Hope Ahead? Varying Approaches Progress Artificial Pancreas

Miriam E Tucker

June 15, 2015

BOSTON — The addition of glucagon to a closed-loop insulin delivery system appears to add extra security in preventing hypoglycemia, but whether the additional benefit justifies the increased complexity and cost remains one of the open questions in the field of so-called "artificial-pancreas" technology.

Here at the American Diabetes Association (ADA) 75th Scientific Sessions, the latest data were presented by researchers from several of the teams developing these systems.

Incremental progress is steady; the remaining challenges include the prevention of hypoglycemia, which the systems have greatly reduced but not eliminated entirely, as well as postprandial glucose spikes resulting from delayed absorption of subcutaneously infused insulin.

Current investigational artificial-pancreas systems use already available insulin pumps and continuous glucose sensors plus experimental algorithms, some with the software housed in smartphones, to direct the insulin delivery based on initial inputs and sensor readings. The systems that include glucagon use a second pump to deliver that hormone and are sometimes referred to as a "bionic pancreas."

"We have had the technology of insulin pump and [continuous glucose monitoring] for some time now, yet closing the loop optimally through integrating these technologies remains the 'holy grail' of diabetes management. The field is evolving fast. We are now seeing the results of studies using these technologies implemented safely in the outpatient setting," Neda Rasouli, MD, associate professor of medicine, division of endocrinology, metabolism, and diabetes, at the University of Colorado, Aurora, told Medscape Medical News.

She added, "It is still too early to decide whether a fully automated or hybrid system would work better. Is it enough to use an insulin-alone system, or do other hormones such as glucagon, or possibly pramlintide, need to be added to the insulin delivery system? We might end up with different options tailored for specific patient populations."

Scientists at the meeting also stressed that it will still be a few years before any of these systems are commercially available, likely around 2018. Nor do they represent a "cure" for type 1 diabetes but, rather, a "bridge" until such time as a cell-based cure is discovered.

First Head-to-Head Studies Show Dual-Hormone System Adds Benefit

Two randomized crossover trials involving a total 61 patients, presented in the special president's oral abstract session on June 9, are the first-ever head-to-head comparisons of insulin-only vs insulin-plus-glucagon systems.

The data were presented by Ahmad Haidar, PhD, from Institut de Recherches Cliniques de Montréal and the division of experimental medicine, department of medicine, McGill University, Montreal, Quebec.

One of the two trials involved 33 children aged 9 to 17 years who wore each of three systems — insulin-only closed loop, insulin-plus-glucagon closed loop, or conventional insulin-pump therapy — in a camp setting for 3 nights each. Findings from that study were simultaneously published online June 8 in Lancet Diabetes & Endocrinology.

Dr Haidar also presented data for another randomized crossover trial involving 21 adults and 7 children (aged 12 to 70 years) in the home setting, with 2 nights per intervention.

In the two trials together, overall mean glucose levels were 140 mg/dL with conventional pump therapy vs identical values of 122 mg/dL for both the single- and dual-hormone closed-loop systems.

Time spent in hyperglycemia (>144 mg/dL) was also much lower for both closed-loop systems (23% for single-hormone and 21% for dual-hormone vs 48% for conventional pump therapy).

The main difference between the two closed-loop systems was seen in time spent in hypoglycemia (<72 mg/dL), at 5.1% for conventional pump, 3.1% for single hormone, and 1.0% for dual hormone. The number of hypoglycemic events was 29, 11, and 3, respectively.

Insulin delivery did not differ between the artificial-pancreas systems. Glucagon was used for a total of 65% of all study nights, with an average nightly dose of 0.03 mg.

Dr Haidar told Medscape Medical News, "It's important to mention that the single-hormone system was better than conventional pump therapy, so it's progressive improvement....We see improvement with a single-hormone system, but when we add glucagon, we see even more improvement."

He added that although there were no adverse effects seen with the small doses of glucagon used in the study, the long-term effects are unknown. "We need to study the safety of chronic doses of glucagon for 6 months [or] 1 year. We have no idea."

David Marrero, PhD, the ADA's healthcare and education president and a patient with type 1 diabetes himself, told Medscape Medical News, "The dual-hormone system makes plenty of sense to me. Clearly, the problem with insulin delivery is if you overdo it, you live with it. It is very much more technically complicated....But having said that, I think it's the right approach. I really think it makes more sense, and I think the data were consistent with that."

However, he added, "I think all of these systems are dependent on sensor technology and the ability to make accurate glucose assessment, and that's still not where we want it to be."

Other Studies Support Both Dual- and Single-Hormone Systems

The most prominent team working on dual-hormone "bionic-pancreas" technology is led by Ed Damiano, PhD, from Boston University, Massachusetts, who gave a keynote talk about his group's work in April at the American Association of Clinical Endocrinologists' 2015 Annual Scientific and Clinical Congress.

At ADA, Dr Damiano's coinvestigator, Steven J Russell, MD, PhD, from the diabetes unit at Massachusetts General Hospital and Harvard Medical School in Boston, presented the team's latest data, this time in 19 preadolescent children aged 6 to 11 years in a camp setting, where they wore the "bionic-pancreas" system and conventional pump therapy for 5 days and nights each.

Initialized with only the patients' weights, after 24 hours, the "bionic" system produced lower overall mean blood glucose levels (138 vs 168 mg/dL; P < .001), less time below 60 mg/dL (1.2% vs 2.8%; P < .001), and less time above 180 mg/dL (16.5% vs 36.3%; P < .001) than the conventional pump.

