Type 1 diabetes (T1D) is one of the most common chronic childhood diseases and its incidence has doubled during the last decade. The goals of intensive management of diabetes were established in 1993 by the Diabetes Control and Complications Trial (DCCT) (1). Children with T1D and their caregivers continue to face the challenge to maintain blood glucose levels in the near-normal range. It is important to prevent sustained hyperglycaemia which is associated with long-term microvascular and macrovascular complications and to avoid recurrent episodes of hypoglycaemia or hyperglycaemia, especially in young children, which may have adverse effects on cognitive function and impede efforts to achieve the recommended glycaemic targets.
Advances in the use of technology that may help maintain the metabolic control goals for young people with T1D were centred on continuous subcutaneous insulin infusion (CSII) (2–4), continuous glucose monitoring (CGM) (5–7), and combining both technologies into a closed-loop system (8–10).
The dilemma in paediatrics of patient selection for insulin pump therapy was found to be most successful in those with more frequent self-monitoring of blood glucose (SMBG) and younger age prior to pump initiation (2). Similarly, those who used a dual-wave bolus probably paid closer attention to their management and had lower HbA1c levels (3). The advantage of using a pre-meal bolus to improve postprandial glucose levels was shown to offer another potential method to improve glycaemic control (4).
SMBG is an important component of therapy in patients with diabetes, especially in the paediatric age group. Standard use of glucose meters for SMBG provides only intermittent single blood glucose levels, without giving the ‘whole picture’ of glucose variability during the 24 h, and especially during the night, when blood glucose levels are seldom measured. Therefore, the use of a device such as real-time continuous glucose monitoring (RT-CGM) that provides continuous glucose measurements can help patients optimise glycaemic control. These devices may have the potential to increase the proportion of patients who are able to maintain target HbA1c values, to decrease glucose excursions and to decrease the risk of severe hypoglycaemia. Previous studies in paediatric T1D patients (11,12) have demonstrated that the frequency of CGM use was significantly associated with the effect of lowering HbA1c levels. The important STAR 3 study of 485 patients (156 children) with T1D showed the benefit of sensor-augmented pump therapy over remaining on multiple daily injections (MDI) (10). The Juvenile Diabetes Research Foundation Continuous Glucose Monitoring (JDRF-CGM) studies were initially described in the 2009 Yearbook (13). Further reports of youths and adults in this study found that those with initial low HbA1c levels (< 7%) show a significant benefit from the use of CGM (5). Prolonged nocturnal hypoglycaemia was shown to continue to be a common occurrence in the entire cohort using CGM (7). Thus, there is an obvious need for closing the loop. Many patients with diabetes and especially parents of diabetic children dream about the invention of an ‘artificial pancreas’. CSII and RT-CGM can be combined to form closed-loop systems. Insulin is then delivered according to RT-CGM data, as directed by a control algorithm, rather than at pre-programmed rates. Few closed-loop prototypes have been developed with advanced control algorithms, such as those that are based on model predictive control (14). The group at Cambridge studied 19 young people in closed-loop systems and was able to demonstrate that exercise and diet variations could be aptly managed (9). It is expected that closed-loop studies in young people will continue to multiply in future years.
T1D is characterised by immune-mediated pancreatic β-cell destruction. Thus, a major goal in the treatment of T1D in youth will be in the area of prevention. The identification of increased levels of inflammatory markers in the SEARCH study of young people with T1D may provide an important clue (15). Most of the studies countered the diabetes process by immunomodulation and/or enhancement of β-cell proliferation and regeneration (16). An initial pilot trial of a tumour necrosis factor α (TNF-α) binding agent, Entanercept, showed benefit in preserving C-peptide production in 18 young people with newly diagnosed T1D.
HbA1c levels were also lower in the treatment group (5.9% ± 0.5% vs. 6.98% ± 1.2%; p < 0.05) (17). Similarly, β-cell function was shown to be preserved in children receiving the lower of two doses of ingested human recombinant interferon-α (hrINF-α) in comparison with subjects who received placebo (18). A future larger trial of both of these agents will be of interest.
In this review of the literature we have tried to select recent publications that offer some insight into these issues in paediatric patients with T1D.
Continuous subcutaneous insulin infusion therapy – insulin pumps
Predictors of glycaemic control in patients with type 1 diabetes commencing continuous subcutaneous insulin infusion therapy
S. Shalitin, M. Gil, R. Nimri, L. de Vries, M. Y. Gavan, M. Phillip
Institute of Endocrinology and Diabetes, Schneider Children’s Medical Center, Petah Tikva, Israel
Diabet Med 2010; 27: 339–47
Background: Technological improvements of CSII have led to its increased use. However, selecting the best candidates for CSII poses a major clinical challenge. This retrospective study sought to identify variables that predict glycaemic control in patients with T1D switched to a CSII regimen, with the aim of improving prospective patient selection for this treatment.
