John B. Welsh

Effectiveness of Sensor-Augmented Insulin-Pump Therapy in Type 1 Diabetes

BACKGROUND Recently developed technologies for the treatment of type 1 diabetes mellitus include a variety of pumps and pumps with glucose sensors. METHODS In this 1-year, multicenter, randomized, controlled trial, we compared the efficacy of sensor-augmented pump therapy (pump therapy) with that of a regimen of multiple daily insulin injections (injection therapy) in 485 patients (329 adults and 156 children) with inadequately controlled type 1 diabetes. Patients received recombinant insulin analogues and were supervised by expert clinical teams. The primary end point was the change from the baseline glycated hemoglobin level. RESULTS At 1 year, the baseline mean glycated hemoglobin level (8.3% in the two study groups) had decreased to 7.5% in the pump-therapy group, as compared with 8.1% in the injection-therapy group (P<0.001). The proportion of patients who reached the glycated hemoglobin target (<7%) was greater in the pump-therapy group than in the injection-therapy group. The rate of severe hypoglycemia in the pump-therapy group (13.31 cases per 100 person-years) did not differ significantly from that in the injection-therapy group (13.48 per 100 person-years, P=0.58). There was no significant weight gain in either group. CONCLUSIONS In both adults and children with inadequately controlled type 1 diabetes, sensor-augmented pump therapy resulted in significant improvement in glycated hemoglobin levels, as compared with injection therapy. A significantly greater proportion of both adults and children in the pump-therapy group than in the injection-therapy group reached the target glycated hemoglobin level. (Funded by Medtronic and others; ClinicalTrials.gov number, NCT00417989.)

Threshold-Based Insulin-Pump Interruption for Reduction of Hypoglycemia

BACKGROUND The threshold-suspend feature of sensor-augmented insulin pumps is designed to minimize the risk of hypoglycemia by interrupting insulin delivery at a preset sensor glucose value. We evaluated sensor-augmented insulin-pump therapy with and without the threshold-suspend feature in patients with nocturnal hypoglycemia. METHODS We randomly assigned patients with type 1 diabetes and documented nocturnal hypoglycemia to receive sensor-augmented insulin-pump therapy with or without the threshold-suspend feature for 3 months. The primary safety outcome was the change in the glycated hemoglobin level. The primary efficacy outcome was the area under the curve (AUC) for nocturnal hypoglycemic events. Two-hour threshold-suspend events were analyzed with respect to subsequent sensor glucose values. RESULTS A total of 247 patients were randomly assigned to receive sensor-augmented insulin-pump therapy with the threshold-suspend feature (threshold-suspend group, 121 patients) or standard sensor-augmented insulin-pump therapy (control group, 126 patients). The changes in glycated hemoglobin values were similar in the two groups. The mean AUC for nocturnal hypoglycemic events was 37.5% lower in the threshold-suspend group than in the control group (980 ± 1200 mg per deciliter [54.4 ± 66.6 mmol per liter] × minutes vs. 1568 ± 1995 mg per deciliter [87.0 ± 110.7 mmol per liter] × minutes, P<0.001). Nocturnal hypoglycemic events occurred 31.8% less frequently in the threshold-suspend group than in the control group (1.5 ± 1.0 vs. 2.2 ± 1.3 per patient-week, P<0.001). The percentages of nocturnal sensor glucose values of less than 50 mg per deciliter (2.8 mmol per liter), 50 to less than 60 mg per deciliter (3.3 mmol per liter), and 60 to less than 70 mg per deciliter (3.9 mmol per liter) were significantly reduced in the threshold-suspend group (P<0.001 for each range). After 1438 instances at night in which the pump was stopped for 2 hours, the mean sensor glucose value was 92.6 ± 40.7 mg per deciliter (5.1 ± 2.3 mmol per liter). Four patients (all in the control group) had a severe hypoglycemic event; no patients had diabetic ketoacidosis. CONCLUSIONS This study showed that over a 3-month period the use of sensor-augmented insulin-pump therapy with the threshold-suspend feature reduced nocturnal hypoglycemia, without increasing glycated hemoglobin values. (Funded by Medtronic MiniMed; ASPIRE ClinicalTrials.gov number, NCT01497938.).

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.

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.

