Automated Insulin Delivery in Women with Pregnancy Complicated by Type 1 Diabetes.

BACKGROUND: Hybrid closed-loop insulin therapy has shown promise for management of type 1 diabetes during pregnancy; however, its efficacy is unclear. METHODS: In this multicenter, controlled trial, we randomly assigned pregnant women with type 1 diabetes and a glycated hemoglobin level of at least 6.5% at nine sites in the United Kingdom to receive standard insulin therapy or hybrid closed-loop therapy, with both groups using continuous glucose monitoring. The primary outcome was the percentage of time in the pregnancy-specific target glucose range (63 to 140 mg per deciliter [3.5 to 7.8 mmol per liter]) as measured by continuous glucose monitoring from 16 weeks' gestation until delivery. Analyses were performed according to the intention-to-treat principle. Key secondary outcomes were the percentage of time spent in a hyperglycemic state (glucose level >140 mg per deciliter), overnight time in the target range, the glycated hemoglobin level, and safety events. RESULTS: A total of 124 participants with a mean (±SD) age of 31.1±5.3 years and a mean baseline glycated hemoglobin level of 7.7±1.2% underwent randomization. The mean percentage of time that the maternal glucose level was in the target range was 68.2±10.5% in the closed-loop group and 55.6±12.5% in the standard-care group (mean adjusted difference, 10.5 percentage points; 95% confidence interval [CI], 7.0 to 14.0; P<0.001). Results for the secondary outcomes were consistent with those of the primary outcome; participants in the closed-loop group spent less time in a hyperglycemic state than those in the standard-care group (difference, -10.2 percentage points; 95% CI, -13.8 to -6.6); had more overnight time in the target range (difference, 12.3 percentage points; 95% CI, 8.3 to 16.2), and had lower glycated hemoglobin levels (difference, -0.31 percentage points; 95% CI, -0.50 to -0.12). Little time was spent in a hypoglycemic state. No unanticipated safety problems associated with the use of closed-loop therapy during pregnancy occurred (6 instances of severe hypoglycemia, vs. 5 in the standard-care group; 1 instance of diabetic ketoacidosis in each group; and 12 device-related adverse events in the closed-loop group, 7 related to closed-loop therapy). CONCLUSIONS: Hybrid closed-loop therapy significantly improved maternal glycemic control during pregnancy complicated by type 1 diabetes. (Funded by the Efficacy and Mechanism Evaluation Program; AiDAPT ISRCTN Registry number, ISRCTN56898625.).

Closed-Loop Therapy and Preservation of C-Peptide Secretion in Type 1 Diabetes.

BACKGROUND: Whether improved glucose control with hybrid closed-loop therapy can preserve C-peptide secretion as compared with standard insulin therapy in persons with new-onset type 1 diabetes is unclear. METHODS: In a multicenter, open-label, parallel-group, randomized trial, we assigned youths 10.0 to 16.9 years of age within 21 days after a diagnosis of type 1 diabetes to receive hybrid closed-loop therapy or standard insulin therapy (control) for 24 months. The primary end point was the area under the curve (AUC) for the plasma C-peptide level (after a mixed-meal tolerance test) at 12 months after diagnosis. The analysis was performed on an intention-to-treat basis. RESULTS: A total of 97 participants (mean [±SD] age, 12±2 years) underwent randomization: 51 were assigned to receive closed-loop therapy and 46 to receive control therapy. The AUC for the C-peptide level at 12 months (primary end point) did not differ significantly between the two groups (geometric mean, 0.35 pmol per milliliter [interquartile range, 0.16 to 0.49] with closed-loop therapy and 0.46 pmol per milliliter [interquartile range, 0.22 to 0.69] with control therapy; mean adjusted difference, -0.06 pmol per milliliter [95% confidence interval {CI}, -0.14 to 0.03]). There was not a substantial between-group difference in the AUC for the C-peptide level at 24 months (geometric mean, 0.18 pmol per milliliter [interquartile range, 0.06 to 0.22] with closed-loop therapy and 0.24 pmol per milliliter [interquartile range, 0.05 to 0.30] with control therapy; mean adjusted difference, -0.04 pmol per milliliter [95% CI, -0.14 to 0.06]). The arithmetic mean glycated hemoglobin level was lower in the closed-loop group than in the control group by 4 mmol per mole (0.4 percentage points; 95% CI, 0 to 8 mmol per mole [0.0 to 0.7 percentage points]) at 12 months and by 11 mmol per mole (1.0 percentage points; 95% CI, 7 to 15 mmol per mole [0.5 to 1.5 percentage points]) at 24 months. Five cases of severe hypoglycemia occurred in the closed-loop group (in 3 participants), and one occurred in the control group; one case of diabetic ketoacidosis occurred in the closed-loop group. CONCLUSIONS: In youths with new-onset type 1 diabetes, intensive glucose control for 24 months did not appear to prevent the decline in residual C-peptide secretion. (Funded by the National Institute for Health and Care Research and others; CLOuD ClinicalTrials.gov number, NCT02871089.).

