Diabetes Technology and Treatment in the Pediatric Age Group

Abstract

Introduction

T he diagnosis of diabetes in a child or adolescent puts many strains on both the patient and his/her family. In the diabetes clinic, we face the changes in treatment adherence and glycemic control during transition from childhood to adolescence.

The never-ceasing challenge faced by patients and their caregivers has inspired continuing efforts to find ways and means for achieving better glycemic control. With the help of modern technology, young patients with T1D can live a normal life because they have better options such as with methods of glucose testing and insulin administration. An increasing number of medical facilities now offer treatments that can help the child live an active, fun, and healthy life.

A multicenter analysis reviewed below demonstrates the change in metabolic control in children and adolescents with T1D during the past decade. Previous studies in children and adolescents (1,2) reported the association between lower HbA1c levels and a higher frequency of daily self blood glucose monitoring. The use of a device such as real-time continuous glucose monitoring (CGM) that provides 24-hour continuous glucose measurements 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 hypoglycemia. In the last year, studies reviewed below evaluated the implications and advantages of using CGM alone or as a part of sensor-augmented pump therapy in pediatric patients. The low-glucose suspend (LGS) feature is the beginning of the closed loop pancreas, and the Danne et al. (2011) article reviewed below clearly showed its effectiveness in reducing time spent in hypoglycemia in children with T1D.

T1D is characterized by immune-mediated pancreatic β-cell destruction. Thus, a major goal in the treatment of T1D in youth is in the area of prevention. An important study (reviewed below) used antigen-based (GAD) therapy to try to prevent loss of islet-cell function in newly diagnosed subjects. Both patients with T1D and staff are waiting for the big breakthrough that will lead to a cure of their disease.

Our review of the literature included a Medline search for articles dealing with the following topics: diabetes technology, insulin pump therapy (CSII), continuous glucose monitoring (CGM), closed-loop systems, and new therapies (immune-modulation, etc.) in T1D relating to the pediatric age group (0–18 yrs). We centered on recent key articles that offer some insight into these issues that have appeared between July 1, 2011, and June 30, 2012.

Improved metabolic control in children and adolescents with type 1 diabetes—a trend analysis using prospective multicenter data from Germany and Austria

Rosenbauer J¹, Dost A², Karges B³, Hungele A⁴, Stahl A¹, Bächle C¹, Gerstl EM⁵, Kastendieck C⁶, Hofer SE⁷, Holl RW⁴, and on behalf of the DPV Initiative and the German BMBF Competence Network Diabetes Mellitus

¹Institute of Biometrics and Epidemiology, German Diabetes Center, Leibniz Center at University of Düsseldorf, Düsseldorf, Germany; ²Department of Pediatrics, Friedrich Schiller University of Jena, Jena, Germany; ³Division of Endocrinology and Diabetes, RWTH Aachen University, Aachen, Germany; ⁴Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm, Germany; ⁵Children's Hospital, Passau, Germany; ⁶Children's Hospital Bremen North, Bremen, Germany; and ⁷Department of Pediatrics, Medical University of Innsbruck, Innsbruck, Austria

Diabetes Care 2012; 35 : 80–86

Background

Diabetes treatment has been intensified in pediatric patients by the use of MDI or CSII, use of new short- and long-term insulin analogues, and increased frequency of daily self-monitoring of blood glucose (SMBG). Despite these changes in diabetes therapy, the anticipated improvement in metabolic control in children and adolescents with T1D has not been achieved in all settings.

The aim of the study was to investigate the trend of metabolic control over the past 15 years and to identify potential predictors in German and Austrian children and adolescents with T1D.

Methods

This study was based on a multicenter database for prospective longitudinal documentation of diabetes care in Germany and Austria. Data from 30,708 patients documented in 305 diabetes centers between 1995 and 2009 were analyzed. Generalized linear mixed regression models were used.

Results

Mean age of the cohort (n=30,708, 52.1% males) was 14.6±3.7 years, and mean age at onset and mean diabetes duration were 7.9±4.0 and 6.7±3.6 years, respectively. Overall, 65% of patients were treated with MDI, and 24.9% with CSII. Average HbA1c was 8.4±1.7%; 33.7% of patients achieved HbA1c values <7.5%. Mode of insulin therapy changed during the study period, with increased proportion of patients treated with CSII (from 0.9% in 1995 to 36.6% in 2009). Mean HbA1c decreased from 8.7±1.8% to 8.1±1.5%, with an average annual decrease in HbA1c of 0.054% (p<0.001).

In multiple regression analysis, age, sex, diabetes duration, migration background, BMI-SDS, and daily insulin dose were significant predictors of metabolic control (assessed as HbA1c, proportion with HbA1c >7.5 or >9.0%). Older and female patients, patients with longer diabetes duration, higher insulin dose or a migration background, and patients in the upper BMI-SDS percentile had poorer metabolic control. Mode of insulin therapy was significantly associated only with the proportion of patients having HbA1c >9.0%; patients with more intensive insulin therapy were less frequent in poor metabolic control.

The size of diabetes center was significantly associated with mean HbA1c but not with moderate or poor metabolic control. Adjusted mean HbA1c was higher among patients treated in large centers. Metabolic outcomes did not significantly differ between patients treated in general care or rehabilitation facilities, but rehabilitation patients tended to have poorer metabolic control.

Rate of severe hypoglycemia and hypoglycemic coma decreased significantly over the study period, without a significant variation in diabetic ketoacidosis rate over time.

Conclusions

A significant improvement was found in metabolic control in children and adolescents with T1D during the past decade with a simultaneous decrease in hypoglycemic events. The improvement was not completely explained by changes in the mode of insulin treatment.

