The artificial pancreas—ready for prime time?
Authors: J Hans DeVries
Journal: The Lancet Diabetes & Endocrinology (2017)

In the past few years, automation of insulin delivery—also known as the artificial pancreas or the closed loop—has made tremendous progress. In The Lancet Diabetes & Endocrinology, Lia Bally and colleagues1Bally L Thabit H Kojzar H et al.Day-and-night glycaemic control with closed-loop insulin delivery versus conventional insulin pump therapy in free-living adults with well controlled type 1 diabetes: an open-label, randomised, crossover study.Lancet Diabetes Endocrinol. 2017; (published online Jan 13.)http://dx.doi.org/10.1016/S2213-8587(17)30001-3PubMed Google Scholar report results from a randomised crossover trial comparing day-and-night closed-loop insulin delivery with usual pump therapy (4 weeks each) in 29 adults with well controlled type 1 diabetes (HbA1c <7·5% [58 mmol/mol]). A so-called hybrid closed-loop system was used, in which the participant determined the amount of insulin administered before each meal. Participants had sensor glucose concentration in target range (3·9–10·0 mmol/L) 65·6% (SD 8·1) of the time during usual pump therapy and 76·2% (6·4) of the time during closed-loop delivery—ie, the closed-loop system increased the proportion of time when glucose concentration was in target range by 10·5 percentage points (95% CI 7·6–13·4; p<0·0001). Compared with usual pump therapy, closed-loop delivery reduced mean glucose concentration by 0·4 mmol/L (0·1–0·7, p=0·0226); the proportion of time with glucose concentration above 10·0 mmol/L by 6·9 percentage points (3·5–10·2; p=0·0003) and below 3·9 mmol/L by 50% (37–59, p<0·0001); and glycaemic dispersion (ie, SD of glucose concentration) by 0·5 mmol/L (0·3–0·7, p<0·0001). This Article1Bally L Thabit H Kojzar H et al.Day-and-night glycaemic control with closed-loop insulin delivery versus conventional insulin pump therapy in free-living adults with well controlled type 1 diabetes: an open-label, randomised, crossover study.Lancet Diabetes Endocrinol. 2017; (published online Jan 13.)http://dx.doi.org/10.1016/S2213-8587(17)30001-3PubMed Google Scholar is the latest report from the Cambridge (UK) group of trials assessing the use of day-and-night automated insulin delivery in different patient groups for at least 4 weeks; previous trials have included adults with less well controlled diabetes (HbA1c >7·5%),2Thabit H Tauschmann M Allen JM et al.Home use of an artificial beta cell in type 1 diabetes.N Engl J Med. 2015; 373: 2129-2140Crossref PubMed Scopus (344) Google Scholar children and adolescents,2Thabit H Tauschmann M Allen JM et al.Home use of an artificial beta cell in type 1 diabetes.N Engl J Med. 2015; 373: 2129-2140Crossref PubMed Scopus (344) Google Scholar and, albeit in an uncontrolled trial, pregnant women.3Stewart ZA Wilinska ME Hartnell S et al.Closed-loop insulin delivery during pregnancy in women with type 1 diabetes.N Engl J Med. 2016; 375: 644-654Crossref PubMed Scopus (138) Google Scholar The results in all these trials are remarkably consistent, with a roughly 10% improvement in time with glucose concentration in target range, mainly resulting from a reduction in time in hyperglycaemia in addition to a small reduction in time in hypoglycaemia, which was already low in the participants. Mean glucose concentration is consistently lower in the second half of the night with automated insulin delivery versus the comparator, but there is little difference between groups during daytime because of perturbations due to meals and daily living—a finding also seen in a 4 week trial from another group.4Renard E Farret A Kropff J et al.Day-and-night closed-loop glucose control in patients with type 1 diabetes under free-living conditions: results of a single-arm 1-month experience compared with a previously reported feasibility study of evening and night at home.Diabetes Care. 2016; 39: 1151-1160Crossref PubMed Scopus (87) Google Scholar The Cambridge group's trial in adults with less well controlled diabetes,2Thabit H Tauschmann M Allen JM et al.Home use of an artificial beta cell in type 1 diabetes.N Engl J Med. 2015; 373: 2129-2140Crossref PubMed Scopus (344) Google Scholar done under the umbrella of the [email protected] FP7 consortium, was long enough (12 weeks for each intervention) to report results for HbA1c. Use of closed-loop insulin delivery led to a small but significant 0·3% (95% CI 0·1–0·5, p=0·002) reduction in mean HbA1c compared with sensor-augmented pump therapy. This finding was consistent with results from the other final planned trial of the [email protected] consortium,5Kropff J Del Favero S Place J et al.2 month evening and night closed-loop glucose control in patients with type 1 diabetes under free-living conditions: a randomised crossover trial.Lancet Diabetes Endocrinol. 