Randomized Trial of Closed-Loop Control in Very Young Children with Type 1 Diabetes.

BACKGROUND: The possible advantage of hybrid closed-loop therapy (i.e., artificial pancreas) over sensor-augmented pump therapy in very young children with type 1 diabetes is unclear. METHODS: In this multicenter, randomized, crossover trial, we recruited children 1 to 7 years of age with type 1 diabetes who were receiving insulin-pump therapy at seven centers across Austria, Germany, Luxembourg, and the United Kingdom. Participants received treatment in two 16-week periods, in random order, in which the closed-loop system was compared with sensor-augmented pump therapy (control). The primary end point was the between-treatment difference in the percentage of time that the sensor glucose measurement was in the target range (70 to 180 mg per deciliter) during each 16-week period. The analysis was conducted according to the intention-to-treat principle. Key secondary end points included the percentage of time spent in a hyperglycemic state (glucose level, >180 mg per deciliter), the glycated hemoglobin level, the mean sensor glucose level, and the percentage of time spent in a hypoglycemic state (glucose level, <70 mg per deciliter). Safety was assessed. RESULTS: A total of 74 participants underwent randomization. The mean (±SD) age of the participants was 5.6±1.6 years, and the baseline glycated hemoglobin level was 7.3±0.7%. The percentage of time with the glucose level in the target range was 8.7 percentage points (95% confidence interval [CI], 7.4 to 9.9) higher during the closed-loop period than during the control period (P<0.001). The mean adjusted difference (closed-loop minus control) in the percentage of time spent in a hyperglycemic state was -8.5 percentage points (95% CI, -9.9 to -7.1), the difference in the glycated hemoglobin level was -0.4 percentage points (95% CI, -0.5 to -0.3), and the difference in the mean sensor glucose level was -12.3 mg per deciliter (95% CI, -14.8 to -9.8) (P<0.001 for all comparisons). The time spent in a hypoglycemic state was similar with the two treatments (P = 0.74). The median time spent in the closed-loop mode was 95% (interquartile range, 92 to 97) over the 16-week closed-loop period. One serious adverse event of severe hypoglycemia occurred during the closed-loop period. One serious adverse event that was deemed to be unrelated to treatment occurred. CONCLUSIONS: A hybrid closed-loop system significantly improved glycemic control in very young children with type 1 diabetes, without increasing the time spent in hypoglycemia. (Funded by the European Commission and others; ClinicalTrials.gov number, NCT03784027.).

Implementation of fully closed-loop insulin delivery for inpatients with diabetes: Real-world outcomes.

AIMS: Fully closed-loop insulin delivery has been shown in clinical trials to be safe and improve glucose control compared with standard insulin therapy in the inpatient setting. We investigated the feasibility of implementing the approved CamAPS HX fully closed-loop system in a hospital setting. METHODS: This implementation project was conducted in a large teaching hospital in Cambridge, UK. Healthcare professional training was multimodal including face-to-face workshops, online learning modules and supported by standard operating procedures. Set-up and maintenance of closed-loop devices were undertaken by the inpatient diabetes team. Selection of suitable patients was multidisciplinary and prioritised those with more challenging diabetes management. Demographic and clinical data were collected from electronic health records and diabetes data management platforms. RESULTS: In the 12 months since the closed-loop system was implemented, 32 inpatients (mean ± SD age 61 ± 16 years, 8 females, 24 males) used closed-loop insulin delivery during their admission, across medical and surgical wards in the hospital with a total of 555 days of closed-loop glucose control (median [IQR]: 14 [6, 22] days per inpatient). The time spent in target glucose range 3.9-10.0 mmol/L was 53.3 ± 18.3%. Mean glucose was 10.7 ± 1.9 mmol/L with 46.0 ± 18.2% of time spent with glucose >10.0 mmol/L. Time spent with sensor glucose below 3.9 mmol/L was low (median [IQR]: 0.38 [0.00, 0.85]). There were no episodes of severe hypoglycaemia or diabetic ketoacidosis during closed-loop use. CONCLUSIONS: We have demonstrated that the fully closed-loop system can be safely and effectively implemented by a diabetes outreach team in complex medical and surgical inpatients with challenging glycaemic control.

UK's Association of British Clinical Diabetologist's Diabetes Technology Network (ABCD-DTN): Best practice guide for hybrid closed-loop therapy.

