Combining continuous glucose monitoring and insulin pumps to automatically tune the basal insulin infusion in diabetes therapy: a review <s> Evidence of clinical effectiveness and safety <s> Abstract Background: Nocturnal hypoglycemia is a significant problem. From 50% to 75% of hypoglycemia seizures occur at night. Despite the development of real-time glucose sensors (real-time continuous glucose monitor [CGM]) with hypoglycemic alarms, many patients sleep through these alarms. The goal of this pilot study was to assess the feasibility using a real-time CGM to discontinue insulin pump therapy when hypoglycemia was predicted. Methods: Twenty-two subjects with type 1 diabetes had two daytime admissions to a clinical research center. On the first admission their basal insulin was increased until their blood glucose level was <60 mg/dL. On the second admission hypoglycemic prediction algorithms were tested to determine if hypoglycemia was prevented by a 90-min pump shutoff and to determine if the pump shutoff resulted in rebound hyperglycemia. Results: Using a statistical prediction algorithm with an 80 mg/dL threshold and a 30-min projection horizon, hypoglycemia was prevented 60% of the time. ... <s> BIB001 </s> Combining continuous glucose monitoring and insulin pumps to automatically tune the basal insulin infusion in diabetes therapy: a review <s> Evidence of clinical effectiveness and safety <s> Arguably, a minimally invasive system using subcutaneous (s.c.) continuous glucose monitoring (CGM) and s.c. insulin delivery via insulin pump would be a most feasible step to closed-loop control in type 1 diabetes mellitus (T1DM). Consequently, diabetes technology is focusing on developing an artificial pancreas using control algorithms to link CGM with s.c. insulin delivery. The future development of the artificial pancreas will be greatly accelerated by employing mathematical modeling and computer simulation. Realistic computer simulation is capable of providing invaluable information about the safety and the limitations of closed-loop control algorithms, guiding clinical studies, and out-ruling ineffective control scenarios in a cost-effective manner. Thus computer simulation testing of closed-loop control algorithms is regarded as a prerequisite to clinical trials of the artificial pancreas. In this paper, we present a system for in silico testing of control algorithms that has three principal components: (1) a large cohort of n=300 simulated "subjects" (n=100 adults, 100 adolescents, and 100 children) based on real individuals' data and spanning the observed variability of key metabolic parameters in the general population of people with T1DM; (2) a simulator of CGM sensor errors representative of Freestyle Navigator™, Guardian RT, or Dexcom™ STS™, 7-day sensor; and (3) a simulator of discrete s.c. insulin delivery via OmniPod Insulin Management System or Deltec Cozmo(®) insulin pump. The system has been shown to represent adequate glucose fluctuations in T1DM observed during meal challenges, and has been accepted by the Food and Drug Administration as a substitute to animal trials in the preclinical testing of closed-loop control strategies. <s> BIB002 </s> Combining continuous glucose monitoring and insulin pumps to automatically tune the basal insulin infusion in diabetes therapy: a review <s> Evidence of clinical effectiveness and safety <s> OBJECTIVE ::: The aim of this study was to develop a partial closed-loop system to safely prevent nocturnal hypoglycemia by suspending insulin delivery when hypoglycemia is predicted in type 1 diabetes. ::: ::: ::: RESEARCH DESIGN AND METHODS ::: Forty subjects with type 1 diabetes (age range 12-39 years) were studied overnight in the hospital. For the first 14 subjects, hypoglycemia (<60 mg/dl) was induced by gradually increasing the basal insulin infusion rate (without the use of pump shutoff algorithms). During the subsequent 26 patient studies, pump shutoff occurred when either three of five (n = 10) or two of five (n = 16) algorithms predicted hypoglycemia based on the glucose levels measured with the FreeStyle Navigator (Abbott Diabetes Care). ::: ::: ::: RESULTS ::: The standardized protocol induced hypoglycemia on 13 (93%) of the 14 nights. With use of a voting scheme that required three algorithms to trigger insulin pump suspension, nocturnal hypoglycemia was prevented during 6 (60%) of 10 nights. When the voting scheme was changed to require only two algorithms to predict hypoglycemia to trigger pump suspension, hypoglycemia was prevented during 12 (75%) of 16 nights. In the latter study, there were 25 predictions of hypoglycemia because some subjects had multiple hypoglycemic events during a night, and hypoglycemia was prevented for 84% of these events. ::: ::: ::: CONCLUSIONS ::: Using algorithms to shut off the insulin pump when hypoglycemia is predicted, it is possible to prevent hypoglycemia