Comment

It is encouraging to see that the metabolic control of patients with T1D improves during the years, with the hope to decrease the rate of micro- and macro-vascular complications. The changes in the mode of insulin treatment can explain the better achievements of glycemic control, and indeed multiple trials have tried to look at which is the best mode of therapy to improve metabolic control in patients with T1D. However, other factors, such as improvement in resources, organization, attitudes of diabetes care teams, and patient education also may have accounted for the observed trend.

Changes in treatment adherence and glycemic control during the transition to adolescence in type 1 diabetes

Rausch JR¹, Hood KK¹, Delamater A², Pendley JS³, Rohan JM^1,4, Reeves G⁵, Dolan L⁶, Drotar D^1,4

¹Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; ²Department of Pediatrics, University of Miami, Miami, Florida; ³Division of Behavioral Health, Alfred I. DuPont Hospital for Children, Wilmington, Delaware; ⁴Department of Psychology, University of Cincinnati, Cincinnati, Ohio; ⁵Division of Pediatric Endocrinology, Alfred I. DuPont Hospital for Children, Wilmington, Delaware; and ⁶Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio

Diabetes Care, 2012; 35 : 1219–1224

Background

It has long been recognized that glycemic control for youth with T1D worsens during adolescence. However, the timing and the reasons for the increase in HbA1c levels have not been clear.

Methods

In all, 225 youth (ages 9–11 years) were followed for two years to evaluate change between treatment adherence (blood glucose monitoring frequency [BGMF]) and resulting glycemic control (HbA1c levels).

Results

HbA1c levels increased from 8.2% to 8.6% (p<0.001) and BGMF decreased from 4.9 to 4.5 checks/day (p<0.02) over the two-year period. One less blood glucose check per day predicted an increase in HbA1c of 1.26%.

Conclusions

Although many studies have evaluated older adolescents, this report focused on the transition to adolescences and BGMF. Preventive intervention in early adolescence could help to maintain adherence and glycemic control in later adolescence.

Comment

This study emphasizes early adolescence as a time to intervene to maintain glycemic control in later adolescence. The authors note that other relevant contributors to glycemic control, such as dosing adequacy and timing of insulin administration, also need to be evaluated. They do not address missed insulin boluses, although two-thirds of the youth were on insulin pumps at the one- and two-year follow-up times, and this data could have been obtained from pump downloads. Another issue needing to be addressed in the future will be how to persuade the early adolescents to continue to do frequent blood glucose checking. Many challenges still remain.

Does the timing of insulin pump therapy initiation after type 1 diabetes onset have an impact on glycemic control?

Shalitin S^1,2, Lahav-Ritte T², Lebenthal Y ^1,2, deVries L^1,2, Phillip M^1,2

¹The Jesse Z and Lea Shafer Institute of Endocrinology and Diabetes, National Center for Childhood Diabetes, Schneider Children's Medical Center of Israel and Felsenstein Medical Research Center, Petach Tikva; and ²Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

Diabetes Technology & Therapeutics 2012; 14 : 1–9

Background

Over the past decade, continuous subcutaneous insulin infusion (CSII) has become a standard treatment option for patients with T1D. CSII mimics physiologic insulin release better than multiple daily injection (MDI) therapy and allows for greater flexibility in food intake and physical activity. Given these benefits, it raises the question “Is it a requirement to wait to offer CSII to patients with T1D only after MDI therapy has failed?”

This study sought to determine if starting CSII in patients with T1D within one year of diagnosis results in better long-term glycemic control than starting it later.

Methods

This retrospective observational study included 488 patients (273 females) with T1D attending a major tertiary-care hospital. Inclusion criteria were: age <40 years, initiation of CSII treatment during the period from January 1998 to December 2008, use of CSII for ≥1 year, and follow-up for at least one year after CSII initiation. The medical charts were reviewed for background, disease-related, and treatment-related data.

Study end points were: mean HbA1c value and rates of severe hypoglycemia and diabetic ketoacidosis (DKA) events during use of CSII. Findings were compared between patients who started CSII within 1 year of diagnosis (Group 1, n=93) or later (Group 2, n=395).

Results

There were no significant differences between the groups in gender, ethnic distribution, or the indication for CSII initiation. Sixty-seven (13.7%) patients discontinued CSII therapy after more than one year of pump use, without a significant difference between the groups.

Compared with Group 2, Group 1 patients were characterized by a significantly younger age at CSII initiation (10.7±5.7 vs. 16.4±7.0 years, p<0.001), more frequent blood glucose monitoring (5.4±1.8 vs. 3.9±1.5 times per day, p<0.001), and shorter total duration of diabetes (4.3±2.1 vs. 11.9±6.4 years, p<0.001) and of CSII therapy (3.6±2.1 vs. 4.7±2.5 years, p<0.001). There were no significant between-group differences in mean HbA1c level, attainment of target HbA1c, or rates of severe hypoglycemia or DKA events after CSII initiation.

The percentage of patients who achieved good glycemic control was higher among those offered CSII due to recurrent hypoglycemic episodes than those offered CSII due to an above-target HbA1c level, with no difference between Group 1 and Group 2. On multiple logistic regression analysis, the significant factor that predicted achievement of the HbA1c target was the mean daily number of SMBG with CSII therapy.

Conclusions

Starting pump therapy at an early disease stage has no added benefit for glycemic control over time than starting later. The timing of CSII initiation should be tailored to the individual patient by the diabetes care team.

Comment

This study showed that initiation of CSII therapy during the first year after T1D onset is more common among younger patients with newly diagnosed disease.

It may be speculated that the relatively higher percentage of Group 1 patients in pubertal Tanner stages 2–4, relative to Group 2, at both CSII initiation and the last visit, contributed to the increased HbA1c levels in Group 1, resulting in a non-significant between-group difference in glycemic control. However, a comparison of mean HbA1c between the different pubertal stages in both groups failed to yield significant differences as well.

