Application of novel dual wave meal bolus and its impact on glycated hemoglobin A1c level in children with type 1 diabetes

Transcription

1 Pediatric Diabetes 2009: 10: doi: /j x All rights reserved # 2008 The Authors Journal compilation # 2008 Blackwell Munksgaard Pediatric Diabetes Original Article Application of novel dual wave meal bolus and its impact on glycated hemoglobin A1c level in children with type 1 diabetes Pańkowska E, Szypowska A, Lipka M, Szpotańska M, B1azik M, Groele L. Application of novel dual wave meal bolus and its impact on glycated hemoglobin A1c level in children with type 1 diabetes. Pediatric Diabetes 2009: 10: Background: An insulin pump is an advanced technology offering new options of bolus normal (N), dual wave (D-W) or square wave (S-W) bolus to deliver mealtime insulin. Objectives: To assess the impact of D-W/S-W boluses on metabolic control (glycated haemoglobin A1c, HbA1c) and to estimate the paediatric patients compliance with implementation of this system in daily practice. Methods: The cross-sectional study included 499 records of patients aged 0 18 yr. Data from the insulin pump memory provided information on the number of D-W/S-W boluses during a 2-wk period, the insulin requirement (U/kg/d) and the percentage of basal insulin. The HbA1c value (%) and the patient s weight were determined during medical examinations. Mealtime dose of insulin in D-W/S-W bolus was calculated based on the amount of carbohydrate and fat/protein products. Results: The number of applied D-W/S-W boluses was /14 d (ranged 0 95), while 18.8% of patients did not program D-W/S-W boluses. The lowest HbA1c value was found in the group using two and/ or more D-W/S-W boluses per day (p ¼ 0.001) compared with the group administrating less than one D-W/S-W bolus/d. Patients with HbA1c level,7.5% had a statistically higher relevant number of D-W/S-W boluses, (95% CI: ) vs (95% CI: ) (p, 0.001), while there was no correlation between the number of boluses and HbA1c in patients in the remission phase (,0.5 IU/kg/d) (r ¼ 0.012, p ¼ 0.930). Conclusions: Patients using at least one D-W/S-W bolus per day achieved a recommended level of HbA1c. Paediatric patients with type 1 diabetes mellitus were found to be able to apply D-W/S-W boluses in daily selftreatment process based on food counting. Ewa Pańkowska, Agnieszka Szypowska, Maria Lipka, Monika Szpotańska, Marlena B1azik, Lidia Groele The Second Department of Paediatrics, Medical University of Warsaw, Warsaw, Poland Key words: CSII HbA1c meal bolus T1DM Corresponding author: Ewa Pańkowska, MD, The Second Department of Paediatrics, Medical University of Warsaw, ul. Dzialdowska 1/3, Warsaw, Poland. Tel: ; fax: ; epankowska@interia.pl Submitted 24 May Accepted for publication 4 September 2008 According to the recommendations of the International Society of Paediatric and Adolescent Diabetes, the optimal metabolic control in children and adolescents with type 1 diabetes mellitus (T1DM) should be kept at glycated haemoglobin A1c (HbA1c) not higher than 7.5%, fasting plasma glucose at 5 8 mmol/l and postprandial glycaemia in the range of 5 10 mmol/l (1, 2). So far, it is commonly known that the majority of patients with T1DM are still far from achieving these values. Therefore, an effort is being made to search for 298 new technologies to effectively improve metabolic control of children with diabetes. Continuous subcutaneous insulin infusion (CSII) uses rapid-acting insulin analogues and is a method of administrating insulin that simulates the physiological insulin profile more precisely than multiple daily injections (MDI). Moreover, CSII is considered to be more effective in achieving better metabolic control in diabetes patients (3 5). Results from previously performed cross-sectional trials, for example The Paediatric Pump Study Group

2 Pańkowska et al. (PPSG) rounds 1 and 2, showed clearly that for paediatric patients treated with insulin pumps, mean HbA1c level is close to 8.0%. Systematic review of studies, which compared the metabolic control in children with diabetes using CSII and MDI, was in favour of CSII. Based on the PPSG studies, it is specified that one of the most important factors, which impacts on the HbA1c level, is the number of boluses applied by patients per day. The study proved that the higher number of boluses correlates with lower HbA1c, and six boluses/d is the critical number that allows to achieve HbA1c,7% (6, 7). Boluses are programmed individually by patients to cover food intake or to correct hyperglycaemia. In standard (normal, N) boluses, insulin is delivered rapidly as a shot. Square wave (S-W) boluses are optional for