2015; 3: 939-947Summary Full Text Full Text PDF PubMed Scopus (177) Google Scholar in which evening-and-night closed-loop control with patient-managed sensor-augmented pump therapy during the day reduced mean HbA1c by 0·2% (0·0–0·4; p=0·047), compared with 24 h use of patient-managed sensor-augmented pump therapy only, in patients with less well controlled diabetes (mean HbA1c 8·2% [65·9 mmol/mol] at baseline). Nevertheless, the total number of patients studied—typically about 30 per trial—is still small. Additionally, although Bally and colleagues' study1Bally L Thabit H Kojzar H et al.Day-and-night glycaemic control with closed-loop insulin delivery versus conventional insulin pump therapy in free-living adults with well controlled type 1 diabetes: an open-label, randomised, crossover study.Lancet Diabetes Endocrinol. 2017; (published online Jan 13.)http://dx.doi.org/10.1016/S2213-8587(17)30001-3PubMed Google Scholar extends the evidence base to patients with well controlled diabetes, other groups such as patients with impaired awareness of hypoglycaemia, an important problem in the management of type 1 diabetes, have not been studied so far. Moreover, patients with poorly controlled diabetes remain understudied, since the mean baseline HbA1c in the studies that selected patients with less well controlled diabetes ranged from 8·2% (65·9 mmol/mol) to 8·5% (69·4 mmol/mol). The next expected step would be larger randomised controlled trials aiming to obtain regulatory approval for artificial pancreas systems. In parallel to this methodologically thorough approach, the first trial6Bergenstal RM Garg S Weinzimer SA et al.Safety of a hybrid closed-loop insulin delivery system in patients with type 1 diabetes.JAMA. 2016; 316: 1407-1408Crossref PubMed Scopus (444) Google Scholar leading to regulatory approval of a (hybrid) closed-loop device (Medtronic MiniMed 670G) was recently reported. The US Food and Drug Administration (FDA) agreed to an uncontrolled before-and-after study, in which 124 participants with a baseline HbA1c of 7·4% (57·4 mmol/mol) used the Medtronic device for 12 weeks following a 2 week baseline assessment. As seen in controlled trials, time with glucose concentration in target range increased (by 5·6% from baseline) through a reduction in both time in hyperglycaemia and time in hypoglycaemia. HbA1c at the end of the trial had decreased to 6·9% (51·9 mmol/mol), despite the fact that mean sensor glucose concentration remained unchanged at 8·3 mmol/L. The participants had weekly contact with study staff, which in an uncontrolled trial raises the possibility of a study effect contributing to the HbA1c reduction seen.7DeVries JH Snoek FJ Kostense PJ Heine RJ Improved glycaemic control in type 1 diabetes patients following participation per se in a clinical trial—mechanisms and implications.Diabetes Metab Res Rev. 2003; 19: 357-362Crossref PubMed Scopus (29) Google Scholar Based on these data, the Medtronic device was approved by the FDA and is expected to enter the US market in April, 2017, and other markets later in the year. This approval means that, thanks to the work of many over decades, the dream of a closed-loop system will finally enter mainstream clinical practice. Indeed, this eagerly awaited moment will be a milestone in the treatment of type 1 diabetes. Many previous advances in diabetes technology have increased the number of decisions to be made on a daily basis by patients, making their self-management more demanding. Now, an advance in diabetes technology will decrease the number of decisions to be made. However, the Medtronic device will be a first-generation closed-loop device with a proportional integrative derivative control algorithm with insulin feedback that can perhaps be improved, and the user still needs to announce meals and exercise to the device. Since this commercial-grade device, similar to research prototype systems, was in closed-loop mode for 87·2% of the time, only patients proficient with both insulin pump and continuous glucose monitoring will be eligible. Importantly, for a true assessment of the merits of closed-loop treatment, large controlled trials are needed. Fortunately, several trials (eg, NCT02985866 and NCT02748018) aiming to assess the use of closed-loop interventions in 240–1500 patients for 6 months will commence this year. Meanwhile, Bally and colleagues' results1Bally L Thabit H Kojzar H et al.Day-and-night glycaemic control with closed-loop insulin delivery versus conventional insulin pump therapy in free-living adults with well controlled type 1 diabetes: an open-label, randomised, crossover study.Lancet Diabetes Endocrinol. 2017; (published online Jan 13.)http://dx.doi.org/10.1016/S2213-8587(17)30001-3PubMed Google Scholar show that these systems have the potential to improve glycaemic control even in patients with well controlled type 1 diabetes. My institution received material support for clinical studies relating to closed-loop systems from Abbott, Dexcom, Insulet, Medtronic, Roche, and Sanofi. Day-and-night glycaemic control with closed-loop insulin delivery versus conventional insulin pump therapy in free-living adults with well controlled type 1 diabetes: an open-label, randomised, crossover studyUse of day-and-night hybrid closed-loop insulin delivery under unsupervised, free-living conditions for 4 weeks in adults with type 1 diabetes and HbA1c below 7·5% is safe and well tolerated, improves glucose control, and reduces hypoglycaemia burden. Larger and longer studies are warranted. Full-Text PDF Open Access