Simple meal announcements and pramlintide delivery versus carbohydrate counting in type 1 diabetes with automated fast-acting insulin aspart delivery: a randomised crossover trial in Montreal, Canada.

BACKGROUND: In type 1 diabetes, carbohydrate counting is the standard of care to determine prandial insulin needs, but it can negatively affect quality of life. We developed a novel insulin-and-pramlintide closed-loop system that replaces carbohydrate counting with simple meal announcements. METHODS: We performed a randomised crossover trial assessing 14 days of (1) insulin-and-pramlintide closed-loop system with simple meal announcements, (2) insulin-and-placebo closed-loop system with carbohydrate counting, and (3) insulin-and-placebo closed-loop system with simple meal announcements. Participants were recruited at McGill University Health Centre (Montreal, QC, Canada). Eligible participants were adults (aged ≥18 years) and adolescents (aged 12-17 years) with type 1 diabetes for at least 1 year. Participants were randomly assigned in a 1:1:1:1:1:1 ratio to a sequence of the three interventions, with faster insulin aspart used in all interventions. Each intervention was separated by a 14-45-day wash-out period, during which participants reverted to their usual insulin. During simple meal announcement interventions, participants triggered a prandial bolus at mealtimes based on a programmed fixed meal size, whereas during carbohydrate counting interventions, participants manually entered the carbohydrate content of the meal and an algorithm calculated the prandial bolus based on insulin-to-carbohydrate ratio. Two primary comparisons were predefined: the percentage of time in range (glucose 3·9-10·0 mmol/L) with a non-inferiority margin of 6·25% (non-inferiority comparison); and the mean Emotional Burden subscale score of the Diabetes Distress Scale (superiority comparison), comparing the insulin-and-placebo system with carbohydrate counting minus the insulin-and-pramlintide system with simple meal announcements. Analyses were performed on a modified intention-to-treat basis, excluding participants who did not complete all interventions. Serious adverse events were assessed in all participants. This trial is registered on ClinicalTrials.gov, NCT04163874. FINDINGS: 32 participants were enrolled between Feb 14, 2020, and Oct 5, 2021; two participants withdrew before study completion. 30 participants were analysed, including 15 adults (nine female, mean age 39·4 years [SD 13·8]) and 15 adolescents (eight female, mean age 15·7 years [1·3]). Non-inferiority of the insulin-and-pramlintide system with simple meal announcements relative to the insulin-and-placebo system with carbohydrate counting was reached (difference -5% [95% CI -9·0 to -0·7], non-inferiority p<0·0001). No statistically significant difference was found in the mean Emotional Burden score between the insulin-and-pramlintide system with simple meal announcements and the insulin-and-placebo system with carbohydrate counting (difference 0·01 [SD 0·82], p=0·93). With the insulin-and-pramlintide system with simple meal announcements, 14 (47%) participants reported mild gastrointestinal symptoms and two (7%) reported moderate symptoms, compared with two (7%) participants reporting mild gastrointestinal symptoms on the insulin-and-placebo system with carbohydrate counting. No serious adverse events occurred. INTERPRETATION: The insulin-and-pramlintide system with simple meal announcements alleviated carbohydrate counting without degrading glucose control, although quality of life as measured by the Emotional Burden score was not improved. Longer and larger studies with this novel approach are warranted. FUNDING: Juvenile Diabetes Research Foundation.

A Randomized Crossover Trial to Compare Automated Insulin Delivery (the Artificial Pancreas) With Carbohydrate Counting or Simplified Qualitative Meal-Size Estimation in Type 1 Diabetes.