on 75% of nights (84% of events) when it would otherwise be predicted to occur. <s> BIB003 </s> Combining continuous glucose monitoring and insulin pumps to automatically tune the basal insulin infusion in diabetes therapy: a review <s> Evidence of clinical effectiveness and safety <s> Background:Hypoglycemia has been identified as a primary barrier to optimal management of diabetes. This observation, in conjunction with the introduction of continuous glucose monitoring (CGM) devices, has set the stage for achieving tight glycemic control with systems that adjust the insulin pump settings based on measured glucose concentrations. Because system safety and system reliability are key considerations, there is a need for algorithms that reduce the risk of hypoglycemia in closed-loop, open-loop, and advisory-mode systems. More specifically, the algorithm presented here is formulated as a component of the independent safety system module proposed in the modular control-to-range architecture.Methods:We developed two algorithms for attenuating insulin pump injections, which we refer to as Brakes and Power Brakes: Brakes is a pump attenuation function computed using CGM information only, while Power Brakes is an attenuation function in which a metabolic state observer with insulin input is used ... <s> BIB004 </s> Combining continuous glucose monitoring and insulin pumps to automatically tune the basal insulin infusion in diabetes therapy: a review <s> Evidence of clinical effectiveness and safety <s> OBJECTIVE ::: To evaluate a sensor-augmented insulin pump with a low glucose suspend (LGS) feature that automatically suspends basal insulin delivery for up to 2 h in response to sensor-detected hypoglycemia. ::: ::: ::: RESEARCH DESIGN AND METHODS ::: The LGS feature of the Paradigm Veo insulin pump (Medtronic, Inc., Northridge, CA) was tested for 3 weeks in 31 adults with type 1 diabetes. ::: ::: ::: RESULTS ::: There were 166 episodes of LGS: 66% of daytime LGS episodes were terminated within 10 min, and 20 episodes lasted the maximum 2 h. LGS use was associated with reduced nocturnal duration ≤2.2 mmol/L in those in the highest quartile of nocturnal hypoglycemia at baseline (median 46.2 vs. 1.8 min/day, P = 0.02 [LGS-OFF vs. LGS-ON]). Median sensor glucose was 3.9 mmol/L after 2-h LGS and 8.2 mmol/L at 2 h after basal restart. ::: ::: ::: CONCLUSIONS ::: Use of an insulin pump with LGS was associated with reduced nocturnal hypoglycemia in those at greatest risk and was well accepted by patients. <s> BIB005 </s> Combining continuous glucose monitoring and insulin pumps to automatically tune the basal insulin infusion in diabetes therapy: a review <s> Evidence of clinical effectiveness and safety <s> Abstract Background: Severe hypoglycemic episodes are a barrier for achieving optimal glycemic control. Sensor-augmented pump (SAP) therapy with insulin in combination with a novel mechanism of automatic insulin shutoff (low glucose suspend [LGS]) can be used to prevent and reduce hypoglycemia. In a prospective study, we investigated the effect of the LGS algorithm on the frequency of hypoglycemia in children and adolescents with type 1 diabetes under real-life conditions. 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 subseqent time periods: SAP without LGS for 2 weeks and then SAP with LGS enabled for 6 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 senso... <s> BIB006 </s> Combining continuous glucose monitoring and insulin pumps to automatically tune the basal insulin infusion in diabetes therapy: a review <s> Evidence of clinical effectiveness and safety <s> 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: <s> BIB007 </s> Combining continuous glucose monitoring and insulin pumps to automatically tune the basal insulin infusion in diabetes therapy: a review <s> Evidence of clinical effectiveness and safety <s> 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. <s> BIB008 </s> Combining continuous glucose monitoring and insulin pumps to automatically tune the basal insulin infusion in diabetes therapy: a review <s> Evidence of clinical effectiveness and safety <s> OBJECTIVE The advent of sensor-augmented pump therapy with a low-glucose suspend (LGS) function (Medtronic Paradigm Veo System), allowing insulin to be automatically suspended for up to 2 h when sensor glucose falls below a preset threshold, has the potential to reduce the duration of hypoglycemia. In this report, we analyzed blood glucose profiles following a full 2-h insulin suspension activated by the LGS function, as well as examined different patterns of use among patients. RESEARCH DESIGN AND METHODS Data from a cohort of participants using the Veo system for up to 6 months were analyzed to determine the time and duration of insulin suspension activated by the LGS function. We further evaluated overnight suspend events with no patient response occurring prior to 3:00 