Dual-hormone Artificial Pancreas Systems Research Articles

Dual-hormone artificial pancreas for management of type 1 diabetes: Recent progress and future directions.

Over the last few years, technological advances have led to tremendous improvement in the management of type 1 diabetes (T1D). Artificial pancreas systems have been shown to improve glucose control compared with conventional insulin pump therapy. However, clinically significant hypoglycemic and hyperglycemic episodes still occur with the artificial pancreas. Postprandial glucose excursions and exercise-induced hypoglycemia represent major hurdles in improving glucose control and glucose variability in many patients with T1D. In this regard, dual-hormone artificial pancreas systems delivering other hormones in addition to insulin (glucagon or amylin) may better reproduce the physiology of the endocrine pancreas and have been suggested as an alternative tool to overcome these limitations in clinical practice. In addition, novel ultra-rapid-acting insulin analogs with a more physiological time-action profile are currently under investigation for use in artificial pancreas devices, aiming to address the unmet need for further improvements in postprandial glucose control. This review article aims to discuss the current progress and future outlook in the development of novel ultra-rapid insulin analogs and dual-hormone closed-loop systems, which offer the next steps to fully closing the loop in the artificial pancreas.

A Novel Dual-Hormone Insulin-and-Pramlintide Artificial Pancreas for Type 1 Diabetes: A Randomized Controlled Crossover Trial.

The rapid insulin-alone artificial pancreas improves glycemia in type 1 diabetes but daytime control remains suboptimal. We propose two novel dual-hormone artificial pancreas systems. We conducted a randomized crossover trial comparing a rapid insulin-alone artificial pancreas with rapid insulin-and-pramlintide and with regular insulin-and-pramlintide artificial pancreas systems in adults with type 1 diabetes. Participants were assigned to the interventions in random order during three 24-h inpatient visits. Each visit was preceded by an outpatient hormonal open-loop run-in period of 10-14 days. The dual-hormone artificial pancreas delivered pramlintide in a basal-bolus manner, using a novel dosing algorithm, with a fixed ratio relative to insulin. The primary outcome was time in the range 3.9-10.0 mmol/L. Compared with the rapid insulin-alone artificial pancreas system, the rapid insulin-and-pramlintide system increased the time in range from 74% (SD 18%) to 84% (13%) (P = 0.0014), whereas the regular insulin-and-pramlintide system did not change the time in range (69% [19%]; P = 0.22). The increased time in range with the rapid insulin-and-pramlintide system was due to improved daytime control (daytime time in range increased from 63% [23%] to 78% [16%], P = 0.0004). There were 11 (1 per 2.5 days) hypoglycemic events (<3.3 mmol/L with symptoms or <3.0 mmol/L irrespective of symptoms) with the rapid insulin-alone system, compared with 12 (1 per 2.3 days) and 18 (1 per 1.4 days) with the rapid and regular insulin-and-pramlintide systems, respectively. Gastrointestinal symptoms were reported after 0% (0 of 112) of meals with the rapid insulin-alone system, compared with 6% (6 of 108) and 11% (11 of 104) with the rapid and regular insulin-and-pramlintide systems, respectively; none of the symptoms were severe. A novel rapid insulin-and-pramlintide artificial pancreas improves glucose control compared with a rapid insulin-alone artificial pancreas (ClinicalTrials.gov number NCT02814123).

Long-Term Safety and Tolerability of Dasiglucagon, a Stable-in-Solution Glucagon Analog

Several groups are developing fully integrated dual-hormone artificial pancreas systems, which deliver insulin or glucagon in response to changes in glucose to maintain euglycemia. These systems hold the potential to transform management of type 1 diabetes, but in order to be realized these systems require a stable-in-solution glucagon analog suitable for chronic use. Dasiglucagon is a novel glucagon analog stable in liquid formulation. The present studies evaluated safety and tolerability of chronically administered dasiglucagon in rats and dogs. Rats and dogs were dosed s.c. daily for 26 and 39 weeks, respectively, in 4 groups of 20 rats with 0 (vehicle), 0.5, 2, or 8 mg/kg/day; 4 groups of 4 beagle dogs with 0, 0.02, 0.1, or 0.3 mg/kg/day. Glucose and insulin levels increased in a dose-dependent manner in all treated animals. In dogs, heart rate increased at the 0.1 and 0.3 mg/kg/day dose level. Liver and kidney weights increased at all dose levels for in both species, and microscopic pathology demonstrated increase in hepatocyte glycogen vacuolation and increase in chronic progressive nephropathy (a normal finding in aging rats). Heart weights increased with no histopathological correlate. All findings showed full/partial recovery after 4-week treatment free periods. Some animals developed anti-drug-antibodies but with no apparent effect on pharmacodynamics. The NOAEL (no observed adverse effect level) dose of 2 mg/kg/day in rats and 0.1 mg/kg/day in dogs represents exposure multiples (AUC) of 22 and 2 compared to anticipated human doses of up to 1 mg/day. Chronic administration of dasiglucagon multiple times above relevant human doses was well tolerated. All findings were consistent with the known pharmacological effects of glucagon. The risk of glycogen accumulation is not considered relevant for humans treated with dasiglucagon to maintain euglycemia. These findings support long-term human testing of dasiglucagon in dual-hormonal artificial pancreas systems. Disclosure J.R. Castle: Consultant; Self; Zealand Pharma A/S. Advisory Panel; Self; Novo Nordisk Inc. M. Elander: Employee; Self; Zealand Pharma A/S. S.A. O'Halloran: None.