A significant correlation was found between the mean daily number of SMBG and better mean HbA1c level, which may represent how well patients are making insulin adjustments in addition to overall adherence to treatment. Patients who started CSII therapy during the first year of diabetes routinely performed more frequent SMBG than those who started later. This finding might be attributed to the younger age of patients in Group 1, which was correlated with more frequent daily SMBG. It also may be related to the more frequent boluses given to patients on CSII than on MDI therapy, so they need to monitor glucose more frequently in order to calculate the correction bolus dose. Perhaps the sooner these skills are learned, the better their implementation.

It is noteworthy that although insulin replacement by CSII more closely resembles the normal physiology than MDI treatment, starting CSII shortly after diabetes onset can be more time-consuming and stressful for both patient and family. The patients and families are burdened not only with the need to cope with the new diagnosis but also with the need to learn new skills and techniques.

This study found that CSII implementation during the first year after diagnosis did not lead to better glycemic control over time than with its initiation later in the course of the disease. However, conducting a prospective randomized controlled study with longitudinal follow-up will allow us to draw more firm conclusions about these results.

Feasibility of prolonged continuous glucose monitoring in toddlers with type 1 diabetes

Tsalikian E¹, Fox L², Weinzimer S³, Buckingham B⁴, White NH⁵, Beck R⁶, Kollman C⁶, Xing D⁶, Ruedy K⁶, Diabetes Research in Children Network (DirecNet) Study Group

¹Pediatric Endocrinology and Diabetes, University of Iowa, Iowa City, IA; ²Pediatric Endocrinology, Nemours Children's Clinic, Jacksonville, FL; ³Department of Pediatrics, Yale University, New Haven, CT; ⁴Pediatric Endocrinology and Diabetes, Stanford University, Stanford, CA; ⁵Department of Pediatrics, Washington University, St. Louis, MO; and ⁶Jaeb Center for Health Research, Tampa, FL

Pediatric Diabetes 2012; 13 : 301–307

Background

Real-time CGM systems offer the potential to assist patients with T1D to optimize glycemic control more safely. Whether frequent CGM use is achievable with current devices in very young children, and the benefits and difficulties that parents perceive in using these devices, has not been established.

The aim of this study was to evaluate the feasibility of daily CGM use over a prolonged period of time in children younger than four years with T1D.

Methods

The study was conducted by the Diabetes Research in Children Network (DirecNet) at five clinical centers. Twenty-three children with T1D <4 years of age, with insulin regimen involving use of either insulin pump (n=10) or ≥2 daily insulin injections (n=13) for at least one month, were provided with a FreeStyle Navigator^® (n=21) or a Paradigm^® (n=2) CGM device. The study protocol included an initial run-in period of 7–14 days, during which a blinded CGM device was used to collect baseline data and to evaluate whether the child/parent was capable of long-term CGM use. A minimum of 4/7 days and at least 96 h of successful glucose values, including ≥24 h overnight was necessary to continue in the 6-month study. In addition, at least three daily blood glucose meters (BGMs) were required. At baseline, mean age was 3.0±0.8 years, mean HbA1c was 8.0±0.8%. The parents were asked to attempt to use the CGM device on a daily basis and were given written instructions on how to use the data provided by CGM and BGM readings to make management decisions. Follow-up visits were conducted at 1, 4, 8, 13, 19, and 26 weeks, and phone calls with a parent were made between each visit to review downloaded glucose data and adjust diabetes management. The CGM satisfaction scale questionnaire was completed by the parent/guardian at 26 weeks. Severe hypoglycemia and other adverse events, including skin reactions, were monitored throughout the study.

Results

Three children dropped out of the study before the end of six months. Among the 20 children who completed six months of follow-up, CGM use in month 6 was ≥6 days/week in 9 (45%), 4–6 days/week in 2 (10%), and <4 days/week in 9 (45%). Skin reactions were minimal. There was no detectable change in mean HbA1c between baseline and six months (7.9% vs. 8.0%, respectively). However, there was a high degree of parental satisfaction with CGM as evaluated with the questionnaire. A high percentage of glucose values were in the hyperglycemic range, and biochemical hypoglycemia was infrequent.

Conclusion

More than 40% of very young children were able to safely use CGM on a near-daily basis after six months. Although improvement in glycemic control was not detected in the group as a whole, parental satisfaction with CGM was high.

Comment

Treatment of very young children with T1D is difficult due to irregular patterns of eating, increased sensitivity to small changes in insulin doses, the requirements to deliver small doses of insulin, and difficulty to recognize hypoglycemia. Hypoglycemic episodes have effects on cognition, and it may play a role in the development of learning disabilities. Chronic hyperglycemia may adversely affect the developing brain, hence the avoidance of frequent or severe hypoglycemia, and persistent hyperglycemia may be critical.

This pilot study has demonstrated that a CGM device can be successfully and safely worn on a frequent basis by very young children with T1D. However, we have to remember that the participants reflect a select group of families. After six months, parental satisfaction with using CGM was remarkably high, despite the lack of improvement in HbA1c. Although CGM appeared to enhance parent quality of life, particularly with respect to avoidance of hypoglycemia, this did not translate into more aggressive management in an attempt to achieve tighter glucose control. Thus, better understanding of barriers to achieve better glycemic control are needed.

A randomized clinical trial to assess the efficacy and safety of real-time continuous glucose monitoring in the management of type 1 diabetes in young children aged 4 to <10 years

Mauras N¹, Beck R², Xing D², Ruedy K², Buckingham B³, Tansey M⁴, White NH⁵, Weinzimer SA⁶, Tamborlane W⁶, Kollman C², and the Diabetes Research in Children Network (DirecNet) Study Group

¹Division of Pediatric Endocrinology, Nemours Children's Clinic, Jacksonville, Florida; ²Jaeb Center for Health Research, Tampa, Florida; ³Division of Pediatric Endocrinology, Stanford University, Stanford, California; ⁴Division of Pediatric Endocrinology, University of Iowa, Iowa City, Iowa; ⁵Department of Pediatrics, Washington University, St. Louis, Missouri; and ⁶Division of Pediatric Endocrinology, Yale University, New Haven, Connecticut

Diabetes Care 2012; 35 : 204–210

Background

The benefits of continuous glucose monitoring (CGM) are most apparent with near-continuous wear of the sensors, in which knowledge gained in identifying glycemic patterns is incorporated into the day-to-day management of the individual's diabetes. The use of CGM has been less well studied in younger children with T1D, a group for whom parents are responsible for diabetes management, and parental fear of hypoglycemia often prevents better glycemic control.