This best practice guide is written with the aim of providing an overview of current hybrid closed-loop (HCL) systems in use within the United Kingdom's (UK) National Health Service (NHS) and to provide education and advice for their management on both an individual and clinical service level. The environment of diabetes technology, and particularly HCL systems, is rapidly evolving. The past decade has seen unprecedented advances in the development of HCL systems. These systems improve glycaemic outcomes and reduce the burden of treatment for people with type 1 diabetes (pwT1D). It is anticipated that access to these systems will increase in England as a result of updates in National Institute of Health and Care Excellence (NICE) guidance providing broader support for the use of real-time continuous glucose monitoring (CGM) for pwT1D. NICE is currently undertaking multiple-technology appraisal into HCL systems. Based on experience from centres involved in supporting advanced technologies as well as from the recent NHS England HCL pilot, this guide is intended to provide healthcare professionals with UK expert consensus on the best practice for initiation, optimisation and ongoing management of HCL therapy.

Healthcare professionals' views about how pregnant women can benefit from using a closed-loop system: Qualitative study.

BACKGROUND: Interest is growing in how closed-loop systems can support attainment of within-target glucose levels amongst pregnant women with type 1 diabetes. We explored healthcare professionals' views about how, and why, pregnant women benefitted from using the CamAPS FX system during the AiDAPT trial. METHODS: We interviewed 19 healthcare professionals who supported women using closed-loop during the trial. Our analysis focused on identifying descriptive and analytical themes relevant to clinical practice. RESULTS: Healthcare professionals highlighted clinical and quality-of-life benefits to using closed-loop in pregnancy; albeit, they attributed some of these to the continuous glucose monitoring component. They emphasised that the closed-loop was not a panacea and that, to gain maximum benefit, an effective collaboration between themselves, the woman and the closed-loop was needed. Optimal performance of the technology, as they further noted, also required women to interact with the system sufficiently, but not excessively; a requirement that they felt some women had found challenging. Even where healthcare professionals felt that this balance was not achieved, they suggested that women had still benefitted from using the system. Healthcare professionals reported difficulties predicting how specific women would engage with the technology. In light of their trial experiences, healthcare professionals favoured an inclusive approach to closed-loop rollout in routine clinical care. CONCLUSIONS: Healthcare professionals recommended that closed-loop systems be offered to all pregnant women with type 1 diabetes in the future. Presenting closed-loop systems to pregnant women and healthcare teams as one pillar of a three-party collaboration may help promote optimal use.

Safe and effective use of a hybrid closed-loop system from diagnosis in children under 18 months with type 1 diabetes.

The management of type 1 diabetes in infancy presents significant challenges. Hybrid closed loop systems have been shown to be effective in a research setting and are now available for clinical use. There are relatively little reported data regarding their safety and efficacy in a real world clinical setting. We report two cases of very young children diagnosed with type 1 diabetes at ages 18 (Case 1) and 7 months (Case 2), who were commenced on hybrid closed-loop insulin delivery using the CamAPS FX™ system from diagnosis. At diagnosis, total daily dose (TDD) was 6 and 3.3 units for Case 1 and 2, respectively. Closed loop was started during the inpatient stay and weekly follow up was provided via video call on discharge. Seven months from diagnosis, Case 1 has an HbA1C of 49 mmol/mol, 61% time in range (TIR, 3.9-10 mmol/L) with 2% time in hypoglycemia (<3.9 mmol/L) with no incidents of very low blood glucose (BG; <3 mmol/L, 54 mg/dL) over 6 months. Given the extremely small TDD of insulin in Case 2, we elected to use diluted insulin (insulin aspart injection, NovoLog, Novo Nordisk Inc., Plainsboro, NJ, Diluting Medium for NovoLog®). Six months from diagnosis, the estimated HbA1c is 50 mmol/mol, TIR 76% with 1% hypoglycemia and no incidents of very low BG (<3 mmol/L, 54 mg/dL) over 6 months. We conclude that the use hybrid closed-loop can be safe and effective from diagnosis in children under 2 years of age with type 1 diabetes.

AiDAPT: automated insulin delivery amongst pregnant women with type 1 diabetes: a multicentre randomized controlled trial - study protocol.