a.m., which allowed us to determine the pattern of sensor glucose values with no patient intervention during and after the period of insulin suspension. RESULTS There were 3,128 LGS events during the 2,493 days evaluated. The median duration was 11.2 min, and 36% of events occurred overnight. There were 126 full 2-h suspend events that occurred overnight with no patient response, occurring before 3:00 a.m. For these events, the mean sensor glucose at the end of the 2-h suspend period was 99 ± 6 mg/dL ([means ± SE] 5.5 ± 0.3 mmol/L). The mean sensor glucose 2 h after insulin delivery resumed was 155 ± 10 mg/dL (8.6 ± 0.6 mmol/L). There were no episodes of severe hypoglycemia or diabetic ketoacidosis. CONCLUSIONS Analyses of sensor glucose patterns following insulin suspension activated by LGS suggest that this technology is safe and unlikely to be associated with adverse outcomes. <s> BIB009 </s> Combining continuous glucose monitoring and insulin pumps to automatically tune the basal insulin infusion in diabetes therapy: a review <s> Evidence of clinical effectiveness and safety <s> Modularity plays a key role in many engineering systems, allowing for plug-and-play integration of components, enhancing flexibility and adaptability, and facilitating standardization. In the control of diabetes, i.e., the so-called “artificial pancreas,” modularity allows for the step-wise introduction of (and regulatory approval for) algorithmic components, starting with subsystems for assured patient safety and followed by higher layer components that serve to modify the patient's basal rate in real time. In this paper, we introduce a three-layer modular architecture for the control of diabetes, consisting in a sensor/pump interface module (IM), a continuous safety module (CSM), and a real-time control module (RTCM), which separates the functions of insulin recommendation (postmeal insulin for mitigating hyperglycemia) and safety (prevention of hypoglycemia). In addition, we provide details of instances of all three layers of the architecture: the APS© serving as the IM, the safety supervision module (SSM) serving as the CSM, and the range correction module (RCM) serving as the RTCM. We evaluate the performance of the integrated system via in silico preclinical trials, demonstrating 1) the ability of the SSM to reduce the incidence of hypoglycemia under nonideal operating conditions and 2) the ability of the RCM to reduce glycemic variability. <s> BIB010 </s> Combining continuous glucose monitoring and insulin pumps to automatically tune the basal insulin infusion in diabetes therapy: a review <s> Evidence of clinical effectiveness and safety <s> Abstract Objective: Nocturnal hypoglycemia is a common problem with type 1 diabetes. In the home setting, we conducted a pilot study to evaluate the safety of a system consisting of an insulin pump and continuous glucose monitor communicating wirelessly with a bedside computer running an algorithm that temporarily suspends insulin delivery when hypoglycemia is predicted. Research Design and Methods: After the run-in phase, a 21-night randomized trial was conducted in which each night was randomly assigned 2:1 to have either the predictive low-glucose suspend (PLGS) system active (intervention night) or inactive (control night). Three predictive algorithm versions were studied sequentially during the study for a total of 252 intervention and 123 control nights. The trial included 19 participants 18–56 years old with type 1 diabetes (hemoglobin A1c level of 6.0–7.7%) who were current users of the MiniMed Paradigm® REAL-Time Revel™ System and Sof-sensor® glucose sensor (Medtronic Diabetes, Northridge, CA). R... <s> BIB011 </s> Combining continuous glucose monitoring and insulin pumps to automatically tune the basal insulin infusion in diabetes therapy: a review <s> Evidence of clinical effectiveness and safety <s> IMPORTANCE ::: Hypoglycemia is a critical obstacle to the care of patients with type 1 diabetes. Sensor-augmented insulin pump with automated low-glucose insulin suspension has the potential to reduce the incidence of major hypoglycemic events. ::: ::: ::: OBJECTIVE ::: To determine the incidence of severe and moderate hypoglycemia with sensor-augmented pump with low-glucose suspension compared with standard insulin pump therapy. ::: ::: ::: DESIGN, SETTING, AND PARTICIPANTS ::: A randomized clinical trial involving 95 patients with type 1 diabetes, recruited from December 2009 to January 2012 in Australia. ::: ::: ::: INTERVENTIONS ::: Patients were randomized to insulin pump only or automated insulin suspension for 6 months. ::: ::: ::: MAIN OUTCOMES AND MEASURES ::: The primary outcome was the combined incidence of severe (hypoglycemic seizure or coma) and moderate hypoglycemia (an event requiring assistance for treatment). In a subgroup, counterregulatory hormone responses to hypoglycemia were assessed using the