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The past few years have seen the clinical development of closed-loop or “artificial pancreas” systems for treating type 1 diabetes, with the first hybrid closed-loop device being approved by the US Food & Drug Administration (FDA) in September 2016 .
medwireNews spoke to Professor Richard Bergenstal (International Diabetes Center at Park Nicollet, Minneapolis, Minnesota, USA), who believes that these devices, which combine glucose sensing and insulin delivery in one system, could represent “a landmark step in the management of type 1 diabetes.”
We also outline key clinical data leading to the approval of the first artificial pancreas, and address some common questions about this innovative approach to controlling glucose levels.
What is an artificial pancreas, and how does it differ from insulin pumps?
The artificial pancreas – developed to measure and adjust blood glucose levels as the pancreas does in people without diabetes – is a medical device that is worn like an insulin pump. A subcutaneous sensor measures glucose levels, which are transmitted wirelessly into a device with a sophisticated computer algorithm that interprets the data and controls delivery of the correct amount of insulin via an insulin pump (Figure 1) .
Bergenstal explains that during the development of the artificial pancreas, “we’ve been adding technology piece by piece, each one having an incremental benefit,” and that combining these technological advances will meet two goals of better glycemic control and reduced burden for patients.
Whereas an insulin pump delivers a small amount of fast-acting insulin continuously throughout the day, with patients testing their own blood sugar levels and delivering boluses at meal times, the artificial pancreas automatically adjusts the amount of insulin entering the body based on glucose levels measured by the sensor.
The autonomous control of insulin delivery both above and below the preset insulin amount depending on glucose levels also differentiates artificial pancreas systems from insulin pumps, which suspend insulin delivery – if linked to a glucose sensor – only when glucose levels are below a preset threshold, or rely entirely on user input .
Why is there a need for artificial pancreas systems?
When using insulin pumps, patients are required to test their blood sugar levels regularly, meaning that there is an unmet need for improved glucose control without a high burden of self-care.
Bergenstal says that artificial pancreas systems will give “better numbers and reduced burden for patients” as glucose monitoring and insulin pump systems work together.
How was the artificial pancreas developed, and what are the key data supporting its use?
Figure 2 outlines the key milestones in the development and clinical testing of the closed-loop systems.
Blood glucose monitors were first introduced into clinical practice in the late 1960s, and the clinical feasibility of insulin pumps was established in the 1970s. Subsequently, minimally invasive continuous glucose monitoring has progressed to precise, factory-calibrated systems that are approved for insulin dosing [3, 4], and these advances have been combined into the artificial pancreas system.
Initial studies carried out in laboratory conditions and hospitals, followed by transitional studies in non-hospital settings, have shown that artificial pancreas systems can improve glucose control in adults, adolescents, and children with type 1 diabetes. More recent trials have demonstrated that it is feasible for patients to use the artificial pancreas at home.
Most studies of the artificial pancreas have been randomized crossover trials, in which each patient receives both treatments, and randomization is used to determine the order in which they are received.
Trials conducted in hospitals demonstrated the feasibility of closed-loop systems to improve overnight glucose control and reduce the risk of nocturnal hypoglycemia.
In a phase II randomized crossover trial involving 19 children and adolescents, Roman Hovorka (University of Cambridge, UK) and colleagues found a nonsignificant increase in the time spent in the target range for plasma glucose (3.91–8.00 mmol/L) with overnight manual closed-loop insulin delivery compared with standard continuous subcutaneous insulin infusion . A subsequent investigation found that automated overnight closed-loop insulin delivery was feasible in young children . Hospital-based studies conducted in adult patients demonstrated that closed-loop systems significantly improved overnight glucose control compared with conventional insulin pump therapy or patients’ usual insulin delivery routine [7,8].
A number of studies carried out in diabetes camps, hotels, and restaurants provided evidence for the implementation of closed-loop systems outside of the hospital setting.
For example, Moshe Phillip (Schneider Children’s Medical Center of Israel, Petah Tikva) and colleagues found a significant reduction in nocturnal hypoglycemia and tighter glucose control when 56 children and adolescents were treated with an automated artificial pancreas compared with a sensor-augmented insulin pump at a diabetes camp . Similarly, a closed-loop system running on a smartphone was shown to reduce daytime and nocturnal hypoglycemia compared with insulin pump treatment among 18 adults staying in a hotel or guesthouse .