BACKGROUND: Pregnant women with type 1 diabetes strive for tight glucose targets (3.5-7.8 mmol/L) to minimise the risks of obstetric and neonatal complications. Despite using diabetes technologies including continuous glucose monitoring (CGM), insulin pumps and contemporary insulin analogues, most women struggle to achieve and maintain the recommended pregnancy glucose targets. This study aims to evaluate whether the use of automated closed-loop insulin delivery improves antenatal glucose levels in pregnant women with type 1 diabetes. METHODS/DESIGN: A multicentre, open label, randomized, controlled trial of pregnant women with type 1 diabetes and a HbA1c of ≥48 mmol/mol (6.5%) at pregnancy confirmation and ≤ 86 mmol/mol (10%) at randomization. Participants who provide written informed consent before 13 weeks 6 days gestation will be entered into a run-in phase to collect 96 h (24 h overnight) of CGM glucose values. Eligible participants will be randomized on a 1:1 basis to CGM (Dexcom G6) with usual insulin delivery (control) or closed-loop (intervention). The closed-loop system includes a model predictive control algorithm (CamAPS FX application), hosted on an android smartphone that communicates wirelessly with the insulin pump (Dana Diabecare RS) and CGM transmitter. Research visits and device training will be provided virtually or face-to-face in conjunction with 4-weekly antenatal clinic visits where possible. Randomization will stratify for clinic site. One hundred twenty-four participants will be recruited. This takes into account 10% attrition and 10% who experience miscarriage or pregnancy loss. Analyses will be performed according to intention to treat. The primary analysis will evaluate the change in the time spent in the target glucose range (3.5-7.8 mmol/l) between the intervention and control group from 16 weeks gestation until delivery. Secondary outcomes include overnight time in target, time above target (> 7.8 mmol/l), standard CGM metrics, HbA1c and psychosocial functioning and health economic measures. Safety outcomes include the number and severity of ketoacidosis, severe hypoglycaemia and adverse device events. DISCUSSION: This will be the largest randomized controlled trial to evaluate the impact of closed-loop insulin delivery during type 1 diabetes pregnancy. TRIAL REGISTRATION: ISRCTN 56898625 Registration Date: 10 April, 2018.

Closed-Loop Insulin Delivery for Glycemic Control in Noncritical Care.

BACKGROUND: In patients with diabetes, hospitalization can complicate the achievement of recommended glycemic targets. There is increasing evidence that a closed-loop delivery system (artificial pancreas) can improve glucose control in patients with type 1 diabetes. We wanted to investigate whether a closed-loop system could also improve glycemic control in patients with type 2 diabetes who were receiving noncritical care. METHODS: In this randomized, open-label trial conducted on general wards in two tertiary hospitals located in the United Kingdom and Switzerland, we assigned 136 adults with type 2 diabetes who required subcutaneous insulin therapy to receive either closed-loop insulin delivery (70 patients) or conventional subcutaneous insulin therapy, according to local clinical practice (66 patients). The primary end point was the percentage of time that the sensor glucose measurement was within the target range of 100 to 180 mg per deciliter (5.6 to 10.0 mmol per liter) for up to 15 days or until hospital discharge. RESULTS: The mean (±SD) percentage of time that the sensor glucose measurement was in the target range was 65.8±16.8% in the closed-loop group and 41.5±16.9% in the control group, a difference of 24.3±2.9 percentage points (95% confidence interval [CI], 18.6 to 30.0; P<0.001); values above the target range were found in 23.6±16.6% and 49.5±22.8% of the patients, respectively, a difference of 25.9±3.4 percentage points (95% CI, 19.2 to 32.7; P<0.001). The mean glucose level was 154 mg per deciliter (8.5 mmol per liter) in the closed-loop group and 188 mg per deciliter (10.4 mmol per liter) in the control group (P<0.001). There was no significant between-group difference in the duration of hypoglycemia (as defined by a sensor glucose measurement of <54 mg per deciliter; P=0.80) or in the amount of insulin that was delivered (median dose, 44.4 U and 40.2 U, respectively; P=0.50). No episode of severe hypoglycemia or clinically significant hyperglycemia with ketonemia occurred in either trial group. CONCLUSIONS: Among inpatients with type 2 diabetes receiving noncritical care, the use of an automated, closed-loop insulin-delivery system resulted in significantly better glycemic control than conventional subcutaneous insulin therapy, without a higher risk of hypoglycemia. (Funded by Diabetes UK and others; ClinicalTrials.gov number, NCT01774565 .).

Day-to-day variability of insulin requirements in the inpatient setting: Observations during fully closed-loop insulin delivery.

The aim of this study was to characterize the variability of exogenous insulin requirements during fully closed-loop insulin delivery in hospitalized patients with type 2 diabetes or new-onset hyperglycaemia, and to determine patient-related characteristics associated with higher variability of insulin requirements. We retrospectively analysed data from two fully closed-loop inpatient studies involving adults with type 2 diabetes or new-onset hyperglycaemia requiring insulin therapy. The coefficient of variation quantified day-to-day variability of exogenous insulin requirements during up to 15 days using fully automated closed-loop insulin delivery. Data from 535 days in 67 participants were analysed. The coefficient of variation of day-to-day exogenous insulin requirements was 30% ± 16%, and was higher between nights than between any daytime period (56% ± 29% overnight [11:00 pm to 4:59 am] compared with 41% ± 21% in the morning [5:00 am to 10:59 am], 39% ± 15% in the afternoon [11:00 am to 4:59 pm] and 45% ± 19% during the evening [5:00 pm to 10:59 pm]; all P < 0.01). There is high day-to-day variability of exogenous insulin requirements in inpatients, particularly overnight, and diabetes management approaches should account for this variability.

