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Could AID Transform Type 2 Diabetes Care?

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While AID has traditionally been used in type 1 diabetes, new data suggests this technology has many of the same benefits in type 2 – namely, improving time in range and A1C while reducing hypoglycemia. Plus, AID dramatically simplifies blood sugar management. 

From continuous glucose monitoring (CGM) to automated insulin delivery (AID) systems, diabetes technologies that began as innovations for people with type 1 diabetes are slowly beginning to reach people with type 2.

For instance, many insurance companies now cover CGMs for people with type 2 diabetes who take insulin as well as those who are not on insulin but have a history of hypoglycemia. And earlier this week, the FDA approved Stelo by Dexcom, a CGM designed specifically for people with type 2 diabetes who are not taking insulin.

However, less progress has been made with reimbursement by insurance companies for AID. Off-label use of AID drew significant attention at the ATTD 2024 conference, with presenters highlighting the benefits for many people with diabetes across a range of settings and systems.

AID improves time in range across different systems and settings

Research shows that AID leads to many of the same benefits in type 2 diabetes as in type 1 diabetes: improved time in range, reduced hypoglycemia, and reduced A1C. Importantly, these benefits were consistent across different study settings and regardless of which AID system was used.

A study of 30 Tandem Control-IQ users with type 2 diabetes found that time in range increased by about 15% from 56% at baseline to 71% at six weeks. This translates to an increase of 3.6 hours per day spent in range.

Dr. Anders Carlson, diabetes medical director at the International Diabetes Center in Minnesota, said this finding is in line with studies in type 1 diabetes as well as the time in target range guidelines for type 1 diabetes.

Outside of clinical trials, research suggests that the benefits of AID extend to people with type 2 diabetes in the “real world.”

In a study presented at ATTD, MiniMed 780G users were able to achieve 71-75% time in range outside of a clinical trial, again meeting the targets for diabetes. “This is really compelling evidence that in a real-world setting, this AID system can work for people with type 2 diabetes,” Forlenza said.

Participants who used the recommended MiniMed 780G settings (i.e. the lowest glucose target) achieved a time in range of 80%.

For Carlson, this finding raises an important question – what are the optimal settings for AID in type 2 diabetes? For instance, since low blood sugar (hypoglycemia) is less of a concern, it may be beneficial to have more aggressive targets from the get-go.

Another study investigated the Omnipod 5 AID system in 24 participants with type 2 diabetes, finding strong improvements in time in range with minimal hypoglycemia. Among those on MDI, time in range increased from 43% at baseline to 58% at six months. Participants on basal insulin only saw even larger improvements in time in range, from 31% at baseline to 65% at six months.

Dr. Anne Peters, professor of medicine at USC, also highlighted reductions in total daily insulin dose among participants on MDI – yet another way in which AID could simplify type 2 diabetes management.

How might combining AID with GLP-1s and SGLT-2s affect glucose levels?

Growing use of GLP-1 receptor agonists, SGLT-2 inhibitors, and diabetes technology poses new questions for the future of diabetes care. That is, how might the combination of technology and medications optimize outcomes for people with type 2 diabetes?

In the Omnipod 5 study, half of the patients were also taking a GLP-1 or SGLT-2. Overall, Omnipod users taking a GLP-1 or SGLT-2 saw greater improvements in time in range compared to those who were only taking insulin. Participants in the GLP-1 or SGLT-2 group saw a 24% increase in time in range from 28% at the start of the study to 62% at eight weeks. Meanwhile, participants not using a GLP-1 or SGLT-2 improved their time in range by 18%, from 35% at baseline to 53% at eight weeks.

Carlson said this finding suggests that combining GLP-1s or SGLT-2s with AID could potentially lead to even better glycemic control than AID alone – though formal studies will be needed to test this hypothesis.

Similarly, Dr. Gregory Forlenza, associate professor of pediatric endocrinology at the University of Colorado, noted the ability of GLP-1s to reduce insulin needs. Combining these powerful medications with AID may help people with type 2 diabetes improve glycemic control and lose weight. It’s possible these improvements could even help people work toward diabetes remission.

What about AID for older adults with type 2 diabetes?

Starting insulin can be challenging for people of all ages, but it can be especially complex for older adults or disabled people with type 2 diabetes who receive home care.