Methods: The medical files of 421 patients with T1D aged 2.6–39.8 years (43.9% younger than 18 years) who initiated CSII treatment and used it for at least 1 year (mean time of CSII use 4.1 ± 2.1 years) were reviewed. Details about their background, disease-related and treatment-related variables were recorded. At pump initiation, the mean age was 15.9 ± 7.2 years, mean diabetes duration 6.4 ± 5.8 years. The end-points were (1) achievement of good glycaemic control, defined by HbA1c stratified by age (American Diabetes Association recommendations), (2) improvement in glycaemic control, defined as a reduction of at least 0.5% in HbA1c from baseline, and (3) change in the rate of severe hypoglycaemic or diabetic ketoacidosis events.
Results: A significant sustained decrease in HbA1c was observed with CSII for an average of 6 years, without increased rates of hypoglycaemia. The rate of severe hypoglycaemic episodes decreased during pump treatment (p = 0.023), whereas the rate of diabetic ketoacidosis increased with CSII (p = 0.004). Achievement of target HbA1c was significantly associated with the following parameters at pump initiation: lower HbA1c, younger age (< 12 years), shorter diabetes duration, and more frequent daily SMBG. Improved glycaemic control was associated with longer CSII use and higher HbA1c at CSII initiation.
Conclusions: Switching patients to CSII resulted in sustained decrease in HbA1c and improved glycaemic control in patients with high HbA1c. Young age, frequent SMBG and lower HbA1c at pump initiation were identified as predictors of achieving glycaemic targets with CSII.
- • Comment: CSII is the most physiological therapy of insulin replacement regimens, and therefore it is expected that pump therapy may be associated with long-term improvement in HbA1c. However, meta-analyses of randomised controlled studies of paediatric cohorts using insulin pumps have shown either no benefit in HbA1c or only modest benefits in the range of 0–0.9% (19). The identification of factors that predict or affect glycaemic control during pump therapy is important for proper patient selection.
This large observational cohort study found that switching to CSII was followed by a sustained decrease in HbA1c, with significant reduction in the rate of severe hypoglycaemic episodes. The predictors that were identified as related to achieving the HbA1c target during CSII treatment may indicate that the best profiting patients from pump therapy were young paediatric patients, those with an already better glycaemic control, and patients who adhere to intensive diabetes management with frequent blood glucose monitoring. In this study, indications for CSII that were significantly associated with achieving HbA1c targets were recurrent hypoglycaemic episodes, needle fear, use for toddlers and above-HbA1c target. These data suggest that the switch to CSII, particularly at younger ages, may reduce the anxiety associated with frequent injections and reduce the frequency of recurrent hypoglycaemic episodes, thus improving treatment compliance and allowing achievement of metabolic control targets. A higher HbA1c at initiation of CSII was significantly associated with a greater reduction in HbA1c during CSII use, which may indicate that a switch to CSII can greatly improve outcome in patients with HbA1c > 9.0%.
Timing of meal insulin boluses to achieve optimal postprandial glycaemic control in patients with type 1 diabetes
E. Cobry, K. McFann, L. Messer, V. Gage, B. VanderWel, L. Horton, H. P. Chase
Barbara Davis Center for Childhood Diabetes, Aurora, CO, USA
Diabetes Tech Ther 2010; 12: 173–7
Background: Families and care providers have assumed that, with the availability of rapid-acting insulins, boluses/injections of insulin prior to food intake are not necessary.
Methods: A prospective study involved 23 subjects with T1D, ages 12–30 years, involving three outpatient clinic visits. The three randomised treatment arms involved bolus insulin administration 20 min prior to a meal (Pre), at the start of the meal (Start) or just after the meal (Post).
Results: Blood glucose levels 60 and 120 min after meal initiation and area under the curve (AUC) were all significantly lower in the Pre arm compared to the Start and Post arms as indicated in the paper.
Conclusions: A bolus of rapid-acting insulin 20 min prior to a meal results in significantly better postprandial glucose control than when the meal insulin bolus is given just prior to the meal or 20 min after meal initiation.
- • Comment: This study shows the need for retraining families and care providers regarding optimal timing of insulin injections to food intake. As blood glucose levels are often the highest of the day in the postprandial periods, this area of care needs attention. The development of new, more rapid-acting insulins may eventually be possible. This will be essential in the development of the closed-loop pancreas, as has already been noted (20).