Hybrid closed-loop glucose control with faster insulin aspart compared with standard insulin aspart in adults with type 1 diabetes: A double-blind, multicentre, multinational, randomized, crossover study.

AIM: To evaluate the use of hybrid closed-loop glucose control with faster-acting insulin aspart (Fiasp) in adults with type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: In a double-blind, multinational, randomized, crossover study, 25 adults with T1D using insulin pump therapy (mean ± SD, age 38 ± 9 years, HbA1c 7.4% ± 0.8% [57 ± 8 mmol/mol]) underwent two 8-week periods of unrestricted living comparing hybrid closed-loop with Fiasp and hybrid closed-loop with standard insulin aspart in random order. During both interventions the CamAPS FX closed-loop system incorporating the Cambridge model predictive control algorithm was used. RESULTS: In an intention-to-treat analysis, the proportion of time sensor glucose was in the target range (3.9-10.0 mmol/L; primary endpoint) was not different between interventions (75% ± 8% vs. 75% ± 8% for hybrid closed-loop with Fiasp vs. hybrid closed-loop with standard insulin aspart; mean-adjusted difference -0.6% [95% CI -1.8% to 0.7%]; p < .001 for non-inferiority [non-inferiority margin 5%]). The proportion of time with sensor glucose less than 3.9 mmol/L (median [IQR] 2.4% [1.2%-3.2%] vs. 2.9% [1.7%-4.0%]; p = .01) and less than 3.0 mmol/L (median [IQR] 0.4% [0.2%-0.7%] vs. 0.7% [0.2%-0.9%]; p = .03) was reduced with Fiasp versus standard insulin aspart. There was no difference in mean glucose (8.1 ± 0.8 vs. 8.0 ± 0.8 mmol/L; p = .13) or glucose variability (SD of sensor glucose 2.9 ± 0.5 vs. 2.9 ± 0.5 mmol/L; p = .90). Total daily insulin requirements did not differ (49 ± 15 vs. 49 ± 15 units/day; p = .45). No severe hypoglycaemia or ketoacidosis occurred. CONCLUSIONS: The use of Fiasp in the CamAPS FX closed-loop system may reduce hypoglycaemia without compromising glucose control compared with standard insulin aspart in adults with T1D.

Fully closed-loop insulin delivery improves glucose control of inpatients with type 2 diabetes receiving hemodialysis.

Inpatient diabetes management of those on hemodialysis poses a major challenge. In a post hoc analysis of a randomized controlled clinical trial, we compared the efficacy of fully automated closed-loop insulin delivery vs. usual care in patients undergoing hemodialysis while in hospital. Compared to control patients receiving conventional subcutaneous insulin therapy, those patients receiving closed-loop insulin delivery significantly increased the proportion of time when a continuous glucose monitor was in the target range of 5.6-10.0 mmol/l by 37.6 percent without increasing the risk of hypoglycemia. Thus, closed-loop insulin delivery offers a novel way to achieve effective and safe glucose control in this vulnerable patient population.

Closed-loop insulin delivery in suboptimally controlled type 1 diabetes: a multicentre, 12-week randomised trial.