hypoglycemic clamp technique. ::: ::: ::: RESULTS ::: Of the 95 patients randomized, 49 were assigned to the standard-pump (pump-only) therapy and 46 to the low-glucose suspension group. The mean (SD) age was 18.6 (11.8) years; duration of diabetes, 11.0 (8.9) years; and duration of pump therapy, 4.1 (3.4) years. The baseline rate of severe and moderate hypoglycemic events in the pump-only group was 20.7 vs 129.6 events per 100 patient months in the low-glucose suspension group. After 6 months of treatment, the event rates decreased from 28 to 16 in the pump-only group vs 175 to 35 in the low-glucose suspension group. The adjusted incidence rate per 100 patient-months was 34.2 (95% CI, 22.0-53.3) for the pump-only group vs 9.5 (95% CI, 5.2-17.4) for the low-glucose suspension group. The incidence rate ratio was 3.6 (95% CI, 1.7-7.5; P <.001). There was no change in glycated hemoglobin in either group: mean, 7.4 (95% CI, 7.2-7.6) to 7.4 (95% CI, 7.2-7.7) in the pump-only group vs mean, 7.6 (95%, CI, 7.4-7.9) to 7.5 (95% CI, 7.3-7.7) in the low-glucose suspension group. Counterregulatory hormone responses to hypoglycemia were not changed. There were no episodes of diabetic ketoacidosis or hyperglycemia with ketosis. ::: ::: ::: CONCLUSIONS AND RELEVANCE ::: Sensor-augmented pump therapy with automated insulin suspension reduced the combined rate of severe and moderate hypoglycemia in patients with type 1 diabetes. ::: ::: ::: TRIAL REGISTRATION ::: anzctr.org.au Identifier: ACTRN12610000024044. <s> BIB012 </s> Combining continuous glucose monitoring and insulin pumps to automatically tune the basal insulin infusion in diabetes therapy: a review <s> Evidence of clinical effectiveness and safety <s> Safety measures to prevent or mitigate hypoglycemia are an important component of open loop, closed loop, and advisory mode insulin therapy control settings in type 1 diabetes. In recent work, we introduce a method for the automatic, gradual attenuation of the insulin pump delivery rate when a risk of hypoglycemia is detected, a method that we refer to as brakes. In the methods presented here, we demonstrate the use of historical glucose measurement data to inform and enhance the ability of the brakes to prevent hypoglycemia in real-time. The updated brakes are based on a patient-specific, time-varying model that reflects the typical trajectory of glycemic fluctuations throughout the day. Historical heightened risk of hypoglycemia throughout the day prompts an increase in the aggressiveness of insulin attenuation as compared to the original brakes that are based on real-time data alone. Through the use of available real-time data supplemented with historical glucose information to assess hypoglycemic risk, we are able to better anticipate and prevent hypoglycemia. <s> BIB013 </s> Combining continuous glucose monitoring and insulin pumps to automatically tune the basal insulin infusion in diabetes therapy: a review <s> Evidence of clinical effectiveness and safety <s> BACKGROUND ::: Predictive low glucose management (PLGM) may help prevent hypoglycemia by stopping insulin pump delivery based on predicted sensor glucose values. ::: ::: ::: MATERIALS AND METHODS ::: Hypoglycemic challenges were simulated using the Food and Drug Administration-accepted glucose simulator with 100 virtual patients. PLGM was then tested with a system composed of a Paradigm(®) insulin pump (Medtronic, Northridge, CA), an Enlite™ glucose sensor (Medtronic), and a BlackBerry(®) (Waterloo, ON, Canada)-based controller. Subjects (n=22) on continuous subcutaneous insulin infusion (five females, 17 males; median [range] age, 15 [range, 14-20] years; median [range] diabetes duration, 7 [2-14] years; median [range] glycated hemoglobin, 8.0% [6.7-10.4%]) exercised until the PLGM system suspended insulin delivery or until the reference blood glucose value (HemoCue(®); HemoCue GmbH, Großostheim, Germany) reached the predictive suspension threshold setting. ::: ::: ::: RESULTS ::: PLGM reduced hypoglycemia (<70 mg/dL) in silico by 26.7% compared with no insulin suspension, as opposed to a 5.3% reduction in hypoglycemia with use of low glucose suspend (LGS). The median duration of hypoglycemia (time spent <70 mg/dL) with PLGM was significantly less than with LGS (58 min vs. 101 min, respectively; P<0.001). In the clinical trial the hypoglycemic threshold during exercise was reached in 73% of the patients, and hypoglycemia was prevented in 80% of the successful experiments. The mean (±SD) sensor glucose at predictive suspension was 92±7 mg/dL, resulting in a postsuspension nadir (by HemoCue) of 77±22 mg/dL. The suspension lasted for 90±35 (range, 30-120) min, resulting in a sensor glucose level at insulin resumption of 97±19 mg/dL. ::: ::: ::: CONCLUSIONS ::: In silico modeling and early feasibility data demonstrate that PLGM may further reduce the severity of hypoglycemia beyond that already