Sensor-Augmented Pump Therapy for A1C Reduction (STAR 3) Study: Results from the 6-month continuation phase

OBJECTIVE To examine the effects of crossing over from optimized multiple daily injection (MDI) therapy to sensor-augmented pump (SAP) therapy for 6 months, and the effects of 18 months’ sustained use of SAP. RESEARCH DESIGN AND METHODS The 6-month, single-crossover continuation phase of Sensor-Augmented Pump Therapy for A1C Reduction (STAR 3) provided SAP therapy to 420 subjects who completed the 1-year randomized study. The primary outcome was change in A1C in the crossover group. RESULTS A1C values were initially lower in the continuing-SAP group than in the crossover group (7.4 vs. 8.0%, P < 0.001). A1C values remained reduced in the SAP group. After 3 months on the SAP system, A1C decreased to 7.6% in the crossover group (P < 0.001); this was a significant and sustained decrease among both adults and children (P < 0.05). CONCLUSIONS Switching from optimized MDI to SAP therapy allowed for rapid and safe A1C reductions. Glycemic benefits of SAP therapy persist for at least 18 months.

Usage and Effectiveness of the Low Glucose Suspend Feature of the Medtronic Paradigm Veo Insulin Pump

Background: Sensor-augmented insulin pumps may be programmed to suspend insulin delivery in response to hypoglycemia. The Medtronic Paradigm® Veo™ pump with automatic low glucose suspend (LGS) was released in 2009. Data from 7 months of real-world use of the system were analyzed to assess usage patterns and effectiveness of LGS. Method: Data from 935 patients totaling 49,867 patient days were collected; the LGS feature was on for 82% of these days. A subset of 278 subjects who used the pump for ≥3 months was analyzed separately; these subjects provided 28,401 patient days of data, with LGS used for 92% of the time. Results: The LGS threshold was most commonly set between 50 and 60 mg/dl. A total of 27,216 LGS events occurred, and 60% began in the afternoon or evening. The median duration of LGS events was 9.87 min, 45% lasted for <5 min, and 11% lasted for >115 min (equivalent to the full extent of the LGS event between 115 and 120 min). Among the episodes lasting for >115 min, the mean sensor glucose (SG) was 58.8 ± 12.4 mg/dl at LGS activation (time 0), rose to 102.2 ± 52.8 mg/dl by the end of the LGS episode (when insulin delivery was automatically resumed), and was 150.1 ± 68.6 mg/dl at 240 min. In the 278-subject subgroup, LGS usage significantly reduced the number of SG readings <50 mg/dl (p = 0.001) and >300 mg/dl (p = 0.001). Conclusions: The LGS feature was on for most of the patient days in the study. Most LGS episodes lasted for <10 min. Use of the LGS feature significantly reduced exposure to hypoglycemia. Profound hyperglycemia resulting from LGS episodes lasting >115 min was not observed.

Hypoglycemia Prevention and User Acceptance of an Insulin Pump System with Predictive Low Glucose Management

Abstract Background: The MiniMed 640G sensor-augmented insulin pump system (Medtronic, Inc., Northridge, CA) can automatically suspend insulin delivery in advance of predicted hypoglycemia and restart it upon recovery. The aims of this analysis were to determine the rate at which predicted hypoglycemia was avoided with this strategy, as well as to assess user acceptance of the system and its insulin management features. Subjects and Methods: Forty subjects with type 1 diabetes used the system for 4 weeks. We retrospectively evaluated performance of the system, using downloaded pump and sensor data, and evaluated user acceptance via questionnaires. Results: There were 2,322 suspend before low events (2.1 per subject-day). The mean (± SD) duration of pump suspension events was 56.4 ± 9.6 min, and the mean subsequent sensor glucose (SG) nadir was 71.8 ± 5.2 mg/dL. SG values following 1,930 (83.1%) of the predictive suspensions did not reach the preset low limit. Nadir SG values of ≤50 and ≤60 mg/dL were seen in 207 (8.9%) and 356 (15.3%) of the predictive suspensions, respectively. Blood glucose (BG) and SG values before and during the study were comparable (P > 0.05). The mean absolute relative difference between paired SG and BG values was 10.9 ± 13.8%. Subjects felt confident using the system, agreed that it helped protect them from hypoglycemia, and wished to continue using it. Conclusions: Automatic insulin pump suspension as implemented in the MiniMed 640G system can help patients avoid hypoglycemia, without significantly increasing hyperglycemia.

