Flexible Insulin Therapy With Glargine Insulin Improved Glycemic Control and Reduced Severe Hypoglycemia Among Preschool-Aged Children With Type 1 Diabetes Mellitus
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2006年12月30日 00:08:29 Saturday
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作者：Ramin Alemzadeh, MD, Tseghai Berhe, MD and David T. Wyatt, MD
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【关键词】 glargine
the Department of Pediatrics, Medical College of Wisconsin, Children's Research Institute, Milwaukee, Wisconsin
ABSTRACT
Background and Objectives. Insulin replacement regimens now stress the importance of administering throughout the day insulin doses that are based on flexible food choices and focusing on improved metabolic control. A flexible multiple daily insulin (FMDI) regimen (premeal lispro plus bedtime glargine) results in lower hemoglobin A1c (HbA1c) levels and fewer hypoglycemic episodes than does a multiple daily insulin (MDI) regimen among school-aged children and adolescents with type 1 diabetes mellitus (DM). The purpose of this study was to determine the feasibility of FMDI therapy for a group of preschool-aged children with type 1 DM who were transitioned from MDI therapy (premeal lispro plus ultralente insulin twice per day), by comparing BMI, total daily insulin requirements, HbA1c levels, and episodes of severe hypoglycemia.
Research Design and Methods. Data were collected over a 2-year period, during quarterly DM clinic visits, from 35 patients (17 female patients and 18 male patients, 4.8 ± 1.0 years of age) who had received MDI insulin therapy for 1 year before being transitioned to a FMDI regimen.
Results. Although there was no significant change in BMI with FMDI therapy (17.1 ± 1.8 kg/m2 vs 17.0 ± 1.7 kg/m2), 43% of patients (6 female subjects and 9 male subjects) were overweight (BMI of >85th percentile for age) both before and after treatment. The total daily insulin requirement (0.67 ± 0.13 U/kg per day vs 0.78 ± 0.14 U/kg per day) and bolus/basal insulin ratio (1.1 ± 0.4 vs 1.9 ± 0.6) were significantly increased and overall glycemic control was improved after transition to FMDI therapy (HbA1c levels: 8.8 ± 0.9% vs 8.3 ± 0.8%). However, HbA1c levels improved only among normal-weight subjects (9.0 ± 1.0% vs 8.3 ± 1.0%) and not among overweight subjects (8.7 ± 0.7% vs 8.4 ± 0.6%) after FMDI therapy. The overall rate of severe hypoglycemia was significantly decreased with the FMDI regimen (25.5 events per 100 patient-years vs 10.6 events per 100 patient-years) but again only for normal-weight children (29.7 events per 100 patient-years vs 7.4 events per 100 patient-years).
Conclusions. The use of FMDI therapy with glargine among preschool-aged children with type 1 DM was associated with improved overall glycemic control and decreased frequency of severe hypoglycemia. Although our study did not have a control group, these findings suggest that FMDI regimens may be a feasible therapeutic alternative to MDI treatment for preschool-aged children with type 1 DM. However, excess body weight status appeared to preclude a desirable therapeutic response in this group of patients.
Key Words: glargine hemoglobin A1c hypoglycemia BMI type 1 diabetes
Abbreviations: DM, diabetes mellitus FMDI, flexible multiple daily insulin MDI, multiple daily insulin HbA1c, hemoglobin A1c ICR, insulin/carbohydrate ratio TDD, total daily dose BG, blood glucose
The incidence of type 1 diabetes mellitus (DM) is increasing rapidly, especially in younger age groups.1 The data from Western European DM centers suggest an annual rate increase of 3% to 4% in the general pediatric population.2 However, the rates of increase were greatest in the age group of 0 to 4 years (6.3%), compared with age 5 to 9 years (3.1%) and 10 to 14 years (2.4%).
Treatment of type 1 DM among infants, toddlers, and preschool-aged children presents a unique set of problems.3,4 Achieving optimal metabolic control is difficult, is complicated by the limited communication skills of the child, and is associated with increased family stress and altered family psychodynamics.3 As a result, intensive insulin therapy is often compromised in an attempt to avoid hypoglycemia. Despite the availability of modern insulin treatment, >50% of patients with childhood-onset, type 1 DM tend to develop detectable DM complications (incipient nephropathy and background retinopathy) after 12 years of DM.5 Inadequate glycemic control during the first 5 years of DM seems to shorten the time to occurrence, which indicates the need to achieve tighter control even among very young patients.5
The Diabetes Control and Complications Trial demonstrated that intensive insulin therapy with either multiple daily insulin (MDI) or continuous subcutaneous insulin infusion regimens resulted in dramatic risk reductions, compared with conventional treatment, for the development and progression of diabetic complications among adults and adolescents.6 The approach of intensive insulin therapy aims to mimic the diurnal insulin pattern seen among nondiabetic individuals. Bolus (short-acting) insulin is given multiple times each day, to optimize glycemic control by limiting postprandial hyperglycemia. Basal insulin, administered in the form of either slow-release preparations with prolonged absorption or continuous subcutaneous insulin infusion, limits preprandial (fasting) hyperglycemia.