established for algorithms that use a threshold-based suspension. <s> BIB014 </s> Combining continuous glucose monitoring and insulin pumps to automatically tune the basal insulin infusion in diabetes therapy: a review <s> Evidence of clinical effectiveness and safety <s> 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 RESULTS Median time at P n = 45) and by 50% from 6.2% to 3.1% ( P n = 36). Mean overnight glucose was lower on control versus intervention nights in both age-groups (144 ± 18 vs. 152 ± 19 mg/dL [ P P = 0.004], respectively). Mean morning blood glucose was 159 ± 29 vs. 176 ± 28 mg/dL ( P 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. <s> BIB015 </s> Combining continuous glucose monitoring and insulin pumps to automatically tune the basal insulin infusion in diabetes therapy: a review <s> Evidence of clinical effectiveness and safety <s> Abstract 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... <s> BIB016 </s> Combining continuous glucose monitoring and insulin pumps to automatically tune the basal insulin infusion in diabetes therapy: a review <s> Evidence of clinical effectiveness and safety <s> Abstract Background: Sensor-augmented pump therapy (SAPT) with algorithms to predict impending low blood glucose and suspend insulin delivery has the potential to reduce hypoglycemia exposure. The aim of this study was to determine whether predictive low glucose management (PLGM) system is effective in preventing insulin-induced hypoglycemia in controlled experiments. Methods: Two protocols were used to induce hypoglycemia in an in-clinic environment. (A) Insulin bolus: Insulin was administered as a manual bolus through the pump. (B) Increased basal insulin: Hypoglycemia was induced by increasing basal rates overnight to 180%. For both protocols, participants were randomized and studied on 2 separate days; a control day with SAPT alone and an intervention day with SAPT and PLGM activated. The predictive algorithm was programmed to suspend basal insulin infusion when sensor glucose was predicted to be <80 mg/dL in 30 min. The primary outcome was the requirement for hypoglycemia treatment (symptomatic hypog... <s> BIB017 </s> Combining continuous glucose monitoring and insulin pumps to automatically tune the basal insulin infusion in diabetes therapy: a review <s> Evidence of clinical effectiveness and safety <s> Introduction Innovations with sensor-augmented pump therapy (SAPT) to reduce hypoglycaemia in patients with type 1 diabetes are an ongoing area of research. The predictive low glucose management (PLGM) system incorporates continuous glucose sensor data into an algorithm and suspends basal insulin before the occurrence of hypoglycaemia. The system was evaluated in in-clinic studies, and has informed the parameters of a larger home trial to study its efficacy and safety in real life. Methods and analysis The aim of this report is to describe the study design and outcome measures for the trial. This is a 6-month, multicentre, randomised controlled home trial to test the PLGM system in children and adolescents with type 1 diabetes. The system is available in the Medtronic MiniMed 640G pump as the ‘Suspend before low’ feature. Following a run-in period, participants are randomised to either the control arm with SAPT alone or the intervention arm with SAPT and Suspend before low. The primary aim of this study is to evaluate the time spent hypoglycaemic (sensor glucose Ethics and dissemination Ethics committee permissions were gained from respective Institutional Review boards. The findings of the study will provide high quality evidence of the ability of the system in the prevention of hypoglycaemia in real life. Trial registration number ACTRN12614000510640, Pre-results. <s> BIB018 </s> Combining continuous glucose monitoring and insulin pumps to automatically tune the basal insulin infusion in diabetes therapy: a review <s> Evidence of clinical effectiveness and safety <s> Abstract Background: Automated insulin management features of the MiniMed® 640G sensor-augmented pump system include suspension in response to predicted low sensor glucose (SG) values (“suspend before low”), suspension in response to existing low SG values (“suspend on low”), and automatic restarting of basal insulin delivery upon SG recovery. The effectiveness of these features was evaluated using CareLink® software data. Methods: Anonymized data from MiniMed 640G system users (n = 4818), MiniMed 530G system users (n = 39,219), and MiniMed Paradigm® Veo™ system users (n = 43,193) who voluntarily uploaded pump and sensor data were retrospectively analyzed. Comparisons were made between days in which system features were enabled at any time and those in which they were not. Comparisons were also made between pump suspension events for which insulin delivery was automatically or manually resumed and between glycemic parameters of users who switched from