age: 22.8; range: 17–40 years). The data were compared between the 12 months of multiple daily injections that preceded continuous subcutaneous insulin infusion and the period after the start of continuous subcutaneous insulin infusion for the whole cohort and by age group.
RESULTS. A significant decrease in hemoglobin A1c was demonstrated after the start of continuous subcutaneous insulin infusion use for the entire cohort (−0.51%) and for the prepubertal (−0.48%), adolescent (−0.26%), and young adult (−0.76%) groups. There was a significant interaction between the change in hemoglobin A1c level and hemoglobin A1c value at initiation of pump therapy (−1.7% for patients with hemoglobin A1c ≥10%; 0.2% for patients with hemoglobin A1c ≤7%). The rate of severe hypoglycemic episodes decreased significantly in the adolescent group, from 36.5 to 11.1 events per 100 patient-years, and in the young adult group, from 58.1 to 23.3. There was no significant change in the rate of diabetic ketoacidosis between the 2 periods. The young adults showed a significant decrease in body mass index standard deviation scores (−0.08 ± 0.37).
CONCLUSIONS. Continuous subcutaneous insulin infusion improves glycemic control in youth with type 1 diabetes, especially in those with a history of poor glycemic control. This improvement is associated with a decrease in the rate of severe hypoglycemia in the absence of weight gain.
Consequent to improvements in pump technology, continuous subcutaneous insulin infusion (CSII) has been gaining popularity among patients with type 1 diabetes.1 In the past 5 years, the number of patients who have started to use pump therapy at our institute has grown steadily.
Theoretically, the portable pump offers the most physiologic way of insulin delivery because it simulates the normal pattern of insulin secretion, namely, continuous 24-hour “basal” delivery superimposed by prandial-related boosts or “boluses.” It also is more flexible and precise than multiple daily injections (MDI). Although intensive CSII originally was assumed to provide better glycemic control than MDI, with a lower risk for severe hypoglycemia and less weight gain,2–4 recent randomized, controlled studies yielded similar results in terms of hemoglobin A1c (HbA1c) and adverse effects.5,6 However, these studies were limited by the short period of CSII therapy. Indeed, in their recent meta-analysis, Weissberg-Benchell et al7 found that the duration of CSII therapy has a major impact on improvement of glycemic control. Specifically, a significant improvement in glycohemoglobin level was noted in the patients who used pump therapy for at least 1 year.
The aim of the present retrospective, paired study was to analyze glycemic control, BMI SD score (SDS), and adverse events in patients who used CSII for at least 12 months after switching from previous therapy with MDI. The study was conducted in a diabetes clinic of a tertiary care center.
Between January 1998 and September 2003, 376 patients with type 1 diabetes (∼27% of our total patient population) started pump therapy at our clinic. We included in the study only patients who were younger than 40 years, had used MDI for at least 12 months during which they were out of remission, and had used CSII thereafter for at least 12 months. In all cases, HbA1c levels were available for at least 12 months before and 12 months after CSII initiation.
The target glycemic goals by age group were as follows: toddlers and preschoolers, 120 to 180 mg% before meals and 140 to 200 mg% 2 hours after meals and at bedtime; aged 6 to 10 years, 90 to 180 mg% before meals and 120 to 180-mg% 2 hours after meals and at bedtime; adolescents and young adults, 90 to 140 mg% before meals, 120 to 180 mg% 2 hours after meals, and 140 to 160 mg% at bedtime. The corresponding target HbA1c levels for the 3 age groups were 7.5 to 8.5%, 7.5 to 8.0%, and 6.5 to 7.5%.
The MDI protocol consisted of intensive insulin therapy (3–4 injections per day) and self-blood-glucose monitoring 2 to 8 times daily. The criteria used in our clinic for switching patients from MDI to CSII therapy were poor glycemic control, recurrent hypoglycemic episodes, and patient preference. Pump therapy was preceded by a training program for the patients and their parents that was conducted by the clinic multidisciplinary team in an outpatient setting according to our in-house protocol. The program consisted of 3 sessions and was similar in style to the one offered at diagnosis. It covered principles and mechanics of pump therapy, insertion-site care, carbohydrate counting, and insulin bolus dosing. Follow-up visits were held more frequently in the first 2 months and then reverted to the regular schedule. The children were asked to perform 7 self-blood-glucose monitorings daily (before meals, after meals, and weekly at 3 am). Insulin dosage was determined by decreasing the average total insulin dosage per day over the preceding 2 weeks by 20%; 50% was given as a basal rate and as premeal boluses. Like for MDI, blood glucose levels >150 mg% were corrected with additional insulin before meals and snacks.
