Safety and Efficacy of an Adaptive Bolus Calculator for Type 1 Diabetes: A Randomized Controlled Crossover Study.

Background: The Advanced Bolus Calculator for Type 1 Diabetes (ABC4D) is a decision support system using the artificial intelligence technique of case-based reasoning to adapt and personalize insulin bolus doses. The integrated system comprises a smartphone application and clinical web portal. We aimed to assess the safety and efficacy of the ABC4D (intervention) compared with a nonadaptive bolus calculator (control). Methods: This was a prospective randomized controlled crossover study. Following a 2-week run-in period, participants were randomized to ABC4D or control for 12 weeks. After a 6-week washout period, participants crossed over for 12 weeks. The primary outcome was difference in % time in range (%TIR) (3.9-10.0 mmol/L [70-180 mg/dL]) change during the daytime (07:00-22:00) between groups. Results: Thirty-seven adults with type 1 diabetes on multiple daily injections of insulin were randomized, median (interquartile range [IQR]) age 44.7 (28.2-55.2) years, diabetes duration 15.0 (9.5-29.0) years, and glycated hemoglobin 61.0 (58.0-67.0) mmol/mol (7.7 [7.5-8.3]%). Data from 33 participants were analyzed. There was no significant difference in daytime %TIR change with ABC4D compared with control (median [IQR] +0.1 [-2.6 to +4.0]% vs. +1.9 [-3.8 to +10.1]%; P = 0.53). Participants accepted fewer meal dose recommendations in the intervention compared with control (78.7 [55.8-97.6]% vs. 93.5 [73.8-100]%; P = 0.009), with a greater reduction in insulin dosage from that recommended. Conclusion: The ABC4D is safe for adapting insulin bolus doses and provided the same level of glycemic control as the nonadaptive bolus calculator. Results suggest that participants did not follow the ABC4D recommendations as frequently as control, impacting its effectiveness. Clinical Trials Registration: clinicaltrials.gov NCT03963219 (Phase 5).

The Accuracy of Continuous Glucose Sensors in People with Diabetes Undergoing Hemodialysis (ALPHA Study).

Objectives: Real-time and intermittently scanned continuous glucose monitoring are increasingly used for glucose monitoring in people with diabetes requiring renal replacement therapy, with limited data reporting their accuracy in this cohort. We evaluated the accuracy of Dexcom G6 and Abbott Freestyle Libre 1 glucose monitoring systems in people with diabetes undergoing hemodialysis. Methods: Participants on hemodialysis with diabetes (on insulin or sulfonylureas) were recruited. Paired sensor glucose from Dexcom G6 and Freestyle Libre 1 were recorded with plasma glucose analyzed using the Yellow Springs Instrument (YSI) method at frequent intervals during hemodialysis. Analysis of accuracy metrics included mean absolute relative difference (MARD), Clarke error grid (CEG) analysis and proportion of CGM values within 15% and 20% or 15 and 20 mg/dL of YSI reference values for blood glucose >100 or ≤100 mg/dL, respectively (% 15/15, % 20/20). Results: Forty adults (median age 64.7 [60.2-74.4] years) were recruited. Overall MARD for Dexcom G6 was 22.7% (2656 matched glucose pairs), and 11.3% for Libre 1 (n = 2785). The proportions of readings meeting %15/15 and %20/20 were 29.1% and 45.4% for Dexcom G6, respectively, and 73.5% and 85.6% for Libre 1. CEG analysis showed 98.9% of all values in zones A and B for Dexcom G6 and 99.8% for Libre 1. Conclusions: Our results indicate Freestyle Libre 1 is a reliable tool for glucose monitoring in adults on hemodialysis. Further studies are required to evaluate Dexcom G6 accuracy in people on hemodialysis.

Real-time continuous glucose monitoring immediately after severe hypoglycaemia requiring emergency medical services: A randomised controlled trial.

