ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: N Engl J Med. 2019 Oct 31;381(18):1707–1717. doi: 10.1056/NEJMoa1907863. PMID: 31618560

Despite advances in diabetes care, attaining good glycemic outcomes in patients with type 1 diabetes (T1DM) remains challenging and often is not achieved. For example, the targets set by the American Diabetes Association are met in only a minority of patients. It is hoped that the use of a closed-loop system (also referred to as an ‘artificial pancreas’) that automates aspects of insulin delivery might offer the potential to attain the desired glycemic outcomes. Meta-analyses have suggested that closed-loop systems are effective. Currently, one closed-loop system, the Medtronic MiniMed 670G, is in commercial use in the USA, but randomized trials are needed to assess its efficacy and safety. A system that modulates basal insulin delivery but does not administer automated boluses, is referred to as a “hybrid” closed-loop system.

This 6-month randomized, multicenter trial, a parallel-group, unblinded, randomized trial was conducted at 7 university centers in the USA. Patients with T1DM were assigned in a 2:1 ratio to receive a closed-loop system (Control-IQ, Tandem Diabetes Care) or a sensor-augmented pump (control group). The closed-loop system used an algorithm with a dedicated hypoglycemia safety module, automated correction boluses, and overnight intensification of basal insulin delivery designed to consistently target near-normal glycemia each morning.

168 T1DM patients (age range 14–71 years) were randomized (112 to closed-loop; 56 controls). Baseline HbA1c ranged from 5.4 to 10.6%. All completed the trial. The primary outcome (% time glucose level in target range, 70–180 mg/dl [3.9–10.0 mmol/L] by continuous glucose-monitoring) increased in the closed-loop group from (mean±S.D.) 61±17% at baseline to 71±12% after 6 months, but remained unchanged at 59±14% in controls (mean adjusted absolute difference, −11%; 95% CI, −9 to −14; P <0.001). Differences between closed-loop and control were larger during the nighttime (midnight to 0600 h), with % time in target 76% and 59%, respectively.

All main secondary outcomes all met the prespecified criterion for significance, favoring the closed-loop system. The mean absolute difference in % time with glucose <70 mg/dl was −0.88% (P <0.001). The mean adjusted absolute difference in HbA1c after 6 months was −0.33% (P =0.001). In the closed-loop group, the median %time spent in closed-loop mode was 90% over 6 months.

Importantly, no serious hypoglycemic events occurred in either group. 17 adverse events were reported in 16 patients in the closed-loop group, and 2 adverse events in 2 patients in the control group (P =0.05). Diabetic ketoacidosis occurred in 1 participant on closed-loop due to pump infusion set failure; 13 other hyperglycemia or ketosis events occurred in 12 patients on closed-loop, and 2 events in 2 patients in controls; almost all these events were adjudicated as due to infusion set failures. There were 3 other serious adverse events in the closed-loop group (hospitalizations for concussion, otitis, and cardiac bypass surgery) and none in the control group.

Of note, in March 2019 use of the Control-IQ software used by the closed-loop group was temporarily suspended as a precaution after a software error was found. No serious adverse events occurred, but in some instances this led to erroneous discontinuation of insulin delivery for up to several hours, or an erroneous bolus when insulin delivery restarted. Patients continued to use the system in open-loop mode until a software update was remotely deployed to patients via a Web-based software updater. This suspension affected 33 patients on closed-loop for up to 4 weeks (median, 14 days). The analyses included all data recorded during this period, even if the closed-loop mode was not in use.

Strengths of the trial include the inclusion of patients across a wide range of baseline characteristics, 100% patient retention, and good adherence to both intervention and control devices. Continuous glucose monitoring was used to assess outcomes, with minimal reliance on blood glucose measurements. The trial was conducted without remote monitoring by investigators, to reflect real-world use (8, 9, 10, 11). The authors rightly point out limitations of the trial. There were more unscheduled contacts in the closed-loop group, attributed to the use of a new device, and the insulin pumps used by the controls did not have a feature to suspend insulin infusion for predicted hypoglycemia, which is now available on some pumps and has been shown to avoid hypoglycemia. Interpretation of the results must be viewed in the context of the characteristics of the participants and the university-based clinics setting. At trial enrollment, 70% had already been using CGM and 79% an insulin pump, which are substantially more than in typical T1DM patients, and could reflect a strong interest in and willingness to use a closed-loop system among patients who were already familiar with such devices (4, 5, 6, 7).

In conclusion, over a 6-month period, this closed-loop system increased % of time that glucose levels were in target, and reduced hyperglycemia, hypoglycemia, and HbA1c compared to a sensor-augmented pump.

References:

1. American Diabetes Association. Glycemic targets: Standards of Medical Care in Diabetes — 2019. Diabetes Care 2019;42:Suppl 1:S61–S70.

2. Foster 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;21:66–72.

3. Kovatchev B. The artificial pancreas in 2017: the year of transition from research to clinical practice. Nat Rev Endocrinol 2018;14:74–76.

4. Kovatchev B. A century of diabetes technology: signals, models, and artificial pancreas control. Trends Endocrinol Metab 2019;30:432–444.

5. Bekiari E, Kitsios K, Thabit H, et al. Artificial pancreas treatment for outpatients with type 1 diabetes: systematic review and meta-analysis. BMJ 2018;361:k1310–k1310.

6. Weisman 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;5:501–512.

7. Bergenstal RM, Garg S, Weinzimer SA, et al. Safety of a hybrid closed-loop insulin delivery system in patients with type 1 diabetes. JAMA 2016;316:1407–1408.

8. Brown S, Raghinaru D, Emory E, Kovatchev B. First look at Control-IQ: a new-generation automated insulin delivery system. Diabetes Care 2018;41:2634–2636.

9. Nathan DM, Genuth S, Lachin J, et al. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977–986.

10. Tauschmann 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;392:1321–1329.

11. Abraham MB, Nicholas JA, Smith GJ, et al. Reduction in hypoglycemia with the predictive low-glucose management system: a long-term randomized controlled trial in adolescents with type 1 diabetes. Diabetes Care 2018;41:303–310.