In the October 4, 2016 issue of JAMA, a research letter was published with the results of a safety study of a hybrid closed-loop insulin delivery system in patients with type 1 diabetes (T1D). I have personally been interested in this artificial pancreas since I was diagnosed with T1D in 1998.
The system uses both an insulin pump and a continuous glucose monitor (CGM) that sends its data to a proprietary algorithm to adjust the insulin pump rate (up, down, or off if needed) as well as blood glucose monitoring that is needed to calibrate the CGM.
Patients aged 14 to 75 years with type 1 diabetes for at least 2 years, glycated hemoglobin (HbA1c) less than 10%, and more than 6 months of insulin pump use were recruited from 10 centers (9 in the United States, 1 in Israel) between June 2, 2015, and November 11, 2015. Patients were required to periodically calibrate sensors and enter carbohydrate estimates for meal boluses. Every midnight, multiple parameters were automatically adjusted by the algorithm.
Of the 124 participants (mean age, 37.8 years [SD, 16.5]; men, 44.4%), mean diabetes duration was 21.7 years, mean total daily insulin dose was 47.5 U/d (SD, 22.7), and mean HbA1c was 7.4% (SD, 0.9). Over 12 389 patient-days, no episodes of severe hypoglycemia or ketoacidosis were observed. There were 28 device-related adverse events (Table 1) that were resolved at home. There were 4 serious adverse events (appendicitis, bacterial arthritis, worsening rheumatoid arthritis, Clostridium difficile diarrhea) and 117 adverse events not related to the system, including 7 episodes of severe hyperglycemia due to intercurrent illness or other nonsystem causes.
The system was in closed-loop mode for a median of 87.2% of the study period (interquartile range, 75.0%- 91.7%). Glycated hemoglobin levels changed from 7.4% (SD, 0.9) at baseline to 6.9% (SD, 0.6) at study end (Table 2). From baseline to the end of the study, daily dose of insulin changed from 47.5 U/d to 50.9 U/d, and weight changed from 76.9 kg to 77.6 kg. The percentage of sensor glucose values within the target range changed from 66.7% at baseline to 72.2% at study end. The percentage of sensor glucose values below and above the target and glycemic variability are also shown in Table 2. Sensor and reference glucose values collected during the hotel stays were in good agreement, with an overall mean absolute relative difference of 10.3% (SD, 9.0).
To our knowledge, this is the largest outpatient study to date 5,6 and it demonstrated that hybrid closed-loop automated insulin delivery was associated with few serious or device-related adverse events in patients with type 1 diabetes. Limitations include lack of a control group, restriction to relatively healthy and well-controlled patients, the relatively short duration, and an imbalance between the length of the study periods. Differences in HbA1c levels may be attributable to participation in the study. A similar study in children (NCT02660827) is under way. Longer-term registry data and randomized studies are needed to further characterize the safety and efficacy of the hybrid closed-loop system.
The U.S. Food and Drug Administration approved Medtronic’s MiniMed 670G hybrid closed looped system on September 28, 2016. The study above published in JAMA was used for the FDA’s approval process. The glucose target used in the study was not mentioned so I assume it was 120 mg/dL as the Medtronic website states in the comments section that the Auto Mode target will be 120 mg/dL. It is also my understanding that the Auto Mode target cannot be changed by the patient. Thus for those with T1D following a low carbohydrate diet, I suspect this will not produce satisfactory results. Personally, I would not be satisfied with a glucose target of 120 mg/dL or a mean glucose of 150.8 mg/dL (Table 2 above). Use of the device resulted in an improvement in HbA1c from 7.4 to 6.9%, the patients required more insulin 47.5 to 50.9 IU/day, and gained body weight as a result from 76.9 to 77.6 kg. Use of body weight alone is not helpful in understanding whether the weight gain was lean body mass, fat, or some of both. Either way, that dose of insulin (50.9 IU/day) is 61.6% more than my current dose (31.5 IU/day) on a low carb diet. In my opinion, the lower insulin dose which is afforded by a low carb diet has many potential benefits, both short term (less hypoglycemia) and long term (less risk of insulin resistance, dyslipidemia, hypertension, cardiovascular disease, cancer, Alzheimer’s). So it will take time for the system to be tested in real world conditions so that the manufacturer/FDA will allow the patient to set their own glucose target value. However, I will be watching this with interest as I think it does have the potential for improvement in my glycemic control.