Effect of artificial pancreas systems on glycaemic control in patients with type 1 diabetes: a systematic review and meta-analysis of outpatient randomised controlled trials

Closed-loop artificial pancreas systems have been in development for several years, including assessment in numerous varied outpatient clinical trials. We aimed to summarise the efficacy and safety of artificial pancreas systems in outpatient settings and explore the clinical and technical factors that can affect their performance. We did a systematic review and meta-analysis of randomised controlled trials comparing artificial pancreas systems (insulin only or insulin plus glucagon) with conventional pump therapy (continuous subcutaneous insulin infusion [CSII] with blinded continuous glucose monitoring [CGM] or unblinded sensor-augmented pump [SAP] therapy) in adults and children with type 1 diabetes. We searched Medline, Embase, and the Cochrane Central Register of Controlled Trials for studies published from 1946, to Jan 1, 2017. We excluded studies not published in English, those involving pregnant women or participants who were in hospital, and those testing adjunct medications other than glucagon. The primary outcome was the mean difference in percentage of time blood glucose concentration remained in target range (3·9-10 mmol/L or 3·9-8 mmol/L, depending on the study), assessed by random-effects meta-analysis. This study is registered with PROSPERO, number 2015:CRD42015026854. We identified 984 reports; after exclusions, 27 comparisons from 24 studies (23 crossover and one parallel design) including a total of 585 participants (219 in adult studies, 265 in paediatric studies, and 101 in combined studies) were eligible for analysis. Five comparisons assessed dual-hormone (insulin and glucagon), two comparisons assessed both dual-hormone and single-hormone (insulin only), and 20 comparisons assessed single-hormone artificial pancreas systems. Time in target was 12·59% higher with artificial pancreas systems (95% CI 9·02-16·16; p<0·0001), from a weighted mean of 58·21% for conventional pump therapy (I2=84%). Dual-hormone artificial pancreas systems were associated with a greater improvement in time in target range compared with single-hormone systems (19·52% [95% CI 15·12-23·91] vs 11·06% [6·94 to 15·18]; p=0·006), although six of seven comparisons compared dual-hormone systems to CSII with blinded CGM, whereas 21 of 22 single-hormone comparisons had SAP as the comparator. Single-hormone studies had higher heterogeneity than dual-hormone studies (I2 79% vs 66%). Bias assessment characteristics were incompletely reported in 12 of 24 studies, no studies masked participants to the intervention assignment, and masking of outcome assessment was not done in 12 studies and was unclear in 12 studies. Artificial pancreas systems uniformly improved glucose control in outpatient settings, despite heterogeneous clinical and technical factors. None.

The Efficacy of Single- and Dual-Hormone Artificial Pancreas Systems at Regulating Glucose Levels During Continuous and Interval Exercise in Type 1 Diabetes

The Efficacy of Single- and Dual-Hormone Artificial Pancreas Systems at Regulating Glucose Levels During Continuous and Interval Exercise in Type 1 Diabetes

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

The added benefit of glucagon in artificial pancreas systems for overnight glucose control in type 1 diabetes has not been fully explored. 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. 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. The study was conducted in a home setting. Twenty-eight type 1 diabetes participants (21 adults and seven adolescents) participated in the study. Dual-hormone artificial pancreas, single-hormone artificial pancreas, and conventional pump therapy was activated from 9:00 PM to 7:00 AM. 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. 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. 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.