the MiniMed Paradigm Veo system to the MiniMed 640G sy... <s> BIB019 </s> Combining continuous glucose monitoring and insulin pumps to automatically tune the basal insulin infusion in diabetes therapy: a review <s> Evidence of clinical effectiveness and safety <s> BACKGROUND ::: Predictions based on continuous glucose monitoring (CGM) data are the basis for automatic suspension and resumption of insulin delivery by a predictive low-glucose management feature termed "suspend before low," which is part of the Medtronic MiniMed® 640G combined insulin pump and CGM system. This study assessed the safety and performance characteristics of the system in an in-clinic setting at eight sites. ::: ::: ::: MATERIALS AND METHODS ::: In-clinic standardized increases in basal insulin delivery rates were used to induce nocturnal hypoglycemia in subjects (14-75 years) with type 1 diabetes wearing the MiniMed 640G system. The "suspend before low" feature was set at 65 mg/dL, and as a result, the predictive algorithm suspended insulin delivery when the forecasted glucose was predicted to be ≤85 mg/dL in 30 min (a 20 mg/dL safety buffer). Reference plasma glucose values (Yellow Springs Instruments [YSI], Yellow Springs, OH) were used to establish hypoglycemia and were defined as ≥2 consecutive values ≤65 mg/dL. ::: ::: ::: RESULTS ::: Eighty subjects were screened. Among the 69 successful completers, 27 experienced a hypoglycemic event and 42 did not, a prevention rate of 60%. The mean (±standard deviation) YSI value at the time of pump suspension was 101 ± 18.5 mg/dL, and the mean duration of the 68 "suspend before low" events was 105 ± 27 min. At 120 min after the start of the pump suspension events, the mean YSI value was 102 ± 34.6 mg/dL. ::: ::: ::: CONCLUSION ::: The MiniMed 640G "suspend before low" feature prevented 60% of induced predicted hypoglycemic events without significant rebound hyperglycemia. <s> BIB020 </s> Combining continuous glucose monitoring and insulin pumps to automatically tune the basal insulin infusion in diabetes therapy: a review <s> Evidence of clinical effectiveness and safety <s> OBJECTIVE ::: To investigate whether predictive low glucose management (PLGM) of the MiniMed 640G system significantly reduces the rate of hypoglycemia compared with the sensor-augmented insulin pump in children with type 1 diabetes. ::: ::: ::: RESEARCH DESIGN AND METHODS ::: This randomized, two-arm, parallel, controlled, two-center open-label study included 100 children and adolescents with type 1 diabetes and glycated hemoglobin A1c ≤10% (≤86 mmol/mol) and using continuous subcutaneous insulin infusion. Patients were randomly assigned to either an intervention group with PLGM features enabled (PLGM ON) or a control group (PLGM OFF), in a 1:1 ratio, all using the same type of sensor-augmented insulin pump. The primary end point was the number of hypoglycemic events below 65 mg/dL (3.6 mmol/L), based on sensor glucose readings, during a 14-day study treatment. The analysis was performed by intention to treat for all randomized patients. ::: ::: ::: RESULTS ::: The number of hypoglycemic events below 65 mg/dL (3.6 mmol/L) was significantly smaller in the PLGM ON compared with the PLGM OFF group (mean ± SD 4.4 ± 4.5 and 7.4 ± 6.3, respectively; P = 0.008). This was also true when calculated separately for night (P = 0.025) and day (P = 0.022). No severe hypoglycemic events occurred; however, there was a significant increase in time spent above 140 mg/dL (7.8 mmol/L) in the PLGM ON group (P = 0.0165). ::: ::: ::: CONCLUSIONS ::: The PLGM insulin suspension was associated with a significantly reduced number of hypoglycemic events. Although this was achieved at the expense of increased time in moderate hyperglycemia, there were no serious adverse effects in young patients with type 1 diabetes. <s> BIB021 </s> Combining continuous glucose monitoring and insulin pumps to automatically tune the basal insulin infusion in diabetes therapy: a review <s> Evidence of clinical effectiveness and safety <s> OBJECTIVE Short-term studies with automated systems that suspend basal insulin when hypoglycemia is predicted have shown a reduction in hypoglycemia; however, efficacy and safety have not been established in long-term trials. RESEARCH DESIGN AND METHODS We conducted a 6-month, multicenter, randomized controlled trial in children and adolescents with type 1 diabetes using the Medtronic MiniMed 640G pump with Suspend before low (predictive low-glucose management [PLGM]) compared with sensor-augmented pump therapy (SAPT) alone. The primary outcome was percentage time in hypoglycemia with sensor glucose (SG) RESULTS In an intent-to-treat analysis of 154 subjects, 74 subjects were randomized to SAPT and 80 subjects to PLGM. At baseline, the time with SG 20 min) also declined with PLGM (SAPT vs. PLGM: events/patient-year 227 vs. 139, P CONCLUSIONS In children and adolescents with type 1 diabetes, PLGM reduced hypoglycemia without deterioration in glycemic control. <s> BIB022