delivering insulin during an extended period of time, while in the dual wave (D-W), option insulin is released immediately for an extended time period. Programming boluses requires setting up three parameters: amount of insulin in N bolus, amount of insulin in extended bolus and the time period (number of hours). In our search, we found only three studies that had examined the effectiveness of D-W/S-W bolus application in controlling postprandial glycaemia but not HbA1c (8 10). In these reports, the time during which glycaemic changes were observed, depending on the type of bolus (N, D-W or S-W), was relatively short. Until now, there was no report on the impact of modern insulin pumps and of the optional choice between the three (N, S-W and D-W) types of boluses on HbA1c in children and adolescents treated with CSII. The aims of the study were to assess whether the use of D-W or S-W boluses has an impact on metabolic control (HbA1c) and to estimate the paediatric patients compliance with implementation of this system in daily practice. Methods This cross-sectional study was conducted at the Department of Paediatrics of the Medical University of Warsaw based on 560 patient pump records (p-r) justified by the study protocol. Only records from the Minimed Medtronic MiniMed 508 or Paradigm 712, 722 pumps with rapid-acting insulin aspart or lispro were considered. Data collection Data were collected in the outpatient clinic during routine visits. The analysis included demographic data, body weight, HbA1c, insulin dose per kilogram, number of D-W/S-W boluses and percentage of basal insulin (% basal insulin). Data concerning insulin adjustment: total insulin daily dose, % basal insulin and number of S-W/D-W boluses were downloaded from the pump memory into a personal computer using a COM-STATION and PUMPS &METERS software version 7.0. Records from the last two consecutive weeks were analyzed. Procedure of programming mealtime insulin Since 2003, a new procedure of using D-W/S-W boluses has been implemented in the Department of Paediatrics of the Medical University of Warsaw. This procedure was built based on the three main assumptions: meals containing fat and/or proteins should be covered by insulin (e.g., carbohydrate products), meal absorption depends on the type of nutrition product (e.g., rich on fat meals are absorbed during an extended period of time) and insulin dose should be programmed separately for carbohydrate products in N bolus and for fat or/and protein ingredients in the S-W bolus (11, 12). A new, fat protein exchange factor was added to the food counting system defined as 100 kcal of fat and/or protein foods. Finally, it was established that the dose of insulin in the N bolus should be calculated based on the number of carb unit (exchanges), while the dose for the S-W bolus should be counted as the number of fat protein units (FPUs) multiplied by insulin ratios (dose of insulin that covers 10 g of carbohydrate product or 100 kcal from fat/protein products). Total dose of insulin calculated for a meal was counted as the sum of insulin dose in N and S-W boluses. A procedure was also created to establish the time period for extended (S-W) boluses programmed for at least 3 h or longer, given the food was rich in fat. The time was extended to 3 h for a meal containing 1 FPU, to 4 h for 2 FPU, 5 h for 3 FPU and, finally, to 8 h when a meal included more than 3 FPU (300 kcal). Education All patients were educated by the ÔWarsaw School Program for dosing mealtime insulin in pump therapy. Trainings in food counting and dosing of insulin took place in an outpatient clinic and included two 1.5-h meetings in groups consisting of one to three families. The education sessions included theoretical parts during which patients were explained the rules of a healthy diet, type of nutrition products, the dependency of the absorption process on the type of food and its impact on postprandial glycaemic profile. Moreover, patients were trained to calculate the number of carb units, FPUs, to adapt the type of bolus for a specific meal and to program the time of the S-W bolus. Examples of practice exercises can be found in Table 1. Compliance Compliance was assessed by the number of D-W/S-W boluses administered during a 2-wk period. We assumed that D-W/S-W bolus reflects the level of Pediatric Diabetes 2009: 10:

3 Table 1. The Warsaw School Procedure for calculating mealtime insulin dose D-W bolus and HbA1c in T1DM children Meal Ingredients Nutrition data Carb unit (CU) and fat protein unit (FPU) Insulin-tocarbohydrate ratio (U/L) CU OR FPU Dose of insulin Normal bolus Square wave bolus/period of time Hot-dog Bread 50 g; sausage 100 g; mustard 10 g Total kcal 484; carbohydrate 29.5 g; protein 15.7 g; fat 28.2 g 3 CU; 3 FPU ¼ 3U ¼ 3 U/5 h compliance with implementation of this procedure into daily practice. The low D-W/S-W bolus level was defined as a number of boluses in the range,0 14/2 wk (0 1/d), middle level when number of boluses were between 14 and 28/2 wk (,2 3/d) and high when number of boluses were.28/2 wk (.3/d). The blood for HbA1c was collected during the study visit at the time for downloading pumps memory and measured by using the certified BioRad Variant with non-diabetic values ranging from 4.0 to 5.8%. HbA1c was calculated automatically with the VARIANT algorithm. Results were aligned with diabetes control and complications trial (DCCT). Statistical methods Results are presented as mean values with standard deviations (SDs). Differences in outcomes were evaluated by using one-way analysis of variance ANOVA or Kruskal Wallis test (non-parametric ANOVA). The comparisons between groups were made by using unpaired t test or for non-parametric data Mann Whitney U-statistic. Correlations were made by using Spearman rank correlation. p, 0.05 was considered statistically significant. Results Compliance of three bolus options in CSII According to the study protocol, 499 patient records were included in the analysis. Sixty-one p-r did not meet conditions: 28 were over 18 yr of age; 33 used less than three boluses per day (n ¼ 33). Characteristic of study group is presented in Table 2. The average number of boluses was ; 94/499 p-r; 18.8% of the study group did not program D-W/S-W boluses/2 wk. The higher HbA1c value (%) ( vs ; p, 0.001) and the lower insulin requirement (U/kg/d) ( vs ; p, 0.002) were observed in the group of patients who did not use the D-W/S-W boluses vs. the group of users of this bolus option (with no influence of the age). The group with low compliance consisted of 269 p-r, middle level of compliance counted 110 p-r and high level consisted of 120 p-r. The lowest HbA1c was noted in the group with high level of compliance ( Table 2. The characteristic of study group n 499 Gender (girls/boys) 246/253 Age (yr) Diabetes duration (yr) Age of diabetes onset (yr) Glycated hemoglobin A1c (%) Daily insulin dose (IU/kg/d) Basal insulin (%) Data are presented as mean SD. vs vs %, p, 0.001) (Fig. 1). No significant difference in the age of patients or in insulin requirement has been observed between the three groups. The mean (SD) % basal insulin in group with low level of compliance was %, in group with middle level of compliance was % and in group with high level was %. However, a diversity in % basal insulin (0 14 D-W/S-W vs D-W/S-W, p, 0.05; 0 14 D-W/S W vs..28 D-W/S-W, p, 0.001; D-W/S-W vs..28 D-W/ S-W, p. 0.05) was noted. The impact of D-W/S-W boluses on metabolic control The Spearman rank analysis performed on the whole study group showed a significant, negative correlation >28b 14-28b 0-14b HbA1c (%) Fig. 1. Significant differences in glycated hemoglobin A1c (HbA1c) (p, 0.001) between groups in relation to the number of dual wave/ square wave boluses (b) applied during the 2-wk period. 300 Pediatric Diabetes 2009: 10:

4 Pańkowska et al. between the number of boluses and HbA1c. A relevant correlation was established regardless of age, both for prepubertal and pubertal children (1 10 yr. r ¼ 20.18, p ¼ 0.01) (10 18 yr. r ¼ 20.3, p, 0.001). The examined group was stratified based on the remission phase, defined by insulin requirement (0.5 IU/kg/d), into two groups: the non-r group with.0.5 IU/kg/ d and a remission phase group R with 0.5 IU/kg/d. Patients from group R were younger and had lower HbA1c than patients in the non-r group (Table 3). In the group R, no significant correlation between HbA1 level and the number of D-W/S-W boluses has been found (r ¼ , p ¼ 0.930) in contrast to the non-r group (r ¼ , p, 0.001). Patients with the HbA1c value below 7.5% (n ¼ 295) used the D-W/S-w boluses more often than patients with the HbA1c value.7.5% (n ¼ 165) (19.5/2 wk 18.4 vs , p, 0.001). Percentage of basal insulin on total daily dose because of S-W boluses A relevant, negative correlation between the number of S-W boluses and % basal insulin was determined. For patients using less than 14 S-W boluses during a 2-wk period, basal insulin requirement was %, and respectively, in patients using more than 1 S-W bolus/d, the % basal insulin was %. Discussion Data presented in this study reveal the consequences of using D-W/S-W boluses on metabolic control and basal insulin requirement in paediatric patients treated with CSII. Patients using at least one D-W/S-W bolus per day had a better metabolic control (HbA1c) than patients who programmed boluses occasionally. This correlation was particularly significant for patients who were not in remission. The critical number of D-W/ S-W boluses was established to be one per day. Interestingly, introduction of boluses correlates with HbA1c not only in pubertal patients who exhibited a higher insulin requirement than pre-pubertal children but also, generally, in young patients. Obtained results suggest a relationship between D- W/S-W boluses and % basal insulin. Patients with at least one to three D-W/S-W boluses programmed per day had a significantly lower requirement for basal insulin than patients using only N boluses. This analysis of patients compliance with implementation of the Warsaw School Program shows that paediatric patients, regardless of age, are able to use in their daily practice the food counting system, including carb unit and FPU calculations. Despite the fact that our proposal for counting mealtime insulin was rather technical and complex, around 80% of our patients used D-W/S-W bolus at least once. According to the fact that the whole study population was educated in the same, healthy rules of nutrition, where the total calories intake should be covered by carbohydrates, fat and protein contains, it is difficult to suspect that patients did not use the boluses because of the vegetarian diet. The careful analysis of food intake was not the subject of this study. Strength and limitations This analysis was conducted on a group of 499 patient records, representing different age and stages of diabetes. To our knowledge, this is the first study on the novel options of programming mealtime insulin performed on such a large group of patients using insulin pumps. Limiting is the lack of prospective observations; thereby, the word Ôimpact becomes too highlightened. Additionally, analysis of data gathered only during a 2-wk period might not be adequate to compare the HbA1c values; yet, however, the study period reflects the patient s habits and compliance. Our work shows no data on the postprandial glycaemic profile, which was the primary end-point in studies concerning programming mealtime insulin in pump therapy (using D-W boluses). Discussion of important differences in results; implication of study The impact of using D-W boluses on the glycaemic profile was analyzed by Lee et al. (10) Conclusions Table 3. Metabolic control, number of D-W/S-W boluses and insulin requirement of the study group in relation to the remission phase Insulin requirement 0.5 IU/kg/d (n ¼ 57).0.5 IU/kg/d (n ¼ 435) p-value Glycated hemoglobin A1c (%) Age (yr) Diabetes duration (yr) Number of S-W/D-W boluses Total daily dose of insulin(u/kg/d) Basal insulin (%) D-W, dual wave bolus; S-W, square wave bolus. Data are presented as mean SD. Pediatric Diabetes 2009: 10:

5 D-W bolus and HbA1c in T1DM children drawn by authors of the mentioned work were in accordance with our observations being that fat and protein can cause elevation of postprandial glucose concentration, fat ingestion may result in delaying gastric emptying and, finally, insulin dose should be taken into consideration for carbohydrate, fat and protein intake. Based on the study conducted on 10 diabetic subjects, a significant lower postprandial glycaemia profile was noted during a 5-h period in patients using a D-W bolus compared with subjects using only N boluses for meals rich in fat. Authors concluded that D-W bolus is better in controlling postprandial glycaemia. Interestingly, a relevant difference in glucose concentration was observed 5 h after food intake and later. Moreover, these results indicate that S-W bolus should be programmed for more than 3 h. The efficacy of extending insulin delivery to 8 h was investigated by Jones et al. (9). In the study, authors compared the glycaemic profile with respect to the time of insulin delivery for S-W and N boluses. Work by Chase et al. (8) was the first to compare the efficacy of the four mealtime insulin delivery methods in handling postprandial glycaemic profile. The study concluded that D-W bolus most effectively controls the postprandial glucose profile after meals rich in carbohydrates and fats. The extended boluses were programmed for 2 h. Our findings confirm the observations reported by Chase et al. Both works analyzed the same aspects of insulin delivery but applied diverse methodologies based on different glucose measuring tools continuous glucose monitoring and conducted and different study design and controlled study. All studies were carried out in small groups counting subjects. Compared with our study, protocol guidelines of the above studies were various; generally, they