The aim of this study was to evaluate the efficacy, safety, and effect of CGM on quality of life in young children.

Methods

A randomized control trial was conducted by the Diabetes Research in Children Network (DirecNet). Inclusion criteria were: children with T1D aged 4–10 years, HbA1c ≥7.0%, who were treated with basal-bolus therapy using either CSII or MDI for the prior three months with no plans to switch the insulin modality within the next six months.

After a run-in phase, 146 children (mean age 7.5±1.7 years, 64% on CSII, median diabetes duration 3.5 years) were randomly assigned to unblinded CGM or to usual care. Parents were instructed on the use of the device and encouraged to use the sensor on a daily basis. They were instructed to continue testing with the blood glucose meter (BGM) each day and to verify the accuracy of the CGM glucose measurement with the BGM before making management decisions. Parents of participants in both the CGM and control groups were provided with detailed instructions on how to use CGM and BGM data, respectively, to make real-time insulin dose adjustments, and on using computer software to retrospectively review the glucose data to alter insulin dosing.

The primary outcome was reduction in HbA1c at 26 weeks by ≥0.5% without the occurrence of severe hypoglycemia.

Results

The 26-week primary outcome visit was completed by 93% of patients in the CGM group and 94% in the control group. A decrease ≥0.5% in HbA1c occurred in 19% of the participants in the CGM group and in 28% in the control group (p=0.17). Mean change in HbA1c was similar between groups. Outcomes in subgroups based on age, sex, race/ethnicity, parent education level, insulin modality (CSII vs. MDI), baseline HbA1c, or BMI also did not differ between groups.

Glycemic outcomes measured with CGM showed no significant differences between treatment groups with respect to percent of values within, above, and below the target range. Severe hypoglycemia rates were similarly low in both groups. CGM wear decreased over time, with only 41% averaging at least 6 days/week at 26 weeks. There was no correlation between CGM use and the change in HbA1c. CGM wear was well tolerated, and parental satisfaction with CGM was high. However, parental fear of hypoglycemia was not reduced.

Conclusions

In young children, no benefit on glycemic control was found when using a CGM, despite high parental satisfaction with CGM.

Comment

As experienced with new technologies was gained, the expectations from the CGM to change the life of many patients with diabetes, and especially in the pediatric age group, was enormous. Monitoring of blood glucose is an important component of therapy in patients with diabetes. Standard use of glucose meters for self monitoring blood glucose (SMBG) provides only intermittent, single blood glucose levels, without illustrating the glucose variability during the 24 hours, and especially during the night, when blood glucose levels are seldom measured. Therefore, the use of a device such as the CGM that provides continuous glucose measurements 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 hypoglycemia.

However, this study demonstrated that in young children, no benefit on glycemic control was found with using a CGM. Despite the fact that wearing a sensor provides parental reassurance and comfort on a daily basis, sensor wear might not alter an underlying fear of hypoglycemia. In fact, it is possible that observing downward trends of the CGM glucose levels actually might have made some parents less aggressive in trying to achieve tighter glycemic control due to their fear of hypoglycemia. Other factors that may contribute to the lack of control improvement with the use of CGM may be related to limited use of CGM glucose data in the daily management of diabetes, and target glucose levels that were too high.

Satisfaction with continuous glucose monitoring in adults and youths with type 1 diabetes

Tansey M¹, Laffel L², Cheng J³, Beck R³, Coffey J¹, Huang E⁴, Kollman C³, Lawrence J⁵, Lee J⁶, Ruedy K³, Tamborlane W⁷, Wysocki T⁸, Xing D³ on behalf of Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group

¹Department of Pediatrics, University of Iowa, Iowa City, IA; ²Joslin Diabetes Center, Pediatrics, Boston, MA; ³Jaeb Center for Health Research, Tampa, FL; ⁴University of Chicago, Medicine, Chicago, IL; ⁵Department of Research and Epidemiology, Kaiser Permanente Southern California, Pasadena, CA; ⁶University of Michigan, Child Health Evaluation and Research Unit, Ann Arbor, MI; ⁷Yale University School of Medicine, Pediatrics, New Haven, CT; ⁸Nemours Children's Clinic, Center for Pediatric Psychology Research, Jacksonville, FL

Diabetic Medicine 2011; 28 : 1118–1122

Background

The Juvenile Diabetes Research Foundation (JDRF) Continuous Glucose Monitoring (CGM) Study Group demonstrated that frequent usage (>6 days/week) of continuous monitoring in patients with T1D results in lower HbA1c levels and avoidance of biochemical hypoglycemia. Consistent usage of CGM has been difficult to achieve, especially among children and adolescents.

To identify ways to reduce barriers to more consistent monitoring, it is important to understand how patients perceive the benefits and barriers of CGM. The aim was to describe satisfaction with CGM in patients with T1D; to correlate CGM satisfaction scores with usage; and to identify common themes in perceived benefits and barriers of monitoring reported by adults, youth, and the parents of youth in the JDRF–CGM trials.

Methods

Participants in the JDRF trial completed after 6 months of monitoring the CGM Satisfaction Scale (CGM-SAT), and also responded to open-ended questions of positive and negative attributes regarding CGM.

