Robert H. Slover

Reduction in Duration of Hypoglycemia by Automatic Suspension of Insulin Delivery: The In-Clinic ASPIRE Study

BACKGROUND The efficacy of automatic suspension of insulin delivery in induced hypoglycemia among subjects with type 1 diabetes was evaluated. SUBJECTS AND METHODS In this randomized crossover study, subjects used a sensor-augmented insulin pump system with a low glucose suspend (LGS) feature that automatically stops insulin delivery for 2 h following a sensor glucose (SG) value ≤70 mg/dL. Subjects fasted overnight and exercised until their plasma glucose (measured with the YSI 2300 STAT Plus™ glucose and lactate analyzer [YSI Life Sciences, Yellow Springs, OH]) value reached ≤85 mg/dL on different occasions separated by washout periods lasting 3-10 days. Exercise sessions were done with the LGS feature turned on (LGS-On) or with continued insulin delivery regardless of SG value (LGS-Off). The order of LGS-On and LGS-Off sessions was randomly assigned. YSI glucose data were used to compare the duration and severity of hypoglycemia from successful LGS-On and LGS-Off sessions and to estimate the risk of rebound hyperglycemia after pump suspension. RESULTS Fifty subjects attempted 134 sessions, 98 of which were successful. The mean±SD hypoglycemia duration was less during LGS-On than during LGS-Off sessions (138.5±76.68 vs. 170.7±75.91 min, P=0.006). During LGS-On compared with LGS-Off sessions, mean nadir YSI glucose was higher (59.5±5.72 vs. 57.6±5.69 mg/dL, P=0.015), as was mean end-observation YSI glucose (91.4±41.84 vs. 66.2±13.48 mg/dL, P<0.001). Most (53.2%) end-observation YSI glucose values in LGS-On sessions were in the 70-180 mg/dL range, and none was >250 mg/dL. CONCLUSIONS Automatic suspension of insulin delivery significantly reduced the duration and severity of induced hypoglycemia without causing rebound hyperglycemia.

A Randomized Trial of a Home System to Reduce Nocturnal Hypoglycemia in Type 1 Diabetes

OBJECTIVE Overnight hypoglycemia occurs frequently in individuals with type 1 diabetes and can result in loss of consciousness, seizure, or even death. We conducted an in-home randomized trial to determine whether nocturnal hypoglycemia could be safely reduced by temporarily suspending pump insulin delivery when hypoglycemia was predicted by an algorithm based on continuous glucose monitoring (CGM) glucose levels. RESEARCH DESIGN AND METHODS Following an initial run-in phase, a 42-night trial was conducted in 45 individuals aged 15–45 years with type 1 diabetes in which each night was assigned randomly to either having the predictive low-glucose suspend system active (intervention night) or inactive (control night). The primary outcome was the proportion of nights in which ≥1 CGM glucose values ≤60 mg/dL occurred. RESULTS Overnight hypoglycemia with at least one CGM value ≤60 mg/dL occurred on 196 of 942 (21%) intervention nights versus 322 of 970 (33%) control nights (odds ratio 0.52 [95% CI 0.43–0.64]; P < 0.001). Median hypoglycemia area under the curve was reduced by 81%, and hypoglycemia lasting >2 h was reduced by 74%. Overnight sensor glucose was >180 mg/dL during 57% of control nights and 59% of intervention nights (P = 0.17), while morning blood glucose was >180 mg/dL following 21% and 27% of nights, respectively (P < 0.001), and >250 mg/dL following 6% and 6%, respectively. Morning ketosis was present <1% of the time in each arm. CONCLUSIONS Use of a nocturnal low-glucose suspend system can substantially reduce overnight hypoglycemia without an increase in morning ketosis.

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

Slover RH, Welsh JB, Criego A, Weinzimer SA, Willi SM, Wood MA, Tamborlane WV. Effectiveness of sensor‐augmented pump therapy in children and adolescents with type 1 diabetes in the STAR 3 study.

Predictive Low-Glucose Insulin Suspension Reduces Duration of Nocturnal Hypoglycemia in Children Without Increasing Ketosis