Although the use of continuous subcutaneous insulin infusion is increasing,7 9 insulin injection therapy remains the most common treatment method for children with type 1 DM. The short-acting insulin analogs lispro (Humalog; Lilly Pharmaceuticals, Indianapolis, IN) and aspart (Novolog; Novo-Nordisk Pharmaceuticals, Princeton, NJ) can be given in small doses throughout the day and can be matched to the carbohydrate intake and timed to give the family flexibility at mealtimes.10 12 Once- or twice-daily administration of intermediate-acting and long-acting insulins, which may mimic physiologic basal insulin secretion, are also important in intensive glycemic control.13,14 Indeed, use of the long-acting insulin glargine (Lantus; Aventis Pharmaceuticals, Bridgewater, NJ) was shown to improve glycemic control and to reduce the frequency of hypoglycemia in a group of toddlers, children, and adolescents with type 1 or 2 DM.15 Because there has been no specific evaluation of flexible multiple daily insulin (FMDI) therapy with glargine among preschool-aged children with type 1 DM, we studied its feasibility and efficacy by comparing the hemoglobin A1c (HbA1c) levels, BMI, and frequency of severe hypoglycemic episodes among these patients before and after initiation of FMDI therapy.
METHODS
Study Subjects
Thirty-five preschool-aged children (age range: 2.6 6.3 years) who had completed 1 year of FMDI therapy were included in the study. All children were cared for in the Children's Hospital of Wisconsin Diabetes Center (affiliated with the Medical College of Wisconsin). Before initiation of the FMDI regimen (bedtime glargine and premeal lispro insulin), all patients received a MDI regimen (premeal lispro and ultralente insulin twice per day) for 1 year. After transitioning from MDI to FMDI therapy, all patients received FMDI therapy for 1 year. Before initiation of the FMDI regimen, the DM educators reviewed with the parents/guardians new insulin algorithms for calculation of insulin bolus dosing and supplemental insulin treatment for high blood glucose (BG) levels. Patients were evaluated at quarterly (every 3 months) DM clinic visits. Most patients also contacted the team every 6 to 8 weeks for review of BG records, as performed previously with the MDI regimen. Data were collected retrospectively for 1 year before FMDI therapy initiation (during MDI treatment) and for the first year of FMDI therapy. At each clinic visit, BG records were reviewed and HbA1c levels, BMI, and Tanner stage were determined.
Hypoglycemia data from patients' BG logs were recorded at each visit for the preceding 3 months and were expressed as events per 100 patient-years. Severe hypoglycemic episodes were defined as BG levels of <50 mg/dL (<2.8 mmol/L) associated with unconsciousness, with or without seizure. Moderate hypoglycemia was defined as BG levels of <60 mg/dL (<3.3 mmol/L), with or without behavioral impairment. This study was approved by the institutional review board of the Children's Hospital of Wisconsin for the retrospective review of patients' clinic charts; informed consent was not required. Details that might reveal the identity of the subjects were omitted from data collection.