CGM-SAT assesses the impact of CGM on diabetes management, family relationships, emotions, and behavior. Respondents rate their agreement or disagreement using a 5-point Likert scale for 44 items. The psychometric properties identify two subdomains: “benefits” and “hassles”; a higher score reflects greater benefits or fewer hassles with CGM use.

Results

Of the total 224 adults (≥18 years) and 213 youths (8–18 years) who completed either parent (n=192) or youth (n=208) responses, 55% were female and 81% were pump users. In adults, median diabetes duration was 18 years and baseline HbA1c was 7.2±0.8%; in youths, median duration was 6 years and baseline HbA1c was 7.6±0.9%. The adults and parents had higher total and two subscale scores than youths (p<0.001). Frequent users (≥6 days/week) had higher overall scores and higher benefit and lower hassle scores (p<0.001) compared with infrequent users (<4 days/week). Similar patterns were observed in adults, youths, and parents, as well as both pump and injection-treated patients.

Specific CGM-SAT item scores were compared according to CGM usage for adults, youths, and parents, with items ranked by the greatest difference between frequent and infrequent users. The greatest difference in item scores between frequent and least frequent users among all age groups and parents were related to the burden of using the devices on the hassle subscale.

Among all groups of respondents, 43%–53% reported that seeing glucose trends and graphs were the best aspects of CGM; the ability to self-correct out-of-range glucose levels, the large amount of available data, and the ability to detect hypoglycemia were other benefits. Barriers to use included alarms, body issues (insertion sites and size of transmitter/receiver), and pain with sensor insertion. Self-reported benefits of, and barriers to, CGM use did not differ substantially according to frequency of CGM use.

Conclusions

As frequent use of CGM is associated with improved glycemic control without increased hypoglycemia, it is important to overcome barriers, reinforce benefits, and set realistic expectations for this technology in order to promote its more consistent and frequent use in individuals with T1D.

Comment

Participants reported higher scores for CGM-SAT on the benefits subscale than on the hassles subscale. This reflects the recognition of the hassles related to painful insertion and the recognition that use requires significant attention to detail, requiring more effort than expected. High CGM satisfaction in this study may be attributable to the selection of study participants. All were monitoring blood glucose levels 5–7 times/day, had to be practicing intensive therapy, and had successfully worn a CGM device for 1 week before randomization. Participants were also provided with CGM devices and sensors at no cost.

Frequent users reported greater satisfaction and had higher scores compared with infrequent users. This suggests that persons using CGM who perceive the benefits and wear the device frequently are less bothered by the hassles, while those persons who wear the device infrequently focus more on the hassles than the benefits. In response to open-ended questions, many participants appreciated that CGM provided previously unavailable data on glucose trends/graphs, as well as the ability to self-correct out-of-range glucose levels in real time. Conversely, between a quarter and a third of youths reported challenges with CGM alarms, insertion, and site/body issues related to the need to wear the device. Thus, it may be possible to encourage more frequent usage by focusing on the benefits of the technology and in pre-emptive counseling that provides realistic expectations and effective strategies to overcome the difficulties in using these devices. Future improvements in CGM systems that make them less painful and easier to use may result in more consistent use by more patients.

Sensor-augmented pump therapy for A1C reduction (STAR 3) study: results from the 6-month continuation phase

Bergenstal RM, Tamborlane WV, Ahmann A, Buse JB, Dailey G, Davis SN, Joyce C, Perkins BA, Welsh JB, Willi SM, Wood MA, STAR 3 Study Group

International Diabetes Center at Park Nicollet, Minneapolis, Minnesota

Diabetes Care 211; 34 : 2403–5

Background

The STAR-3 Trial (3) was reviewed in the ATTD yearbook previously. The aim of the multicenter, randomized trial was to compare the efficacy of sensor-augmented pump (SAP) therapy with that of MDI in 485 patients with inadequately controlled (HbA1c 7.4% to 9.5%) T1D. The initial manuscript showed the effectiveness of SAP therapy (HbA1c 7.5%) over MDI (HbA1c 8.1%; p<0.001) after 12 months. In addition to this 6-month follow-up report, two reviews relating to i) the pediatric patients in STAR-3, and ii) Health-Related Quality of Life (HRQOL) for treatment subjects will also be reviewed below.

Methods

This was a six-month single crossover continuation phase for 190 of the 204 subjects who initially received MDI in year one of the trial. The primary outcome was change in HbA1c in the crossover group.

Results

The HbA1c values decreased from 8.0% to 7.6% at both 15 and 18 months (p<0.001). The maximum HbA1c improvements in the crossover group occurred with sensor wear >60% of the time.

Conclusion

The crossover study confirmed the data of the original SAP study group.

Comment

The improvement in HbA1c levels for the control group after crossing over to SAP therapy confirms the original report. An interesting finding was that the initial SAP group (from year one) continued to do well (HbA1c levels of 7.5% at both 15 and 18 months). This was accomplished with sensor wear >40% of the time from 12 to 18 months. One wonders if “metabolic-memory” allowed for the good glycemic control in spite of the reduced use of the SAP.

Effectiveness of sensor-augmented pump therapy in children and adolescents with type 1 diabetes in the STAR 3 study

Slover RH ¹ , Welsh JB ² , Criego A ³ , Weinzimer SA ⁴ , Willi SM⁵, Wood MA ⁶ , Tamborlane WV ⁴

¹ Barbara Davis Center for Childhood Diabetes, Aurora, CO; ²Medtronic, Inc., Northridge, CA; ³Park Nicollet Clinic St Louis Park, MN; ⁴Department of Pediatrics, Yale School of Medicine, New Haven, CT; ⁵Children's Hospital of Philadelphia, Philadelphia, PA; ⁶Devos Children's Hospital, Grand Rapids, MI, USA

Ped Diabetes 2012; 13 : 6–11

Background

As noted above, the initial STAR-3 report related to all 485 randomized adult and pediatric patients. STAR-3 has been considered by many to be one of the most important clinical studies relating to T1D to date in the 21st century. The current report now focuses specifically on the pediatric patients.

