Closed-loop insulin delivery systems for patients with diabetes
Authors: Satish K Garg, Viral Shah
Journal: The Lancet Digital Health (2019)

The global prevalence of diabetes continues to increase1WHODiabetes.http://www.who.int/mediacentre/factsheets/fs312/en/Date: 2018Date accessed: January 10, 2019Google Scholar and currently an estimated 150–200 million people need insulin therapy for diabetes management.2Garg SK Rewers AH Akturk HK Ever-increasing insulin-requiring patients globally.Diabetes Technol Ther. 2018; 20: S21-S24Crossref PubMed Scopus (37) Google Scholar Despite several advances in insulin analogues and insulin delivery methods, a US national registry study3Foster NC Beck RW Miller KM et al.State of type 1 diabetes management and outcomes from the T1D Exchange in 2016–2018.Diabetes Technol Ther. 2019; 21: 66-72Crossref PubMed Scopus (948) Google Scholar, 4Davies MJ D'Alessio DA Fradkin J et al.Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).Diabetes Care. 2018; 41: 2669-2701Crossref PubMed Scopus (1595) Google Scholar reported that fewer than 30% of people with type 1 diabetes achieve optimal glycaemic control (glycated haemoglobin [HbA1c] <7%). Suboptimal glycaemic control (HbA1c >7%) has been associated with increased long-term microvascular and macrovascular complications in patients with diabetes. Additionally, more than 67% of patients with diabetes are overweight or obese.3Foster NC Beck RW Miller KM et al.State of type 1 diabetes management and outcomes from the T1D Exchange in 2016–2018.Diabetes Technol Ther. 2019; 21: 66-72Crossref PubMed Scopus (948) Google Scholar Hypoglycaemia (glucose concentration <70 mg/dL) remains a major obstacle for the optimisation of insulin therapy as a result of non-physiological administration of insulin and inability to dose insulin correctly. Therefore, automated insulin delivery has the potential to minimize or eliminate hypoglycaemia—especially at night—and improve glycaemic control in patients with diabetes who require insulin therapy. In The Lancet Digital Health, Pierre-Yves Benhamou and colleagues investigated the use of the Diabeloop Generation 1 (DBLG1) hybrid closed-loop system in adults with type 1 diabetes in a real-life setting.5Benhamou P-Y Franc S Reznik Y et al.Closed-loop insulin delivery in adults with type 1 diabetes in real-life conditions: a 12-week multicentre, open-label randomised controlled crossover trial.Lancet Digital Health. 2019; 1: e17-e25Summary Full Text Full Text PDF Scopus (111) Google Scholar In this 12-week, multicentre, open-label, randomised controlled crossover trial, the authors compared the proportion of time that the glucose concentration was within the target range (3·9–10·0 mmol/L) in patients using the closed-loop DBLG1 system with those in the sensor-assisted pump therapy group (open-loop). The DBLG1 system improved glucose control compared with sensor-assisted pump therapy (time spent in target range 68·5% [SD 9·4] vs 59·4% [10·2]; mean difference 9·2% [95% CI 6·4–11·9]; p<0·0001). The distinguishing feature of this trial is that the study was done at centres where the workforce had little experience of hybrid closed-loop systems, indicating the ease of use of the DBLG1 system. The study was done over a 12-week period and is the first randomised controlled trial to date to use patch pumps. The proportion of time spent in the target glucose range was around 10% higher in the DBLG1 group than the sensor-assisted pump therapy group, with a non-significant reduction in HbA1c (mean difference −0·15% [95% CI −0·33 to 0·03]; p=0·098). The observed reduction in HbA1c is lower than would be expected with a 10% improvement in time spent in the target glucose range.6Garg SK Weinzimer SA Tamborlane WV et al.Glucose outcomes with the in-home use of a hybrid closed-loop insulin delivery system in adolescents and adults with type 1 diabetes.Diabetes Technol Ther. 2017; 19: 155-163Crossref PubMed Scopus (387) Google Scholar For a difference of 10% in mean time spent in the target range, the HbA1c concentration can vary by 0·3–0·5%.7Beck RW Bergenstal RM Riddlesworth TD et al.Validation of time in range as an outcome measure for diabetes clinical trials.Diabetes Care. 2019; 42: 400-405Crossref PubMed Scopus (386) Google Scholar, 8Bergenstal RM Beck RW Close KL et al.Glucose management