Application of novel dual-wave meal bolus and its impact on glycated haemoglobin A1c level in children with type 1 diabetes
E. Pankowska, A. Szypowska, M. Lipka, M. Szpotanska, M. Blazik, L. Groele
Second Department of Pediatrics, Medical University of Warsaw, Warsaw, Poland
Pediatric Diabetes 2009; 10: 298–303
Background: One of the most important factors, which impacts on a better HbA1c level, is an increased number of boluses applied by the patient per day. Boluses are programmed individually by patients to cover food intake or to correct hyperglycaemia. In the insulin pump the bolus can be delivered in several modes: standard (normal, N), in which insulin is delivered rapidly on demand to match food intake and to correct hyperglycaemia, square wave (S-W), in which insulin is delivered during an extended period of time, and dual wave (D-W), which combines a normal bolus with a square wave bolus, which allows a certain percentage of insulin to be programmed for immediate delivery and the remainder over an extended time period. The aims of the current study were to assess in the paediatric age group the implementation of treatment with different boluses, and to evaluate whether the use of D-W/S-W boluses has an impact on HbA1c.
Methods: The study included 499 records of patients aged 0–18 years. Data from the insulin pump memory provided information on the number of D-W/S-W boluses during a 2-week period, insulin dosage, and the percentage of basal insulin. Mealtime insulin dose in D-W/S-W bolus was calculated based on the amount of carbohydrate, fat and protein in the food.
Results: The number of applied D-W/S-W boluses was 16.6 ± 0.77 per 14 days. In all 18.8% of patients did not use D-W/S-W boluses. A better glycaemic control was found in patients using ≥ 2 D-W/S-W boluses/day compared to those who programmed boluses occasionally, especially in patients who were not in remission.
Patients with at least 1–3 D-W/S-W boluses/day had a significantly lower requirement for basal insulin than patients using only N boluses.
Conclusions: Paediatric patients using at least one D-W/S-W bolus/day achieved better glycaemic control.
- • Comment: The option of delivering insulin in different bolus modes for different contents of the meals offered by modern insulin pumps can improve the HbA1c. It has to be considered that the meal fat and protein content should be covered by an extended insulin infusion, probably due to its slower absorption compared with the carbohydrate content.
Continuous Glucose Monitoring
Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group
The introduction of new real-time CGM systems has raised great interest because these devices may have the potential to increase the proportions of patients who are able to maintain target HbA1c values, to decrease glucose excursions, and to decrease the risk of severe hypoglycaemia. In order to try and address these issues, the JDRF-CGM Study Group initiated some trials during the last few years. The Study Group included 10 participating centres. Major eligibility criteria included age ≥ 8 years, T1D for at least 1 year, and use of either an insulin pump or MDI.
In a multicentre randomised controlled trial, the JDRF-CGM Study Group evaluated the effectiveness of CGM compared with standard blood glucose monitoring in 451 adults and children ≥ 8 years old with T1D, 322 of whom had baseline HbA1c levels ≥ 7% (21). The patients in the CGM group were asked to use the CGM on a daily basis for 6 months. Patients were provided with instructions on how to make real-time insulin dose adjustments.
They found that in patients with baseline HbA1c levels ≥ 7%, CGM improved the glycaemic control during 6 months of follow-up without increasing the risk of hypoglycaemia in adults ≥ 25 years of age, whereas in younger patients the improvement was more limited. CGM use was substantially higher in adults than in children, and as a presumed consequence the benefit of the device in lowering the HbA1c was greater in adults than in children (13).
Results of other studies of this group are presented in the next three abstracts.
Effect of continuous glucose monitoring in well-controlled type 1 diabetes
Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group
Diabetes Care 2009; 32: 1378–83
Background: Hypoglycaemia remains the major limiting factor for achieving euglycaemia in T1D. The introduction of real-time glucose monitoring (CGM) may have the potential to increase the proportion of patients who are able to maintain target HbA1c values and limit the risk of severe hypoglycaemia. The aim of this randomised trial was to evaluate the efficacy and safety of CGM in well-controlled children and adults with T1D.
Methods: The study included 129 adults and children (29 subjects aged 8–14 years, 33 subjects aged 15–24 years and 67 adults ≥ 25 years old) with intensively treated T1D (HbA1c < 7%) who were randomly assigned to continuous or standard glucose monitoring for 26 weeks. Patients in both groups were provided with instructions on how to use the devices, and to make real-time insulin dose adjustments. The main outcomes were HbA1c level, time with glucose level ≤ 70 mg/dl, and severe hypoglycaemic events.