OBJECTIVE Nocturnal hypoglycemia can cause seizures and is a major impediment to tight glycemic control, especially in young children with type 1 diabetes. We conducted an in-home randomized trial to assess the efficacy and safety of a continuous glucose monitor–based overnight predictive low-glucose suspend (PLGS) system. RESEARCH DESIGN AND METHODS In two age-groups of children with type 1 diabetes (11–14 and 4–10 years of age), a 42-night trial for each child was conducted wherein each night was assigned randomly to either having the PLGS system active (intervention night) or inactive (control night). The primary outcome was percent time <70 mg/dL overnight. RESULTS Median time at <70 mg/dL was reduced by 54% from 10.1% on control nights to 4.6% on intervention nights (P < 0.001) in 11–14-year-olds (n = 45) and by 50% from 6.2% to 3.1% (P < 0.001) in 4–10-year-olds (n = 36). Mean overnight glucose was lower on control versus intervention nights in both age-groups (144 ± 18 vs. 152 ± 19 mg/dL [P < 0.001] and 153 ± 14 vs. 160 ± 16 mg/dL [P = 0.004], respectively). Mean morning blood glucose was 159 ± 29 vs. 176 ± 28 mg/dL (P < 0.001) in the 11–14-year-olds and 154 ± 25 vs. 158 ± 22 mg/dL (P = 0.11) in the 4–10-year-olds, respectively. No differences were found between intervention and control in either age-group in morning blood ketosis. CONCLUSIONS In 4–14-year-olds, use of a nocturnal PLGS system can substantially reduce overnight hypoglycemia without an increase in morning ketosis, although overnight mean glucose is slightly higher.

Diabetic ketoacidosis with intracerebral complications

Abstract: Purpose: To describe 11 instances of severe diabetic ketoacidosis (DKA) with secondary intracerebral complications (ICCs), nine of whom were treated early and showed complete recovery.

Acceptability and Utility of the mySentry Remote Glucose Monitoring System

Background: The mySentry system (Medtronic Inc.) is the first to amplify and relay continuous glucose monitoring (CGM) and insulin pump data to a remote site within the house. Its usability and acceptability were evaluated in families having a child with type 1 diabetes. Methods: Each enrolled family included a child (age 7–17 years) who used a Paradigm REAL-Time Revel sensor-augmented insulin pump (Medtronic). After a 1-week run-in phase, families set up and used the mySentry system for a 3-week study phase. Opinion surveys were completed by parents, and pump and CGM data were collected and analyzed retrospectively. No formal hypothesis testing was performed, and the study was not powered to detect changes in nocturnal glycemia. Results: Thirty-five families completed the study. Enrolled children (61.1% female) had a mean (± standard deviation) age of 11.9 ± 2.70 years and a mean age at initiation of pump therapy of 7.1 ± 3.19 years. Baseline survey results indicated that most parents were fearful of their unawareness of their childrens nocturnal glucose excursions. The mySentry system met the predefined acceptability criteria for general experience, product usability, and training materials. There were no unanticipated device-related adverse effects. Among children who experienced nocturnal hypo- or hyperglycemic episodes in both phases of the study, there was a trend toward less frequent and less prolonged episodes during mySentry use. Conclusion: The mySentry system met all predefined criteria for acceptability and did not demonstrate safety issues. Alerting parents to abnormal glucose values or trends may attenuate nocturnal hypoglycemia and hyperglycemia by prompting appropriate and timely intervention.

Effects of Frequency of Sensor-Augmented Pump Use on HbA1c and C-Peptide Levels in the First Year of Type 1 Diabetes.

Intensive glucose control after the onset of type 1 diabetes has been suggested to preserve C-peptide production (1–3). In people with type 1 diabetes, sensor-augmented pump (SAP) use improved glycemic control, particularly when used >6 days/week (4). As previously reported, subjects with type 1 diabetes were randomized to either 3 days of in-hospital hybrid closed-loop therapy followed by SAP therapy or usual care (5). In the primary intent-to-treat analysis, no significant differences existed in HbA1c or C-peptide between the two groups at 1 year. In our post hoc analysis, we hypothesized that more frequent sensor use in the SAP group would be associated with lower HbA1c levels and preservation of C-peptide production at 1 year. Subjects in the SAP group ( n = 46) were stratified by median SAP use of 12.4 h/day. HbA1c and C-peptide levels were compared at baseline and 3, 6, 9, 12, and 24 months. At 12 months of follow-up, the median HbA1c values for those with SAP …

Erratum. Predictive Low-Glucose Insulin Suspension Reduces Duration of Nocturnal Hypoglycemia in Children Without Increasing Ketosis. Diabetes Care 2015;38:1197–1204

In the print version of the article cited above, the clinical trial registry number should have been reported as NCT01823341, ClinicalTrials.gov, rather than NCT01591681. The online version reflects this change. Bruce A. Buckingham, Dan Raghinaru, Fraser Cameron, B. Wayne Bequette, H. Peter Chase, David M. Maahs, Robert Slover, R. Paul Wadwa, Darrell M. Wilson, Trang Ly, Tandy Aye, Irene Hramiak, Cheril Clarson, Robert Stein, Patricia H. Gallego, John Lum, Judy Sibayan, Craig Kollman, and Roy W. Beck, for the In Home Closed Loop Study Group Diabetes Care Volume 38, September 2015 1813

Accuracy of a Fourth-Generation Continuous Glucose Monitoring System in Children and Adolescents with Type 1 Diabetes