During MDI and after a period of stabilization on pump therapy, patients were seen routinely at 2- to 3-month intervals. At each visit, weight and height were measured, insulin adjustments were made, and capillary HbA1c was measured using an automated immunochemical technique (DCA 2000; Bayer Diagnostics Inc, Tarrytown, NY; reference range: 4.3–6.3%). Insulin dose adjustments were guided by the observed pattern of blood glucose and the target levels. As part of the routine clinic procedure, the team was available 24 hours a day for all patient calls and faxes. The same practitioners cared for the children/adolescents and the young adults.
Hypoglycemia was defined as symptoms that were relieved by the ingestion of glucose or food and/or a capillary blood glucose level of <70 mg%. Severe hypoglycemia was defined as any hypoglycemic event that required assistance from another person or resulted in seizure or coma. All events of hypoglycemia and their severity (mild, severe, or severe with coma) were recorded carefully at each visit or telephone call in the standard follow-up form in the patients' files.
Data on background characteristics, HbA1c, BMI, severe hypoglycemic episodes, and diabetic ketoacidosis (DKA) events before and after initiation of CSII therapy were collected from the patient files and compared between the 1-year period before (MDI) and after initiation of CSII for the whole group and by patient age (prepubertal, adolescent, or young adult).
The data were analyzed using BMDP Statistical Software.8 Categorical variables were compared using Pearson's χ2 test or Fisher's exact test, as appropriate. Analysis of variance (ANOVA) was used for continuous variables with Bonferroni correction for multiple comparisons. We also used paired t tests for certain variables. Longitudinal continuous data were compared across groups using ANOVA with repeated measures. P ≤ .05 was considered statistically significant.
A total of 279 patients met the inclusion criteria and were subdivided by age at commencement of CSII therapy into 3 groups: prepubertal group (23 patients; median age: 5.4; range: 1.6–8.6 years), adolescent group (127 patients; median age: 13.7; range: 9–17 years), and young adult group (129 patients; median age: 22.8; range: 17–40 years). The characteristics of the study population are presented in Table 1. The duration of CSII use ranged from 1 to 6 years (mean: 2.4 ± 1.8 years).
The HbA1c levels over time for the entire cohort and for each age group are presented in Fig 1 and Table 2. There was no significant change in HbA1c levels during the year of MDI therapy, before initiation of CSII. Therefore, the HbA1c levels at the start of CSII therapy were used in the analysis. The mean HbA1c level was significantly lower during CSII therapy than during MDI therapy (−0.51%; P < .001) for the entire cohort and for the prepubertal (−0.48%; P < .05), adolescent (−0.26%; P < .05), and young adult (−0.76%; P < .001) groups. On ANOVA, there was a significant interaction between the change in HbA1c levels and age group (P < .005) and a significant interaction between the decrease in HbA1c levels and duration of CSII therapy for the first 3 years (P < .001 for each additional year; Fig 1). There was no additional significant decrease in HbA1c during the fourth year.
As shown in Fig 2, there was a significant interaction between the change in HbA1c level and the HbA1c level at initiation of pump therapy (−1.7% for HbA1c ≥10% and 0.2% for HbA1c ≤7%; P < .001). No relation was found between the duration of diabetes before onset of CSII and change in HbA1c during CSII therapy.
Adverse events are presented in Table 3. There were no episodes of severe hypoglycemia in the prepubertal group. In the adolescent and young adult groups, the number of severe hypoglycemic episodes (per 100 patient-years) decreased significantly from baseline to 1 year after initiation of CSII therapy (P < .01 and P < .05, respectively).
The rate of DKA increased in the prepubertal group from 0 events per patient-year to 0.22 (P = .057), but there was no significant change in this parameter in the other 2 groups. Most of the DKA events during pump therapy were caused by technically interrupted insulin supply.
BMI SDS tended to decrease during CSII therapy in the entire cohort (−0.05 ± 0.01; P = .06). The change was significant for the young adult group (−0.08 ± 0.37; P = .016). No significant change was noted between boys and girls (ΔBMI SDS: −0.03 ± 0.6 and −0.06 ± 0.8, respectively). The rate of catheter-site infection was 2.7 events per 100 patient-years of follow-up.