Results: At the end of the study, hypoglycaemia with blood glucose levels ≤ 70 mg/dl was less frequent in the CGM group than in the control group, but without a statistically significant difference. Time with glucose levels ≤ 70 or >180 mg/dl was significantly lower in the CGM group than in the control group. Mean HbA1c at the end of the study (adjusted for baseline) was significantly better in the CGM group. In the three age groups results of treatment group comparisons were similar to those of the overall analysis. No significant difference was found in the rate of severe hypoglycaemic episodes between the CGM and the control groups.
Conclusions: Better HbA1c level and less time with hypoglycaemia or hyperglycaemia (> 180 mg/dl) suggest that CGM is beneficial for individuals with T1D who have already achieved the metabolic control target.
- • Comment: Hypoglycaemia remains a major limiting factor in achieving glycaemic control targets (22). In a previous reported randomised trial of 322 adults and children (29 children aged 8–14 years were included in the study) with T1D and baseline HbA1c level ≥ 7%, the JDRF-CGM Study Group demonstrated that CGM improved HbA1c levels without increasing the frequency of hypoglycaemia in adults > 25 years of age, whereas the decrease in HbA1c levels in the paediatric population was more limited (13).
The same group in the present study tried to look whether there are any benefits in the use of CGM in a population with T1D with excellent metabolic control. We have to realise that these patients already at baseline adhere to intensive diabetes management with frequent blood glucose monitoring, averaging 6–7 times/day. As expected, consistent with pre-study management behaviours, adherence to GCM use was high during this study in all age groups.
The study demonstrated that even well-controlled patients can benefit from the use of CGM. The use of CGM in these patients helped them to keep the good HbA1c level or even improve it, with increased time within target glucose levels (70–180 mg/dl) and decreased time with hypoglycaemic levels (< 70 mg/dl) also in the paediatric age group. However, the use of CGM did not resolve the problem of severe hypoglycaemic episodes, which still remains a cardinal problem especially among paediatric patients with T1D.
Effectiveness of continuous glucose monitoring in a clinical care environment. Evidence from the Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Trial
Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group
Diabetes Care 2010; 33: 17–22
Background: Achieving and maintaining HbA1c targets with minimal glucose excursions is the aim of diabetes patients and their caregivers. Previous JDRF-CGM studies demonstrated the efficacy of CGM in a controlled environment of a randomised trial with intensive subject monitoring and supervision. The aim of this study was to examine if CGM is effective in the management of T1D in the standard clinical practice.
Methods: After the end of a 6-month randomised controlled trial evaluating the use of CGM in T1D patients (8,9), the device was initiated in the control group of the study (n = 214, 73 subjects were 15–24 years old, 61 subjects were 8–14 years old) with less intensive training and follow-up compared with those of the trial itself. Patients had an outpatient training session, four visits in the clinic and two follow-up phone calls during a 6-month period. The primary outcome was a change in HbA1c after 6 months in subjects with baseline HbA1c ≥ 7%.
Results: There was a significant decrease (p < 0.001) in the use of CGM after 6 months in all age groups, although less in the adult group. In subjects with a baseline HbA1c≥ 7%, the frequency of CGM use was associated with a significant HbA1c reduction after 6 months. Subjects who used the device consistently saw a significant increase in the amount of time spent in the target glucose range and decreased exposure to hyperglycaemia. A trend was observed in the decrease of severe hypoglycaemic episodes after 6 months (p = 0.08).
Conclusions: This extension arm of the study also demonstrated that sustained frequent use of CGM is less likely in children and adolescents. However, frequent use of the device in a clinical care setting may improve metabolic control.
Prolonged nocturnal hypoglycaemia is common during 12 months of continuous glucose monitoring in children and adults with type 1 diabetes
Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group
Diabetes Care 2010; 33: 1004–8
Background: Even with the use of advanced technology of insulin analogues and insulin pumps, severe hypoglycaemia, especially nocturnal, is common in T1D patients. The aim of the present study was to evaluate the amount of nocturnal hypoglycaemia during 12 months of CGM use, and factors associated with it among patients who participated in the JDRF-CGM randomised trial.
Methods: The CGM data were evaluated from midnight to 6.00 am. Only patients with readings from at least 42 nights during 12 months (n = 176, 64 patients 8–14 years old and 42 patients 15–24 years old) and only nights having at least 4 h of glucose readings were included in the analysis. A hypoglycaemic event was defined as the occurrence of at least two CGM glucose values ≤ 60 mg/dl within a 20-min period. The percentage of nights with at least one hypoglycaemic event was computed for each patient.