A Randomized Crossover Study to Assess Overnight Glucose Control with Single-Hormone and Dual-Hormone Artificial Pancreas Systems in Children with Type 1 Diabetes in a Diabetes Camp

A Randomized Crossover Study to Assess Overnight Glucose Control with Single-Hormone and Dual-Hormone Artificial Pancreas Systems in Children with Type 1 Diabetes in a Diabetes Camp

Comparison of dual-hormone artificial pancreas, single-hormone artificial pancreas, and conventional insulin pump therapy for glycaemic control in patients with type 1 diabetes: an open-label randomised controlled crossover trial

The artificial pancreas is an emerging technology for the treatment of type 1 diabetes and two configurations have been proposed: single-hormone (insulin alone) and dual-hormone (insulin and glucagon). We aimed to delineate the usefulness of glucagon in the artificial pancreas system. We did a randomised crossover trial of dual-hormone artificial pancreas, single-hormone artificial pancreas, and conventional insulin pump therapy (continuous subcutaneous insulin infusion) in participants aged 12 years or older with type 1 diabetes. Participants were assigned in a 1:1:1:1:1:1 ratio with blocked randomisation to the three interventions and attended a research facility for three 24-h study visits. During visits when the patient used the single-hormone artificial pancreas, insulin was delivered based on glucose sensor readings and a predictive dosing algorithm. During dual-hormone artificial pancreas visits, glucagon was also delivered during low or falling glucose. During conventional insulin pump therapy visits, patients received continuous subcutaneous insulin infusion. The study was not masked. The primary outcome was the time for which plasma glucose concentrations were in the target range (4·0-10·0 mmol/L for 2 h postprandially and 4·0-8·0 mmol/L otherwise). Hypoglycaemic events were defined as plasma glucose concentration of less than 3·3 mmol/L with symptoms or less than 3·0 mmol/L irrespective of symptoms. Analysis was by modified intention to treat, in which we included data for all patients who completed at least two visits. A p value of less than 0·0167 (0·05/3) was regarded as significant. This trial is registered with ClinicalTrials.gov, number NCT01754337. The mean proportion of time spent in the plasma glucose target range over 24 h was 62% (SD 18), 63% (18), and 51% (19) with single-hormone artificial pancreas, dual-hormone artificial pancreas, and conventional insulin pump therapy, respectively. The mean difference in time spent in the target range between single-hormone artificial pancreas and conventional insulin pump therapy was 11% (17; p=0·002) and between dual-hormone artificial pancreas and conventional insulin pump therapy was 12% (21; p=0·00011). There was no difference (15; p=0·75) in the proportion of time spent in the target range between the single-hormone and dual-hormone artificial pancreas systems. There were 52 hypoglycaemic events with conventional insulin pump therapy (12 of which were symptomatic), 13 with the single-hormone artificial pancreas (five of which were symptomatic), and nine with the dual-hormone artificial pancreas (0 of which were symptomatic); the number of nocturnal hypoglycaemic events was 13 (0 symptomatic), 0, and 0, respectively. Single-hormone and dual-hormone artificial pancreas systems both provided better glycaemic control than did conventional insulin pump therapy. The single-hormone artificial pancreas might be sufficient for hypoglycaemia-free overnight glycaemic control. Canadian Diabetes Association; Fondation J A De Sève; Juvenile Diabetes Research Foundation; and Medtronic.

Overnight Control with Single-Hormone and Dual-Hormone Artificial Pancreas Systems in Type 1 Diabetes: An Outpatient Randomized Trial—Preliminary Results

The addition of subcutaneous glucagon to artificial pancreas systems may provide an additional countermeasure to hypoglycemia. In an ongoing randomized, crossover, multicentre trial comparing overnight outpatient interventions with dual-hormone (insulin and glucagon) artificial pancreas (DHAP), single-hormone (insulin) artificial pancreas (SHAP) and conventional pump therapy (CSII), we have studied 10 of 28 patients with type 1 diabetes. Each patient completed 6 10-hour study nights (2 nights per intervention). The first night of each intervention was preceded by a 90–110 g CHO standardized meal, while the second night was preceded by a 60 minute exercise session followed by a 60–80 g CHO standardized meal. The primary outcome was the proportion of time spent in target range (4.0–8.0 mmol/L as measured by the glucose sensor) from 11 p.m.–7 a.m. Preliminary analysis in 10 subjects (7 male, 3 female; age 28–69 years; mean A1c 7.5%) showed that relative to CSII, both DHAP and SHAP increased the time spent in target range (DHAP 76.4%, SHAP 72.6%, CSII 49.9%; p=NS for SHAP vs. DHAP, otherwise p<0.01). DHAP was associated with the smallest risk of hypoglycemia (% time spent <4.0 mmol/L for DHAP 5.0%, SHAP 19.7%, CSII 27.9%; p=NS for CSII vs. SHAP, otherwise p<0.01). Hypoglycemia requiring oral treatment (<3.3 mmol/L if symptomatic, otherwise <3.0 mmol/L) occurred in 5 CSII nights compared to 4 SHAP nights and 1 DHAP night. Preliminary results suggest that SHAP and DHAP are equally superior to CSII at regulating overnight glucose levels, but that an artificial pancreas strategy incorporating glucagon may have additional benefits in reducing hypoglycemia.