Methods

A total of 82 children (ages 7–12 years) and 74 adolescents (ages 13–18 years) were randomized to continue MDI with SMBG or to use the SAP system for the one-year study.

Results

Baseline HbA1c values were similar in subjects randomized to the SAP (8.26±0.55%) and MDI (8.30±0.53%) groups. All subsequent HbA1c values showed significant (p<0.05) treatment group differences favoring SAP therapy. Compared with the MDI group, subjects in the SAP group were more likely to meet age-specific HbA1c targets and had lower AUC values for hyperglycemia with no increased risk of hypoglycemia. Glucose variability improved in the SAP group compared to the MDI group.

Conclusions

SAP therapy was shown to allow both children and adolescents with marginally or inadequately controlled type 1 diabetes to reduce HbA1c values, hyperglycemic excursions, and glycemic variability in a rapid, sustainable, and safe manner.

Comment

In addition to lower mean HbA1c levels, the percentage of youth meeting age-specific HbA1c goals was significantly greater for the SAP group. As both an insulin pump and a CGM will be necessary in closed-loop insulin therapy, it was important to demonstrate that the combination was tolerable and effective in both age groups. It is apparent that the combined effect of an insulin pump used with a continuous glucose monitor is greater than the effect of either used individually (1+1=3).

Health-related quality of life and treatment satisfaction in the sensor-augmented pump therapy for A1C reduction 3 (STAR 3) trial

Rubin RR^1,2, Peyrot M^1,3, STAR 3 Study Group

¹Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland; ²Department of Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, Maryland; and ³Department of Sociology, Loyola University Maryland, Baltimore, Maryland

Diabetes Technol Ther 2012; 14 : 143–52

Background

In a third report related to STAR-3 (see above two reports), the acceptance of SAP therapy in the subjects and caregivers (for children) was evaluated. Patient acceptance of new therapies is essential for their adoption and effective use.

Methods

STAR 3, a randomized 12-month clinical trial, compared SAP therapy with MDI+SMBG in 485 adult and pediatric patients. Within- and between-treatment arm changes in generic health-related quality of life (HRQOL), diabetes-specific HRQOL (fear of hypoglycemia), and treatment satisfaction were assessed (significance criterion p<0.01).

Results

Diabetes-specific HRQOL (Hypoglycemia Fear Survey Worry and Behavior subscale scores) improved more in SAP adults than in MDI adults. Hypoglycemia behavior scores improved more for SAP caregivers. Key treatment satisfaction measures (Insulin Delivery System Rating Questionnaire measures of Convenience, Efficacy, and Overall Preference) improved more in SAP adult, children, and caregiver groups than in the corresponding MDI groups (all p<0.001); all exceeded the criterion for minimal detectable difference.

Conclusions

In the first-ever large-scale study of SAP therapy compared with optimal conventional therapy, SAP therapy had significant advantages for hypoglycemia fear in adults and caregivers and for treatment satisfaction in adults, children, and caregivers.

Comment

Results suggest that switching from MDI+SMBG to SAP therapy can be a safe and feasible choice for motivated patients seeking more precise insulin delivery and more frequent blood glucose monitoring data to achieve improved blood glucose control. This data will be particularly important in the future as it becomes possible to move subjects to closed-loop therapy.

Sensor-augmented pump therapy from onset of type 1 diabetes: late follow-up results of the Pediatric Onset Study

Kordonouri O¹, Hartmann R¹, Pankowska E², Rami B³, Kapellen T⁴, Coutant R⁵, Lange K⁶, Thomas Danne¹

¹Diabetes Centre for Children and Adolescents, Kinder- und Jugendkrankenhaus, Hannover, Germany; ²Department of Paediatric Diabetology and Birth Defects, Medical University of Warsaw, Warsaw, Poland; ³Department of Paediatrics, Medical University of Vienna, Vienna, Austria; ⁴Universitätsklinik und Poliklinik für Kinder und Jugendliche, Leipzig, Germany; ⁵Département de Pédiatrie, Centre Hospitalier Universitaire, Angers, France; ⁶Department of Medical Psychology, Hannover Medical School, Hannover, Germany

Pediatric Diabetes 2012; 13: 515–18

Background

Previously, it was reported that children and adolescents with frequent use of sensors throughout the first year of T1D had significantly lower HbA1c values at 12 months of treatment than those with less frequent or without sensor use (4). Thus, the aim of this study was to evaluate the metabolic control and β-cell function one year after the end of the intervention (24 months after diabetes onset).

Methods

Of 154 study patients in the Pediatric Onset Study, 131 were re-examined 24 months after diabetes onset (49.6% boys, age at onset 8.9±4.3 years). Of which, 62 patients belonged to the primary group of the main study applying a sensor-augmented pump system (SAP) during the first year and 69 patients to the control group performing conventional insulin pump therapy with self-monitoring blood glucose (SMBG). There were no differences between the groups in the age, gender, or body mass index distribution. At 24 months after diabetes onset, HbA1c, fasting blood glucose, and C-peptide were centrally measured.

Results

At the 24-month follow-up visit, a total of 65 patients (58 from the primary group, 7 from the control) used the SAP (52.4%), whereas 46.0% from the control group had continued with conventional insulin pump therapy and 1.6% from the control group had switched to MDI.