Nutritional Assessment
All parents and caregivers used carbohydrate counting for 1 year before initiation of the FMDI regimen with glargine. Parents/guardians received nutrition and meal-planning recommendations and education on the application of carbohydrate counting to the FMDI regimen by a nutritionist, on the basis of established guidelines.16 Caregivers were encouraged to limit children's snack size to 1 carbohydrate exchange if they wanted to avoid additional insulin injections. Food labels, exchange lists, food models, and restaurant reference guides were used as educational tools. At each quarterly visit, carbohydrate-counting skills were assessed. Growth parameters, including height, weight, percentile for age, and BMI, were assessed at each visit. On the basis of the guidelines of the National Center for Health Statistics, a BMI of >85th percentile for age was considered overweight and was the criterion to classify children as normal weight or overweight.17
Insulin Dosage Calculations and HbA1c Determination
Before transitioning to the FMDI regimen, all patients were stabilized with lispro insulin (Humalog vial or Humalog Pen; Lilly) as bolus insulin before meals and ultralente insulin (Lilly) as basal insulin before breakfast and supper for 1 year. Each child's total daily dose (TDD) of insulin was then used to calculate the starting bolus and basal doses for the FMDI regimen. The total daily premeal lispro dose was estimated at 60% of the first-year TDD. The insulin/carbohydrate ratio (ICR) was then approximated by dividing the total daily units of premeal lispro by the total daily mealtime carbohydrate exchanges (1 exchange = 15 g of carbohydrate). For example, a child who averaged 9 daily carbohydrate exchanges and had a TDD of 15 units would be scheduled to receive a daily premeal lispro dose of 9.0 units (60% of TDD) and would have an estimated ICR of 1.0 (9.0 daily premeal units divided by 9 daily carbohydrate exchanges). The initial supplemental or correction dose of lispro insulin to be added to this carbohydrate dose was also based on the estimated ICR. For instance, the child with an ICR of 1.0 would receive a correction lispro dose of 1.0 unit (rounded to the nearest 0.5 unit) for every 100 mg/dL (5.6 mmol/L) that the BG level was above or below a target range of 80 to 150 mg/dL (4.4 8.3 mmol/L). This initial insulin dosage algorithm was individualized for most patients during the year, to accommodate variable insulin sensitivity. In addition, families were instructed to adjust the ICR and correction dose on the basis of 2-hour postprandial BG determinations. The remaining 40% of the TDD of insulin was given as a single dose of glargine insulin (Lantus; Aventis Pharmaceuticals) at bedtime.
Because preschool-aged children demonstrate unpredictable eating habits, mealtime lispro insulin was administered 15 to 30 minutes after the meal.10 For children who were at day care or kindergarten, lunchtime lispro insulin was administered by day care personnel or school nurses, respectively. All insulin dose changes were made initially through consultation with the clinic every 2 weeks for the first 1 to 2 months, through fax or telephone contact, and then independently by families of patients according to the basic guidelines taught. HbA1c levels were determined with a Bayer DCA 2000 instrument (Bayer Diagnostics, Tarrytown, NY), with a nondiabetic range of 4.5% to 5.7%.
Statistical Analyses
The reported values represent the mean ± SD. Baseline characteristics were compared with t tests and 2 tests; when differences were found, they were controlled for in additional analyses. The HbA1c data were analyzed with paired t tests and 1-way analysis of variance. The rates of moderate and severe hypoglycemia were analyzed with a generalized estimating equation approach with a Poisson regression. P < .05 was considered significant.
RESULTS
There was no significant change in mean BMI before and after initiation of FMDI therapy (17.1 ± 1.8 kg/m2 vs 17.0 ± 1.7 kg/m2). The prevalence of overweight patients before and 1 year after FMDI therapy was unchanged (6 female subjects and 9 male subjects, 43%).
There was a significant reduction in HbA1c levels after 1 year of FMDI therapy (8.8 ± 0.9% vs 8.3 ± 0.8%, P < .01). However, HbA1c levels improved only among normal-weight children (9.0 ± 1.0% vs 8.3 ± 1.0%, P < .05) and not among overweight subjects (8.7 ± 0.7% vs 8.4 ± 0.6%). After 1 year of FMDI therapy, 22% of the patients (8 of 35 subjects; 4 female subjects and 4 male subjects) maintained or achieved HbA1c levels of <8.0%, and 20% of patients (7 of 35 subjects; 3 female subjects and 4 male subjects) showed improvement in HbA1c levels of 1.0%.
The rates of severe hypoglycemia were significantly reduced in the entire group (25.5 events per 100 patient-years vs 10.6 events per 100 patient-years, P < .05) and in the normal-weight subgroup (29.7 events per 100 patient-years vs 7.4 events per 100 patient-years, P < .001) but not in the overweight subgroup. There was no history of hypoglycemic seizures during FMDI therapy. The frequencies of moderate hypoglycemia were similar between the MDI regimen and the FMDI regimen (92.1 events per 100 patient-years vs 84.7 events per 100 patient-years). None of the patients experienced diabetic ketoacidosis in the last 1 year of MDI therapy and during 1 year of the FMDI regimen.
DISCUSSION
It was shown previously that the use of glargine in the pediatric population improves glycemic control among children and adolescents with type 1 DM.15,18,19 Our study extends this observation to include preschool-aged children. In our study, there was significant group improvement in glycemic control with FMDI therapy (reduced HbA1c levels) and a decreased rate of severe hypoglycemia, despite tighter control. However, this benefit was limited to normal-weight children.