AIMS: Severe hypoglycaemia requiring emergency medical services remains prevalent despite advances in all aspects of diabetes self-management. Real-time continuous glucose monitoring (RTCGM) technologies can reduce the risk of severe hypoglycaemia for adults with type 1 diabetes, but the impact of these devices has not been assessed in the acute phase after an episode of severe hypoglycaemia. METHODS: We recruited and randomised 35 adults with type 1 diabetes in the acute period after an episode of severe hypoglycaemia requiring emergency medical services and randomised participants to RTCGM with alerts and alarms, or usual care with self-monitored blood glucose for 12 weeks with intermittent blinded CGM. The primary outcome was the difference between groups in percentage time spent in hypoglycaemia (≤3.0 mmol/L, 55 mg/dL). RESULTS: Thirty participants completed the study (median (IQR) age, duration of diabetes, and BMI was 43 (36-56) years, 26 (19-37) years, and 24.9 (21.9-29.0) kg/m2 , respectively). Sufficient CGM data was available for 15 participants in RT-CGM group and 8 in SMBG group for the primary outcome analysis. The RTCGM group had a significantly larger reduction in exposure to glucose below 3.0 mmol/L (RTCGM -0.16 [-1.23 to 0.01] vs. SMBG 1.58 [0.41 to 3.48], p = 0.03) and episodes of nocturnal hypoglycaemia (RT-CGM -0.03 [-0.15 to 0.02] vs. SMBG 0.05 [-0.03 to 0.40], p = 0.02). Episodes of severe hypoglycaemia were significantly lower in the RTCGM group (RTCGM 0.0 vs. SMBG 4.0, p 0.04). CONCLUSIONS: RTCGM implemented acutely after an episode of severe hypoglycaemia is feasible and clinically effective with important implications for hypoglycaemia management pathways and self-monitoring cost effectiveness.

Safety and Feasibility of the PEPPER Adaptive Bolus Advisor and Safety System: A Randomized Control Study.

Background: The Patient Empowerment through Predictive Personalized Decision Support (PEPPER) system provides personalized bolus advice for people with type 1 diabetes. The system incorporates an adaptive insulin recommender system (based on case-based reasoning, an artificial intelligence methodology), coupled with a safety system, which includes predictive glucose alerts and alarms, predictive low-glucose suspend, personalized carbohydrate recommendations, and dynamic bolus insulin constraint. We evaluated the safety and efficacy of the PEPPER system compared to a standard bolus calculator. Methods: This was an open-labeled multicenter randomized controlled crossover study. Following 4-week run-in, participants were randomized to PEPPER/Control or Control/PEPPER in a 1:1 ratio for 12 weeks. Participants then crossed over after a washout period. The primary end-point was percentage time in range (TIR, 3.9-10.0 mmol/L [70-180 mg/dL]). Secondary outcomes included glycemic variability, quality of life, and outcomes on the safety system and insulin recommender. Results: Fifty-four participants on multiple daily injections (MDI) or insulin pump completed the run-in period, making up the intention-to-treat analysis. Median (interquartile range) age was 41.5 (32.3-49.8) years, diabetes duration 21.0 (11.5-26.0) years, and HbA1c 61.0 (58.0-66.1) mmol/mol. No significant difference was observed for percentage TIR between the PEPPER and Control groups (62.5 [52.1-67.8] % vs. 58.4 [49.6-64.3] %, respectively, P = 0.27). For quality of life, participants reported higher perceived hypoglycemia with the PEPPER system despite no objective difference in time spent in hypoglycemia. Conclusions: The PEPPER system was safe, but did not change glycemic outcomes, compared to control. There is wide scope for integrating PEPPER into routine diabetes management for pump and MDI users. Further studies are required to confirm overall effectiveness. Clinical trial registration: ClinicalTrials.gov NCT03849755.

Glycemic Variability and Hypoglycemic Excursions With Continuous Glucose Monitoring Compared to Intermittently Scanned Continuous Glucose Monitoring in Adults With Highest Risk Type 1 Diabetes.