Although the use of CSII for the management of type 1 diabetes is steadily increasing, this mode of therapy is more costly in the short run than MDI. Therefore, it is important to identify patients who will benefit most. In the present study, we summarized the data of a large and heterogeneous group of patients who switched from MDI to CSII during routine follow-up in a diabetes clinic. We found that the reduction in HbA1c levels was related to patient age, level of glycemic control at the time of CSII initiation, and duration of CSII therapy. Overall, the improvement in glycemic control (decrease of ∼0.5% in HbA1c) is in line with the meta-analysis of Pickup et al,9 which included 12 randomized, controlled trials that compared CSII with MDI in adults with type 1 diabetes, and the meta-analysis of Weissberg-Benchell et al,7 which included a large number of paired and randomized studies in adults, adolescents, and children. It is noteworthy, however, that in the study of Weissberg-Benchell et al,7 the improvement in glycemic control occurred only in patients who were treated with CSII for at least 1 year. We, too, found an additive improvement in HbA1c for each additional year of CSII therapy, for up to 3 years. This finding might explain why in 2 earlier randomized crossover studies that were conducted in our institute to compare 4 to 6 months of MDI with 4 to 6 months of CSII in children,5,6 we failed to find a significant difference in glycemic control between the 2 modalities. It is possible that a period of adaptation with the pump technology is necessary to gain the maximal benefit. This finding suggests that for the proper evaluation of the contribution of CSII to glycemic control, patients should be followed for >1 year. The 0.5% reduction in HbA1c level over time is clinically significant, as the Diabetes Control and Complications Trial (DCCT) reported a 21% to 49% decreased risk for microvascular complications with every 1% decrease in HbA1c.10
The oldest (young adult) group showed the most favorable response to CSII (−0.76%), followed by the youngest (prepubertal) group (−0.48%). The adolescent group had the smallest improvement (−0.26%). As shown before by the DCCT group11 and others,12 diabetes management is a challenge in adolescents, who tend to be noncompliant with therapy.13,14 Furthermore, their poor eating practices lead to inconsistent meals and boluses that can counterbalance the advantage of the better basal insulin replacement that CSII offers. The better improvement in the younger group compared with the adolescents might be explained by parental supervision15 and in the older group by greater motivation. Other randomized crossover studies also noted that better glycemic control was achieved during CSII therapy compared with MDI when the patients were either adult16 or prepubertal,17 whereas there was no difference in glycemic control in adolescents.5,6
A favorable reduction in HbA1c level was significantly related to the glycemic control of the patient at the time of CSII initiation. Although HbA1c level increased slightly in those with very good initial glycemic control (HbA1c ≤7%), it decreased in those with poor control (HbA1c >8%). In the latter group, there was a reduction of ∼0.5% for each additional 1% of HbA1c at the time of pump initiation. Patients with intermediate values (HbA1c 7%–8%) before therapy showed no change in metabolic control. These findings are in line with the paired study in adults that was conducted by Bode et al.18 Therefore, this information should be given to patients who have good glycemic control and wish to switch to CSII therapy to improve further their diabetic control.
The decrease in HbA1c levels in our study was associated with a significant reduction in the rate of severe hypoglycemic events. By contrast, the DCCT reported a negative correlation between glycemic control and the frequency of severe hypoglycemia.19 Several studies have shown a reduction in the rate of severe hypoglycemia during CSII compared with MDI in both adults18 and children.20,21 This response probably is a consequence of the programmed changes that can be made with CSII in basal insulin delivery to compensate for periods of decreased (eg, early night hours) or increased (dawn phenomenon) insulin need.22 Indeed, using the continuous subcutaneous glucose sensor, our group recently showed that the areas under the curve for nocturnal and 24-hour hypoglycemia were significantly larger during MDI than CSII23 for the same level of HbA1c. These findings have important implications considering that hypoglycemia is the limiting factor in the implementation of intensive therapy in children and adolescents.11 Considering our adequate documentation of hypoglycemic events, the lack of hypoglycemia in our prepubertal patients during MDI therapy probably was attributable to the small size of the group and the short (1-year) pre-CSII interval.
Patients who achieve improved glycemic control with intensive therapy complain of weight gain.11,20 This issue has particular significance in children and adolescents, who tend to have erratic eating behaviors24 and worry about their body image.25 However, in our study, despite the continuous improvement in glycemic control in the 2 younger groups, they showed no change in BMI SDS, and the oldest group even had a significant reduction. This finding might be attributable to the lower insulin requirements during CSII therapy5 and the decreased need for snacks, which confers a distinct advantage to CSII.
Among the possible hazards of CSII is the susceptibility of patients to the rapid development of DKA secondary to pump or infusion-set failure.26 In our series, there was a trend for an increase in the rate of DKA events only in the prepubertal group, similar to the findings of Weinzimer et al.27 The lack of an increase in the older patients18,20 suggests that DKA is an infrequent complication of CSII therapy. In addition, no cases of significant catheter-site infection were documented.
Continuous subcutaneous insulin infusion improves glycemic control in children and adolescents with type 1 diabetes, especially those with a history of moderate to poor glycemic control. This improvement is associated with a decrease in the rate of severe hypoglycemia, in the absence of a significant increase in DKA, major catheter-site infection, or weight gain.
- Accepted December 14, 2005.
- Address correspondence to Naomi Weintrob, MD, The Institute for Endocrinology and Diabetes, National Center of Childhood Diabetes, Schneider Children's Medical Center of Israel, 14 Kaplan St, Petah Tiqwa 49 202, Israel. E-mail:
The authors have indicated they have no financial relationships relevant to this article to disclose.