Elderly people have a higher risk of severe hypoglycemia and hypoglycemia or ketoacidosis. Diabetes management for older adults can also be complicated by impaired cognition or dementia, reduced mobility, and difficulty accessing care.

In this context, the CLOSE AP+ study investigated AID assisted by nurses in people with type 2 diabetes unable to manage their own multiple daily injections (MDI) at home. CLOSE AP+ tested Control-IQ technology in 25 participants who had an average age of 70 years.

At 12 weeks, time in range improved significantly, from 37% to 63%. Time below range was less than 1%, while time above range was under 10%. Overall, Reznik highlighted that a majority of participants reached the American Diabetes Association guidelines for older people with diabetes. These guidelines recommend:

  • At least 50% time in range (70-180 mg/dL)
  • Less than 1% time below range (<70 mg/dL)
  • Less than 10% time above range (>250 mg/dL)

It’s also worth noting that participants using Control-IQ technology saw a significant 1.3% reduction in A1C. Over 90% of participants reached an A1C of less than 8% by the end of the trial, without any increase in severe hypoglycemia. Dr. Yves Renzik, professor of endocrinology at CHU Caen Normandy in France, also highlighted high patient confidence and high nurse satisfaction with the AID system in this study.

Ultimately, the CLOSE AP+ study showed that AID can be used safely in people with type 2 diabetes who require home nursing care. This confirms the benefits of AID extend beyond the “standard” person with type 2 diabetes to older adults and people with disabilities.

The bottom line

Numerous presentations at ATTD 2024 demonstrated that AID is safe and effective for people with type 2 diabetes. Both clinical trials and real-world data show that this technology increases time in range and improves A1C while minimizing hypoglycemia.

“I want to emphasize that across a wide variety of real world and clinical trial evidence sets, and across very different AID systems, everyone is either doing a great job hitting a goal for time in range or achieving a massive improvement in glucose control,” Forlenza said. He noted that AID leads to time in range increases of 15% to 24% in people with type 2 diabetes, nearly double the improvements typically seen in type 1 diabetes.

However, several questions remain to be answered regarding optimal settings, bolusing, and the potential of AID when combined with GLP-1s and SGLT-2s. Carlson highlighted the following areas for further research:

  • Are people on MDI the only candidates for AID? Or could AID be used in all people with type 2, regardless of their insulin needs and whether or not they’re meeting glycemic goals?
  • Is previous experience with technology necessary for successful use of AID in people with type 2 diabetes?
  • Does AID help with diabetes self-management (such as carb awareness)?
  • What role will primary care providers provide in supporting AID in this population?

Beyond glycemic data, it’s also important to consider user experience with AID. Overall, the data suggests that people with type 2 diabetes had good satisfaction and confidence in using these systems. Even people who hadn’t previously used diabetes devices reported a positive experience with AID, Peters noted.

“I honestly wasn’t sure my patients would like AID – many were technology-naive people,” Peters said. “But they loved it and they wanted to stay on it because they felt it improved their glycemic control.”

The Artificial Pancreas: What Is It and When’s It Coming?

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You’ve probably heard about the artificial pancreas, but are you up to speed on what’s happening in this rapidly evolving field?

First of All, What Is It Really?

The artificial pancreas (AP) is a device that mimics the blood sugar function of a healthy pancreas. It has three parts: a sensor for continuous glucose monitoring, a pump to deliver insulin, and a laptop or cell-phone component that directs the pump to deliver insulin as needed.

Most systems will deliver insulin alone, but some will be able to deliver both insulin and glucagon*.

How It’s Different from CGM

Artificial pancreas systems are often called “closed-loop” because they talk to both the sensor and the pump, bridging the gap between the two. The goal is to make a continuous loop without the need for human intervention. In testing so far, AP systems have often resulted in more time in target glucose ranges with less hypoglycemia, and they have also shined in controlling blood sugars overnight. They are not a cure by any means, but they are a huge improvement and will allow for diabetes management to go a little more on autopilot in the near future.

50 Years in the Making

The first precursors of the artificial pancreas date back to the 1970s. In the 50 years since, improvements have been made on all fronts: control algorithms are getting more predictive and less reactive, and pumps and glucose sensors are getting more accurate. Yet many challenges remain, such as the need for faster insulin, more stable glucagon, and systems that can work without user intervention, e.g., during meals and exercise.