indicator (GMI): a new term for estimating A1c from continuous glucose monitoring.Diabetes Care. 2018; 41: 2275-2280Crossref PubMed Scopus (282) Google Scholar Emerging data7Beck RW Bergenstal RM Riddlesworth TD et al.Validation of time in range as an outcome measure for diabetes clinical trials.Diabetes Care. 2019; 42: 400-405Crossref PubMed Scopus (386) Google Scholar, 8Bergenstal RM Beck RW Close KL et al.Glucose management indicator (GMI): a new term for estimating A1c from continuous glucose monitoring.Diabetes Care. 2018; 41: 2275-2280Crossref PubMed Scopus (282) Google Scholar supports the use of these data (time spent in the target glucose range) for the day-to-day management of diabetes instead of HbA1c concentrations. However, HbA1c measurement remains an important metric for population health and long-term follow-up of diabetes complications. Measurement of time spent in the target glucose range is not yet accepted by the US and EU regulatory authorities for the approval of newer therapeutics and diabetic technologies. DBLG1 is the second hybrid closed-loop system approved by the European Medicines Agency for patients with type 1 diabetes. The first hybrid closed-loop system, Medtronic 670G, approved by the US Food and Drug Administration in September, 2016, and by the European Medicines Agency on June 25, 2018, has been shown to reduce overall and nocturnal hypoglycaemia and improve glycaemic control (ie, increased proportion of time spent in target glucose range).6Garg SK Weinzimer SA Tamborlane WV et al.Glucose outcomes with the in-home use of a hybrid closed-loop insulin delivery system in adolescents and adults with type 1 diabetes.Diabetes Technol Ther. 2017; 19: 155-163Crossref PubMed Scopus (387) Google Scholar However, to date, the use of hybrid closed-loop systems in Europe and the USA has been limited because of the high cost, implementation challenges, and patient-related factors, such as patients being required to record and enter carbohydrate intake in the 670G system for meal boluses and the need for repeated continuous glucose monitor calibrations. The development of continuous glucose monitors has been rapid and now most monitors have similar accuracy to blood glucose meters (mean absolute relative difference <10%).9Shah VN Laffel LM Wadwa RP Garg SK Performance of a factory-calibrated real-time continuous glucose monitoring system utilizing an automated sensor applicator.Diabetes Technol Ther. 2018; 20: 428-433Crossref PubMed Scopus (96) Google Scholar Factory-calibrated interoperable continuous glucose monitors, which do not require any further calibration, could be integrated with any insulin pump for automated insulin delivery or closed-loop systems,10Garg SK Akturk HK A new era in continuous glucose monitoring: food and drug administration creates a new category of factory-calibrated nonadjunctive, interoperable class II medical devices.Diabetes Technol Ther. 2018; 20: 391-394Crossref PubMed Scopus (25) Google Scholar which are likely to be more acceptable for patients and providers and could improve efficacy and safety. The development of interoperable continuous glucose monitors might represent a new pathway for faster regulatory approval of future systems. Future versions of the DBLG1 hybrid closed-loop system that incorporate factory calibrated interoperable continuous glucose monitors would improve glycaemic outcomes and patient satisfaction. The key to future success of hybrid closed-loop systems will rely on minimising or eliminating hypoglycaemia, especially at night when hypoglycaemia is most frequent, and patients are most susceptible, and reducing the overall burden of diabetes management for patients and providers. In the study by Benhamou and colleagues,5Benhamou P-Y Franc S Reznik Y et al.Closed-loop insulin delivery in adults with type 1 diabetes in real-life conditions: a 12-week multicentre, open-label randomised controlled crossover trial.Lancet Digital Health. 2019; 1: e17-e25Summary Full Text Full Text PDF Scopus (111) Google Scholar the use of DBLG1 resulted in a significant reduction in hypoglycaemia; by about half that observed in the sensor-assisted pump therapy group. However, a higher number of severe hypoglycaemic episodes were observed in patients using the DBLG1 hybrid closed-loop system than sensor-assisted pump therapy,5Benhamou P-Y Franc S Reznik Y et al.Closed-loop insulin delivery in adults with type 1 diabetes in real-life conditions: a 12-week multicentre, open-label randomised controlled crossover trial.Lancet Digital Health. 