Combining Glucose Monitoring and Insulin Infusion in an Integrated Device: A Narrative Review of Challenges and Proposed Solutions.

The introduction of automated insulin delivery (AID) systems has enabled increasing numbers of individuals with type 1 diabetes (T1D) to improve their glycemic control largely. However, use of AID systems is limited due to their complexity and costs associated. The user must wear both a continuously monitoring glucose system and an insulin infusion pump. The glucose sensor and the insulin catheter must be inserted at two different body sites using different insertion devices. In addition, the user must pair and manage the different systems. These communicate with the AID software implemented on the pump or on a third device such as a dedicated display device or smart phone application. These components might be developed and commercialized by different manufacturers, which in turn can cause difficulties for patients seeking technical support. A possible solution to these challenges would be to integrate the glucose sensor and insulin catheter into a single device. This would allow the glucose sensor and insulin catheter to be inserted simultaneously, eliminating the need for pairing, and simplifying system management. In recent years, different technologies have been developed and evaluated in clinical investigations that combine the glucose sensor and the insulin catheter in one platform. The consistent finding of all these studies is that integration has no adverse effect on insulin infusion and glucose measurements provided that certain conditions are met. In this review, we discuss the perceived challenges of such an approach and discuss possible solutions that have been proposed

Assessing the efficacy, safety and utility of closed-loop insulin delivery compared with sensor-augmented pump therapy in very young children with type 1 diabetes (KidsAP02 study): an open-label, multicentre, multinational, randomised cross-over study protocol

Introduction: Diabetes management in very young children remains challenging. Glycaemic targets are achieved at the expense of high parental diabetes management burden and frequent hypoglycaemia, impacting quality of life for the whole family. Our objective is to assess whether automated insulin delivery can improve glycaemic control and alleviate the burden of diabetes management in this particular age group. Methods and analysis: The study adopts an open-label, multinational, multicentre, randomised, crossover design and aims to randomise 72 children aged 1-7 years with type 1 diabetes on insulin pump therapy. Following screening, participants will receive training on study insulin pump and study continuous glucose monitoring devices. Participants will be randomised to 16-week use of the hybrid closed-loop system (intervention period) or to 16-week use of sensor-augmented pump therapy (control period) with 1-4 weeks washout period before crossing over to the other arm. The order of the two study periods will be random. The primary endpoint is the between-group difference in time spent in the target glucose range from 3.9 to 10.0 mmol/L based on sensor glucose readings during the 16-week study periods. Analyses will be conducted on an intention-to-treat basis. Key secondary endpoints are between group differences in time spent above and below target glucose range, glycated haemoglobin and average sensor glucose. Participants' and caregivers' experiences will be evaluated using questionnaires and qualitative interviews, and sleep quality will be assessed. A health economic analysis will be performed. Ethics and dissemination: Ethics approval has been obtained from Cambridge East Research Ethics Committee (UK), Ethics Committees of the University of Innsbruck, the University of Vienna and the University of Graz (Austria), Ethics Committee of the Medical Faculty of the University of Leipzig (Germany) and Comité National d'Ethique de Recherche (Luxembourg). The results will be disseminated by peer-reviewed publications and conference presentations

Evaluating Glucose Control With a Novel Composite Continuous Glucose Monitoring Index.

OBJECTIVE: The objective was to describe a novel composite continuous glucose monitoring index (COGI) and to evaluate its utility, in adults with type 1 diabetes, during hybrid closed-loop (HCL) therapy and multiple daily injections (MDI) therapy combined with real-time continuous glucose monitoring (CGM). METHODS: COGI consists of three key components of glucose control as assessed by CGM: Time in range (TIR), time below range (TBR), and glucose variability (GV) (weighted by 50%, 35% and 15%). COGI ranges from 0 to 100, where 1% increase of time 7.5-10%, had significantly higher COGI during 12 weeks of HCL compared to sensor-augmented pump therapy, mean (SD), 60.3 (8.6) versus 69.5 (6.9), P 7.5% to 9.9%, use of real-time CGM led to improved COGI, 49.8 (14.2) versus 58.2 (9.1), P < .0001. In MDI users with impaired awareness of hypoglycemia, use of real-time CGM led to improved COGI, 53.4 (12.2) versus 66.7 (11.1), P < .001. CONCLUSIONS: COGI summarizes three key aspects of CGM data into a concise metric that could be utilized to evaluate the quality of glucose control and to demonstrate the incremental benefit of a wide range of treatment modalities

Variability of Insulin Requirements Over 12 Weeks of Closed-Loop Insulin Delivery in Adults With Type 1 Diabetes.

OBJECTIVE: To quantify variability of insulin requirements during closed-loop insulin delivery. RESEARCH DESIGN AND METHODS: We retrospectively analyzed overnight, daytime, and total daily insulin amounts delivered during a multicenter closed-loop trial involving 32 adults with type 1 diabetes. Participants applied hybrid day-and-night closed-loop insulin delivery under free-living home conditions over 12 weeks. The coefficient of variation was adopted to measure variability of insulin requirements in individual subjects. RESULTS: Data were analyzed from 1,918 nights, 1,883 daytime periods and 1,564 total days characterized by closed-loop use over 85% of time. Variability of overnight insulin requirements (mean [SD] coefficient of variation 31% [4]) was nearly twice as high as variability of total daily requirements (17% [3], P < 0.001) and was also higher than variability of daytime insulin requirements (22% [4], P < 0.001). CONCLUSIONS: Overnight insulin requirements were significantly more variable than daytime and total daily amounts. This may explain why some people with type 1 diabetes report frustrating variability in morning glycemia.Seventh Framework Programme of the European Union (ICT FP7- 247138). Additional support for the Artificial Pancreas work by JDRF, National Institute for Health Research Cambridge Biomedical Research Centre and Wellcome Strategic Award (100574/Z/12/Z). Abbott Diabetes Care supplied discounted continuous glucose monitoring devices, sensors, and communication protocol to facilitate real-time connectivity. We acknowledge support by the staff at the Addenbrooke’s Wellcome Trust Clinical Research Facility. Jasdip Mangat and John Lum (Jaeb Center) supported development and validation of the closed-loop system. Josephine Hayes (University of Cambridge) provided administrative support. Karen Whitehead (University of Cambridge) provided laboratory support. We acknowledge support by the staff at Profil Institut; Krisztina Schmitz-Grozs provided support as a research physician, Martina Haase supported the study as an insulin pump expert, and Maren Luebkert, Kirstin Kuschma and Elke Przetak provided administrative, coordinating and documentation support.This is the author accepted manuscript. The final version is available from the American Diabetes Association via http://dx.doi.org/10.2337/dc15-262

Use of PaQ®, a Simple 3-Day Basal/Bolus Insulin Delivery Device, Reduces Barriers to Insulin Therapy in Patients With Type 2 Diabetes

PaQ (CeQur SA) is a simple to use patch-on device which provides set basal rates and bolus insulin on demand. PaQ was designed to minimize barriers to insulin therapy. In addition to feasibility of use, safety and effi cacy (reported elsewhere), this study analyzed the impact of the use of PaQ on patient reported outcomes (PRO) including; barriers against insulin treatment, diabetes related distress and negative attitudes towards insulin therapy in twenty patients with type 2 diabetes (T2D) on a stable multiple daily injections (MDI) insulin regimen. This single center, open label, single arm study was comprised of three 2-week periods; baseline (MDI), transition from MDI to PaQ, and PaQ treatment. Three validated questionnaires were completed at the end of the baseline and PaQ treatment periods; Barriers to Insulin Treatment - Questionnaire (BIT), Problem Areas In Diabetes -Scale (PAID) and Insulin Treatment Appraisal Scale (ITAS). Nineteen patients (age 59 ±5 y, T2D duration 15±7 y, 21% female, A1C 7.7 ±0.7%) completed the questionnaires at the two measurement points. There was a strong and signifi cant effect of PaQ in the mean BIT total score (2.5 to 2.1, difference (D)=0.4 ±0.6; p = .01, effect size (d) = 0.70). Patients perceived less hardship from insulin therapy (overall improvement d = 0.35), less stigmatization by insulin injection (overall improvement d=0.28) and less fear of hypoglycemia (overall reduction d=0.29). Diabetes related distress was slightly reduced (PAID 21.7 to 21.0, D=0.7 ±6.7, p = 0.79, d= 10). A non-signifi cant reduction was also seen in the mean ITAS score (42.80 to 40.80, D=2.0 ±6.5, p = .20, d= 31). The study is limited by both the uncontrolled design and small sample size, however, the results and the moderate to large effect sizes suggest that the use of PaQ has benefi cial and clinically relevant effects to overcome barriers to and negative appraisal of insulin treatment, without increasing other diabetes related distress

Assessing the effectiveness of 3 months day and night home closed-loop insulin delivery in adults with suboptimally controlled type 1 diabetes: a randomised crossover study protocol.

INTRODUCTION: Despite therapeutic advances, many people with type 1 diabetes are still unable to achieve optimal glycaemic control, limited by the occurrence of hypoglycaemia. The objective of the present study is to determine the effectiveness of day and night home closed-loop over the medium term compared with sensor-augmented pump therapy in adults with type 1 diabetes and suboptimal glycaemic control. METHODS AND ANALYSIS: The study will adopt an open label, three-centre, multinational, randomised, two-period crossover study design comparing automated closed-loop glucose control with sensor augmented insulin pump therapy. The study will aim for 30 completed participants. Eligible participants will be adults (≥18 years) with type 1 diabetes treated with insulin pump therapy and suboptimal glycaemic control (glycated haemoglobin (HbA1c)≥7.5% (58 mmol/mmol) and ≤10% (86 mmol/mmol)). Following a 4-week optimisation period, participants will undergo a 3-month use of automated closed-loop insulin delivery and sensor-augmented pump therapy, with a 4-6 week washout period in between. The order of the interventions will be random. All analysis will be conducted on an intention to treat basis. The primary outcome is the time spent in the target glucose range from 3.9 to 10.0 mmol/L based on continuous glucose monitoring levels during the 3 months free living phase. Secondary outcomes include HbA1c changes; mean glucose and time spent above and below target glucose levels. Further, participants will be invited at baseline, midpoint and study end to participate in semistructured interviews and complete questionnaires to explore usability and acceptance of the technology, impact on quality of life and fear of hypoglycaemia. ETHICS AND DISSEMINATION: Ethical approval has been obtained at all sites. Before screening, all participants will be provided with oral and written information about the trial. The study will be disseminated by peer-review publications and conference presentations. TRIAL REGISTRATION NUMBER: NCT01961622 (ClinicalTrials.gov)

Day and night home closed-loop insulin delivery in adults with type 1 diabetes: three-center randomized crossover study.

OBJECTIVE: To evaluate the feasibility of day and night closed-loop insulin delivery in adults with type 1 diabetes under free-living conditions. RESEARCH DESIGN AND METHODS: Seventeen adults with type 1 diabetes on insulin pump therapy (means ± SD age 34 ± 9 years, HbA1c 7.6 ± 0.8%, and duration of diabetes 19 ± 9 years) participated in an open-label multinational three-center crossover study. In a random order, participants underwent two 8-day periods (first day at the clinical research facility followed by 7 days at home) of sensor-augmented insulin pump therapy (SAP) or automated closed-loop insulin delivery. The primary end point was the time when sensor glucose was in target range between 3.9 and 10.0 mmol/L during the 7-day home phase. RESULTS: During the home phase, the percentage of time when glucose was in target range was significantly higher during closed-loop compared with SAP (median 75% [interquartile range 61-79] vs. 62% [53-70], P = 0.005). Mean glucose (8.1 vs. 8.8 mmol/L, P = 0.027) and time spent above target (P = 0.013) were lower during closed loop, while time spent below target was comparable (P = 0.339). Increased time in target was observed during both daytime (P = 0.017) and nighttime (P = 0.013). CONCLUSIONS: Compared with SAP, 1 week of closed-loop insulin delivery at home reduces mean glucose and increases time in target without increasing the risk of hypoglycemia in adults with relatively well-controlled type 1 diabetes.This is the author accepted manuscript. The final version can be found published here: http://care.diabetesjournals.org/content/37/7/1931.abstract

Time spent in hypoglycemia according to age and time-of-day: Observations during closed-loop insulin delivery.

OBJECTIVE We aimed to assess whether percentage of time spent in hypoglycemia during closed-loop insulin delivery differs by age-group and time-of-day. METHODS We retrospectively analyzed data from hybrid closed-loop studies involving young children (2-7 years), children and adolescents (8-18 years), adults (19-59 years), and older adults (≥60 years) with type 1 diabetes. Main outcome was time spent in hypoglycemia <3.9mmol/l. Eight weeks of data for 88 participants were analyzed. RESULTS Median time spent in hypoglycemia over the 24-hour period was highest in children and adolescents (4.4%; [IQR 2.4-5.0]) and very young children (4.0% [3.4-5.2]), followed by adults (2.7% [1.7-4.0]), and older adults (1.8% [1.2-2.2]); p<0.001 for difference between age-groups. Time spent in hypoglycemia during nighttime (midnight-05:59) was lower than during daytime (06:00-23:59) across all age-groups. CONCLUSION Time in hypoglycemia was highest in the pediatric age-group during closed-loop insulin delivery. Hypoglycemia burden was lowest overnight across all age-groups