proposed to calculate the total dose for bolus based on amount of carbohydrate and then sharply divide it into two parts: first one for N bolus and second one for S-W bolus (8 10). However, we propose an alternative protocol in which the insulin dose for carbohydrate and for fat protein meals would be calculated separately. It also seems that the period of time in which the S-W bolus should be programmed is still unclear and has to be investigated. Unanswered questions and future research Results of the three above mentioned studies and of our analysis clearly show that the new option of delivering meal insulin offered by modern insulin pumps improves the postprandial glycaemic profile as well as HbA1c in T1DM patients. Our findings confirm that fat and protein ingested in a meal should be covered by insulin delivered over an extended time period. This conclusion contradicts the traditional, only for carbohydrate present in taken food, approach of administrating mealtime insulin. It is still unknown how fat meals increase the concentration of postprandial glucose and which pathway is most strongly involved in this phenomenon. Some experimental studies concerning the role of glucagon in glucose homeostasis could partially give an explanation and indicate the direction for future studies (13 15). Conclusions Implementation of S-W boluses as a part of D-W boluses results in lower HbA1c in paediatric patients with T1DM. Applying mentioned boluses at least once a day help to achieve the recommended HbA1c level. Most paediatric patients are able to carry out all bolus options offered by the novel pump therapy. S-W and D-W boluses influence on basal insulin requirements regardless of patient s age. According to the findings of the Warsaw School Program, the presented strategy is feasible in diabetes regime and effective in managing children with diabetes. References 1. REWERS M, PIHOKER C, DONAGHUE K, HANAS R, SWIFT P, KLINGENSMITH G.J. Assessment and monitoring of glycemic control in children and adolescents with diabetes. Pediatr Diabetes 2007: 8: ASSOCIATION AD. Standards of medical care in diabetes Diabetes Care 2008: Suppl. 1: S1 S2. 3. COLQUITT JL, GREEN C, SIDHU MK, HARTWELL D, WAUGH N. Clinical and cost-effectiveness of continuous subcutaneous insulin infusion for diabetes. Health Technol Assess 2004: 8: WEISSBERG-BENCHELL J, ANTISDEL-LOMAGLIO J, SESHADRI R. Insulin pump therapy: a meta-analysis. Diabetes Care 2003: 26: 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. BMJ 2002: 324: DANNE T, BATTELINO T, KORDONOURI O. et al. A crosssectional international survey of continuous subcutaneous insulin infusion in 377 children and adolescents with type 1 diabetes mellitus from 10 countries. Pediatr Diabetes 2005: 6: DANNE T, BATTELINO T, JAROSZ-CHOBOT P. et al. Establishing glycemic control with continuous subcutaneous insulin infusion in children with type 1 diabetes: experience from the PedPump Study in 17 countries. Diabetologia 2008: 9: CHASE HP, SAIB SZ, MACKENZIE T, HANSEN MM, GARG S.K. Post-prandial glucose excursions following four methods of bolus insulin administration in subjects with type 1 diabetes. Diabet Med 2002: 19: JONES SM, QUARRY JL, CALDWELL-MCMILLAN M, MAUGER DT, GABBAY RA. Optimal insulin pump dosing and postprandial glycemia following a pizza meal using the continuous glucose monitoring system. Diabetes Technol Ther 2005: 7: LEE SW, CAO M, SAJID S. et al. The dual-wave bolus feature in continuous subcutaneous insulin infusion pumps controls prolonged post-prandial hyperglycaemia 302 Pediatric Diabetes 2009: 10:

6 Pańkowska et al. better than standard bolus in type 1 diabetes. Diabetes Nutr Metab 2004: 17: SZYPOWSKA A, PANKOWSKA E, LIPKA M. [Guidelines concerning insulin dosage in children and adolescents with type 1 diabetes on continuous subcutaneous insulin infusion]. Endokrynol Diabetol Chor Przemiany Materii Wieku Rozw 2006: 12: SZYPOWSKA A, PAŃKOWSKA E, LIPKA M, PROCNER- CZAPLIŃSKA M, TRIPPNEBACH-DULSKA H, KO1ODZIEJSKA B. Model eduakcji dzieci i m1odzie_zy chorujących na cukrzycę typu 1 oraz ich rodzin w zakresie funkcjonalnej insulinoterapii. Medycyna Metaboliczna 2006: 10: DOBBS R, SAKURAI H, SASAKI H. et al. Glucagon: role in the hyperglycemia of diabetes mellitus. Science 1975: 187: GERICH JE, LORENZI M, HANE S, GUSTAFSON G, GUILLEMIN R., FORSHAM P.H. Evidence for a physiologic role of pancreatic glucagon in human glucose homeostasis: studies with somatostatin. Metabolism 1975: 24: SHERWIN RS, FISHER M, HENDLER R, FELIG P. Hyperglucagonemia and blood glucose regulation in normal, obese and diabetic subjects. N Engl J Med 1976: 294: Pediatric Diabetes 2009: 10: