Alexandra Lubina-Solomon

Home use of closed-loop insulin delivery for overnight glucose control in adults with type 1 diabetes: a 4-week, multicentre, randomised crossover study.

BACKGROUND Closed-loop insulin delivery is a promising option to improve glycaemic control and reduce the risk of hypoglycaemia. We aimed to assess whether overnight home use of automated closed-loop insulin delivery would improve glucose control. METHODS We did this open-label, multicentre, randomised controlled, crossover study between Dec 1, 2012, and Dec 23, 2014, recruiting patients from three centres in the UK. Patients aged 18 years or older with type 1 diabetes were randomly assigned to receive 4 weeks of overnight closed-loop insulin delivery (using a model-predictive control algorithm to direct insulin delivery), then 4 weeks of insulin pump therapy (in which participants used real-time display of continuous glucose monitoring independent of their pumps as control), or vice versa. Allocation to initial treatment group was by computer-generated permuted block randomisation. Each treatment period was separated by a 3-4 week washout period. The primary outcome was time spent in the target glucose range of 3·9-8·0 mmol/L between 0000 h and 0700 h. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01440140. FINDINGS We randomly assigned 25 participants to initial treatment in either the closed-loop group or the control group, patients were later crossed over into the other group; one patient from the closed-loop group withdrew consent after randomisation, and data for 24 patients were analysed. Closed loop was used over a median of 8·3 h (IQR 6·0-9·6) on 555 (86%) of 644 nights. The proportion of time when overnight glucose was in target range was significantly higher during the closed-loop period compared to during the control period (mean difference between groups 13·5%, 95% CI 7·3-19·7; p=0·0002). We noted no severe hypoglycaemic episodes during the control period compared with two episodes during the closed-loop period; these episodes were not related to closed-loop algorithm instructions. INTERPRETATION Unsupervised overnight closed-loop insulin delivery at home is feasible and could improve glucose control in adults with type 1 diabetes. FUNDING Diabetes UK.

Recovery of Hypoglycemia Awareness in Long-Standing Type 1 Diabetes: A Multicenter 2 × 2 Factorial Randomized Controlled Trial Comparing Insulin Pump With Multiple Daily Injections and Continuous With Conventional Glucose Self-Monitoring (HypoCOMPaSS)

OBJECTIVE To determine whether impaired awareness of hypoglycemia (IAH) can be improved and severe hypoglycemia (SH) prevented in type 1 diabetes, we compared an insulin pump (continuous subcutaneous insulin infusion [CSII]) with multiple daily injections (MDIs) and adjuvant real-time continuous glucose monitoring (RT) with conventional self-monitoring of blood glucose (SMBG). RESEARCH DESIGN AND METHODS A 24-week 2 × 2 factorial randomized controlled trial in adults with type 1 diabetes and IAH was conducted. All received comparable education, support, and congruent therapeutic targets aimed at rigorous avoidance of biochemical hypoglycemia without relaxing overall control. Primary end point was between-intervention difference in 24-week hypoglycemia awareness (Gold score). RESULTS A total of 96 participants (mean diabetes duration 29 years) were randomized. Overall, biochemical hypoglycemia (≤3.0 mmol/L) decreased (53 ± 63 to 24 ± 56 min/24 h; P = 0.004 [t test]) without deterioration in HbA1c. Hypoglycemia awareness improved (5.1 ± 1.1 to 4.1 ± 1.6; P = 0.0001 [t test]) with decreased SH (8.9 ± 13.4 to 0.8 ± 1.8 episodes/patient-year; P = 0.0001 [t test]). At 24 weeks, there was no significant difference in awareness comparing CSII with MDI (4.1 ± 1.6 vs. 4.2 ± 1.7; difference 0.1; 95% CI −0.6 to 0.8) and RT with SMBG (4.3 ± 1.6 vs. 4.0 ± 1.7; difference −0.3; 95% CI −1.0 to 0.4). Between-group analyses demonstrated comparable reductions in SH, fear of hypoglycemia, and insulin doses with equivalent HbA1c. Treatment satisfaction was higher with CSII than MDI (32 ± 3 vs. 29 ± 6; P = 0.0003 [t test]), but comparable with SMBG and RT (30 ± 5 vs. 30 ± 5; P = 0.79 [t test]). CONCLUSIONS Hypoglycemia awareness can be improved and recurrent SH prevented in long-standing type 1 diabetes without relaxing HbA1c. Similar biomedical outcomes can be attained with conventional MDI and SMBG regimens compared with CSII/RT, although satisfaction was higher with CSII.

Restoration of Self-awareness of Hypoglycemia in Adults With Long-standing Type 1 Diabetes: Hyperinsulinemic-hypoglycemic clamp substudy results from the HypoCOMPaSS trial

OBJECTIVE Impaired awareness of hypoglycemia (IAH) and defective counterregulation significantly increase severe hypoglycemia risk in type 1 diabetes (T1D). We evaluated restoration of IAH/defective counterregulation by a treatment strategy targeted at hypoglycemia avoidance in adults with T1D with IAH (Gold score ≥4) participating in the U.K.-based multicenter HypoCOMPaSS randomized controlled trial. RESEARCH DESIGN AND METHODS Eighteen subjects with T1D and IAH (mean ± SD age 50 ± 9 years, T1D duration 35 ± 10 years, HbA1c 8.1 ± 1.0% [65 ± 10.9 mmol/mol]) underwent stepped hyperinsulinemic-hypoglycemic clamp studies before and after a 6-month intervention. The intervention comprised the HypoCOMPaSS education tool in all and randomized allocation, in a 2 × 2 factorial study design, to multiple daily insulin analog injections or continuous subcutaneous insulin infusion therapy and conventional glucose monitoring or real-time continuous glucose monitoring. Symptoms, cognitive function, and counterregulatory hormones were measured at each glucose plateau (5.0, 3.8, 3.4, 2.8, and 2.4 mmol/L), with each step lasting 40 min with subjects kept blinded to their actual glucose value throughout clamp studies. RESULTS After intervention, glucose concentrations at which subjects first felt hypoglycemic increased (mean ± SE from 2.6 ± 0.1 to 3.1 ± 0.2 mmol/L, P = 0.02), and symptom and plasma metanephrine responses to hypoglycemia were higher (median area under curve for symptoms, 580 [interquartile range {IQR} 420–780] vs. 710 [460–1,260], P = 0.02; metanephrine, 2,412 [−3,026 to 7,279] vs. 5,180 [−771 to 11,513], P = 0.01). Glycemic threshold for deterioration of cognitive function measured by four-choice reaction time was unchanged, while the color-word Stroop test showed a degree of adaptation. CONCLUSIONS Even in long-standing T1D, IAH and defective counterregulation may be improved by a clinical strategy aimed at hypoglycemia avoidance.

Unsupervised home use of an overnight closed‐loop system over 3–4 weeks: a pooled analysis of randomized controlled studies in adults and adolescents with type 1 diabetes

To compare overnight closed‐loop and sensor‐augmented pump therapy in patients with type 1 diabetes by combining data collected during free‐living unsupervised randomized crossover home studies.

Accuracy of continuous glucose monitoring during three closed-loop home studies under free-living conditions.

Abstract Objectives: Closed-loop (CL) systems modulate insulin delivery based on glucose levels measured by a continuous glucose monitor (CGM). Accuracy of the CGM affects CL performance and safety. We evaluated the accuracy of the Freestyle Navigator® II CGM (Abbott Diabetes Care, Alameda, CA) during three unsupervised, randomized, open-label, crossover home CL studies. Materials and Methods: Paired CGM and capillary glucose values (10,597 pairs) were collected from 57 participants with type 1 diabetes (41 adults [mean±SD age, 39±12 years; mean±SD hemoglobin A1c, 7.9±0.8%] recruited at five centers and 16 adolescents [mean±SD age, 15.6±3.6 years; mean±SD hemoglobin A1c, 8.1±0.8%] recruited at two centers). Numerical accuracy was assessed by absolute relative difference (ARD) and International Organization for Standardization (ISO) 15197:2013 15/15% limits, and clinical accuracy was assessed by Clarke error grid analysis. Results: Total duration of sensor use was 2,002 days (48,052 h). Overall sensor accuracy for the capillary glucose range (1.1–27.8 mmol/L) showed mean±SD and median (interquartile range) ARD of 14.2±15.5% and 10.0% (4.5%, 18.4%), respectively. Lowest mean ARD was observed in the hyperglycemic range (9.8±8.8%). Over 95% of pairs were in combined Clarke error grid Zones A and B (A, 80.1%, B, 16.2%). Overall, 70.0% of the sensor readings satisfied ISO criteria. Mean ARD was consistent (12.3%; 95% of the values fall within ±3.7%) and not different between participants (P=0.06) within the euglycemic and hyperglycemic range, when CL is actively modulating insulin delivery. Conclusions: Consistent accuracy of the CGM within the euglycemic–hyperglycemic range using the Freestyle Navigator II was observed and supports its use in home CL studies. Our results may contribute toward establishing normative CGM performance criteria for unsupervised home use of CL.

Unsupervised overnight closed loop insulin delivery during free living: analysis of randomised cross-over home studies in adults and adolescents with type 1 diabetes.

BACKGROUND The closed-loop system (artificial pancreas) delivers insulin in a glucose-responsive manner by the use of a control algorithm that automatically directs insulin delivery, based on real-time sensor glucose concentrations. Results from hospital-based studies have shown improved overnight glucose control and reduced risk of hypoglycaemia in type 1 diabetes. We aimed to assess whether unsupervised closed-loop systems can provide a realistic treatment option in patients with type 1 diabetes. METHODS We combined data from two open-label, phase 2, randomised, cross-over, unsupervised home trials of people with type 1 diabetes, one in 24 adults (mean age 43 years [SD 12], HbA1c 8·0% [0·9]) and the other in 16 adolescents (15·6 [3·6], 8·1 [0·8]). In each trial, after training on study devices, participants were allocated to two periods of sensor-augmented pump therapy either with or without overnight closed loop that used a model predictive control algorithm to direct insulin delivery. Allocation sequence was done with a computer-generated random code. Each period lasted 4 weeks in adults and 3 weeks in adolescents. Primary outcome for both trials was time when sensor glucose was in the target range (3·9-8·0 mmol/L). Analysis was by intention to treat. Participants (or parents) gave written informed consent. The trials are registered with ClinicalTrials.gov, numbers NCT01440140 and NCT01221467. FINDINGS Closed loop was started by participants on their own volition on 866 (89%) of 978 nights. The proportion of time when sensor glucose was in the target range between 0000 h and 0800 h was increased by a mean of 18·4% (95% CI 13·5-23·4, p<0·0001) during closed loop compared with no closed loop. Closed loop significantly reduced mean overnight sensor glucose by 0·9 mmol/L (95% CI 0·4-1·3, p=0·0001), and reduced the proportion of time when sensor glucose values were suggestive of hyperglycaemia (>8·0 mmol/L) (15·9%, 10·7-21·0; p<0·0001) and hypoglycaemia (<3·9 mmol/L) (median 0·9, IQR 0·2-2·2; p=0·014). Lower mean overnight glucose was associated with increased overnight insulin delivery (p<0·0001) without changing total daily insulin amount (p=0·84). INTERPRETATION Extended use of overnight closed loop at home without supervision is feasible in adults and adolescents with type 1 diabetes. Clinically significant reduction in overnight glucose was observed accompanied by reduced time spent by patients in hypoglycaemia. To our knowledge, such combined effect has not been documented with any other means of intensified conventional insulin delivery. Longer term studies are warranted to assess its clinical potential. FUNDING Diabetes UK, Juvenile Diabetes Research Foundation, NIHR Cambridge Biomedical Research Centre.

Cardiac Autonomic Regulation and Repolarization During Acute Experimental Hypoglycemia in Type 2 Diabetes

Hypoglycemia is associated with increased cardiovascular mortality in trials of intensive therapy in type 2 diabetes mellitus (T2DM). We previously observed an increase in arrhythmias during spontaneous prolonged hypoglycemia in patients with T2DM. We examined changes in cardiac autonomic function and repolarization during sustained experimental hypoglycemia. Twelve adults with T2DM and 11 age- and BMI-matched control participants without diabetes underwent paired hyperinsulinemic clamps separated by 4 weeks. Glucose was maintained at euglycemia (6.0 mmol/L) or hypoglycemia (2.5 mmol/L) for 1 h. Heart rate, blood pressure, and heart rate variability were assessed every 30 min and corrected QT intervals and T-wave morphology every 60 min. Heart rate initially increased in participants with T2DM but then fell toward baseline despite maintained hypoglycemia at 1 h accompanied by reactivation of vagal tone. In control participants, vagal tone remained depressed during sustained hypoglycemia. Participants with T2DM exhibited greater heterogeneity of repolarization during hypoglycemia as demonstrated by T-wave symmetry and principal component analysis ratio compared with control participants. Epinephrine levels during hypoglycemia were similar between groups. Cardiac autonomic regulation during hypoglycemia appears to be time dependent. Individuals with T2DM demonstrate greater repolarization abnormalities for a given hypoglycemic stimulus despite comparable sympathoadrenal responses. These mechanisms could contribute to arrhythmias during clinical hypoglycemic episodes.

Sustained Reduction in Severe Hypoglycemia in Adults With Type 1 Diabetes Complicated by Impaired Awareness of Hypoglycemia: Two-Year Follow-up in the HypoCOMPaSS Randomized Clinical Trial

OBJECTIVE Severe hypoglycemia is a feared complication of type 1 diabetes; yet, few trials have targeted prevention using optimized self-management (educational, therapeutic, and technological support). We aimed to investigate whether improved awareness and reduced severe hypoglycemia, achieved during an intensive randomized clinical trial (RCT), were sustained after return to routine care. RESEARCH DESIGN AND METHODS Ninety-six adults with type 1 diabetes (29 ± 12 years’ duration) and impaired awareness of hypoglycemia at five U.K. tertiary referral diabetes centers were recruited into a 24-week 2 × 2 factorial RCT (HypoCOMPaSS). Participants were randomized to pump (continuous subcutaneous insulin infusion [CSII]) or multiple daily injections (MDIs) and real-time continuous glucose monitoring (RT-CGM) or self-monitoring of blood glucose (SMBG), with equal education/attention to all groups. At 24 weeks, participants returned to routine care with follow-up until 24 months, including free choice of MDI/CSII; RT-CGM vs. SMBG comparison continued to 24 months. Primary outcome was mean difference (baseline to 24 months [between groups]) in hypoglycemia awareness. RESULTS Improvement in hypoglycemia awareness was sustained (Gold score at baseline 5.1 ± 1.1 vs. 24 months 3.7 ± 1.9; P < 0.0001). Severe hypoglycemia rate was reduced from 8.9 ± 12.8 episodes/person-year over the 12 months prestudy to 0.4 ± 0.8 over 24 months (P < 0.0001). HbA1c improved (baseline 8.2 ± 3.2% [66 ± 12 mmol/mol] vs. 24 months 7.7 ± 3.1% [61 ± 10 mmol/mol]; P = 0.003). Improvement in treatment satisfaction and reduced fear of hypoglycemia were sustained. There were no significant differences between interventions at 24 months. CONCLUSIONS Optimized insulin replacement and glucose monitoring underpinned by hypoglycemia-focused structured education should be provided to all with type 1 diabetes complicated by impaired awareness of hypoglycemia.

Low–Blood Glucose Avoidance Training Improves Glycemic Variability in Adults With Type 1 Diabetes Complicated by Impaired Awareness of Hypoglycemia: HypoCOMPaSS Trial

The Comparison of Optimized MDI Versus Pumps With or Without Sensors in Severe Hypoglycemia (HypoCOMPaSS) trial was a prospective, multicenter, randomized controlled trial examining the restoration of impaired awareness of hypoglycemia (IAH) and the prevention of severe hypoglycemia (SH) in adults with type 1 diabetes using multiple daily injections (MDI) compared with continuous subcutaneous insulin infusion (CSII), with or without adjunctive real-time continuous glucose monitoring (RT-CGM), using a 2 × 2 factorial design (1). Few studies are currently available to compare the difference in glucose variability (GV) between MDI and CSII and between self-monitored blood glucose (SMBG) and RT-CGM (2–4). These studies showed an improvement in GV in favor of CSII and RT-CGM. However, none of them included participants with IAH or history of SH. The aim of this study is to compare the changes in GV between MDI and CSII and between SMBG and RT-CGM group in this specific patient group with type 1 diabetes with IAH or recurrent SH. A total of 96 participants were recruited for the study. Each participant undertook 7 days of blinded CGM using Medtronic iPro at baseline and prior to each of the four weekly visits during the 24-week randomized controlled trial period. GV was measured as glucose SD and coefficient of variation (%CV), calculated using available Excel formulas published online (5). Overall, there were decreases in GV between baseline and week …

Factors Associated With Glycemic Control During Free-Living Overnight Closed-Loop Insulin Delivery in Children and Adults With Type 1 Diabetes

Unsupervised free-living overnight home use of closed-loop insulin delivery is feasible, safe, and effective in adolescents1 and adults2 with type 1 diabetes, but outcomes vary between individuals. Understanding factors influencing glucose outcomes may help to identify vulnerable populations, guide design of future studies, and lead to enhanced control algorithms. To explore associations between demographic characteristics, the use of closed-loop and glucose performance, we pooled data from 2 multicenter trials, 1 involving adolescents,1 and 1 involving adults2 with type 1 diabetes. Both studies adopted an open-label, cross-over, randomized controlled study design. Participants were randomly assigned to 4 (adults) or 3 (adolescents) weeks of sensor-augmented pump therapy with or without overnight closed-loop. An identical model-predictive-control algorithm was used in both studies.3 Participants were instructed to start the system at home after their evening meal and to discontinue it before breakfast the next morning. Detailed methods and results are reported elsewhere.1-2 In the present work, Pearson’s correlation coefficients quantified the relationship between baseline demographic factors (age, BMI, HbA1c, total daily dose), participant-level utility characteristics (average duration of closed-loop application, average start time of closed-loop) and closed-loop outcomes between midnight and 08:00 (mean glucose, time in target between 70 and 145 mg/dl, time below 70 mg/dl) (Table 1). Age and time below target were rank-normal transformed. Associations with gender were evaluated applying Spearman correlation. Multiple linear regression analysis quantified the amount of explained variability of closed-loop outcomes using demographic and utility characteristics. Table 1. Pearson’s Correlation Coefficients Between Closed-Loop Outcomes and Demographic and Utility Characteristics (N = 40). Forty participants completed the studies, including 24 adults (age 43 ± 12 years [mean ± SD]; HbA1C 64.9 ± 8.9mmol/mol, 8.1 ± 0.8%; BMI 26.0 ± 3.5kg/m2; total daily insulin dose 0.5 ± 0.1U/kg/day) and 16 adolescents (age 15.6 ± 2.1 years; HbA1C 63.9 ± 9.4mmol/mol, 8.0 ± 0.9%; BMI 22.4 ± 3.7kg/m2; total daily insulin dose 0.8 ± 0.2U/kg/day). Data on 866 closed-loop nights were analyzed. HbA1c at baseline was associated with mean glucose during closed-loop nights (r = .52, P = .001) and time with hypoglycemia (r = –.43, P = .006), but not time in target (r = –.26, P = .101). Early closed-loop start and longer closed-loop application tended to increase time in target (P = .064). There was an age-associated reduction in time in target (r = –.33, P = .038), perhaps reflecting the association between older age and shorter period of closed-loop use (r = –.58, P < .001). Of the variance in mean glucose, 33% was explained by the regression model (P = .028), with HbA1c as the only significant predictor (P = .001). For time below target, the explained variance was 36% (P = .017); earlier closed-loop start time (P = .017) and HbA1c (P = .008) were significant predictors. Only 20% of variance in time in target was explained by the regression model. The strength of the current work is that the data were collected during free-living unsupervised home closed-loop use. Weaknesses include that we did not capture at all or with low confidence other potentially influential factors such as socioeconomic and educational status, exercise patterns, and meal size and composition. In conclusion, in adolescents and adults with type 1 diabetes undergoing overnight closed-loop, baseline HbA1c is correlated with mean overnight glucose but not time in target range. Despite closed-loop, a lower HbA1c level remains a risk factor for nocturnal hypoglycemia. Improved time in target may be observed if overnight closed-loop is started earlier and applied for longer.