The Future Is Almost Here

In June of 2017, Medtronic launched the first commercialized product, Minimed 670G.

The Medtronic device is a “hybrid” system due to the need to manually interact for meals and exercise. Hailed as a major advance towards a fully-automated artificial pancreas system, the 670G will be followed by other closed-loop systems in the coming months and years, with more and more academic group and industry collaborations being announced.

MiniMed 670G

One such effort – the IDCL (International Diabetes Closed Loop) Trial – is another example of the degree of collaboration between academic centers and industry. Led by the University of Virginia in conjunction with centers in Europe, companies like TypeZero Technologies, Tandem Diabetes Care, Dexcom and Roche Diagnostics are also involved. Other companies like Insulet (Omnipod) and Bigfoot are developing AP systems as well.

If You Just Can’t Wait

Alongside conventional development of AP systems, “Do It Yourself” or DIY movements spearheaded by patient and engineering communities are gaining visibility with a reported 400+ PWD currently using DIY artificial pancreas systems. Initiatives such as DIYPS.org and #wearenotwaiting are providing information on the internet to help people with diabetes build their own AP systems using commercially available CGM and pumps while providing information on how to set up control algorithms.

These systems require a great deal of user learning and commitment. While probably not for everyone and regulatory authorities sending out caveats on the potential risks involved, they can be a way for people to access artificial pancreas technology now before other systems are cleared for use.

At the 2017 Taking Control Of Your Diabetes Conference & Health Fair in San Diego, there was a panel discussion with five people who experimented with DIY systems and shared their thoughts, advice, and personal experiences.  You can watch the seminar and hear what they had to say here.

As a result, we can expect several artificial pancreas options in the coming years, which is amazing news! Systems will differ, but the goal will be the same: to reduce the burden of living with diabetes until a cure is found. We look forward to seeing more and more options in this space, and send kudos to all involved for their perseverance, passion, and commitment!

*Glucagon causes the liver to release stored glucose, raising blood sugar levels. It can be used to treat severe hypoglycemia.

The Latest and Greatest in Insulin Pumps and Sensor Technology

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diabetes pumps and sensors

I love pumps and sensors!

As a certified diabetes educator (or as I prefer to say, type 1 coach), I have started literally hundreds of patients on insulin pumps over the last few decades. I have a disclaimer: I do not wear a pump and do not have type 1 diabetes. But I have worked in the field from clinics to ski and summer camps, as a dog sled driver for little munchkins with our team of sled dogs, to backpacking and canoe trips – all with people who do have type 1 diabetes. Sometimes I grunt and groan when I get up to start an adventure, but then I meet up with the group and see someone taking shots! My emotions turn to glee when someone has a pump and a sensor…I realize it sometimes feels like being the bionic man or woman with all this technology but hey, what’s wrong with being such a diabetes stud or studdette?

So what is so cool about pump and sensor technology?

Well, if you’re like me and you like to participate in group sports or activities, the technology is amazing. Let’s say you are just starting off on an adventure (whatever that may be) with a group and you note on your sensor that your blood glucose (BG) is 50 mg/dL.

Argh.

Who wants to stop the whole team from proceeding? But then you realize you can take in some carbohydrates, lower your basal rate temporarily, and watch your sensor to see if you are coming up and are not only good to go, but where you will be in 5, 10, 15, 20 minutes…you get the idea.

What are the options available right now to help you manage your diabetes?

The Omnipod insulin pump is the only full functioning patch pump, meaning it is programmable with insulin-to-carb ratios, target BG, correction factors, etc. so your math is done for you. At this time, the Omnipod pump does not integrate with a sensor but you can certainly use the Dexcom sensor independently.

There are also two patch pumps that are not programmable and have a bolus only option (OneTouch Via) and basal/bolus option (V-Go). These are more likely options for those with type 2 diabetes.