Results: Median percentage of nights with hypoglycaemia per subject was 7.4%, with duration of hypoglycaemia ≥ 2 h on 23% of the nights with hypoglycaemia. A higher incidence of nocturnal hypoglycaemia over 12 months was associated with baseline lower HbA1c levels (p < 0.001) and occurrence of nocturnal hypoglycaemia during baseline blinded CGM use (p < 0.001).
Frequency of nocturnal hypoglycaemia was not associated with age or insulin modality (insulin pump vs. MDI).
Conclusions: Prolonged nocturnal hypoglycaemia is a relatively frequent event, especially in patients with lower HbA1c levels, without a significant difference between children and adults.
- • Comment: Recurrent episodes of hypoglycaemia, especially at young ages, may cause short- and long-term adverse effects on cognitive function, lead to hypoglycaemia unawareness, and be associated with significant emotional morbidity for the child and parents. Fear of hypoglycaemia, especially during the night, may compromise quality of life for the family, and jeopardise efforts for better metabolic control. The results of this study demonstrate the scope of the problem. Maybe the development of closed-loop systems with the fine tuning of feedback control of insulin delivery based on real-time CGM data will help to minimise this problem.
Suspended insulin infusion during overnight closed-loop glucose control in children and adolescents with type 1 diabetes
D. Elleri,1,2J. M. Allen,1,2M. Nodale,2M. E. Wilinska,1,2C. L. Acerini,1D. B. Dunger,1,2R. Hovorka1,2
1Department of Paediatrics and2Institute of Metabolic Science, University of
Cambridge, Cambridge, UK
Diabet Med 2010; 27: 480–4
Background: Some physicians have expressed concern that an interruption of insulin delivery when hypoglycaemia is predicted during overnight closed-loop glucose control might result in hyperglycaemia.
Methods: In seven young people aged 14.2 ± 2.1 years with T1D (duration 6.9 ± 4.0 years), insulin delivery was discontinued for 165 min [median interquartile range (IQR) 105–210] when hypoglycaemia was predicted. The prediction algorithm was based on the model predictive control approach.
Results: Plasma glucose was 6.2 ± 3.2 mmol/l (mean ± SD) at the time insulin was suspended and reached a nadir of 5.2 ± 2.7 mmol/l after 60 min of insulin suspension. The lowest observed plasma glucose level was 3.0 mmol/l at 45 min after pump suspension. When insulin delivery resumed, mean plasma glucose was 6.4 ± 2.2 mmol/l and it peaked 60 min later at 7.9 ± 2.1 mmol/l. The maximum observed plasma glucose within 120 min of resuming the insulin was 11.6 mol/l.
Conclusions: Suspension of insulin delivery during closed-loop glucose control was not associated with an increased risk of hyperglycaemia.
- • Comment: Although the number of subjects reported (seven) was small, useful data on the safety of discontinuing insulin in a closed-loop system was provided. Studies during the night, when young people are most apt to experience severe hypoglycaemia and when routine blood glucose testing is usually not done, are particularly important. Future studies should also report data on blood ketone monitoring.
Manual closed-loop insulin delivery in children and adolescents with type 1 diabetes: a phase 2 randomised crossover trial
R. Hovorka,1,2J. M. Allen,1,2D. Elleri,1,2L. J. Chassin,1,2J. Harris,2D. Xing,3C. Kollman,3T. Hovorka,1A. M. Larsen,1M. Nodale,1A. De Palma,1M. E. Wilinska,1,2C. L. Acerini,1,2D. B. Dunger1,2
1Department of Paediatrics and2Institute of Metabolic Science, University of Cambridge, Cambridge, UK, and3Jaeb Center for Health Research, Tampa, FL, USA
Lancet 2010; 375: 743–51
Background: Closed-loop systems link continuous glucose measurements to insulin delivery. The aim of this trial was to establish whether closed-loop insulin delivery could control overnight blood glucose in young people.
Methods: Three randomised crossover studies were undertaken in 19 patients aged 5–18 years with T1D of duration 6.4 years (SD 4.0). They compared standard CSII and closed-loop delivery (n = 13; APCam01); closed-loop delivery after rapidly and slowly absorbed meals (n = 7; APCam02); and closed-loop delivery and standard treatment after exercise (n = 10; APCam03). Allocation was by computer-generated random code. Participants were masked to plasma and sensor glucose. In APCam01, investigators were masked to plasma glucose. During closed-loop nights, glucose measurements were fed every 15 min into a control algorithm calculating rate of insulin infusion, and a nurse adjusted the insulin pump. During control nights, patients’ standard pump settings were applied. Primary outcomes were time for which plasma glucose concentration was 3.91–8.00 mmol/l or ≤ 3.90 mmol/l. Analysis was per protocol.