Following encouraging results in hospital and transitional studies, home-based trials of the artificial pancreas have been completed as of 2014. Such studies have been described as “the final benchmark testing environment” .
Some home studies were performed with remote supervision for safety reasons. In a randomized crossover trial, 21 patients completed 6 weeks of artificial pancreas use with remote monitoring supervision. In this study, the use of overnight closed-loop insulin delivery reduced nocturnal hypoglycemia and improved the time spent within the target glucose range compared with sensor-augmented pump therapy .
Additionally, unsupervised home studies conducted in adults and adolescents demonstrated that day and night closed-loop insulin delivery significantly improved time spent within target glucose range compared with insulin pump therapy [12, 13].
In the largest outpatient study to date, Bergenstal and team found that wearing a hybrid closed-loop device for 3 months resulted in reductions in day and night hypoglycemia and hyperglycemia, and improved the time spent in target glucose range, compared with baseline data from insulin pump use in 124 participants . The results of this study formed the basis of the FDA’s approval of the hybrid device – Medtronic's MiniMed 670G – in September 2016 .
Whilst most studies to date have involved patients with poor glycemic control, a crossover trial published in early 2017 showed that closed-loop insulin delivery used day and night at home offered improved glycemic control even among patients who were well-controlled when self-monitoring their glucose levels .
Who can use the hybrid closed-loop system approved by the FDA, and when will it be available?
The FDA approved the MiniMed 670G hybrid closed-loop system to monitor glucose levels and provide appropriate insulin doses in patients with type 1 diabetes aged 14 years and over. A clinical trial is currently underway to determine the safety and efficacy of this system in children aged between 7 and 13 years . The device is expected to become available in the USA in spring 2017 .
Bergenstal says that “people with type 1 diabetes, especially those who are struggling with overnight difficulties, and those with hypoglycemia or hypoglycemia unawareness who are afraid to try to tighten their glucose control and therefore run much higher than they need to” are the patients who stand to benefit the most from using an artificial pancreas. He observes that this is a large group of people, with around half of type 1 diabetes patients struggling with low blood glucose.
How does a ‘hybrid’ device differ from a fully closed-loop device?
The MiniMed 670G device is referred to as “the world’s first artificial pancreas” because it responds to both high and low glucose levels, and automatically adjusts insulin levels with little or no input from the user. However, patients need to enter information about mealtime carbohydrates for the device to deliver bolus insulin doses, meaning that it is called a “hybrid” rather than a completely closed-loop system .
“The ideal system is going to be one where there’s less and less patient-dependent interaction, and that reacts much faster to the individual’s needs,” says Bergenstal.
Are there any risks associated with the use of an artificial pancreas?
In a statement released when the MiniMed 670G system was approved , the FDA noted that the associated risks “may include hypoglycemia, hyperglycemia, as well as skin irritation or redness around the device’s infusion patch.” They add that the current version of the device is not safe for use by children aged 6 years or younger and in patients who require fewer than 8 units of insulin per day.
As part of the approval of the MiniMed 670G device, the FDA requires a post-marketing study to be conducted to better understand how the system works in real-world settings.
Additional adverse events reported in clinical trials of closed-loop systems include headaches and dizziness .
Is there an advantage to bihormonal over single hormone systems?
In nondiabetic people, the effect of insulin is counteracted by glucagon, whereas glucagon secretion (in addition to insulin production) is impaired in those with type 1 diabetes. Therefore, the use of both hormones in an artificial pancreas is “a logical and feasible option” for managing hypoglycemia [reviewed in 18].
A small study comparing closed-loop control with insulin plus glucagon versus insulin plus placebo found that high gain pulses of glucagon decreased the frequency of hypoglycemia relative to placebo . More recently, Edward Damiano (Boston University, Massachusetts, USA) and colleagues showed that a bihormonal artificial pancreas significantly improved glycemic control compared with an insulin pump among adults and adolescents .