OBJECTIVE: Qualitative meal-size estimation has been proposed instead of quantitative carbohydrate (CHO) counting with automated insulin delivery. We aimed to assess the noninferiority of qualitative meal-size estimation strategy. RESEARCH DESIGN AND METHODS: We conducted a two-center, randomized, crossover, noninferiority trial to compare 3 weeks of automated insulin delivery with 1) CHO counting and 2) qualitative meal-size estimation in adults with type 1 diabetes. Qualitative meal-size estimation categories were low, medium, high, or very high CHO and were defined as <30 g, 30-60 g, 60-90 g, and >90 g CHO, respectively. Prandial insulin boluses were calculated as the individualized insulin to CHO ratios multiplied by 15, 35, 65, and 95, respectively. Closed-loop algorithms were otherwise identical in the two arms. The primary outcome was time in range 3.9-10.0 mmol/L, with a predefined noninferiority margin of 4%. RESULTS: A total of 30 participants completed the study (n = 20 women; age 44 (SD 17) years; A1C 7.4% [0.7%]). The mean time in the 3.9-10.0 mmol/L range was 74.1% (10.0%) with CHO counting and 70.5% (11.2%) with qualitative meal-size estimation; mean difference was -3.6% (8.3%; noninferiority P = 0.78). Frequencies of times at <3.9 mmol/L and <3.0 mmol/L were low (<1.6% and <0.2%) in both arms. Automated basal insulin delivery was higher in the qualitative meal-size estimation arm (34.6 vs. 32.6 units/day; P = 0.003). CONCLUSIONS: Though the qualitative meal-size estimation method achieved a high time in range and low time in hypoglycemia, noninferiority was not confirmed.

Empagliflozin add-on therapy to closed-loop insulin delivery in type 1 diabetes: a 2 × 2 factorial randomized crossover trial.

There is a need to optimize closed-loop automated insulin delivery in type 1 diabetes. We assessed the glycemic efficacy and safety of empagliflozin 25 mg d-1 as add-on therapy to insulin delivery with a closed-loop system. We performed a 2 × 2 factorial randomized, placebo-controlled, crossover two-center trial in adults, assessing 4 weeks of closed-loop delivery versus sensor-augmented pump (SAP) therapy and empagliflozin versus placebo. The primary outcome was time spent in the glucose target range (3.9-10.0 mmol l-1). Primary comparisons were empagliflozin versus placebo in each of closed-loop or SAP therapy; the remaining comparisons were conditional on its significance. Twenty-four of 27 randomized participants were included in the final analysis. Compared to placebo, empagliflozin improved time in target range with closed-loop therapy by 7.2% and in SAP therapy by 11.4%. Closed-loop therapy plus empagliflozin improved time in target range compared to SAP therapy plus empagliflozin by 6.1% but by 17.5% for the combination of closed-loop therapy and empagliflozin compared to SAP therapy plus placebo. While no diabetic ketoacidosis or severe hypoglycemia occurred during any intervention, uncomplicated ketosis events were more common on empagliflozin. Empagliflozin 25 mg d-1 added to automated insulin delivery improves glycemic control but increases ketone concentration and ketosis compared to placebo.

Alleviating carbohydrate counting with a FiASP-plus-pramlintide closed-loop delivery system (artificial pancreas): Feasibility and pilot studies.

AIM: To assess whether a FiASP-and-pramlintide closed-loop system has the potential to replace carbohydrate counting with a simple meal announcement (SMA) strategy (meal priming bolus without carbohydrate counting) without degrading glycaemic control compared with a FiASP closed-loop system. MATERIALS AND METHODS: We conducted a 24-hour feasibility study comparing a FiASP system with full carbohydrate counting (FCC) with a FiASP-and-pramlintide system with SMA. We conducted a subsequent 12-day outpatient pilot study comparing a FiASP-and-placebo system with FCC, a FiASP-and-pramlintide system with SMA, and a FiASP-and-placebo system with SMA. Basal-bolus FiASP-and-pramlintide were delivered at a fixed ratio (1 U:10 µg). Glycaemic outcomes were measured, surveys evaluated gastrointestinal symptoms and diabetes distress, and participant interviews helped establish a preliminary coding framework to assess user experience. RESULTS: Seven participants were included in the feasibility analysis. Time spent in 3.9-10 mmol/L was similar between both interventions (81%-84%). Four participants were included in the pilot analysis. Time spent in 3.9-10 mmol/L was similar between the FiASP-and-placebo with FCC and FiASP-and-pramlintide with SMA interventions (70%), but was lower in the FiASP-and-placebo with SMA intervention (60%). Time less than 3.9 mmol/L and gastrointestinal symptoms were similar across all interventions. Emotional distress was moderate at baseline, after the FiASP-and-placebo with FCC and SMA interventions, and fell after the FiASP-and-pramlintide with SMA intervention. SMA reportedly afforded participants flexibility and reduced mealtime concerns. CONCLUSIONS: The FiASP-and-pramlintide system has the potential to substitute carbohydrate counting with SMA without degrading glucose control.

Reducing the need for carbohydrate counting in type 1 diabetes using closed-loop automated insulin delivery (artificial pancreas) and empagliflozin: A randomized, controlled, non-inferiority, crossover pilot trial.

AIM: To assess whether adding empagliflozin to closed-loop automated insulin delivery could reduce the need for carbohydrate counting in type 1 diabetes (T1D) without worsening glucose control. MATERIALS AND METHODS: In an open-label, crossover, non-inferiority trial, 30 adult participants with T1D underwent outpatient automated insulin delivery interventions with three random sequences of prandial insulin strategy days: carbohydrate counting, simple meal announcement (no carbohydrate counting) and no meal announcement. During each sequence of prandial insulin strategies, participants were randomly assigned empagliflozin (25 mg/day) or not, and crossed over to the comparator. Mean glucose for carbohydrate counting without empagliflozin (control) was compared with no meal announcement with empagliflozin (in the primary non-inferiority comparison) and simple meal announcement with empagliflozin (in the conditional primary non-inferiority comparison). RESULTS: Participants were aged 40 ± 15 years, had 27 ± 15 years diabetes duration and HbA1c of 7.6% ± 0.7% (59 ± 8 mmol/mol). The system with no meal announcement and empagliflozin was not non-inferior (and thus reasonably considered inferior) to the control arm (mean glucose 10.0 ± 1.6 vs. 8.5 ± 1.5 mmol/L; non-inferiority p = .94), while simple meal announcement and empagliflozin was non-inferior (8.5 ± 1.4 mmol/L; non-inferiority p = .003). Use of empagliflozin on the background of automated insulin delivery with carbohydrate counting was associated with lower mean glucose, corresponding to a 14% greater time in the target range. While no ketoacidosis was observed, mean fasting ketones levels were higher on empagliflozin (0.22 ± 0.18 vs. 0.13 ± 0.11 mmol/L; p < .001). CONCLUSIONS: Empagliflozin added to automated insulin delivery has the potential to eliminate the need for carbohydrate counting and improves glycaemic control in conjunction with carbohydrate counting, but does not allow for the elimination of meal announcement.

Comparison Between Closed-Loop Insulin Delivery System (the Artificial Pancreas) and Sensor-Augmented Pump Therapy: A Randomized-Controlled Crossover Trial.

Objective: Several studies have shown that closed-loop automated insulin delivery (the artificial pancreas) improves glucose control compared with sensor-augmented pump therapy. We aimed to confirm these findings using our automated insulin delivery system based on the iPancreas platform. Research Design and Methods: We conducted a two-center, randomized crossover trial comparing automated insulin delivery with sensor-augmented pump therapy in 36 adults with type 1 diabetes. Each intervention lasted 12 days in outpatient free-living conditions with no remote monitoring. The automated insulin delivery system used a model predictive control algorithm that was a less aggressive version of our earlier dosing algorithm to emphasize safety. The primary outcome was time in the range 3.9-10.0 mmol/L. Results: The automated insulin delivery system was operational 90.2% of the time. Compared with the sensor-augmented pump therapy, automated insulin delivery increased time in range (3.9-10.0 mmol/L) from 61% (interquartile range 53-74) to 69% (60-73; P = 0.006) and increased time in tight target range (3.9-7.8 mmol/L) from 37% (30-49) to 45% (35-51; P = 0.011). Automated insulin delivery also reduced time spent below 3.9 and 3.3 mmol/L from 3.5% (0.8-5.4) to 1.6% (1.1-2.7; P = 0.0021) and from 0.9% (0.2-2.1) to 0.5% (0.2-1.1; P = 0.0122), respectively. Time spent below 2.8 mmol/L was 0.2% (0.0-0.6) with sensor-augmented pump therapy and 0.1% (0.0-0.4; P = 0.155) with automated insulin delivery. Conclusions: Our study confirms findings that automated insulin delivery improves glucose control compared with sensor-augmented pump therapy. ClinicalTrials.gov no. NCT02846831.