2019; 1: e17-e25Summary Full Text Full Text PDF Scopus (111) Google Scholar which were partly due to technical issues and patient-related errors. Future systems need to be easy to use and minimise patient input to reduce these errors. The use of patch pumps in this system might help reduce tube-related issues on the delivery device, such as infusion set occlusion or kinking, resulting in insulin delivery interruption and hyperglycaemia. However, the system still needs further improvement in ease of use to minimise severe hypoglycaemia in patients with type 1 diabetes. The DBLG1 hybrid closed-loop system required patients to enter their carbohydrate intake but did not consider protein or fat intake. Future systems should consider all calorie intake (carbohydrate, protein, and fat) and automatically deliver the insulin bolus based on increases in sensor glucose concentration. The current system had a default target sensor glucose concentration of 110 mg/dL, which could be adjusted between 100 and 130 mg/dL. By contrast, the MiniMed 670 G system had a fixed target sensor glucose concentration of 120 or 150 mg/dL (target of 150 mg/dL was designed for exercise only), whereby a lower adjustable target resulted in increased insulin delivery. In both DBLG1 and Medtronic 670 G hybrid closed-loop systems, the achieved mean sensor glucose concentrations were higher than the targets.5Benhamou P-Y Franc S Reznik Y et al.Closed-loop insulin delivery in adults with type 1 diabetes in real-life conditions: a 12-week multicentre, open-label randomised controlled crossover trial.Lancet Digital Health. 2019; 1: e17-e25Summary Full Text Full Text PDF Scopus (111) Google Scholar, 6Garg SK Weinzimer SA Tamborlane WV et al.Glucose outcomes with the in-home use of a hybrid closed-loop insulin delivery system in adolescents and adults with type 1 diabetes.Diabetes Technol Ther. 2017; 19: 155-163Crossref PubMed Scopus (387) Google Scholar This could be partly due to the fact that, to date, no optimal ultra-fast-acting insulins have been identified. We hope novel hybrid closed-loop systems will allow patients and health-care providers to adjust sensor glucose targets to individualise treatment. For example, pregnant patients with type 1 diabetes usually require lower glucose targets for improved maternal and gestational outcomes.11Feig DS Donovan LE Corcoy R et al.Continuous glucose monitoring in pregnant women with type 1 diabetes (CONCEPTT): a multicentre international randomized controlled trial.Lancet. 2017; 390: 2347-2359Summary Full Text Full Text PDF PubMed Scopus (338) Google Scholar Future hybrid closed-loop systems must be cost effective, easy to implement, customisable, and preferably non-calibrated so that most patients who require insulin can benefit from these new technologies. Otherwise, such systems will only be used by a minority of patients, and the majority will be left behind. SKG reports grants and non-financial support from Eli Lilly, T1D Exchange, the National Institutes of Health, JDRF, and MannKind; grants, personal fees, and non-financial support from Medtronic, Novo-Nordisk, Sanofi, and Lexicon; grants from Dexcom and Senseonics; personal fees and non-financial support from Zealand Pharmaceuticals and Roche; and non-financial support from the American Diabetes Association, outside the submitted work. VS reports grants and personal fees from Sanofi and Dexcom; and grants from EyeNuk, the Center for Women's Health Research at the University of Colorado, Jaeb Center for Health Research (Type 1 Diabetes Exchange), DiaComp, the National Insitutes of Health, and the Colorado Clinical and Translational Sciences Institute at the University of Colorado, outside the submitted work. Closed-loop insulin delivery in adults with type 1 diabetes in real-life conditions: a 12-week multicentre, open-label randomised controlled crossover trialThe DBLG1 system improves glucose control compared with sensor-assisted insulin pumps. This finding supports the use of closed-loop technology combined with appropriate health care organisation in adults with type 1 diabetes. Full-Text PDF Open Access