BACKGROUND: The achievement of glycaemic control remains challenging for patients with type 1 diabetes. We assessed the effectiveness of day-and-night hybrid closed-loop insulin delivery compared with sensor-augmented pump therapy in people with suboptimally controlled type 1 diabetes aged 6 years and older. METHODS: In this open-label, multicentre, multinational, single-period, parallel randomised controlled trial, participants were recruited from diabetes outpatient clinics at four hospitals in the UK and two centres in the USA. We randomly assigned participants with type 1 diabetes aged 6 years and older treated with insulin pump and with suboptimal glycaemic control (glycated haemoglobin [HbA1c] 7·5-10·0%) to receive either hybrid closed-loop therapy or sensor-augmented pump therapy over 12 weeks of free living. Training on study insulin pump and continuous glucose monitoring took place over a 4-week run-in period. Eligible subjects were randomly assigned using central randomisation software. Allocation to the two study groups was unblinded, and randomisation was stratified within centre by low (<8·5%) or high (≥8·5%) HbA1c. The primary endpoint was the proportion of time that glucose concentration was within the target range of 3·9-10·0 mmol/L at 12 weeks post randomisation. Analyses of primary outcome and safety measures were done in all randomised patients. The trial is registered with ClinicalTrials.gov, number NCT02523131, and is closed to accrual. FINDINGS: From May 12, 2016, to Nov 17, 2017, 114 individuals were screened, and 86 eligible patients were randomly assigned to receive hybrid closed-loop therapy (n=46) or sensor-augmented pump therapy (n=40; control group). The proportion of time that glucose concentration was within the target range was significantly higher in the closed-loop group (65%, SD 8) compared with the control group (54%, SD 9; mean difference in change 10·8 percentage points, 95% CI 8·2 to 13·5; p<0·0001). In the closed-loop group, HbA1c was reduced from a screening value of 8·3% (SD 0·6) to 8·0% (SD 0·6) after the 4-week run-in, and to 7·4% (SD 0·6) after the 12-week intervention period. In the control group, the HbA1c values were 8·2% (SD 0·5) at screening, 7·8% (SD 0·6) after run-in, and 7·7% (SD 0·5) after intervention; reductions in HbA1c percentages were significantly greater in the closed-loop group compared with the control group (mean difference in change 0·36%, 95% CI 0·19 to 0·53; p<0·0001). The time spent with glucose concentrations below 3·9 mmol/L (mean difference in change -0·83 percentage points, -1·40 to -0·16; p=0·0013) and above 10·0 mmol/L (mean difference in change -10·3 percentage points, -13·2 to -7·5; p<0·0001) was shorter in the closed-loop group than the control group. The coefficient of variation of sensor-measured glucose was not different between interventions (mean difference in change -0·4%, 95% CI -1·4% to 0·7%; p=0·50). Similarly, total daily insulin dose was not different (mean difference in change 0·031 U/kg per day, 95% CI -0·005 to 0·067; p=0·09) and bodyweight did not differ (mean difference in change 0·68 kg, 95% CI -0·34 to 1·69; p=0·19). No severe hypoglycaemia occurred. One diabetic ketoacidosis occurred in the closed-loop group due to infusion set failure. Two participants in each study group had significant hyperglycaemia, and there were 13 other adverse events in the closed-loop group and three in the control group. INTERPRETATION: Hybrid closed-loop insulin delivery improves glucose control while reducing the risk of hypoglycaemia across a wide age range in patients with suboptimally controlled type 1 diabetes. FUNDING: JDRF, NIHR, and Wellcome Trust.

Closed-Loop Insulin Delivery during Pregnancy in Women with Type 1 Diabetes.

BACKGROUND: In patients with type 1 diabetes who are not pregnant, closed-loop (automated) insulin delivery can provide better glycemic control than sensor-augmented pump therapy, but data are lacking on the efficacy, safety, and feasibility of closed-loop therapy during pregnancy. METHODS: We performed an open-label, randomized, crossover study comparing overnight closed-loop therapy with sensor-augmented pump therapy, followed by a continuation phase in which the closed-loop system was used day and night. Sixteen pregnant women with type 1 diabetes completed 4 weeks of closed-loop pump therapy (intervention) and sensor-augmented pump therapy (control) in random order. During the continuation phase, 14 of the participants used the closed-loop system day and night until delivery. The primary outcome was the percentage of time that overnight glucose levels were within the target range (63 to 140 mg per deciliter [3.5 to 7.8 mmol per liter]). RESULTS: The percentage of time that overnight glucose levels were in the target range was higher during closed-loop therapy than during control therapy (74.7% vs. 59.5%; absolute difference, 15.2 percentage points; 95% confidence interval, 6.1 to 24.2; P=0.002). The overnight mean glucose level was lower during closed-loop therapy than during control therapy (119 vs. 133 mg per deciliter [6.6 vs. 7.4 mmol per liter], P=0.009). There were no significant differences between closed-loop and control therapy in the percentage of time in which glucose levels were below the target range (1.3% and 1.9%, respectively; P=0.28), in insulin doses, or in adverse-event rates. During the continuation phase (up to 14.6 additional weeks, including antenatal hospitalizations, labor, and delivery), glucose levels were in the target range 68.7% of the time; the mean glucose level was 126 mg per deciliter (7.0 mmol per liter). No episodes of severe hypoglycemia requiring third-party assistance occurred during either phase. CONCLUSIONS: Overnight closed-loop therapy resulted in better glucose control than sensor-augmented pump therapy in pregnant women with type 1 diabetes. Women receiving day-and-night closed-loop therapy maintained glycemic control during a high proportion of the time in a period that encompassed antenatal hospital admission, labor, and delivery. (Funded by the National Institute for Health Research and others; Current Controlled Trials number, ISRCTN71510001.).

Hypoglycaemia incidence and recovery during home use of hybrid closed-loop insulin delivery in adults with type 1 diabetes.

