Novel Systems Could Expand 'Hybrid Closed-Loop' Field in Diabetes 

Miriam E. Tucker

June 24, 2018

ORLANDO — Three novel investigational "hybrid closed-loop" insulin delivery systems show promise for improving blood glucose levels in people with type 1 diabetes.

Dr Irl B. Hirsch

Findings for the three systems — the tubing-free Omnipod (Insulet) hybrid closed-loop system (Horizon Automated Glucose Control System), the artificial intelligence-enriched Diabeloop DBLG1 system, and the dual-hormone system — were all presented June 24 here at the American Diabetes Association (ADA) 2018 Scientific Sessions.

Hybrid closed-loop refers to systems that combine insulin pumps, continuous glucose monitors (CGMs), and an algorithm that allows the two devices to interact so that the pump adjusts insulin delivery based on CGM readings. But they are called hybrid because thus far these systems can't entirely automatically counter post-meal glucose spikes or prevent all hypoglycemic episodes. The term artificial pancreas is also used loosely to refer to these systems.

The new data were discussed during a press briefing moderated by Irl B. Hirsch, MD, of the University of Washington, Seattle.

"From my point of view, these are all very exciting new advances in diabetes technology, especially for people with type 1 diabetes," he commented. 

However, he also addressed the commonly raised concern that these technologies may take a long time to reach the majority of patients with type 1 diabetes. "I worry about this when I see my own patients," Hirsch said, noting that only 30% of patients with type 1 diabetes in the United States use insulin pumps, and even at the top diabetes centers, only 29% are currently using CGMs.

"Without even considering costs, there's the need for the infrastructure and offices for training and follow-up. How can we do a better job of getting these important tools to our patients who need them the most?"

But Hirsch also noted that 80% of patients in his practice are now using CGMs. A major reason, he said, has been the much-improved reimbursement, and especially Medicare's decision in 2017 to cover CGMs.

And the state of Washington's Medicaid program — as of earlier this year — covers both the Dexcom and Freestyle Libre CGMs for all ages, whereas previously they were only covered for pediatric patients.

"So I think as long as the reimbursement continues to hold true, we're going to see increases," he said.

Omnipod Prototype Performs in Adults in Free-Living Conditions

First up was a 5-day feasibility study of a hybrid closed-loop system using the Omnipod's personalized Model Predictive Control algorithm in 11 adults with type 1 diabetes who wore the system while staying in a hotel with unrestricted meals and daily moderate-intensity exercise, reported by Bruce Buckingham, MD, a pediatric endocrinologist at Stanford University, California.

Compared with 7 days of prior open-loop separate pump and CGM use, overall mean glucose improved from 156 to 150 mg/dL (P = .46), with a decrease in time below a glucose level of 70 mg/dL from 5.1% to 1.9% (P = .001) and time above 180 mg/dL from 8.5% to 4.5% (P = .01).

Overnight results were similar, with time spent below 70 mg/dL reduced from 5.7% to just 0.7%. 

Time in target glucose range (70–180 mg/dL) was 11.2% higher overall, and 13.2% higher overnight, with the hybrid closed-loop versus standard care. Hypoglycemia was reduced by 3.2% overall and by 5% overnight.

"Additional longer-term studies will evaluate the Omnipod [Model Predictive Control] algorithm under free-living conditions with extended use in patients of all ages with type 1 diabetes...The algorithm is continually being improved," Buckingham said. 

French Hybrid Closed-Loop Could Reach European Market Soon

Next Sylvia Franc, MD, of Sud-Francilien Hospital, Corbeil-Essonnes, France, presented data for the Diabeloop DBLG1 closed-loop system, which uses artificial intelligence to "safely automate insulin delivery decisions."

Dr Sylvia Franc

The customizable system allows for personalized algorithm settings for targets, meals, physical activity, and special events, and has telemedicine capability.

In a previous study presented at the ADA meeting last year, the system performed well in "difficult situations" such as heavy meals, with a threefold improvement in time in glucose range (70–180 mg/dL) overnight. 

