At Last...Closing the Loop?

November 1, 2016

The world of diabetes treatment saw another momentous change when the FDA approved the first closed-loop insulin delivery system. What's next?

The world of diabetes treatment saw another momentous change on September 28, 2016, when the FDA approved the first closed-loop insulin delivery system, for those 14 years of age or older, with type 1 diabetes (T1DM).1 While the MiniMed 670G, from Medtronic, allows patients for the most part to have their basal insulin automatically adjusted, they still must enter bolus doses manually, thus, this is not truly an “artificial pancreas.”

With this new device, slated to be available in spring 2017, will the number of insulin pump users jump? Estimates place the current proportion of insulin pump users at ~30% of individuals with T1DM in the US, and ~10-15% use a continuous glucose monitor (CGM).

Three components make up what’s termed a hybrid closed-loop insulin pump: the insulin pump, a CGM, and a small device that stores the control algorithm. This algorithm coordinates insulin delivery based on the real-time glucose levels detected by the CGM.

Amidst all of the recent headlines, it’s easy to forget that a closed-loop system is hardly a new idea. Back in 1960, Weller first studied semi-continuous glucose monitoring. Kadish introduced the first portable insulin pump in 1964. It wasn’t until the 1990s that concerns over a potentially increased risk of infection and lack of compatible devices led to a switch from the intravascular to the subcutaneous route.

CGM uses a needle implanted subcutaneously; an electrode measures interstitial glucose concentration by changes in the electric current. Glucose readings can be provided every 1 to 5 minutes. One of the main advantages of CGM is that patients and physicians can detect trends, due to having a much greater number of data points than finger sticks. Another is that patients can set alarms to alert them to impending hypoglycemia or hyperglycemia. Yet, there are drawbacks -- are up to 200+ readings a day too much information for patients and their health care teams? Patients still must calibrate CGM readings with those from a glucometer several times per day, and when glucose is quickly changing, you can’t rely solely on these readings to decide on insulin dose adjustments.

The FDA’s approval was based on data from a study by Bergenstal and colleagues of 124 patients with type 1 diabetes ranging from 14 to 75 years of age.2 HbA1c declined from 7.4% at baseline to 6.9% at the study’s end. Target range sensor glucose values increased from 66.7% at baseline to 72.2% at the conclusion of the study. There were no severe hypoglycemia episodes. Though this clinical trial is, to date, the largest known outpatient closed-loop study, some limitations were noted, such as: the lack of a control group, and the imbalance between the length of study periods. Study participation may have accounted for the differences in HbA1c.

What about decreasing hypoglycemia by also including glucagon, in what’s termed a bi-hormonal closed-loop insulin pump? Studies in diabetes camp settings demonstrated significant reductions in mean glucose and the amount of time in hypoglycemia.3,4 For now, one of the obstacles to such a system is the need for a second insulin pump with which to deliver glucagon; both hormones could be stored in a single pump with two distinct chambers.

What’s next? Watch for larger studies of use of this device in real-world settings, and of its use in children between the ages of 7-13. The company expects this will be on the market this coming spring.

The current insulin analogues take approximately 90-120 minutes to reach peak impact on reducing glucose, and along with the lag time of interstitial fluid glucose, may hinder the nimbleness of these new systems, especially during times when glucose fluctuates rapidly, such as during exercise and meals. Will a bi-hormonal pump be a solution? How will patient experiences in large numbers drive tweaks in the next generation of these pumps? These and many other questions may be addressed in the future, as the next chapter in this intriguing advance unfolds.

References:

1. FDA approves first automated insulin delivery device for type 1 diabetes. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm522974.htm. 28 Sept 2016.

2. Bergenstal RM, et al. Safety of a hybrid closed-loop insulin delivery system in patients with type 1 diabetes. JAMA. 15 Sept 2016.

3. Russell SJ, et al. Outpatient glycemic control with a bionic pancreas in type 1 diabetes. N Engl J Med. 2014;371(4):313-325.

4. Russell SJ, et al. Day and night glycaemic control with a bionic pancreas versus conventional insulin pump therapy in preadolescent children with type 1 diabetes: a randomised crossover trial. Lancet Diabetes Endocrinol. 2016;4(3):233-243.