Many studies were performed to assess the effectiveness and the safety of basal insulin suspension algorithms both in clinic under controlled conditions BIB001 BIB003  BIB008 BIB014 BIB017  BIB020 and at home under real-life conditions BIB011  BIB005 BIB006  BIB015 BIB012  BIB021 BIB022 . The effectiveness is intended as the ability of the algorithm to reduce or prevent hypoglycemia and was generally assessed by metrics like number/rate of hypoglycemic events, time spent in hypoglycemia, percentage of values in hypoglycemia, minimum glucose value (or nadir) per suspension event and area under the curve (AUC) for hypoglycemic excursions. The safety is intended as the ability of the algorithm not to produce rebounds in hyperglycemia and adverse events, like diabetes ketoacidosis, that can result from an extended suspension of basal insulin delivery. Metrics commonly used to assess algorithm's safety are mean glucose concentration, glycated hemoglobin (HbA1c), time spent in hyperglycemia, percentage of values in hyperglycemia, glucose values at restart of basal insulin, 2 h and 4 h after restart of basal insulin, morning glycemia and morning blood ketones. The Medtronic LGS/TS algorithm was tested both in single-arm BIB005 BIB006 and randomized controlled clinical trials BIB008 BIB012  . Evidences from these trials support the effectiveness of the algorithm in reducing hypoglycemia, at the price of a slight increase in hyperglycemia that, however, was not associated with an increase of HbA1c or the occurrence of ketoacidosis. For example, in the ASPIRE In-Home study  , a randomized trial in which 247 subjects were randomly assigned to sensor-augmented pump therapy (SAP) or SAP + LGS for 3 months, AUC for nocturnal hypoglycemic events was reduced by 37.5% in the LGS group compared to the control group. Regarding the 2-h suspension events, 4 h after the event start, 26% of CGM values were above 200 mg/ dl and the mean CGM value (168 ± 64.6 mg/dl) was pretty close to the hyperglycemic region. Nevertheless, no significant change in HbA1c was observed. In a 6-month randomized study comparing SAP + LGS therapy with pump therapy (no CGM) in patients with hypoglycemia unawareness, the rate of severe (coma and seizure) and moderate (requiring other person assistance) hypoglycemic events decreased from 129.6 to 28.4 events per 100 patient-months with no significant change in HbA1c BIB012 . In a partial analysis conducted in 24 patients BIB009 , the investigators found a discrepancy between first morning CGM value, that was 144 ± 9 mg/dl, and first morning SMBG value, that was 185 ± 9 mg/dl, after overnight 2-h suspension events (n = 324). Moreover on 14 occasions, there were more than one 2-h suspension per night. In these cases, mean morning meter value was 239 ± 22 mg/dl and mean morning sensor value was 112 ± 18 mg/dl. The authors stated these events were caused by sensor's calibration error, underlying the importance of relying on an accurate CGM sensor. These clinical trials also confirmed the evidence reported in Agrawal et al. BIB007 BIB016 that most of LGS/ TS suspension events were manually interrupted by the user, with a percentage of events of duration less than 10 min ranging between 48% BIB009 and 66% BIB006 . An investigational Medtronic device with the PLGM feature was assessed by Abraham et al. in experiments of insulin-induced BIB017 and exercise-induced  hypoglycemia and under real-life conditions BIB022 BIB018 , demonstrating the effectiveness of the algorithm in reducing hypoglycemia and hypotreatment requirements. The commercial MiniMed 640G system was assessed in a single-arm outpatient study  , a single-arm inpatient study with nocturnal hypoglycemia induced by increased insulin delivery BIB020 , and a randomized controlled trial conducted in children and adolescents BIB021 . In study by Choudhary et al., mean suspension event duration was 56.4 ± 9.6 min, mean of subsequent CGM nadir was 71.8 ± 5.2 mg/dl and CGM did not reach the preset low threshold in 83.1% of events  . Basal insulin delivery was manually restarted by the user in 26.7% of events, result of the improved strategy for basal insulin resumption in the PLGM feature. In in-clinic experiments, the 60% of hypoglycemic events (defined as two consecutive BG samples ≤ 65 mg/dl) were prevented with PLGM BIB020 . In their randomized clinical trial comparing SAP with and without PLGM, Battelino et al. found that PLGM allowed a significant reduction of number of events below 65 mg/dl, at the price of an increase of time above 140 mg/dl, which was significantly longer in the PLGM group BIB021 . Nevertheless, time above 180 mg/dl and time above 250 mg/dl were comparable in the two groups. Moreover, no significant difference in the number of events below 50 mg/dl was observed, indicating