The Tandem insulin pump does have a tube that most folks find a minor inconvenience. Its great new claim to fame is that, as the software is updated (and technology is changing so fast!), you can update your pump via the cloud. How cool is that! Your pump does not get outdated since the pump software is updated. This includes future changes, such as Dexcom sensor data on the screen, auto-suspend as needed with hypoglycemia, and the eventual goal of a fully integrated sensor and pump where the pump responds to the data from the sensor and alters insulin delivery.

tandem and dexcom cgm

The Medtronic insulin pump company has led the charge not only with a sensor integrated pump where the sensor data is seen on the pump screen, but where the pump responds to low blood glucose values and impending lows, and adjusts basal rates as needed based on your basal history. Be warned, this is not a cure and still requires diligence on your part or the system will fail. Fasting blood glucose values have been shown to be excellent – generally close to the pump set target range of 120 mg/dL.

MiniMed 670G

You can always choose to continue with injections and utilize one of two sensors. Dexcom (glucose readings every 5 minutes on a receiver or your cell phone) or the new Freestyle Libre that allows you to scan your sensor patch and see your glucose on a receiver.

And where is all of this going?

Oh – it is so exciting! I am confident that in the next five years a fully automated system will be available with minimal input from the user. Tandem, Omnipod and Medtronic are all working on fully integrated pumps as responsibly fast as they can. In addition, other options are coming too, including a dual hormone system that has reservoirs for insulin and glucagon to keep you safe. And with the new insulin from Novo Nordisk that is reputed to start absorption in 2.5 minutes (wow!) one of the big barriers to insulin delivery may have just been resolved.

Although a cure is what we are all hoping for, technology is the next best thing.

Embrace it and stay tuned!

Automated Insulin Delivery (Artificial Pancreas, Closed Loop)

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artifiical pancreas

 

The development of automated insulin delivery has many names – artificial pancreas, hybrid closed loop, Bionic Pancreas, predictive low glucose suspend – but all share the same goal: using continuous glucose monitors (CGMs) and smart algorithms that decide how much insulin to deliver via pump. The goal of these products is to reduce/eliminate hypoglycemia, improve time-in-range, and reduce hyperglycemia – especially overnight.

See below for an overview of the automated insulin delivery field, focused on companies working to get products approved. Do-it-yourself automated insulin delivery systems like OpenAPS and Loop are not included here, though they are currently available and used by a growing number of motivated, curious users.

We’ve also included helpful links to articles on specific product and research updates, as well as some key questions.

Who is Closing the Loop and How Fast Are They Moving?

Below we include a list of organizations working to bring automated insulin delivery products to market – this includes their most recently announced public plans for pivotal studies, FDA submissions, and commercial launch. The organizations are ordered from shortest to longest time to a pivotal study, though these are subject to change. This list excludes those without a commercial path to market (e.g., academic groups). The first table focuses on the US, with European-only systems listed in the second table.

Updated: November 4, 2017

US Products

Company / Organization Product Latest Timing in the US
Medtronic MiniMed 670G/Guardian Sensor 3 – hybrid closed loop that automates basal insulin delivery (still requires meal boluses) FDA-approved and currently launching this fall to ~35,000 Priority Access Program participants in the US. Pump shipments to non-Priority Access customers will start in October, with sensors and transmitters to ship by the end of 2017 or early 2018. Medtronic is experiencing a global CGM sensor shortage that won’t resolve until spring 2018.
Tandem t:slim X2 pump with built-in predictive low glucose suspend (PLGS) algorithm; Dexcom G5 CGM

t:slim X2 pump with built-in Hypoglycemia-Hyperglycemia Minimizer algorithm; Dexcom G6 CGM (including automatic correction boluses)

 Launch expected in summer 2018. Pivotal trial now underway, with FDA submission expected in early 2018.

Launch expected in the first half of 2019. Pivotal trial to begin in the first half of 2018.
Insulet OmniPod Horizon: pod with built-in Bluetooth and embedded hybrid closed loop algorithm, Dash touchscreen handheld, and Dexcom G6 CGM

User will remain in closed loop even when Dash handheld is out of range

 Launch by end of 2019 or early 2020, with a pivotal study in 2018
Bigfoot Biomedical Smartphone app, insulin pump (acquired from Asante), and a next-gen version of Abbott’s FreeStyle Libre CGM sensor (continuous communication)

The smartphone is expected to serve as the window to the system and complete user interface

 Launch possible in 2020, with a pivotal trial expected in 2018
Beta Bionics Bionic Pancreas iLet device: dual chambered pump with built-in algorithm; hybrid or fully closed loop; insulin-only or insulin+glucagon; custom infusion set, Dexcom CGM

Likely to launch as insulin-only product, with glucagon to be optionally added later

Currently using Zealand’s pumpable glucagon analog

 Insulin-only: possible US launch in the first half of 2020, with a pivotal trial to start in the beginning of 2019.

Insulin+glucagon (bihormonal) pivotal trial expected to start in the beginning of 2019. Timing of FDA submission and launch depend on a stable glucagon, among other things.

European Products

Company / Organization Product Latest Timing in Europe
Medtronic MiniMed 640G/Enlite Enhanced – predictive low glucose management

MiniMed 670G/Guardian Sensor 3 – hybrid closed loop that automates basal insulin delivery (still requires meal boluses)

 Currently available in Europe

No timing recently shared. Approval was previously expected in summer 2017
Diabeloop Diabeloop algorithm running on a wireless handheld, Cellnovo patch pump, Dexcom CGM Pivotal trial expected to complete in February/March 2018. Possible European launch in 2018
Roche, Sensonics, TypeZero Will use Senseonics’ 180-day CGM sensor, Roche pump and TypeZero algorithm Pivotal trial expected to begin in Europe in early 2018
Cellnovo, TypeZero Cellnovo patch pump with integrated TypeZero algorithm; presumably a Dexcom CGM Aims for a 2018 European launch. No pivotal trial details shared

Helpful Links

Medtronic: MiniMed 670G

Tandem

Insulet

Bigfoot

Beta Bionics

Test Drives:

test drive – UVA’s Overnight Closed-Loop Makes for Great Dreams. Kelly participates in UVA’s overnight closed loop trial and reports back on an incredible opportunity for the field to move fast, reduce anxiety, and beat timelines.

test drive – Kelly and Adam take UVA’s DiAs artificial pancreas system home 24/7 for a three-month study. Their key takeaways, surprises, and next steps.

Key Questions for the Artificial Pancreas

Are patient expectations too high? If we expect too much out of first-generation artificial pancreas systems – e.g., “I don’t have to do anything to get a 6.5% A1c with no hypoglycemia” – we might be disappointed. Like any new product, early versions of the artificial pancreas are going to have their glitches and shortcomings. Undoubtedly, things will improve markedly over time as algorithms advance, devices get more accurate and smaller, insulin gets faster, infusion sets improve, and we all get more experience with automated insulin delivery. But it takes patience and persistence to weather the early generations to get to the truly breakthrough products. We would not have today’s small insulin pumps without the first backpack-sized insulin pump; we would not have today’s CGM without the Dexcom STS, Medtronic Gold, and GlucoWatch; we would not be walking around with smartphones were it not for the first brick-sized cellphones. Our research trial experience with automated insulin delivery recalibrated our expectations a bit – these systems are going to be an absolutely terrific advance for many patients, but they will not replace everything out of the gate. Let’s all remember that devices need to walk first, then run, and it’s okay if the first systems are more conservative from a safety perspective.

What fraction of patients will be willing to wear some type of automated insulin delivery system? Right now, many estimate that ~30% of US type 1’s wear a pump, and about 15% to 20% wear CGM. There are a lot of reasons why that may be the case, including cost, hassle, no perceived benefit, no desire to switch from current therapy, wearing a device on the body, alarm fatigue, etc. Will automated insulin delivery address enough of these challenges to expand the market?

Will healthcare providers embrace automated insulin delivery? Today, healthcare providers lose money when they prescribe pumps and CGM – they are very time consuming to train, prescribe, and obtain reimbursement for. We need to make sure that automated insulin delivery systems make providers’ lives easier, not more complicated.

Will there be a thriving commercial environment and reimbursement? It’s extremely expensive to develop and test closed-loop systems, and companies will only develop them if there is a commercial environment that supports a reasonable business. Reimbursement is a major part of that, and it’s hard to know if insurance companies will pay for closed-loop systems for a wide population of patients. We are optimistic that reimbursement will be there, especially if systems can simultaneously lower A1c, reduce hypoglycemia, and improve time-in-range.

What’s the right balance between automation and human manual input? The holy grail is a fully-automated, reactive closed loop that requires no meal or exercise input. But insulin needs to get faster to make that a reality. For now, daytime systems need to deal with balancing human input with automation, and there’s an associated patient learning curve. How much should automated insulin delivery systems ask patients to do? How do we ensure patients do not forget how to manage their diabetes (“de-skilling”) as systems grow in their automation abilities?

Insulin-only or insulin+glucagon? Ultimately, we believe that the question is partially one of patient preferences. There will be some patients who may want the extra glycemic control offered by the dual-hormone approach and will be willing to accept a bit more risk or a more aggressive algorithm. An insulin+glucagon system could be helpful for those with hypoglycemia unawareness, and if such a system makes it to the market, some patients will certainly want to give it a try. We believe a range of options is a good thing for people with diabetes, since all systems and products have pros and cons. Ultimately, cost considerations may present the largest factor in adoption. An insulin+glucagon system certainly brings multiple cost elements to consider – a second hormone, a dual-chambered pump, custom infusion sets, potentially higher training, etc. It’s hard to know at this point how the relative costs/benefits will exactly compare to insulin-only systems.

Medtronic launches new user-friendly insulin pump design in US

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Medtronic has announced that its MiniMed 360G system with SmartGuard technology has been launched in the United States.

“This latest innovation demonstrates Medtronic’s vision to transform diabetes care to enable greater freedom and better health through a commitment to continually improving both outcomes and user experience,” Alejandro Galindo, president of the intensive insulin management business at Medtronic, said in a press release.

The FDA approved the system for the treatment of patients aged at least 16 years with diabetes. The new system features an insulin pump hardware platform and user-friendly design that will combine personalized diabetes management with industry-leading clinical performance, according to the release.

The system uses the Contour Next Link 2.4 blood glucose meter from Ascensia Diabetes Care to provide highly accurate blood glucose test results. Results are transmitted to calculate boluses using the Bolus Wizard calculator to calibrate the continuous glucose monitor sensor to help prevent manual entry errors, according to the release.

The SmartGuard technology is designed to trigger an alarm when continuous glucose monitoring levels reach a low threshold and releases insulin if the patient is unaware of the alarm.

“Low blood sugar at night is of particular concern, when up to 75% of severe hypoglycemia occurs and patients are unlikely to be aware of symptoms while they are asleep,” Satish Garg, MD, editor-in-chief of Diabetes Technology & Therapeutics and professor of pediatrics and medicine and director of the adult diabetes program at the University of Colorado Denver, Barbara Davis Center for Childhood Diabetes, said in the release. “The ability to automate the suspension of insulin at night is an important feature, as prolonged hypoglycemia could be life-threatening.”

Remote, Minimally Invasive Atrial Fibrillation Detection by Medtronic.

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Medtronic has just released the smallest implantable cardiac monitoring device currently available on the market. The compact Reveal LINQ monitor is also the only implantable cardiac monitor that collects data continuously and wirelessly for up to three years; not only can the device store data, but it communicates remotely with a MyCareLink patient monitor, which taps Medtronic’s Carelink® Network. This powerful tool provides doctors with patient data and notifications, empowering physicians to make earlier clinical decisions based on CareLink’s customizable, actionable and comprehensive reports. The Reveal LINQ implantable ECG monitor is designed for patients at risk for cardiac arrhythmia or patients that show symptoms that may suggest cardiac arrhythmia. It provides unparalleled preventative care by notifying cardiologists of detected atrial fibrillation events, classed by rhythm using an exclusive detection algorithm.

Remote, Minimally Invasive Atrial Fibrillation Detection by MedtronicLINQ     Reveal Linq     Reveal-XT-and-Linq

FDA Panel Supports AV Block Indication for BiV Pacing.

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 Indications for biventricular (BiV) pacing should be extended to include patients with systolic heart failure and first-, second-, or third-degree atrioventricular (AV) block, the FDA‘s Circulatory System Devices advisory panel decided here yesterday by a thin majority vote.

Their important caveat: BiV pacing in first-degree AV block should be only for patients for whom there is “a verifiable confidence that ventricular pacing is going to be necessary most of the time,” said panel chair Dr Richard L Page (University of Wisconsin, Madison) during the proceedings. With the panel having overwhelmingly decided that BiV pacing would be both safe (by a six to one vote) and effective (unanimously), a lone abstention on the third issue of whether benefits would outweigh attendant risks led Page to cast a tie-breaking vote in support of the expanded indication.