Intensive insulin therapy has been associated commonly with excess weight gain.20,21 This did not occur in this group of preschool-aged children or in a previously reported group of children and adolescents.12 However, 43% of patients in the current study were overweight before and after FMDI therapy. Similarly, Libman et al22 demonstrated that there has been an overall increasing trend in the prevalence of overweight children and adolescents (12.6% to 36.8%) at the onset of insulin-treated DM over a period of 20 years. These observations indicate that the prevalence of overweight among children with type 1 DM is increasing in parallel with the trend in the general population.23 Additional comparison of our DM clinic children with a regional healthy population of children might confirm similar rates of excess weight, but such regional data are not currently available.
In our study, not only did the overall glycemic control improve, but also 20% (7 patients) of FMDI-treated patients showed 1.0% improvement in HbA1c levels. This degree of reduction in HbA1c levels was associated with a 21% to 49% decreased risk of microvascular complications in the Diabetes Control and Complications Trial.6,24 Furthermore, 22% of patients maintained or achieved optimal glycemic control, as defined by HbA1c levels of <8.0% for pediatric patients.25 However, the improvement in glycemic control (HbA1c levels) was observed only for normal-weight children and not for overweight children, who reported similar energy intake and daily insulin dose (corrected for body weight).26 The most likely explanation for these paradoxical data for overweight children is that the energy intake was underreported or underestimated, yielding a lispro bolus insulin dose that was not appropriately matched to the actual meal carbohydrate intake.27 This mismatch may represent an attempt by anxious parents to prevent hypoglycemia.
The duration of prepubertal DM is a significant predictor of retinopathy among young adults. It has been reported that the effect of time on the risk of retinopathy and microalbuminuria is not uniform, with an increasing delay in the onset of complications among those with longer prepubertal duration.28 This indicates that great caution may need to be exercised in setting glycemic targets for young children, who are at increased risk of hypoglycemia. Hypoglycemia has often been considered a common complication of good metabolic control.29,30 However, studies with new insulin analogs suggested that improved control can be attained without an increase in hypoglycemic events.31,32 Allen et al33 showed that improved glycemic control and frequent BG monitoring but not intensive insulin therapy were related to frequent hypoglycemia, in contrast to the Diabetes Control and Complications Trial findings.29 In our study, the baseline frequencies of severe hypoglycemia were similar for normal-weight and overweight children. The rate of severe hypoglycemia decreased significantly among normal-weight children during FMDI therapy. Severe hypoglycemia is usually associated with management errors, vigorous physical activities, psychosocial stresses, <3 injections per day, and a low bolus/basal insulin ratio.34 Because the peak effects of ultralente and intermediate-acting insulins13,14 may not coincide with food intake, the use of these insulin preparations may worsen hypoglycemia during intensive physical activity. Although FMDI treatment resulted in higher TDDs for our population, insulin was redistributed throughout the day, with a larger proportion given as bolus insulin adjusted for BG levels and imminent carbohydrate intake. This might have reduced the likelihood of a mismatch between the insulin present during the day and the actual insulin needs. Therefore, appropriate physiologic replacement of insulin with FMDI therapy using glargine,15 frequent BG monitoring, and active problem-based training were the likely reasons for decreased rates of severe hypoglycemia33 36 and improved metabolic control. However, it can be suggested that, because children were 1 year older, they were able to recognize and report mild/moderate hypoglycemia before progressing to coma and seizures or BG levels of <50 mg/dL. The corresponding improvement in glycemic control may be partly attributable to reduced parental fear of hypoglycemia and anticipatory overfeeding.
Increased risk of frequent mild/moderate hypoglycemia is usually seen among individuals with type 1 DM who have high BG variability and low average BG concentrations, DM of long duration, low BMI, self-reported impaired awareness of hypoglycemia, and participation in vigorous physical activities.37,38 Among our patients, there was no correlation between hypoglycemia frequency and BMI and/or duration of DM. However, the rate of moderate hypoglycemia did not decrease. The reasons for this finding likely include underreporting of hypoglycemia by children who may not always recognize symptoms of hypoglycemia.
CONCLUSIONS
The use of FMDI therapy with glargine among preschool-aged children with type 1 DM was associated with improved overall glycemic control and decreased frequency of severe hypoglycemia. Although the current study did not have a control group, our findings suggest that the FMDI regimen may be a feasible therapeutic alternative to MDI treatment for preschool-aged children with type 1 DM. However, body weight status appeared to preclude a desirable therapeutic response in this group of patients. Additional studies to evaluate the relationship between the pattern of weight gain, glycemic control, and parental fear of hypoglycemia are needed.
FOOTNOTES
Accepted Sep 20, 2004.
No conflict of interest declared.
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