Results: Seventeen patients were studied for 33 closed-loop and 21 continuous infusion nights. Primary outcomes did not differ significantly between treatment groups in APCam01 (12 analysed; target range, median 52%, IQR 43–83, closed-loop vs. 39%, IQR 15–51, standard treatment, p = 0.06; ≤ 3.90 mmol/l, 1%, IQR 0–7 vs. 2%, IQR 0–41, p = 0.13), APCam02 (six analysed; target range, rapidly absorbed meal 53%, IQR 48–57 vs. slowly absorbed meal 55%, IQR 37–64, p = 0.97; ≤ 3.90 mmol/l, 0%, IQR 0–4 vs. 0%, IQR 0–0, p = 0.16) and APCam03 (nine analysed; target range 78%, IQR 60–92, closed-loop vs. 43%, IQR 25–65, control, p = 0.0245, not significant at corrected level; ≤ 3.90 mmol/l, 10%, IQR 2–15 vs. 6%, IQR 0–44, p = 0.27). A secondary analysis of data documented increased time in the target range (60%, IQR 51–88 vs. 40%, IQR 18–61; p = 0.0022) and reduced time for which glucose concentrations were ≤ 3.90 mmol/l (2.1%, IQR 0.0–10.0 vs. 4.1%, IQR 0.0–42.0; p = 0.0304). No events with plasma glucose concentration < 3.0 mmol/l were recorded during closed-loop delivery, compared with nine events during standard treatment.
Conclusions: Closed-loop systems could reduce the risk of nocturnal hypoglycaemia in children and adolescents with T1D.
- • Comment: Although a small sample size (19 patients) and a conglomerate of three studies, this study demonstrates the usefulness of closed-loop systems overnight to reduce the risk of nocturnal hypoglycaemia and improve overall glycaemic control in youth. Interestingly, the data also show that glucose control with manual closed-loop delivery was not adversely affected by exercise or the consumption of rapidly and slowly absorbed meals. Improved sensing accuracy and more sophisticated applications to improve daytime control will provide a significant step toward developing a fully automatic closed-loop system.
Effectiveness of sensor-augmented insulin pump therapy in type 1 diabetes
R. M. Bergenstal,1W. V. Tamborlane,2A. Ahmann,3J. B. Buse,4G. Dailey,5S. N. Davis,6C. Joyce,7T. Peoples,8B. A. Perkins,9J. B. Welsh,8S. M. Willi,10M. A. Wood,11for the STAR 3 Study Group
1International Diabetes Center at Park Nicollet, Minneapolis, MN, USA,2Yale University, New Haven, CT, USA,3Oregon Health and Science University, Portland, OR, USA,4University of North Carolina School of Medicine, Chapel Hill, NC, USA,5Scripps Institute, La Jolla, CA, USA,6University of Maryland School of Medicine, Baltimore, MD, USA,7Memorial University of Newfoundland, Health Science Center, St John’s, NL, Canada,8Medtronic, Northridge, CA, USA,9Toronto General Hospital, Toronto, ON, Canada,10Children’s Hospital of Philadelphia, Philadelphia, PA, USA, and11Helen DeVos Children’s Hospital, Grand Rapids, MI, USA
N Engl J Med 2010; 363: 311–20
Background: Insulin pumps and CGM sensors represent technologies designed to assist patients with T1D in safely reaching glycaemic goals. Recent studies have suggested that patients who used sensor-augmented pump therapy with adherence to CGM had improved HbA1c levels without an increased rate of hypoglycaemia. The aim of this multicentre randomised controlled trial was to compare the efficacy of sensor-augmented pump therapy with that of a regimen of MDI in 485 patients (329 adults and 156 children) with inadequately controlled T1D for 1 year.
Methods: Patients eligible for the study were those with T1D, aged 7–70 years, who had received MDI that included long-acting analogue insulin during the previous 3 months and who had glycated haemoglobin of 7.4–9.5%. Patients were randomly assigned to receive either sensor-augmented pump therapy or a regimen of MDI. Primary end-point was the change from the baseline glycated haemoglobin level at 1 year.