Panelist Dr David Kandzari (Piedmont Heart Institute, Atlanta, GA), explaining his abstention to heartwire , said that the pivotal Medtronic-sponsored BLOCK-HF trial supporting the extended indication didn’t follow patients long enough to capture BiV pacing’s inevitable long-term risks. “We just didn’t have that kind of information. I think if we saw more compelling reductions in clinical outcomes with the therapy other than just avoidance of heart-failure hospitalization, it would have been a much easier decision,” he said. “Even quality of life was not compellingly different.”

Page observed for heartwire that “everybody wrestled with risk vs benefit, but at the end of the day, the majority felt that the benefit outweighed the risk.”

Why BiV Pacing, and Why Not in All First-Degree AV Block?

BLOCK-HF randomized 691 patients with any degree of AV block, NYHA class 1–3 heart failure, and an LVEF<50% implanted with three-lead devices programmed to either BiV pacing or to standard RV pacing. As previously reported by heartwire , a primary end point composite of all-cause mortality, HF-related urgent care, or a >15% increase in LV end-systolic volume index (LVESVI) fell by a significant one-fourth over three years in the BiV group.

BiV pacemakers have been heretofore reserved for cardiac resynchronization therapy (CRT) in heart-failure patients with prolonged QRS intervals and an LVEF <35%. BiV pacing is now only sometimes used off-label in patients like those in BLOCK-HF, but it’s likely to become much more common if the FDA takes the panel’s advice on the Medtronic application. If the new BiV niche is approved, clinicians would likely more routinely use BiV pacemakers for AV block whether on-label with Medtronic units or off-label with those of other companies. That goes for BiV pacemakers with or without defibrillating capability, so-called CRT-D and CRT-P devices, respectively, both of which were allowed in BLOCK-HF.

The panel included only patients with first-degree AV block expected to need a lot of RV pacing in the proposed indication because they have the greatest need to avoid it. RV pacing necessarily induces ventricular dyssynchrony and so can exacerbate heart failure, whereas BiV imposes synchrony. But a lower-risk, lower-cost dual-chamber pacemaker could well be enough for patients with first-degree AV block that doesn’t require much RV pacing.

Hazard Ratio (95% CI) for BLOCK-HF Primary End Point*, BiV Pacing vs RV Pacing

Group Hazard ratio (95% CI)
CRT-P (n=484) 0.72 (0.57–0.90)
CRT-D (n=207) 0.74 (0.56–1.00)
Total cohort 0.73 (0.59–0.89)
*Composite of all-cause mortality, HF-related urgent care, or a >15% increase in LVESVI
CRT-P=pacing-only cardiac resynchronization therapy device
CRT-D=defibrillating cardiac resynchronization therapy device
Source: FDA document

The FDA questioned whether the third lead’s risks, given an estimated attendant complication risk of 6.3%, were worth any benefits when compared with, for example, BLOCK-HF’s only slight improvement in HF events; it was a major issue with panelists, too.

Electrophysiologist Dr Patricia A Kelly (Community Medical Center, Missoula, MT) described how BiV pacemakers entail late risks that wouldn’t have been evident in the pivotal trial, persuading a number of other panelists. “The risks of the LV lead extend past the peri-implant period. Generator life is shorter, there are more generator changes, there’s the attendant increase in risk of infection with every generator change. The risks are more significant than they [seem] if we just look at the risks we’ve been presented today.” Kelly voted “no” to whether the expanded indication’s benefits outweigh risks.

Panelist Dr David D Yuh (Yale University, New Haven, CT) agreed and voted the same way. “As a surgeon, having had to put in a lot of epicardial LV leads for coronary sinus leads that have failed, I appreciate the persistent added risk associated with BiV systems in terms of generator changes and lead changes,” he said. “The majority of benefit in terms of heart-failure admissions or treatments was realized in the first year, and these more downstream risks I think do accumulate and eventually overwhelm that.”

Divisive Primary End Point

The FDA also had reservations about the trial’s primary outcome, a benefit driven by improvements by LVESVI, with far less coming from the two clinical components, especially mortality.