Glucose excursion was assessed prior to and post hypoglycaemia to increase understanding of hypoglycaemia incidence and recovery during hybrid closed-loop insulin delivery. We retrospectively analysed data from 60 adults with type 1 diabetes who received, in a crossover randomized design, day-and-night hybrid closed-loop insulin delivery and insulin pump therapy, the latter with or without real-time continuous glucose monitoring. Over 4-week study periods, we identified hypoglycaemic episodes, defined as sensor glucose <3.0 mmol/L, and analysed sensor glucose relative to the onset of hypoglycaemia. We identified 377 hypoglycaemic episodes during hybrid closed-loop intervention vs 662 during control intervention (P < .001), with a predominant reduction of nocturnal hypoglycaemia. The slope of sensor glucose prior to hypoglycaemia was steeper during closed-loop intervention than during control intervention (P < .01), while insulin delivery was reduced (P < .01). During both day and night, participants recovered from hypoglycaemia faster when treated by closed-loop intervention. At 120 minutes post hypoglycaemia, sensor glucose levels were higher during closed-loop intervention compared to the control period (P < .05). In conclusion, closed-loop intervention reduces the risk of hypoglycaemia, particularly overnight, with swift recovery from hypoglycaemia leading to higher 2-hour post-hypoglycaemia glucose levels.

Faster insulin action is associated with improved glycaemic outcomes during closed-loop insulin delivery and sensor-augmented pump therapy in adults with type 1 diabetes.

We aimed to evaluate the relationship between insulin pharmacodynamics and glycaemic outcomes during closed-loop insulin delivery and sensor-augmented pump therapy. We retrospectively analysed data from a multicentre randomized control trial involving 32 adults with type 1 diabetes receiving day-and-night closed-loop insulin delivery and sensor-augmented pump therapy over 12 weeks. We estimated time-to-peak insulin action (t max,IA ) and insulin sensitivity ( S I ) during both interventions, and correlated these with demographic factors and glycaemic outcomes. During both interventions, t max,IA was positively correlated with pre- and post-intervention HbA1c (r = 0.50-0.52, P < .01) and mean glucose (r = 0.45-0.62, P < .05), and inversely correlated with time sensor glucose, which was in target range 3.9 to 10 mmol/L (r = -0.64 to -0.47, P < .05). Increased body mass index was associated with higher t max,I and lower S I (both P < .05). During closed-loop insulin delivery, t max,IA was positively correlated with glucose variability ( P < .05). Faster insulin action is associated with improved glycaemic control during closed-loop insulin delivery and sensor-augmented pump therapy.

Lived Experience of Fully Closed-Loop Insulin Delivery in Adults with Type 1 Diabetes.

Introduction: The Closing the Loop in Adults With Type 1 Diabetes (CLEAR) randomized crossover study compared a novel fully closed-loop insulin delivery system with no carbohydrate entry or mealtime bolusing (CamAPS HX), with standard insulin pump therapy and glucose sensor in adults with type 1 diabetes and suboptimal glycemic outcomes. This qualitative substudy aimed to understand the psychosocial impact of using the fully automated system. Materials and Methods: Adults participating in the CLEAR study were invited to take part in a virtual semistructured interview after they had completed 8 weeks using the fully closed-loop system. Recruitment continued until there was adequate representation and data saturation occurred. Interviews were anonymized and transcribed for in-depth thematic analysis using an inductive-deductive approach. Study participants were also asked to complete questionnaires assessing diabetes distress, hypoglycemia confidence, and closed-loop treatment satisfaction. Results: Eleven participants (eight male and three female; age range 26-66 years) were interviewed. After an initial adjustment period, interviewees reported enjoying a reduction in diabetes burden, freed-up mental capacity, and improved mood. All were happy with overnight glycemic outcomes, with the majority reporting benefits on sleep. Although experiences of postprandial glucose outcomes varied, all found mealtimes easier and less stressful, particularly when eating out. Negatives raised by participants predominantly related to the insulin pump hardware, but some also reported increased snacking and challenges around resuming carbohydrate counting at trial closeout. Conclusions: In adults with type 1 diabetes, use of a fully closed-loop insulin delivery system had significant quality-of-life benefits and provided a welcome break from the day-to-day demands of living with diabetes. Clinical Trial Registration: NCT04977908.

Eighteen-Month Hybrid Closed-Loop Use in Very Young Children With Type 1 Diabetes: A Single-Arm Multicenter Trial.

