System Improves Less-Than-Ideally Controlled Type 1 Diabetes

BERLIN — An investigational "hybrid closed-loop" insulin delivery system improved blood glucose control and reduced the risk for hypoglycemia among children and adults with suboptimally controlled type 1 diabetes.

The findings were presented October 3 here at the European Association for the Study of Diabetes (EASD) 2018 Annual Meeting by Martin Tauschmann, MD, of the Wellcome Trust-MRC Institute of Metabolic Science and department of paediatrics, University of Cambridge, UK, and simultaneously published in The Lancet.

In "hybrid" closed-loop systems comprising algorithm-based communication between an insulin pump and continuous glucose monitor (CGM), the basal insulin delivery is automated to minimize both low and high blood glucose readings, but the patient must still enter information about carbohydrate consumption.

One such system, Medtronic's MiniMed 670G, also known as an "artificial pancreas," was approved by the US Food and Drug Administration in 2016. That approval was based on data from a pivotal nonrandomized, single-arm safety trial involving 124 patients with type 1 diabetes aged 14 to 75 years.

The new multicenter, multinational, randomized 12-week trial investigated the use of a different algorithm from that employed by the MiniMed 670G developed at Cambridge University. It enrolled children as young as 6 years of age and focused on adults and children with suboptimal glycemic control, defined as an HbA_1c of 7.5% to 10.0%.

In an accompanying editorial, pediatric endocrinologists Alfonso Galderisi, MD, University of Padua, Italy, and Jennifer L. Sherr, MD, PhD, Yale University, New Haven, Connecticut, write: "The present work provides the gold standard of a randomized trial done across the age spectrum in those with glycemic control that is more representative of what is encountered in clinical practice."

Moreover, they comment: "It lays the framework for patients and providers, as well as regulators and insurers, to understand the true scope of who could benefit from such systems, allowing the circle of those considered reasonable candidates for such technologies to be enlarged."

Improved Glycemic Control Seen in Real-World Setting

The 86 patients were recruited from outpatient diabetes clinics at four centers in the United Kingdom and two in the United States. They were aged 6 years and older, and all had HbA_1c levels of 7.5% to 10.0%, despite using insulin pumps for at least 1 year.

They were randomized to use either a hybrid close-loop or sensor-augmented pump therapy (in which the sensor readings appear on the pump, but the two devices don't communicate) for 12 weeks in their "real-world" lives. They were given no specific instructions pertaining to diet or exercise.

Both groups used a modified noncommercialized version of an older Medtronic insulin pump along with the commercially available Enlite 3 glucose sensor (also Medtronic) and a fingerstick glucose meter.

With the hybrid closed-loop group, the Cambridge algorithm was built into an app on a smartphone rather than being integrated into the pump.

The primary endpoint, proportion of time spent in target glucose range of 3.9 to 10.0 mmol/L (70 to 180 mg/dL), was 10.8% higher among the 46 patients in the hybrid closed-loop group than in the 40 controls (65% vs 54%; P < .0001). Improvements were seen in all age groups (< 13, 13 to 21, and ≥ 22 years) and both sexes.

All patients in the closed-loop group experienced improvements in percentage of time spent in target range, with greater improvements seen among those with higher baseline HbA_1c. Reductions in HbA_1c occurred in both groups, with significantly lower values in the closed-loop group than controls (mean difference, 0.36%; 7.4% vs 7.7%; P < .0001).

Time spent with sensor glucose values below 3.9 mmol/L (70 mg/dL) (hypoglycemia) was significantly lower with the closed-loop system (P = .013). There were no episodes of severe hypoglycemia in either group.

The closed-loop system also significantly improved mean glucose and glucose variability during daytime (P = .0003) and overnight (P < .001), although the effect was more pronounced during the night.

All of those endpoints were achieved without any increase in total daily insulin delivery in the closed-loop group, and bodyweight didn't significantly change in either group.

Technical Issues a Barrier; No Cure Yet for Diabetes...

However, the editorialists note, "it is possible that both the sample size studied and duration of follow-up might have hampered the ability to detect whether long-term use of these systems would have resulted in a difference between groups. Recognizing that the obesity epidemic has not spared those with type 1 diabetes, it will be crucial to follow weight changes as these devices become more commonplace in clinical practice."

One patient in the closed-loop group experienced diabetic ketoacidosis because of infusion set failure. Indeed, the authors note that a study limitation was the "number of devices comprising our hybrid closed-loop system, which increased the risk of device and connectivity problems, and resulted in more frequent nonprotocol contacts to address technical issues."

Commenting on the technical issues, Galderisi and Sherr say, "Although a commercial product would probably overcome many of these difficulties, patients will still be responsible for filling the pump's insulin reservoir and changing the insulin infusion sets...Current methods for detection of infusion set failures, namely patient education, will need to be replaced, or at least supplemented, by algorithms to help alert patients to such an event promptly to avoid serious outcomes."

And of course, the editorialists point out, "Hybrid closed-loop technology does not represent a cure of diabetes. It holds the promise to allow those living with diabetes to achieve more targeted glycemic control, thereby reducing the risk of long-term complications."

Asked how the Cambridge algorithm compares with that of the Medtronic 670G and others currently in development, Tauschmann told Medscape Medical News, "Overall, you can say hybrid-closed loop systems are safe, but you can't really say one algorithm is better than another...You might get different results with different algorithms, but all perform better than what’s available now with just a pump and a sensor."

The study was funded by JDRF. Tauschmann has reported receiving speaker honoraria from Medtronic and Novo Nordisk. Galderisi has received research support from Dexcom. Sherr serves as a consultant to Medtronic Diabetes, is on advisory boards for Bigfoot Biomedical, Eli Lilly, and Insulet, and has received research support from Medtronic and Insulet.

European Association for the Study of Diabetes (EASD) 2018 Annual Meeting; October 3, 2018; Berlin, Germany.

Lancet. Published online October 3, 2018. Full text, Editorial

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