that basal insulin suspension may not be sufficient to avoid episodes of profound hypoglycemia. The superiority of PLGM compared to LGS/TS was proved by Danne et al. in silico using the UVA/Padova T1D simulator BIB014 . Zhong et al. analysed the data of 851 users who transitioned from Paradigm Veo to MiniMed 640G and observed a statistically significant reduction of excursions below 70 mg/dl and above 300 mg/dl BIB019 . As far as noncommercial algorithms are concerned, the algorithm based on Kalman filter prediction developed by Buckingham et al. BIB011 was tested for reduction of overnight hypoglycemia in a large 42-night randomized controlled clinical trial involving 45 adolescents and adults, 45 children aged 11-14 and 37 children aged 4-10 [38, 39, 46] . The algorithm was running in a bedside laptop communicating with the Paradigm Veo pump and the Medtronic Enlite sensor. Results showed that the prediction-based suspension algorithm was effective in reducing hypoglycemia in all age groups. In adults and adolescents, median hypoglycemia AUC was reduced by 81% and the percentage of nights with at least one CGM value < 60 mg/dl was 21% in the intervention group versus 18:37 33% in the control group  . In children, median time below 70 mg/dl was about 50% lower in the intervention group. However, in subjects aged 11 or older, the percentage of nights followed by morning glycemia > 180 mg/dl was statistically significantly higher in the intervention groups compared to the control groups (42% vs 32% in 11-14 year-olds; 27% vs 21% in > 14 year-olds)  BIB015 . Despite the higher occurrence of morning hyperglycemia in patients using the suspension algorithm, no significant increase in morning blood ketones and no serious adverse event was observed BIB015  . All the aforementioned clinical trials were performed with either detection-based or prediction-based suspension algorithms. The attenuation algorithms proposed by University of Virginia, Brakes and Power Brakes, were assessed in silico using the first release of the UVA/Padova T1D Simulator BIB002 . In Hughes et al. BIB004 , two simulated scenarios were generated in which hypoglycemia was induced by increasing the basal insulin delivery rate and by an insulin bolus with missed meal, respectively. In the first scenario, both Brakes and Power Brakes were effective in reducing the number of subjects experiencing hypoglycemia (from 59% to 26% and 7%, respectively). In the second scenario, Brakes was able to reduce the duration of hypoglycemic events but did not succeed in preventing any of them. Better results were achieved by Power Brakes, which, taking into account previously injected insulin for glucose prediction, was able to prevent 32/90 hypoglycemic events. Hughes et al. also showed that combining Power Brakes with a hypoglycemic treatment advisor, which suggests 15 g of rescue carbohydrates when predicted glucose goes below 80 mg/dl, almost all the hypoglycemic events were prevented BIB004 . The variant of Power Brakes with historical CGM data as additional input was tested in silico in an ad-hoc scenario generated by the UVA/Padova T1D Simulator, in which a random increase in the patient's basal rate was introduced to artificially simulate a circadian increase in the patient's insulin sensitivity BIB013 . Results showed that the addition of historical CGM data allowed to modestly improve the performance of Brakes in preventing hypoglycemia, although an assessment of these techniques in either real clinical studies or more realistic in silico experiments is necessary to better understand the potential benefits of using historical data to enhance pump attenuation algorithms. The SSM variant of Power Brakes was also assessed in silico, in a single-day experiment generated by the UVA/Padova T1D Simulator, in which patient's insulin sensitivity and basal insulin rate were perturbed to generate a suboptimal treatment scenario BIB010 . Compared to the conventional therapy, the SSM was able to effectively reduce hypoglycemia (0% time in hypoglycemia), at the price of an upward shift of the glucose profiles. However, this shift was compensated when the module of the closed-loop system responsible for recommending both positive and negative basal insulin adjustments (Range Correction Module) was activated under the supervision of the SSM. Although the encouraging results obtained in these short in silico experiments, to the best of our knowledge, Brakes and Power Brakes were never assessed as standalone algorithms in clinical trials, but only in closed-loop control trials, where they have been embedded in the SSM, making impossible to distinguish their effectiveness from that of the closed-loop controller. In addition, the effectiveness and safety of such algorithms have never been tested in more realistic long-duration in silico clinical trials when new and more reliable simulators were released   . 