Closed-loop insulin delivery: understanding when and how it is effective
Authors: Pierre-Yves Benhamou, Yves Reznik
Journal: The Lancet Digital Health (2020)

Type 1 diabetes remains a threat that exposes young patients to potential premature mortality. Risk factors include hypoglycaemic episodes, ketoacidotic crisis, diabetic nephropathy, and poor metabolic control, which can lead to major cardiovascular events.1Rawshani A Sattar N Franzén S et al.Excess mortality and cardiovascular disease in young adults with type 1 diabetes in relation to age at onset: a nationwide, register-based cohort study.Lancet. 2018; 392: 477-486Summary Full Text Full Text PDF PubMed Scopus (323) Google Scholar To address the question of metabolic control and hypoglycaemic risk, automatic insulin delivery through the use of closed-loop devices has been extensively studied during the past decade, with several algorithms using a single or dual hormonal approach. Reviews of randomised trials reported that a monohormonal artificial pancreas could increase the time spent in the optimal glucose range by 9 to 11 percentage points, reduce the time patients were hypoglycaemic by half, and improve HbA1c by 0·3 percentage points, compared with sensor-assisted insulin pump therapy.2Weisman A Bai JW Cardinez M Kramer CK Perkins BA 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.Lancet Diabetes Endocrinol. 2017; 5: 501-512Summary Full Text Full Text PDF PubMed Scopus (283) Google Scholar, 3Bekiari E Kitsios K Thabit H et al.Artificial pancreas treatment for outpatients with type 1 diabetes: systematic review and meta-analysis.BMJ. 2018; 361k1310Crossref PubMed Scopus (240) Google Scholar In this issue of The Lancet Digital Health, Boris Kovatchev and colleagues4Kovatchev BP Kollar L Anderson SM et al.Evening and overnight closed- loop control versus 24/7 continuous closed-loop control for type 1 diabetes: a randomised crossover trial.Lancet Digital Health. 2020; (published online Jan 3)https://doi.org/10.1016/S2589-7500(19)30218-3Summary Full Text Full Text PDF Scopus (24) Google Scholar explored the performance of a hybrid, single-hormone closed-loop system in 80 adult patients with type 1 diabetes.4Kovatchev BP Kollar L Anderson SM et al.Evening and overnight closed- loop control versus 24/7 continuous closed-loop control for type 1 diabetes: a randomised crossover trial.Lancet Digital Health. 2020; (published online Jan 3)https://doi.org/10.1016/S2589-7500(19)30218-3Summary Full Text Full Text PDF Scopus (24) Google Scholar To our knowledge, this is the longest crossover trial reported to date. This trial supports that the Control-IQ algorithm is a robust system, because the reported time in range (70–180 mg/dL; 3·9–10·0 mmol/L) improved by 8·4% (95% CI 6·4–10·4) with evening and overnight closed-loop control compared with sensor-assisted pump therapy, whereas the time in range achieved with 24/7 continuous closed-loop control (69·5%, SD 10·9) was consistent with the time in range (71%, SD 12) published in a pivotal 2019 trial that used the same algorithm.5Brown SA Kovatchev BP Raghinaru D et al.Six-month randomized, multicenter trial of closed-loop control in type 1 diabetes.N Engl J Med. 2019; 381: 1707-1717Crossref PubMed Scopus (388) Google Scholar The main contribution of this study is that it establishes—with an elegant design—that most of the glycaemic benefits of permanent, 24/7 continuous closed-loop therapy can be attributed to the results achieved during the evening and overnight period. Extension of closed-loop therapy from overnight to 24 h had only a marginal incremental improvement (about 2%). Two other studies previously reported an important benefit of closed-loop control during the night but with a non-negligible daytime improvement.6Tauschmann M Thabit H Bally L et al.Closed-loop insulin delivery in suboptimally controlled type 1 diabetes: a multicentre, 12-week randomised trial.Lancet. 2018; 392: 1321-1329Summary Full Text Full Text PDF PubMed Scopus (218) Google Scholar, 7Benhamou PY 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 (107) Google Scholar Another interesting finding of this study was that embedding the control algorithm directly in the pump reduced the incidence of connectivity issues and contributed to the glycaemic outcome, shown in a post-hoc analysis. Time in closed-loop control increased from 87% (95% CI 59–97) with the mobile controller to 93% (86–98) with the embedded system.4Kovatchev BP Kollar L Anderson SM et al.Evening and overnight closed- loop control versus 24/7 continuous closed-loop control for type 1 diabetes: a randomised crossover trial.Lancet Digital Health. 