- ↵Maniatis AK, Klingensmith GJ, Slover RH, Mowry CJ, Chase HP. Continuous subcutaneous insulin infusion therapy for children and adolescents: an option for routine care. Pediatrics.2001;107 :351– 356
- ↵Plotnick LP, Clark LM, Brancati FL, Erlinger T. Safety and effectiveness of insulin pump therapy in children and adolescents with type 1 diabetes. Diabetes Care.2003;26 :1142– 1146
- ↵Weintrob N, Benzaquen H, Galatzer A, et al. Comparison of continuous subcutaneous insulin infusion and multiple daily injection regimens in children with type 1 diabetes: a randomized open crossover trial. Pediatrics.2003;112 :559– 564
- ↵Weissberg-Benchell J, Antisdel-Lomaglio J, Seshadri R. Insulin pump therapy: a meta-analysis. Diabetes Care.2003;26 :1079– 1087
- ↵Dixon WJ, ed. BMDP Statistical Software. Los Angeles, CA:. University of California Press; 1993
- ↵Pickup J, Mattock M, Kerry S. Glycaemic control with continuous subcutaneous insulin infusion compared with intensive insulin injections in patients with type 1 diabetes: meta-analysis of randomised controlled trials. Br Med J.2002;324 :1– 6
- ↵Diabetes Control and Complications Trial Research Group. Effect of intensive diabetes treatment on the development and progression of long-term complications in adolescents with insulin-dependent diabetes mellitus: Diabetes Control and Complications Trial. J Pediatr.1994;125 :177– 188
- ↵Couper JJ, Taylor J, Fotheringham MJ, Sawyer M. Failure to maintain the benefits of home-based intervention in adolescents with poorly controlled type 1 diabetes. Diabetes Care.1999;22 :1933– 1937
- ↵Weissberg-Benchell J, Glasgow AM, Tynan WD, Wirtz P, Turek J, Ward J. Adolescent diabetes management and mismanagement Diabetes Care.1995;18 :77– 83
- ↵Neumark-Sztainer D, Patterson J, Mellin A, et al. Weight control practices and disordered eating behaviors among adolescent females and males with type 1 diabetes: associations with sociodemographics, weight concerns, familial factors, and metabolic outcomes. Diabetes Care.2002;25 :1289– 1296
- ↵Scottish Study Group for the Care of the Young Diabetic. Factors influencing glycemic control in young people with type 1 diabetes in Scotland: a population-based study (DIABAUD2). Diabetes Care.2001;24 :239– 244
- ↵Hanaire-Broutin H, Melki V, Bessieres-Lacombe S, Tauber JP. Comparison of continuous subcutaneous insulin infusion and multiple daily injection regimens using insulin lispro in type 1 diabetic patients on intensified treatment: a randomized study. The Study Group for the Development of Pump Therapy in Diabetes. Diabetes Care.2000;23 :1232– 1235
- ↵Kaufman FR, Halvorson M, Kim C, Pitukcheewanont P. Use of insulin pump therapy at nighttime only for children 7–10 years of age with type 1 diabetes. Diabetes Care.2000;23 :579– 582
- ↵Bode BW, Steed RD, Davidson PC. Reduction in severe hypoglycemia with long-term continuous subcutaneous insulin infusion in type I diabetes. Diabetes Care.1996;19 :324– 327
- ↵Boland EA, Grey M, Oesterle A, Fredrickson L, Tamborlane WV. Continuous subcutaneous insulin infusion. A new way to lower risk of severe hypoglycemia, improve metabolic control, and enhance coping in adolescents with type 1 diabetes. Diabetes Care.1999;22 :1779– 1784
- ↵Kaufman FR, Halvorson M, Fisher L, Pitukcheewanont P. Insulin pump therapy in type 1 pediatric patients. J Pediatr Endocrinol Metab.1999;12 :759– 764
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- ↵Weintrob N, Schechter A, Benzaquen H, et al. Glycemic patterns detected by continuous subcutaneous glucose sensing in children and adolescents with type 1 diabetes mellitus treated by multiple daily injections vs continuous subcutaneous insulin infusion. Arch Pediatr Adolesc Med.2004;158 :677– 684
- ↵Wing RR, Nowalk MP, Marcus MD, Koeske R, Finegold D. Subclinical eating disorders and glycemic control in adolescents with type 1 diabetes. Diabetes Care.1986;9 :162– 167
- ↵Diabetes Control and Complications Trial Research Group. Implementation of treatment protocols in the Diabetes Control and Complications Trial. Diabetes Care.1995;18 :361– 376
- ↵Weinzimer SA, Ahern JAH, Doyle EA, et al. Persistence of benefits of continuous subcutaneous Insulin Infusion in very young children with type 1 diabetes: a follow-up report. Pediatrics.2004;114 :1601– 1605
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