HbA1c was 7.6±1.3% in the 62 patients of the primary group and 7.7±1.2% in the 69 patients of the control group (p=0.493). About 48.8% of patients had HbA1c <7.5%, without a significant difference between the primary and control groups. Frequent sensor use (≥1 sensor/week) during the first year of diabetes was associated with insignificantly lower HbA1c values at 24 months as compared with irregular or even no sensor use. Daily insulin requirements at follow-up and frequency of SMBG did not differ between the primary and control groups. Although fasting C-peptide at follow-up was not significantly different between the primary and control group, patients with frequent sensor use during the first year of diabetes (≥1 sensor/week) had significantly less C-peptide loss within 24 months (30% vs. 41.3%). C-peptide reduction was 0.02±0.18 nmol/L in patients with frequent sensor use compared with 0.07±0.11 nmol/L in those with irregular or even no sensor use (p=0.046).

The frequency of sensor use was the only significant parameter, which was associated with the relative C-peptide change over 24 months (p=0.033).

Conclusions

SAP therapy from onset of diabetes may help to preserve endogenous β-cell function, if patients comply with frequent use of continuous glucose monitoring (CGM).

Comment

The potential benefit of higher levels of C-peptide during the course of T1D has been demonstrated in the longitudinal data analysis in patients participated in the Diabetes Control and Complications Trial (DCCT). Even modest levels of β-cell activity at entry in the DCCT were associated with reduced incidences of retinopathy and nephropathy during the follow-up. Continuing C-peptide secretion was also associated with less frequency of severe hypoglycemia. Thus, finding ways to preserve β-cell activity is a crucial target. A major advantage can be if this target will be reached without drug intervention, as was the rationale of this current study.

Indeed, the frequent use of sensors from onset of T1D was associated with smaller loss of β-cell function up to 24 months of the disease, which may lead to better long-term glycemic control if patients comply with frequent use of CGM.

Prevention of hypoglycemia by using the low glucose suspend (LGS) function in sensor-augmented pump therapy

Danne T, Kordonouri O, Holder M, Haberland H, Golembowski S, Remus K, Blasig S, Wadien T, Zierow S, Hartmann R, Thomas A

Children's Hospital on the Bult, Hannover, Germany

Diabetes Technol Ther 2011; 13 : 1129–34

Background

The first part of the closed-loop pancreas, already approved in many countries, is the low glucose suspend (LGS) function to turn off an insulin pump when a low glucose level (<70 mg/dL or <3.9 mmol/L) is reached on a continuous glucose monitor. This could potentially reduce severe hypoglycemic episodes at night, when 75% of episodes occur in youth.

Methods

Twenty-one patients with type 1 diabetes (10.8±3.8 years old, duration of diabetes 5.9±3.0 years, pump therapy for 3.7±1.7 years, glycated hemoglobin level 7.8±1.1%) from three pediatric centers used the Paradigm® Veo™ system (Medtronic Minimed, Northridge, CA) during two time periods: sensor-augmented pump (SAP) without LGS for two weeks and then SAP with LGS enabled for six weeks. The primary objective was to assess the frequency of hypoglycemic episodes when using the LGS feature with an insulin delivery shutoff of a maximum of 2 h at a sensor glucose level below 70 mg/dL (<3.9 mmol/L).

Results

The number of hypoglycemic excursions/day was significantly reduced when using the LGS feature (p=0.01). The average minutes/day spent in hypoglycemia was reduced when using the SAP and LGS (101±68 vs. 58±33 minutes/day; p=0.002) without a significant difference in mean glucose. Most (84.4%) of the 120-minute (maximum allowed) interruptions in insulin delivery occurred at night.

Conclusions

This study provides evidence that SAP with LGS reduces the frequency of hypoglycemia without compromising safety in youth with T1D.

Comment

This is the first report of use of the LGS modality specifically in children. The main finding was the reduction in time spent in hypoglycemia. It is not known why the number of hypoglycemic episodes was reduced with use of the LGS system, as insulin was discontinued for a set low glucose level and not for a predicted low glucose level. It may be because the subject's epinephrine stores were preserved to prevent future lows as a result of less time spent in hypoglycemia. Although numbers were limited (21 youth from 3 centers), it is likely that future larger data from real-time use will substantiate these exciting results.

Antigen-based therapy with glutamic acid decarboxylase (GAD) vaccine in patients with recent-onset type 1 diabetes: a randomized double-blind trial

Wherrett DK¹, Bundy B², Becker DJ³, DiMeglio LA⁴, Gitelman SE⁵, Goland R⁶, Gottlieb PA⁷, Greenbaum CJ⁸, Herold KC⁹, Marks JB¹⁰, Monzavi R ¹¹, Moran A¹², Orban T¹³, Palmer JP¹⁴, Raskin P¹⁵, Rodriguez H⁴, Schatz D¹⁶, Wilson DM¹⁷, Krischer JP², Skyler JS¹⁰, the Type 1 Diabetes TrialNet GAD Study Group

¹Hospital for Sick Children, University of Toronto, Toronto, ON, Canada; ²University of South Florida, Tampa, FL; ³University of Pittsburgh, Pittsburgh, PA; ⁴Indiana University School of Medicine, Indianapolis, IN; ⁵University of California San Francisco, San Francisco, CA; ⁶Columbia University, New York, NY; ⁷University of Colorado Barbara Davis Center for Childhood Diabetes, Aurora, CO; ⁸Benaroya Research Institute, Seattle, WA; ⁹Yale University School of Medicine, New Haven, CT; ¹⁰Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL; ¹¹Children's Hospital Los Angeles, Los Angeles, CA; ¹²University of Minnesota, Minneapolis, MN; ¹³Joslin Diabetes Center, Boston, MA; ¹⁴University of Washington School of Medicine, Seattle, WA; ¹⁵University of Texas Southwestern Medical School, Dallas, TX; ¹⁶University of Florida, Gainesville, FL; ¹⁷Stanford University, Stanford, CA

Lancet 2011; 378 : 319–327

Background

Glutamic acid decarboxylase (GAD) is a major target of the autoimmune response that occurs in T1D. In animal models of autoimmunity, treatment with a target antigen can modulate aggressive autoimmunity.