BACKGROUND This study evaluated the safety and performance of the Guardian™ continuous glucose monitoring (CGM) system in children and adolescents with type 1 diabetes (T1D). MATERIALS AND METHODS Subjects 2-18 years of age (mean ± standard deviation [SD] 13.1 ± 3.9 years) with T1D and duration of diagnosis ≥1 year were enrolled at 11 sites in the United States and wore two Guardian Sensor 3 sensors in the abdomen and/or buttock. Sensors were connected to a transmitter paired with either a Guardian Connect system (i.e., mobile device with software application allowing display of sensor glucose [SG] values) or a Guardian Link 3 transmitter used as a Glucose Sensor Recorder (GSR). There were 145 participants who underwent a 6-h in-clinic frequent sample testing (FST) on day 1 (n = 54), day 3 (n = 48), or day 7 (n = 43) postsensor insertion. During FST, SG values were compared with a Yellow Springs Instrument (YSI) plasma reference every 5-15 min (n = 124, 7-18 years of age; n = 2, 2-6 years of age), or to a self-monitoring of blood glucose (SMBG) reference every 5-30 min (n = 19, 2-6 years of age). RESULTS The overall mean absolute relative difference (ARD ± SD) between SG and reference values (YSI or SMBG) when calibrating approximately every 12 h, was 10.9% ± 10.7% (3102 paired points) for sensors communicating with the Guardian Connect system and 11.1% ± 10.6% (2624 paired points) for sensors connected to the GSR. The overall percentage of SG values within ±20% of reference values >80 mg/dL or within 20 mg/dL of reference values ≤80 mg/dL was 87.8% for the Guardian Connect system and 86.7% for the GSR, respectively. There was one device-related adverse event of contact dermatitis, but no serious device-related adverse events. CONCLUSIONS The Guardian CGM system demonstrated good accuracy in children and adolescents. These findings support its use in sensor-integrated insulin pump platforms, as well as a standalone technology, for managing diabetes in pediatric populations.

Best Ways and Practices to Avoid Insulin Pump Catheter Occlusions

Over the past decade, significant strides have been made in the technology of insulin delivery and glucose monitoring. Insulin pump use has become standard of care, and the development and improvement of continuous glucose monitoring have not only helped to reduce severe hypoglycemia, but have also placed us firmly on the path to development of closed-loop (artificial pancreas) management of diabetes. Despite the widespread use of continuous subcutaneous insulin infusion (CSII), there has been relatively little improvement in insulin infusion sets. They have been described recently as the Achilles heel of CSII. In fact, a recent joint statement issued by the American Diabetes Association and the European Association for the Study of Diabetes stresses the small number of publications around the use of set occlusions and failures, especially when compared with the high number of adverse events reported to the Food and Drug Administration in the United States. The role of the insulin infusion set is reliable transfer of pumped insulin to a subcutaneous insulin depot. Accurate, uninterrupted delivery can be affected by site placement, duration of use, interstitial pressure, occlusion by cellular debris or insulin, and the material of which the infusion set is made. In order to evaluate the difference in occlusion rate by insulin analogs, in vitro testing of the three commonly available rapid-acting insulin analogs was performed, studying flow rates and pressures over a 5-day period. There were no differences between analogs in the first 48 h at either low or high (bolus) delivery rates. By Day 5, however, there were occlusions that varied with the analog used, with insulin glulisine having the highest rate (40.9%) and insulin aspart the lowest (9.2%). Because use of an infusion set for over 3 days is longer than the recommended duration, the authors concluded that early occlusions are uncommon and independent of insulin type and that sets should be changed at least every 72 h. Furthermore, a randomized trial of insulin infusion set function comparing steel with Teflon (Dupont, Wilmington, DE) catheters failed to demonstrate a difference in occlusion rate. However, 15% of the Teflon sets failed because of kinking during insertion. It has also been demonstrated that median tissue resistance pressure increased significantly with higher infusion rates, and it was suggested that occlusion detection might be better measured using rate-dependent detection thresholds. There is a growing awareness that infusion set failure may result in silent occlusions, especially with low flow volumes such as are used in small children, because CSII uses in-line pressure to determine flow and to trigger occlusion alarms. Such silent occlusions can lead to deterioration in glucose control and to delays in recognition of insulin delivery failure, causing the development of hyperglycemia and ketosis or diabetic ketoacidosis. The research group from Becton Dickinson presents in this issue of the journal a new infusion catheter that adds a side port to the traditional end port. This innovation, presented last year in abstract form at the Advanced Technology and Treatments for Diabetes and the American Diabetes Association scientific sessions, shows real promise in reducing silent occlusions by 74–79%, with no difference in leakage or alarms when compared with currently available infusion sets. Unfortunately, the studies were only short term, and longterm home studies need to be performed before strong conclusions can be made regarding the longer use of these infusion sets. This is a welcome technologic advance, attending as it does to this weakest link in the CSII chain. More work needs to be done in redefining occlusion alarm sensitivity, studying interstitial pressures related to site and duration of use, and creating catheters less likely to fail at insertion or to kink over time.