Results: At 1 year, the baseline mean glycated haemoglobin level (8.3% in both study groups) had decreased to 7.5% in the pump therapy group, compared with 8.1% in the MDI group (p < 0.001). In both adults and children in the pump therapy group, glycated haemoglobin levels fell rapidly from baseline to 3 months and remained lower than levels in the MDI group for the remainder of the study. An increased frequency of sensor use was associated with a greater reduction in glycated haemoglobin levels at 1 year.
The proportion of patients who reached the glycated haemoglobin target was greater in the pump therapy group than in the MDI group, both in adults and children. The rate of severe hypoglycaemia in the pump therapy group did not differ significantly from that in the MDI group, and there was no significant weight gain in either group.
Conclusions: In both adults and children with inadequately controlled T1D, sensor-augmented pump therapy resulted in significant improvement in glycated haemoglobin levels compared with injection therapy. A significantly greater proportion of both adults and children in the pump therapy group than in the MDI group reached the target glycated haemoglobin level, without increasing biochemical hypoglycaemia or the rate of severe hypoglycaemic events.
- • Comment: This trial demonstrated that nearly half the children in the pump therapy group reached the American Diabetes Association age-specific targets for glycated haemoglobin by the end of the study. In contrast to the findings in previous studies, this study suggested that the effects of the combined system were greater than what would be expected from the individual components alone. However, it did not evaluate the effect of insulin pump therapy alone vs. sensor-augmented pump therapy to determine the contribution of each component of the system. In patients with T1D, including children with suboptimal glycaemic control, the use of a sensor-augmented insulin pump can be considered to try to improve glycaemic control.
New therapies in type 1 diabetes
Inflammatory markers are increased in youth with type 1 diabetes: the SEARCH case–control study
J. K. Snell-Bergeon,1N. A. West,1E. J. Mayer-Davis,1A. D. Liese,2S. M. Marcovina,3R. B. D’Agostino,4R. F. Hamman,1D. Dabelea1
1Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO, USA,2Gillings School of Global Public Health and School of Medicine, University of North Carolina, Chapel Hill, Department of Epidemiology and Biostatistics and Center for Research in Nutrition and Health Disparities, NC, USA,3Northwest Lipid Metabolism and Diabetes Research Laboratories, University of Washington, Seattle, WA, USA, and4University of South Carolina, Columbia, SC, and Wake Forest University School of Medicine, SC, USA
J Clin Endocrinol Metab 2010; 95: 2868–76
Background: The objective of the study was to investigate the association of inflammation with obesity, hyperglycaemia and dyslipidaemia in youth with T1D.
Methods: This was a cross-sectional study of youth with and without T1D. The patients were SEARCH case–control participants with T1D (n = 553; mean age 15 years, range 10–22; median duration 2.7 years) and without diabetes (n = 215; mean age 15 years, range 10–22). The main outcome measures were interleukin-6 (IL-6), high-sensitivity C-reactive protein (hsCRP), fibrinogen and leptin.
Results: Inflammatory markers were evaluated by diabetes status, quartiles of glycated haemoglobin and obesity using multiple linear regression analyses, adjusted for age, sex, study site, race/ethnicity, T1D duration, body mass index and pubertal status. Compared with controls, youth with T1D had higher IL-6 and fibrinogen levels at all levels of glycaemia and obesity, and hsCRP levels were significantly higher in youth with T1D in the top three quartiles of glycated haemoglobin (≥ 7.2%) and among normal-weight subjects. Leptin was lower in youth with poor glycaemic control. Higher hsCRP and fibrinogen were correlated with higher total and low-density lipoprotein cholesterol and apolipoprotein B in youth with T1D, whereas higher fibrinogen was correlated with higher low-density lipoprotein and apolipoprotein B in controls.
Conclusions: T1D is characterised by excess inflammation, independent of adiposity and glycaemic control. Even T1D youth in good glycaemic control had higher levels of IL-6 and fibrinogen than controls. Elevated inflammatory markers were associated with an atherogenic lipid profile, which may contribute to accelerated atherosclerosis in youth with T1D.
- • Comment: Although elevated IL-6 and hsCRP levels have been shown previously in youth with T1D, the size of this study and the differences were impressive. One has to wonder at what stage intervention with anti-inflammatory agents might be effective. Other than worrying about Reye’s syndrome, a trial of aspirin therapy would be of interest.