2020; (published online Jan 3)https://doi.org/10.1016/S2589-7500(19)30218-3Summary Full Text Full Text PDF Scopus (24) Google Scholar Finally HbA1c was improved with an absolute difference of 0·3% (95% CI 0·1–0·4). To date, the reported reductions in HbA1c during home studies might seem a weak outcome from a payer's point of view. Yet the advantages of closed-loop therapy are a combination of quantitative outcomes (increase in time in optimal glucose range and reduction in time in hypoglycaemia) as well as qualitative findings (major reduction in the day-to-day burden of diabetes and fear of hypoglycaemia and reliability on technology), which are not documented by HbA1c but better fit with global standard sets of outcome measures.8International Consensus for Health Outcomes MeasurementStandard set for diabetes.https://www.ichom.org/portfolio/diabetes/Date accessed: November 26, 2019Google Scholar Furthermore, post-market surveys, which will more appropriately reflect real life in populations that are not arbitrarily selected as in randomised controlled trials, are needed. The real-life effect of closed-loop control needs to be studied in poorly adherent patients with high baseline HbA1c, who are more prone to long-term complications, or in patients with hypoglycaemia unawareness or who are prone to severe hypoglycaemic episodes. Two closed-loop systems (Minimed 670G; Medtronic; Dublin, Ireland and DBLG1; Diabeloop; Grenoble, France) have been approved for clinical use by the US Food and Drug Administration or received European Conformity (CE) marking from the European Economic Area. The acceptability of all these systems will probably rely more upon usability issues than algorithmic aspects, which seemed to yield similar metabolic outcomes, at least for those systems that were assessed in randomised controlled trials.5Brown SA Kovatchev BP Raghinaru D et al.Six-month randomized, multicenter trial of closed-loop control in type 1 diabetes.N Engl J Med. 2019; 381: 1707-1717Crossref PubMed Scopus (388) Google Scholar, 6Tauschmann M Thabit H Bally L et al.Closed-loop insulin delivery in suboptimally controlled type 1 diabetes: a multicentre, 12-week randomised trial.Lancet. 2018; 392: 1321-1329Summary Full Text Full Text PDF PubMed Scopus (218) Google Scholar, 7Benhamou PY 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 (107) Google Scholar In this respect, connectivity performances and integration of the various components of a given system might make a difference. Separating the algorithmic component in a dedicated controller, such as a smartphone or a smartwatch, could raise connectivity issues but might also provide additional features (ie, real time remote monitoring, physical activity sensors, and interoperability), allowing the user to choose between different pumps.9Anderson SM Dassau E Raghinaru D et al.The international diabetes closed-loop study: testing artificial pancreas component interoperability.Diabetes Technol Ther. 2019; 21: 73-80Crossref PubMed Scopus (9) Google Scholar In this study, severe hypoglycaemia adverse events were not attributed to malfunction of the device or algorithmic error, but to user-directed boluses.4Kovatchev BP Kollar L Anderson SM et al.Evening and overnight closed- loop control versus 24/7 continuous closed-loop control for type 1 diabetes: a randomised crossover trial.Lancet Digital Health. 2020; (published online Jan 3)https://doi.org/10.1016/S2589-7500(19)30218-3Summary Full Text Full Text PDF Scopus (24) Google Scholar In other words, side-effects with so-called automatic devices were the consequences of residual human interventions. Closed-loop therapy stands as a major paradigm shift, in which the user is invited to passively trust the system without proactively interfering with it. Whether closed-loop control should be preferentially used in the nocturnal period is a theoretical question because, in the absence of documented serious side-effects during daytime, it is difficult to conceive that users will switch off closed-loop mode at wake-up. Rather, this study points out that the main contributors to excessive time above or under ideal glucose range during daytime are meals and physical activity. Postprandial periods cover 60–75% of daytime and, with current technology, rely upon meal announcement by the patient. Algorithmic improvements aimed at fully automatic management of meals without any announcement represent the next frontier and will be particularly relevant in adolescents or patients with poor adherence. The adaptation of algorithms to use of ultrafast-acting insulin analogues should also contribute to the reduction of out-of-range glucose values. These improvements, combined with the use of factory-calibrated glucose sensors that are ready to use out of the box without any blind phase and with interoperable pumps and sensors and reduced connectivity issues, should allow the dispersal of closed-loop technology to a broader population. PYB reports speaker honoraria and consultancies from Abbott Diabetes Care, Roche Diagnostics, Eli Lilly, Novo Nordisk, Sanofi, Dexcom, and Insulet, outside the submitted work. YR discloses congress invitations, honoraria, and consultancies from Medtronic, Insulet, Novo Nordisk, Sanofi, and Eli Lilly, outside the submitted work. Evening and overnight closed-loop control versus 24/7 continuous closed-loop control for type 1 diabetes: a randomised crossover trialIn type 1 diabetes, evening and overnight closed-loop control was superior to sensor-augmented pump therapy, achieving most of the glycaemic benefits of 24/7 continuous closed-loop control. Our findings could offer people with type 1 diabetes more flexibility in treatment options with use of automated insulin delivery systems at varying times of day. Full-Text PDF Open Access