This study assessed whether immunization with GAD formulated with aluminum hydroxide (GAD-alum), an adjuvant often used in vaccines, can delay the loss of β cells in recent-onset T1D.

Methods

This was a double-blind, randomized, controlled trial of patients enrolled from 15 sites in the United States and Canada. Patients aged 3–45 years who had been diagnosed with T1D for less than 100 days were enrolled and randomly assigned to receive one of three treatments: 3 injections of 20 μg GAD-alum, 2 injections of 20 μg GAD-alum and 1 of alum, or 3 injections of alum. Injections were given subcutaneously at baseline, 4 weeks later, and 8 weeks after the second injection. The primary outcome was the baseline-adjusted mean area under the curve (AUC) of serum C-peptide during the first 2 h of a 4-h mixed meal tolerance test at 1 year. Secondary outcomes included changes in HbA1c and insulin dose and safety.

Results

In total, 145 patients (80 younger than 16 years) were enrolled and treated with GAD-alum (n=48), GAD-alum plus alum (n=49), or just alum (n=48). Clinical and demographic characteristics were similar between treatment groups at baseline, with the exception that the proportion of females was higher in the GAD-alum plus alum group than in the other two treatment groups. Compliance with the protocol was 98%.

At 1 year, the unadjusted mean 2-h AUC of stimulated C-peptide did not differ significantly between the alum group and either group receiving GAD-alum. The ratio of the population mean of adjusted geometric mean 2-h AUC of C-peptide was similar between the groups: 0.998 (95% CI 0.779–1.22; p=0.98) for GAD-alum vs. alum, and 0.926 (0.720–1.13; p=0.50) for GAD-alum plus alum vs. alum. About 40% loss in mean C-peptide was recorded in all treatment groups at one year, without a difference between the groups.

HbA1c, insulin use, and the occurrence and severity of adverse events did not differ between groups. Treatment effect on C-peptide did not differ in individuals aged 10–18 years from those in younger and older age groups, and baseline GAD titer did not affect treatment effect on C-peptide.

Treatment was well tolerated in all groups, with no evidence of more severe grades of adverse events in the groups receiving GAD-alum than in the group receiving alum alone. Specifically, no symptoms suggestive of stiff person syndrome were noted.

Conclusions

Antigen-based immunotherapy with two or three doses of subcutaneous GAD-alum across 4–12 weeks does not alter the course of loss of insulin secretion during one year in patients with recently diagnosed T1D.

Comment

Previous trials with different drugs (cyclosporin, anti-CD3 antibody, abatacept, etc.) were used to decrease the rate of C-peptide loss. However, these drugs might have a generalized effect on the immune system and increase the risk of immunosuppression or cytokine release syndrome. Therefore, a more specific approach is highly desirable. One such approach is to interfere with the interaction between pathogenic T cells and their target antigens. Immunization with target antigens might promote a regulatory immune response, resulting in down-regulation of autoimmunity or deletion of autoaggressive antigen-specific T cells. GAD has long been recognized as a target antigen in T1D. Treatment with GAD in non-obese diabetic mice, a model of T1D, can prevent diabetes when given before the development of hyperglycemia. This study demonstrated that although antigen-based therapy is a highly desirable treatment and is effective in animal models, translation to human autoimmune disease remains a challenge. However, researchers should not give up hope of preventing or curing T1D.

The feasibility of detecting neuropsychologic and neuroanatomic effects of type 1 diabetes (T1D) in young children

Aye T¹, Reiss AL^2,3,4, Kesler S², Hoang S¹, Drobny J¹, Park Y³, Schleifer K¹, Baumgartner H¹, Wilson DM¹, Buckingham BA¹

¹Department of Pediatrics, Division of Pediatric Endocrinology and Diabetes, Stanford University School of Medicine, Stanford, California; ²Center for Interdisciplinary Brain Sciences Research, Department of Psychiatry, Stanford University School of Medicine, Stanford, California; ³Department of Radiology, Stanford University School of Medicine, Stanford, California; and ⁴Department of Pediatrics, Stanford University School of Medicine, Stanford, California

Diabetes Care 2011; 34 : 1458–62

Background

Studies have found that children who are diagnosed with T1D prior to the age of five have poorer intellectual performance (particularly memory and attention), visual perception, and fine motor speed and coordination. Hypoglycemia is often implicated as the cause of these deficits, but hyperglycemia has also been hypothesized as a cause.

Methods

This cross-sectional study of children ages 3 to 10 years with T1D completed age-appropriate neuropsychologic (NP) testing and magnetic resonance imaging (MRI) of the brain to assess amounts of gray matter (GM), white matter (WM), and hippocampal (HP) structure. Age and gender-matched healthy controls (HC) underwent the same processes.

Results

Controlling for age and sex, and there was a statistically significant difference by age interaction, such that WM and HP volumes did not show the rate of volume increase seen in HC children. Children with a history of hypoglycemic seizures had lower WISC processing speed, full-scale IQ score, working memory and perceptual reasoning on NP testing, in addition to reductions in WM and GM. Higher HbA1c values also correlated with lower verbal comprehension scores.

Conclusion

This is the first study to demonstrate the feasibility of NP testing and MRI studies of the brain in young children, ages 3 to 10 years. Overall, there was not a significant difference in total GM and WM in comparison to HC children. However, a significant age by diagnosis interaction for WM was found. Hypoglycemic seizures were shown to effect NP-testing results, and high HbA1c values correlated with lower verbal comprehension scores.

Comment

This group is to be congratulated for extending the MRI and NP-testing technology to this younger age group. The findings still need confirmation in larger groups; however, the results suggest the need for optimal glucose control and avoidance of SH and hyperglycemia in young children. This will make the pediatric diabetologists work even harder.

Footnotes

Author Disclosure Statement

S.S. declares that no competing financial interests exist. H.P.C. has received a research grant from DexCom, Inc.

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