BACKGROUND: The I-HART CGM study has shown that real-time continuous glucose monitoring (rtCGM) has greater beneficial impact on hypoglycemia than intermittently scanned continuous glucose monitoring (iscCGM) in adults with type 1 diabetes at high risk (Gold score ≥4 or recent severe hypoglycemia using insulin injections). In this subanalysis, we present the impact of rtCGM and iscCGM on glycemic variability (GV). METHODS: Forty participants were recruited to this parallel group study. Following two weeks of blinded rtCGM (DexcomG4), participants were randomized to rtCGM (Dexcom G5; n = 20) or iscCGM (Freestyle Libre; n = 20) for eight weeks. An open-extension phase enabled participants on rtCGM to continue for a further eight weeks and those on iscCGM to switch to rtCGM over this period. Glycemic variability measures at baseline, 8- and 16-week endpoints were compared between groups. RESULTS: At the eight-week endpoint, between-group differences demonstrated significant reduction in several GV measures with rtCGM compared to iscCGM (GRADE%hypoglycemia, index of glycemic control [IGC], and average daily risk range [ADRR]; P < .05). Intermittently scanned continuous glucose monitoring reduced mean average glucose and glycemic variability percentage and GRADE%hyperglycemia compared with rtCGM (P < .05). At 16 weeks, the iscCGM group switching to rtCGM showed significant improvement in GRADE%hypoglycemia, personal glycemic status, IGC, and ADRR. CONCLUSION: Our data suggest most, but not all, GV measures improve with rtCGM compared with iscCGM, particularly those measures associated with the risk of hypoglycemia. Selecting appropriate glucose monitoring technology to address GV in this high-risk cohort is important to minimize the risk of glucose extremes and severe hypoglycemia. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT03028220.

The Bio-inspired Artificial Pancreas for Type 1 Diabetes Control in the Home: System Architecture and Preliminary Results.

BACKGROUND: Artificial pancreas (AP) technology has been proven to improve glucose and patient-centered outcomes for people with type 1 diabetes (T1D). Several approaches to implement the AP have been described, clinically evaluated, and in one case, commercialized. However, none of these approaches has shown a clear superiority with respect to others. In addition, several challenges still need to be solved before achieving a fully automated AP that fulfills the users' expectations. We have introduced the Bio-inspired Artificial Pancreas (BiAP), a hybrid adaptive closed-loop control system based on beta-cell physiology and implemented directly in hardware to provide an embedded low-power solution in a dedicated handheld device. In coordination with the closed-loop controller, the BiAP system incorporates a novel adaptive bolus calculator which aims at improving postprandial glycemic control. This paper focuses on the latest developments of the BiAP system for its utilization in the home environment. METHODS: The hardware and software architectures of the BiAP system designed to be used in the home environment are described. Then, the clinical trial design proposed to evaluate the BiAP system in an ambulatory setting is introduced. Finally, preliminary results corresponding to two participants enrolled in the trial are presented. RESULTS: Apart from minor technical issues, mainly due to wireless communications between devices, the BiAP system performed well (~88% of the time in closed-loop) during the clinical trials conducted so far. Preliminary results show that the BiAP system might achieve comparable glycemic outcomes to the existing AP systems (~73% time in target range 70-180 mg/dL). CONCLUSION: The BiAP system is a viable platform to conduct ambulatory clinical trials and a potential solution for people with T1D to control their glucose control in a home environment.

Switching from Flash Glucose Monitoring to Continuous Glucose Monitoring on Hypoglycemia in Adults with Type 1 Diabetes at High Hypoglycemia Risk: The Extension Phase of the I HART CGM Study.

BACKGROUND: The I HART CGM study showed that real-time continuous glucose monitoring (RT-CGM) has greater beneficial impact on hypoglycemia than intermittent flash glucose monitoring (flash) in adults with type 1 diabetes (T1D) at high risk. The impact of continuing RT-CGM or switching from flash to RT-CGM for another 8 weeks was then evaluated. METHODS: Prospective randomized parallel group study with an extension phase. After a 2-week run-in with blinded CGM, participants were randomized to either RT-CGM or flash for 8 weeks. All participants were then given the option to continue with RT-CGM for another 8 weeks. Glycemic outcomes at 8 weeks are compared with the 16-week endpoint. RESULTS: Forty adults with T1D on intensified multiple daily insulin injections and with impaired awareness of hypoglycemia or a recent episode of severe hypoglycemia were included (40% female, median [IQR] age 49.5 [37.5-63.5] years, diabetes duration 30.0 [21.0-36.5] years, HbA1c 56 [48-63] mmol/mol, and Gold Score 5 [4-5]), of whom 36 completed the final 16-week extension. There was a significant reduction in percentage time in hypoglycemia (<3.0 mmol/L) in the group switching from flash to RT-CGM (from 5.0 [3.7-8.6]% to 0.8 [0.4-1.9]%, P = 0.0001), whereas no change was observed in the RT-CGM group continuing with the additional 8 weeks of RT-CGM (1.3 [0.4-2.8] vs. 1.3 [0.8-2.5], P = 0.82). Time in target (3.9-10 mmol/L) increased in the flash group after switching to RT-CGM (60.0 [54.5-67.8] vs. 67.4 [56.3-72.4], P = 0.02) and remained the same in the RT-CGM group that continued with RT-CGM (65.9 [54.1-74.8] vs. 64.9 [49.2-73.9], P = 0.64). CONCLUSIONS: Our data suggest that switching from flash to RT-CGM has a significant beneficial impact on hypoglycemia outcomes and that continued use of RT-CGM maintains hypoglycemia risk benefit in this high-risk population.

