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.

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.

Analysis of Prevalence, Magnitude and Timing of the Dawn Phenomenon in Adults and Adolescents With Type 1 Diabetes: Descriptive Analysis of 2 Insulin Pump Trials.

OBJECTIVES: To better understand the dawn phenomenon in type 1 diabetes, we sought to determine its prevalence, timing and magnitude in studies specifically designed to assess basal insulin requirements in patients using insulin pumps. METHODS: Thirty-three participants from 2 sensor-augmented insulin pump studies were analyzed. Twenty participants were obtained from a methodologically ideal semiautomated basal analysis trial in which basal rates were determined from repeated fasting tests (the derivation set) and 13 from an artificial pancreas trial in which duration of fasting was variable (the "confirmation" set). Prevalence was determined for the total cohort and for individual trials using the standard definition of an increase in insulin exceeding 20% and lasting ≥90 minutes. Among cases, time of onset and percent change in the magnitude of basal delivery were determined. RESULTS: Seventeen participants (52%) experienced the dawn phenomenon (11 of 20 [55%] in the derivation set and 6 of 13 [46%] in the confirmation set). Time of onset was 3 AM (interquartile range [IQR], 3 to 4:15 AM) in the derivation set and 3 AM (IQR, 3 to 4 AM) in the confirmation set. The magnitude of the dawn phenomenon was a 58.1% (IQR, 28.8% to 110.6%) increase in insulin requirements in the derivation set and 65.5% (IQR, 45.6% to 87.4%) in the confirmation set. CONCLUSIONS: The dawn phenomenon occurs in approximately half of patients with type 1 diabetes; when present, it has predictable timing of onset (generally 3 AM) and a substantial, but highly variable, magnitude. These findings imply that optimization of glycemic control requires clinical emphasis on fasted overnight basal insulin assessment.

Single- and Dual-Hormone Artificial Pancreas for Overnight Glucose Control in Type 1 Diabetes.

CONTEXT: The added benefit of glucagon in artificial pancreas systems for overnight glucose control in type 1 diabetes has not been fully explored. OBJECTIVE: The objective of the study was to compare the efficacy of dual-hormone (insulin and glucagon) artificial pancreas, single-hormone (insulin alone) artificial pancreas, and conventional insulin pump therapy. DESIGN: This study was a three-center, three-arm, open-label, randomized, crossover controlled trial involving three interventions, each applied over a night after a high carbohydrate/high fat meal and a second after exercise to mimic real-life glycemic excursions. SETTING: The study was conducted in a home setting. PATIENTS: Twenty-eight type 1 diabetes participants (21 adults and seven adolescents) participated in the study. INTERVENTIONS: Dual-hormone artificial pancreas, single-hormone artificial pancreas, and conventional pump therapy was activated from 9:00 PM to 7:00 AM. MAIN OUTCOME: The main outcome was a proportion of time in target (4-8 mmol/L) by continuous glucose monitoring from 11:00 PM to 7:00 AM. Analysis was by intention to treat. RESULTS: The median (interquartile range) percentage of time-in-target glucose range was 47% (36%-71%) for conventional therapy, higher on both single-hormone (76% [65%-91%], P < .001) and dual-hormone artificial pancreas (81 [68%-93%], P < .001). The median (interquartile range) time spent below 4 mmol/L was 14% (4%-28%) for conventional therapy, lower on both single-hormone (5% [0%-13%], P = .004) and dual-hormone artificial pancreas (1% [0%-8%], P < .001). There were 14 hypoglycemic events on conventional therapy compared with six incidences on the single-hormone artificial pancreas (P = .059) and three incidences on the dual-hormone artificial pancreas (P = .017). None of these outcomes differed significantly between single- and dual-hormone configurations. CONCLUSIONS: Single- and dual-hormone artificial pancreas systems both provided better glucose control than conventional therapy. Although the dual-hormone configuration did not increase overnight time-in-target glucose levels, an effect on lowering hypoglycemia risk cannot be ruled out.

Evaluation of a clinical tool to test and adjust the programmed overnight basal profiles for insulin pump therapy: a pilot study.

OBJECTIVE: Clinical protocols for basal rate testing and adjustment are needed for effective insulin pump therapy. We evaluated the effects of a continuous glucose monitoring (CGM)-based semiautomated basal algorithm on glycemia. METHODS: We developed and piloted a basal rate analyzer that interpreted CGM data from overnight fasts and recommended dose changes for subsequent nights. Subjects uploaded data online using sensor-augmented pumps for evaluation by the analyzer after each of 5 overnight fasts conducted over 2 to 8 weeks. It was designed to be conservative and iterative, making changes that did not exceed 10% at each iteration. The standard deviation and interquartile range of CGM values from midnight to 7 am (SD12-7am and IQR12-7am) over 3 baseline and 3 postintervention nights, hypoglycemia incidence (CGM values <4.0 mmol/L), and glycated hemoglobin (A1C) were compared. RESULTS: Twenty subjects with mean ages of 38±13 years and A1C 7.6%±0.8% (60±8.7 mmol/mol) underwent the 5 iterations of basal assessments over 5±3 weeks. SD12-7am and IQR12-7am did not change from baseline to postintervention (1.57±0.8 to 1.63±0.8 mmol/L; p=0.35; 3.66±2.07 to 3.47±2.26 mmol/L; p=0.90). However, mean glucose values were lower between 2 to 3 am at baseline compared to postintervention; 3-night hypoglycemia incidence declined from 1.6±1.8 to 0.5±0.7 episodes (p=0.01), and A1C improved from 7.6%±0.8% to 7.4%±0.9% (60%±8.7% to 57%±9.8% mmol/mol; p=0.03). CONCLUSIONS: The use of a basal rate analyzer was associated with reduced hypoglycemia and improved A1C. However, overnight glycemic stability was not improved. Further research into the efficacy of the CGM-based semiautomated algorithm is warranted.