However, several other papers showed good results with predictive algorithms in single-hormone systems, including one presented by Martin Tauschmann, MD, a clinical research fellow at the University of Cambridge, Wellcome Trust-MRC Institute of Metabolic Science, in the United Kingdom.

In that open-label, crossover study, 12 children and adolescents with type 1 diabetes used sensor-augmented insulin-pump therapy or a closed-loop system for 7 nights each.

With the closed-loop system, a model predictive algorithm automatically directed insulin delivery between meals, and overnight and premeal boluses were given manually by participants.

Time spent at normal glucose levels (70 to 180 mg/dL) was significantly greater with the closed-loop system (72% vs 53%; P < .001). Time spent in hypoglycemia (below 70 mg/dL) was low for both groups and did not differ significantly between the two (2.9% for closed-loop, 1.7% with sensor-augmented pump; P = .87).

Similar low percentages of time spent in hypoglycemia were also seen in several multicenter studies based at the University of Virginia, including one that compared closed-loop and sensor-augmented pump therapy among 37 adults who performed unannounced exercise sessions as part of the trial (median time spent at <70 mg/dL was about 1.35% for closed-loop vs 6.7% for sensor-augmented; P < .0001).

Is Glucagon Necessary?

Among all the research groups working on artificial-pancreas technology, the Montreal team is the only one developing algorithms for both insulin-only and insulin-plus-glucagon systems.

"We believe the question of whether you need a dual-hormone system or not is not a simple yes or no. As we move on, I think we will identify a subgroup of patients who would benefit most from the dual-hormone therapy," Dr Haidar told Medscape Medical News, adding that his group is now doing studies in people with hypoglycemic unawareness, who are at greatest risk for severe "lows."

Asked to comment, Francine R Kaufman, MD, vice president of Global Medical Affairs for Medtronic Diabetes, Northridge, California, told Medscape Medical News, "Two hormones are more complicated than one. And certainly two hormones are much more expensive."

She added: "I think what it will come down to is, where is the compelling evidence that those two hormones are so much better that they're worth whatever the cost of two pumps, two infusion sets, and another hormone every day?"

"None of these have been studied long term....We're not going to prevent all hypoglycemia. So, there needs to be a way to address hypoglycemia."

Medtronic Diabetes is the only company that owns both the pump and sensor technologies and already has a system on the market worldwide that shuts off the insulin pump when glucose levels drop below a certain threshold, or (thus far only in Australia and part of Europe) even when glucose levels are predicted to drop too low. Neither system uses glucagon.

Dr Haidar told Medscape Medical News, "You need to justify [use of glucagon]. I personally don't believe everyone needs it.

"Different groups are doing single-hormone artificial pancreas studies, and they seem to be working for most patients. But the glucagon brings additional benefits, which might justify, in some patients, the additional cost and device complexity. This will not be answered unless we do long-term studies comparing the three systems."

This view reflects that of the Juvenile Diabetes Research Foundation (JDRF), which has funded Haidar's work in the past, and that of most of the other teams.

Vincent Crabtree, PhD, JDRF senior manager, new technology development, told Medscape Medical News, "Clinical studies have shown that insulin-only systems can achieve major improvements in nighttime control and can also significantly improve daytime control.

"Bihormonal systems have also shown improvements in glucose control and may offer increased flexibility for people with diabetes. They may be particularly beneficial or preferable to certain patient groups such as athletes, those who severe hypo-unawareness, and children, where the glucagon provides an extra safety benefit."

He added, "Several commercial companies with existing products have announced that first-generation insulin-only artificial-pancreas systems will be available by 2018. Bihormonal systems are also in development but are hampered by lack of stable glucagon, which will not degrade while the device is being worn. JDRF is also working with companies to develop stable glucagon for these systems."

Addressing Postmeal Highs: Artificial Pancreas Will Not Be a Cure

Along with the challenge of preventing hypoglycemia, the research teams are devising a variety of ways to address the problem of postprandial hyperglycemia resulting from slow absorption of subcutaneously infused insulin.

Most of the first-generation systems now in trials require the user to "announce" a meal and deliver at least a "priming" bolus of insulin based on the carbohydrates to be eaten. Some groups are exploring the use of other agents as adjuncts to artificial-pancreas systems, including the glucagonlike peptide agonist liraglutide (Victoza, Novo Nordisk) or pramlintide, to reduce the spikes by slowing carbohydrate absorption.

Other options, including the development of faster insulins and peritoneal implantation of the systems to deliver insulin directly to the liver, are also under study.

Dr Crabtree told Medscape Medical News that JDRF is funding projects to help develop several of those approaches.

Dr Kaufman noted that, ultimately, artificial-pancreas technology is not a "cure," but the hope is that it serves as a bridge until one is found.

"This is the time of diabetes technology. It's not going to be forever. There will be a cellular cure one day."

Dr Rasouli, Dr Marrero, and Dr Tauschmann have disclosed no relevant financial relationships. Dr Haidar stands to obtain a patent for his group's closed-loop technology and is on the speaker's bureau for the Diabetic Children's Foundation. Dr Kaufman is an employee of Medtronic. Dr Russell is an advisor and/or consultant to Tandem Diabetes Care, Companion Medical, Sanofi, Dexcom, Eli Lilly, Abbott Diabetes Care, Insulet, Medtronic Minimed, and International Biomedical.

Lancet Diabetes Endocrinol. Published online June 8, 215. Abstract

American Diabetes Association 2015 Scientific Sessions; June 7 and 9, 2015; Boston, Massachusetts. Abstract 383-OR, Abstract 1059-P, Abstract 222-OR, Abstract 221-OR, Abstract 225-OR

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