In a randomized crossover trial published in late 2016 , researchers demonstrated that a bihormonal artificial pancreas that can be used at home and is initialized only with body mass index provides improved glycemic control compared with usual care among 39 adults with type 1 diabetes.
The study authors explain that since meal announcements are optional and carbohydrate counting is not required, using the bihormonal artificial pancreas could reduce the patient burden associated with management of diabetes.
However, these systems await more extensive testing in wider patient populations. Although Bergenstal says that the research to date on bihormonal artificial pancreases is “encouraging” and the use of a bihormonal system may permit “even tighter glucose control where insulin alone is struggling,” he notes that the bihormonal system is likely to be the “third generation artificial pancreas,” following improvements in insulin-only systems.
Can closed-loop systems be used during pregnancy?
Just one study to date  has tested the artificial pancreas in pregnant women. This crossover trial involving 16 pregnant women showed that overnight closed-loop therapy improved the time spent in target range and reduced mean glucose levels compared with sensor-augmented pump therapy.
Additionally, 14 women continued to use day-and-night closed-loop insulin delivery after the crossover period of the study, with the results suggesting that 24-hour use of the closed-loop system is feasible during pregnancy, delivery, and in the 48 hours after childbirth.
Is the artificial pancreas likely to be approved in countries other than the USA?
The GlucoSitter algorithm – a component of the artificial pancreas system shown to improve glycemic control among children and adolescents in a diabetes camp  – has received a CE Mark in Europe, meaning it conforms with EU health and safety directives . However, no artificial pancreas devices have been approved outside of the USA to date, and the majority of systems are still undergoing testing in clinical trials.
Will it be possible to use the artificial pancreas to treat type 2 diabetes?
The MiniMed 670G system was approved by the FDA for the treatment of type 1 diabetes only, and research studies have focused on patients with type 1 diabetes. However, Bergenstal explains that patients with insulin-dependent type 2 diabetes experience many similar issues to those with type 1 diabetes, such as “getting the dosing right and a variation of needs from day to day.” He cautions that research into the artificial pancreas for patients with type 2 diabetes is preliminary, but early study findings “look encouraging.”
For example, the results of a pilot study suggested that closed-loop insulin delivery is feasible for patients with insulin-dependent type 2 diabetes on the general ward . In this study, Hovorka and colleagues demonstrated an improvement in time spent within the target blood glucose range among patients with insulin-dependent type 2 diabetes who were assigned to closed-loop insulin delivery compared with those assigned to insulin delivery according to local guidelines.
Are there likely to be any barriers to clinical implementation?
From the physician perspective, “some rethinking, some retraining and some new implementation skills” are required before the artificial pancreas can be used in the clinic, believes Bergenstal. He also says that new terminology, such as “closed-loop systems” (devices that combine glucose sensing and insulin delivery in one system) and “changing the insulin active time” (the duration of insulin action that the artificial pancreas system uses to calculate how much insulin to give) will require incorporation into training for healthcare providers.
Bergenstal notes that patients must be committed to working with the artificial pancreas, with a mindset of “I can envision myself wearing technology.” He emphasizes that healthcare providers must communicate to patients that if they put in the time to work with the artificial pancreas, “what is really difficult to start with gets easier and easier.”
Other possible barriers to the use of artificial pancreas systems include the need for recalibrations, periodic replacement of sensors, physician time, lack of software standardization, the need for clinical practice guidelines, cost, and – in the USA – variable reimbursement .
A recent study  also identified physical barriers to wearing glucose monitors and insulin pumps, including discomfort and appearance, which could be targeted to increase device use.
Despite the potential barriers to clinical implementation of the artificial pancreas, Bergenstal thinks that patients’ commitment to using the devices is likely to pay dividends. He explains that in the past, patients could commit to using devices to help manage their diabetes but could still experience disappointing results. With the artificial pancreas, however, “the commitment suddenly pays off,” with patients achieving results that they hoped for, he adds.
Five years from now, when we look back at how diabetes was treated in 2017, “we’re going to say type 1 diabetes is being treated in a whole different way,” says Bergenstal. And he believes that, health insurance and reimbursement permitting, the majority of people with type 1 diabetes could be using an artificial pancreas.
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