Etanercept treatment in children with new-onset type 1 diabetes: pilot randomised placebo-controlled, double-blind study
L. Mastrandera,1,2J. Yu,3T. Behrens,1J. Buchlis,1,2C. Albini,1,2S. Fourtner,1,2T. Quattrin1,2
1Department of Pediatrics, School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA,2Women and Children’s Hospital of Buffalo-Kaleida Health, Buffalo, NY, USA, and3Department of Biostatistics, School of Public Health, University at Buffalo, Buffalo, NY, USA
Diabetes Care 2009; 32: 1244–9
Background: TNF-α and other cytokines play a role in the autoimmune process leading to T1D. Etanercept (a recombinant soluble TNF-α receptor fusion protein) binds to TNF-α, clears it from the circulation, and blocks its biological activity. The aim of this study was to evaluate if Etanercept administration can prolong the partial remission period in children with newly diagnosed T1D.The end-points were percentage change from baseline of HbA1c, C-peptide AUC and insulin dosage.
Methods: A randomised double-blind, placebo-controlled trial of 24 weeks included 18 patients with newly diagnosed diabetes (< 5.7 weeks) aged 7.8–18.2 years, with positive glutamic acid decarboxylase and/or insulin autoantibody and HbA1c > 6%, who were randomly assigned to receive either subcutaneous injection of Etanercept or placebo.
Results: After 24 weeks, the HbA1c level was lower in the Etanercept group compared with the placebo (5.9% ± 0.5% vs. 6.98% ± 1.2%, p < 0.05). At week 24, there was an increase of 39% in the C-peptide AUC in the Etanercept group, whereas in the placebo group C-peptide AUC decreased by 20% (p < 0.05). The insulin dose decreased in the Etanercept group and increased in the placebo (p < 0.05). No severe adverse events were reported.
Conclusions: This pilot study demonstrated that Etanercept may preserve β-cell function with an increase in endogenous insulin production, and better glycaemic control.
- • Comment: In the last decade a lot of studies about agents that may preserve the β-cell function have been published. Most of the agents have a significant effect on the immune system. Although the results of the present study sound promising, we need to remember that it is a small study of short duration, and larger studies are needed to confirm the efficacy and safety of Etanercept in the long term in newly diagnosed paediatric patients with T1D.
Effect of ingested interferon-α on β-cell function in children with new-onset type 1 diabetes
K. I. Rother,1R. J. Brown,1M. M. Morales,2E. Wright,1Z. Duan,1C. Kampbell,1D. M. Harlan,1P. R. Orlander,3S. Brod,2D. S. Hardin,4J. Popovic,5R. C. McEvoy6
1National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA,2University of Texas Medical School, Department of Neurology, Houston, TX, USA,3University of Texas Medical School, Department of Internal Medicine, Houston, TX, USA,4University of Texas Southwestern, Dallas, TX, USA,5Children’s Mercy Hospital and Clinics, Kansas City, MI, USA, and6St Paul Children’s Hospital, St Paul, MI, USA
Diabetes Care 2009; 32: 1250–5
Background: Preservation of β-cell function is an important treatment goal in patients with T1D. Multiple clinical trials attempted to prevent progressive β-cell destruction after onset of T1D using immunosuppressive or immunomodulatory agents. The current trial evaluated the safety and efficacy of ingested hrINF-α to preserve β-cell function in newly diagnosed patients with T1D.
Methods: A prospective randomised placebo-controlled, double-blind, multicentre, parallel group study of 128 patients aged 3–25 years with diabetes duration up to 6 weeks, without other significant concurrent illness, was carried out. Patients were randomly assigned to receive ingested hrINF-α at 5000 or 30,000 units or placebo once daily for 1 year. The primary outcome was the change in meal-stimulated C-peptide AUC from the beginning to the end of the study. A data safety review was performed.
Results: Children treated with hrINF-α lost significantly less of their C-peptide secretion, especially those receiving the low dose (5000 units) in comparison with the placebo (29% ± 54% vs. 56% ± 29%, respectively, p = 0.028). There was no difference in the occurrence of adverse events among the three treatment groups. No difference was found among treatment groups for the decline in HbA1c from screening to 12 months.
Conclusions: This study demonstrated that ingested hrINF-α was a safe medication, and a beneficial effect on β-cell function was observed after 1 year in the 5000-unit group.
- • Comment: Greater residual β-cell function lowers the risk of developing microvascular complications and markedly reduces the risk of hypoglycaemia (23). Preservation of residual endogenous insulin secretion is predicted to have a major impact on metabolic control in T1D patients. This study gives hope in particular for young patients because of its good safety profile, oral use, and beneficial effect on β-cell function. However, the long-term effects of hrINF-α in newly diagnosed T1D patients are still unknown, and further larger studies are needed to determine whether there is any sustained benefit without long-term safety issues.