OBJECTIVE: We aimed to evaluate the longer-term safety and efficacy of hybrid closed-loop (CL) therapy in very young children with type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: Following a 16-week multinational, randomized crossover trial comparing hybrid CL with sensor-augmented pump (SAP) therapy in 74 very young children aged 1-7 years with T1D, participants were invited to an extension phase using CL for a further 18 months. Outcomes were compared with the primary-phase SAP period and primary-phase CL period. RESULTS: After the primary study phase, 60 participants were eligible to enroll in the extension. Of these, 49 consented (mean ± SD age 6.6 ± 1.5 years) to continue use of CL for 18 months. Percentage time in range (TIR) 3.9-10.0 mmol/L was 8.4 percentage points (95% CI 6.7 to 10.1; P < 0.001) higher, while HbA1c was 0.4% ([5.0 mmol/mol], 95% CI 0.3 to 0.6 [3.7 to 6.2]; P < 0.001) lower during the CL extension phase compared with primary-phase SAP period. At 18 months, mean HbA1c was 6.7 ± 0.5% and TIR was 70 ± 7%, compared with 6.7 ± 0.5% and 71 ± 6% in the primary-phase CL period. Time in hypoglycemia (<3.9 mmol/L) was similar between CL extension phase and both primary-phase SAP (P = 0.31) and CL periods (P = 0.70). There were two severe hypoglycemia events and one other serious adverse event during the extension phase. One unexpected serious adverse device effect occurred. CONCLUSIONS: Use of the Cambridge hybrid CL system led to sustained improvements in glycemic control lasting more than 18 months in very young children with T1D.

Impact of Ultra-Rapid Insulin on Boost and Ease-Off in the Cambridge Hybrid Closed-Loop System for Individuals With Type 1 Diabetes.

OBJECTIVE: The objective was to evaluate the safety and efficacy of ultra-rapid-acting insulin with the Boost and Ease-off features of the Cambridge hybrid closed-loop system. METHODS: A secondary analysis of Boost and Ease-off from two double-blind, randomized, crossover hybrid closed-loop studies comparing (1) Fiasp to insulin aspart (n = 25), and (2) Lyumjev to insulin lispro (n = 26) was carried out. Mean glucose on initialization of Boost and Ease-off, change in glucose 60 and 120 minutes after initialization, duration and frequency of use, mean glucose, and time in, above, and below target glucose range were calculated for periods of Boost use, Ease-off use, or neither. RESULTS: Participants used Boost for longer with Fiasp than insulin aspart (median [interquartile range, IQR] = 75 [53-125] minutes vs 60 [49-75] minutes; P = .01). Mean glucose on Boost initialization with Fiasp was 238 ± 62 mg/dL compared with 218 ± 45 mg/dL with insulin aspart (P = .08). Fiasp use resulted in a greater glucose reduction 120 minutes after Boost initialization [-59 ± 34 mg/dL vs -43 ± 31 mg/dL; P = .02]. There were no statistically significant differences in sensor glucose endpoints during Boost or Ease-off periods between Fiasp and aspart. There were no statistically significant differences during Boost or Ease-off periods when comparing Lyumjev with insulin lispro. There were no safety issues when using Boost and Ease-off with ultra-rapid insulins. CONCLUSIONS: The use of Fiasp and Lyumjev during Boost or Ease-off resulted in comparable safety and efficacy to using insulin aspart and lispro.

Postprandial Glucose Excursions with Ultra-Rapid Insulin Analogs in Hybrid Closed-Loop Therapy for Adults with Type 1 Diabetes.

Objective: To evaluate postprandial glucose control when applying (1) faster-acting insulin aspart (Fiasp) compared to insulin aspart and (2) ultra-rapid insulin lispro (Lyumjev) compared to insulin lispro using the CamAPS FX hybrid closed-loop algorithm. Research Design and Methods: We undertook a secondary analysis of postprandial glucose excursions from two double-blind, randomized, crossover hybrid closed-loop studies contrasting Fiasp to standard insulin aspart, and Lyumjev to standard insulin lispro. Endpoints included incremental area under curve (iAUC)-2h, iAUC-4h, 4 h postprandial time in target range, time above range, and time below range. It was approved by independent research ethics committees. Results: Two trials with 8 weeks of data from 51 adults with type 1 diabetes were analyzed and 7137 eligible meals were included. During Lyumjev compared with insulin lispro, iAUC-2h and iAUC-4h were significantly decreased following breakfast (mean difference 92 mmol/L per 2 h (95% confidence interval [CI]: 56 to 127); P < 0.001 and 151 mmol/L per 4 h (95% CI: 74 to 229); P < 0.001, respectively) and the evening meal (P < 0.001 and P = 0.011, respectively). Mean time in target range (3.9-10.0 mmol/L) for 4 h postprandially significantly increased during Lyumjev with a mean difference of 6.7 percentage points (95% CI: 3.3 to 10) and 5.7 percentage points (95% CI: 1.4 to 9.9) for breakfast and evening meal, respectively. In contrast, there were no significant differences in iAUC-2h, iAUC-4h, and the other measures of postprandial glucose control between insulin aspart and Fiasp during breakfast, lunch, and evening meal (P > 0.05). Conclusion: The use of Lyumjev with CamAPS FX closed-loop system improved postprandial glucose excursions compared with insulin lispro, while the use of Fiasp did not provide any advantage compared with insulin aspart. Clinical Trial Registration numbers: NCT04055480, NCT05257460.