Accuracy and Acceptability of the 6-Day Enlite Continuous Subcutaneous Glucose Sensor

OBJECTIVE This study evaluated the performance and acceptability of the Enlite(®) glucose sensor (Medtronic MiniMed, Inc., Northridge, CA). SUBJECTS AND METHODS Ninety adults with type 1 or type 2 diabetes wore two Enlite sensors on the abdomen and/or buttock for 6 days and calibrated them at different frequencies. On Days 1, 3, and 6, accuracy was evaluated by comparison of sensor glucose values with frequently sampled plasma glucose values collected over a 12-h period. Accuracy was assessed at different reference glucose concentrations and during times when absolute glucose concentration rates of change were <1, 1-2, and >2 mg/dL/min. The sensors ability to detect hypoglycemia or hyperglycemia was evaluated with simulated alerts. Subject satisfaction was evaluated with a 7-point Likert-type questionnaire, with a score of 7 indicating strong agreement. RESULTS With abdomen sensors under actual-use calibration (mean, 2.8 ± 0.9 times/day), the overall mean (median) absolute relative difference (ARD) values between sensor and reference values were 13.6% (10.1%); the corresponding buttock sensor ARD values were 15.5% (10.5%). With abdomen sensors under minimal calibration (mean, 1.2 ± 0.9 times/day), the mean (median) ARD values were 14.7% (10.8%). Mean ARD values of abdomen sensors at rates of change of <1, 1-2, and >2 mg/dL/min were 13.6%, 12.9%, and 16.3%, respectively. With abdomen sensors, 79.5% and 94.1% of hypoglycemic and hyperglycemic events, respectively, were correctly detected; 81.9% and 94.9% of hypoglycemic and hyperglycemic alerts, respectively, were confirmed. The failure rates for abdomen and buttock sensors were 19.7% and 13.9%, respectively. Mean responses to survey questions for all subjects related to comfort and ease of use were favorable. CONCLUSIONS The Enlite sensor provided accurate data at different glucose concentrations and rates of change. Subjects found the sensor comfortable and easy to use.

Threshold insulin-pump interruption to reduce hypoglycemia.

1. Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med 2013;368:2059-74. [Erratum, N Engl J Med 2013; 369:98.] 2. Ding L, Ley TJ, Larson DE, et al. Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing. Nature 2012;481:506-10. 3. Nazha A, Cortes J, Faderl S, et al. Activating internal tandem duplication mutations of the FMS-like tyrosine kinase-3 (FLT3ITD) at complete response and relapse in patients with acute myeloid leukemia. Haematologica 2012;97:1242-50. 4. Bisling KE, Brewin JN, McGovern AP, et al. DNMT3A mutations at R882 hotspot are only found in major clones of acute myeloid leukemia. Leuk Lymphoma 2013 July 25 (Epub ahead of print). 5. Welch JS, Ley TJ, Link DC, et al. The origin and evolution of mutations in acute myeloid leukemia. Cell 2012;150:264-78.

Retrospective Analysis of the Real-World Use of the Threshold Suspend Feature of Sensor-Augmented Insulin Pumps

BACKGROUND The automatic Threshold Suspend (TS) feature of the MiniMed 530G system (Medtronic MiniMed, Inc., Northridge, CA), when enabled, suspends insulin delivery for up to 2 h when the sensor glucose (SG) value reaches a preset threshold. MATERIALS AND METHODS SG data from 20,973 patients who enabled the TS feature at their discretion and uploaded pump and sensor data to CareLink(®) (Medtronic MiniMed, Inc.) from October 15, 2013 to July 21, 2014 were analyzed. Comparisons between 758,382 patient-days wherein the TS feature was enabled at any time and 166,791 patient-days in which it was not enabled were made. Further comparisons were made between data collected during daytime (8:00 a.m. to 10:00 p.m.) and nighttime (10:00 p.m. to 8:00 a.m.) hours. Data from subsets of patients who enabled the TS feature all of the time (n=14,673) versus those who never enabled the TS feature (n=2,249) were also compared. Recovery from hypoglycemia during and after 2-h pump suspension events was also assessed. RESULTS The TS feature was enabled on 82% of patient-days. Patient-days in which the TS feature was enabled, compared with patient-days in which it was not, had 69% fewer SG values ≤50 mg/dL (0.64% vs. 2.09%, respectively; P<0.001). The reduction in hypoglycemia seen on TS-enabled days was more pronounced during nighttime than during daytime hours. SG data from full-time users of the TS feature reflected a 62% reduction in values ≤50 mg/dL and a 5.6% reduction in values ≥300 mg/dL compared with data from nonusers (P<0.001 for each). The median SG value at the start of 2-h suspensions was 60 (interquartile range [IQR], 57-66) mg/dL, immediately after was 87 (IQR, 63-123) mg/dL, and 4 h later was 164 (IQR, 117-220) mg/dL. CONCLUSIONS The TS feature, when enabled consistently, reduced hypoglycemic exposure, and for those who had it enabled 100% of the time, hyperglycemia was also reduced.