Metabolic Control With the Bio-inspired Artificial Pancreas in Adults With Type 1 Diabetes: A 24-Hour Randomized Controlled Crossover Study.

BACKGROUND: The Bio-inspired Artificial Pancreas (BiAP) is a closed-loop insulin delivery system based on a mathematical model of beta-cell physiology and implemented in a microchip within a low-powered handheld device. We aimed to evaluate the safety and efficacy of the BiAP over 24 hours, followed by a substudy assessing the safety of the algorithm without and with partial meal announcement. Changes in lactate and 3-hydroxybutyrate concentrations were investigated for the first time during closed-loop. METHODS: This is a prospective randomized controlled open-label crossover study. Participants were randomly assigned to attend either a 24-hour closed-loop visit connected to the BiAP system or a 24-hour open-loop visit (standard insulin pump therapy). The primary outcome was percentage time spent in target range (3.9-10 mmol/l) measured by sensor glucose. Secondary outcomes included percentage time in hypoglycemia (<3.9 mmol/l) and hyperglycemia (>10 mmol/l). Participants were invited to attend for an additional visit to assess the BiAP without and with partial meal announcements. RESULTS: A total of 12 adults with type 1 diabetes completed the study (58% female, mean [SD] age 45 [10] years, BMI 25 [4] kg/m(2), duration of diabetes 22 [12] years and HbA1c 7.4 [0.7]% [58 (8) mmol/mol]). The median (IQR) percentage time in target did not differ between closed-loop and open-loop (71% vs 66.9%, P = .9). Closed-loop reduced time spent in hypoglycemia from 17.9% to 3.0% (P < .01), but increased time was spent in hyperglycemia (10% vs 28.9%, P = .01). The percentage time in target was higher when all meals were announced during closed-loop compared to no or partial meal announcement (65.7% [53.6-80.5] vs 45.5% [38.2-68.3], P = .12). CONCLUSIONS: The BiAP is safe and achieved equivalent time in target as measured by sensor glucose, with improvement in hypoglycemia, when compared to standard pump therapy.

Feasibility study of a bio-inspired artificial pancreas in adults with type 1 diabetes.

BACKGROUND: This study assesses proof of concept and safety of a novel bio-inspired artificial pancreas (BiAP) system in adults with type 1 diabetes during fasting, overnight, and postprandial conditions. In contrast to existing glucose controllers in artificial pancreas systems, the BiAP uses a control algorithm based on a mathematical model of ß-cell physiology. The algorithm is implemented on a miniature silicon microchip within a portable hand-held device that interfaces the components of the artificial pancreas. MATERIALS AND METHODS: In this nonrandomized open-label study each subject attended for a 6-h fasting study followed by a 13-h overnight and post-breakfast study on a separate occasion. During both study sessions the BiAP system was used, and microboluses of insulin were recommended every 5 min by the control algorithm according to subcutaneous sensor glucose levels. The primary outcome was percentage time spent in the glucose target range (3.9-10.0 mmol/L). RESULTS: Twenty subjects (55% male; mean [SD] age, 44 [10] years; duration of diabetes, 22 [12] years; glycosylated hemoglobin, 7.4% [0.7%] [57 (7) mmol/mol]; body mass index, 25 [4] kg/m(2)) participated in the fasting study, and the median (interquartile range) percentage time in target range was 98.0% (90.8-100.0%). Seventeen of these subjects then participated in the overnight/postprandial study, where 70.7% (63.9-77.4%) of time was spent in the target range and, reassuringly, 0.0% (0.0-2.3%) of time was spent in hypoglycemia (<3.9 mmol/L). CONCLUSIONS: The BiAP achieves safe glycemic control during fasting, overnight, and postprandial conditions.