The current study involved 67 patients, 33 who wore the Diabeloop and 34 their usual pump and CGM (open-loop) over 12 weeks under real-life conditions. Time in target range was 69.3% with the hybrid closed-loop versus 56.6% with open loop (P < .0001). Time below 70 mg/dL was 2% versus 4.5%, respectively, overall (P < .001), and 1.3% versus 3.9% overnight (P < .0001). 

Mean blood glucose dropped from 168.5 to 156.0 mg/dL (P = .012). 

Patients were very enthusiastic about the system, Franc said.

One of them told her, "A big thank you from my family who was finally able to sleep peacefully."  Another said, "It changed my family's life and mine...A pure moment of happiness!" 

The system has been submitted for a CE Mark and a decision is expected very soon, Franc told Medscape Medical News.

Pramlintide Addresses Post-Meal Glucose Spikes

Dr Ahmad Haidar

Lastly Ahmad Haidar, PhD, of McGill University, Montreal, Quebec, presented findings for a dual-hormone hybrid closed-loop system that uses both insulin and pramlintide, an amylin analog, a hormone that is lost in type 1 diabetes along with insulin.

Pramlintide slows gastric emptying, suppresses glucagon secretion, and promotes satiety. Sold as an injectable under the brand name Symlin (AstraZeneca), pramlintide has been approved for about a decade for both type 1 and type 2 diabetes.

Haidar and colleagues reasoned that combining pramlintide with insulin in an automated delivery system could overcome the problem of post-meal insulin excursions that persist in most automated delivery systems because of the delay in subcutaneously infused insulin action. 

In a randomized crossover study, 12 adults with type 1 diabetes each wore a different system for three 24-hour periods: first a pump with regular insulin plus pramlintide artificial pancreas, followed by rapid insulin plus pramlintide artificial pancreas, and finally, a rapid insulin-only artificial pancreas.

Separate pumps were used to deliver insulin and pramlintide, which were given in a fixed ratio (as if they were co-formulated). Participants consumed three meals and a bedtime snack in a clinical research facility.

Time spent between 70 and 180 mg/dL was 86% with the rapid insulin plus pramlintide, compared with 74% with rapid insulin alone (P = .001) and 68% with regular insulin and pramlintide (P = .36). Mean glucose levels were 133 mg/dL versus 142 mg/dL (P = .01) and 142 mg/dL (P = .79), respectively. 

Triple Hormone System on Horizon? Would Be "Amazing"

During the question and answer period, Haidar said that future research plans are to test a triple-hormone system that includes insulin, pramlintide, and glucagon as a hypoglycemia rescue.

"We are hoping companies will look at our data and develop a coformulation of insulin and pramlintide," Haider told Medscape Medical News.

Asked by Medscape Medical News for his view on a possible triple-hormone system, Buckingham, who has done extensive research on several types of closed-loop systems, said, "I think it's really exciting...You could really dampen the glucose rise with the meal and could be a little more aggressive with the insulin because you have the glucagon to back it up. You might get away with no carb counting and a full closed-loop system...It would be really amazing."

But Systems That Can Talk to Each Other Are Needed

However, Hirsch also noted that the onslaught of unique closed-loop systems raises interoperability issues.

"I think one of our goals is to make things interchangeable...It is an issue right now because with each system, you have to know the system…And an even bigger issue is the uploading." Various systems, including Tidepool and Glooko, have been developed to address that and continue to be upgraded, Hirsch pointed out.

But he added, "We need to do a better job of standardizing the playing field so these systems can all talk to each other, not just for the patient but for the providers."

Hirsch is a consultant to Abbott, ADOCIA, Bigfoot Biomedical, and Roche Diabetes Care Health and Digital Solutions. He has received research support from Medtronic MiniMed. Buckingham is on advisory panels for ConvaTec and Novo Nordisk, is a consultant to Becton, Dickinson and Company, and Tandem Diabetes Care, and has received research support from Dexcom, Insulet, Medtronic, and Tandem Diabetes Care. Franc is a consultant to Animas Corporation, Johnson & Johnson Diabetes Institute, and Roche Diabetes Care Health and Digital Solutions. Haidar is a consultant to Eli Lilly and receives research support from AgaMatrix and Medtronic MiniMed.

American Diabetes Association 2018 Scientific Sessions. June 22, 2018; Orlando, Florida. Abstract 207-OR, 208-OR, 210-OR.

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