Component % Contribution to Composite Primary End Point by BiV vs RV pacing groups in BLOCK-HF

Primary end point components BiV-pacing arm RV-pacing arm
Death 11.9 7.9
HF urgent care 35.0 32.5
LVESVI up >15% 53.1 59.7
Source: FDA document

The panelists were split on whether the LVESVI results were adequately informative. According to Page, the echo parameter can reflect clinical deterioration, and data from BLOCK-HF and other studies “influenced [much of] the panel that it might be of value as a surrogate.” And he noted the trial’s LVESVI results and two clinical end points went in the same favorable direction. “The concordance of the outcomes among different [patient] groups was striking, and I think for those of us who were persuaded that the benefits outweighed the risks, that was a major factor.”

Others on the panel were less convinced. Dr Richard Lange (University of Texas Health Science Center, San Antonio) said the focus should be on the primary end point’s clinical components. “The changes in LVESVI are not really clinically relevant.” Lange ultimately voted that BiV pacing’s risks outweighed its benefits in the expanded indication.

Panelists also questioned the proposed indication’s inclusion of patients with NYHA class 1 heart failure, which characterizes HF patients who have become asymptomatic on medications.

The trial included patients in NYHA class 1 and so supports their use of BiV pacing, “but I still have real problems with offering a BiV system, with all the attendant baggage associated with that device compared with single chamber systems, to class 1 patients,” Yuh said.

“I’m skeptical that we’d get much bang for the buck,” Lange agreed. “The potential complications are high, including the initial implant complications, and subsequent follow-up and reimplantation. And when we look at the outcome of people with NYHA class 1 symptoms, their outcomes are terrific.”

Responding to a query from Page, Lange said he would support the exclusion of NYHA class 1 patients from any expanded indications, something the panel ultimately did not do.

The FDA Has Approved The First Artificial Pancreas.

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An easier way for diabetics to control their insulin intake

The U.S. Food and Drug Administration has approved its first “artificial pancreas” to automatically control the insulin levels of diabetics.

medtronic

The hormone insulin controls blood sugar levels and is normally produced in the body by the pancreas. But in Type 1 diabetics (and sometimes Type 2), the pancreas just doesn’t make insulin, meaning diabetics’ bodies can’t regulate blood sugar levels. This system, designed by Minneapolis-based medical tech company Medtronic, is a wearable little gadget that stops insulin delivery automatically when glucose levels get too low, hopefully keeping the wearer from going into a diabetic coma. 

Unlike traditional insulin pumps, which require the wearer to still monitor blood sugar levels and manually program the pump to deliver insulin, this one monitors blood sugar for you, and delivers the appropriate amount accordingly. With a traditional pump, the device can keep delivering insulin even when the your blood sugar is too low, lowering levels even further and sometimes causing loss of consciousness. This is especially dangerous during sleep, when you can’t exactly gauge your own blood sugar. Medtronic’s MiniMed 530G system can detect up to 93 percent of hypoglycemia (low blood sugar) episodes, and will sound an alarm to wake you up if your blood sugar gets too low. If you don’t respond, the system will shut off insulin delivery for two hours, hopefully staving off dangerously low blood sugar levels.

One caveat: Medtronic got a warning letter from the FDA only a few weeks ago related to manufacturing processes of their Paradigm Insulin Infusion Pumps (which are used in this system) at their facility in Northridge, Calif. The pumps had been recalled in June because they were malfunctioning and delivering either too much or not enough insulin, and the FDA found the company was not doing enough to verify that the failure wouldn’t happen again. The company said in the press release accompanying the product approval that it had “already addressed many of the observations noted in the warning letter and is committed to resolving the remaining observations as quickly as possible.”

Threshold-Based Insulin-Pump Interruption for Reduction of Hypoglycemia.

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BACKGROUND

The threshold-suspend feature of sensor-augmented insulin pumps is designed to minimize the risk of hypoglycemia by interrupting insulin delivery at a preset sensor glucose value. We evaluated sensor-augmented insulin-pump therapy with and without the threshold-suspend feature in patients with nocturnal hypoglycemia.

METHODS

We randomly assigned patients with type 1 diabetes and documented nocturnal hypoglycemia to receive sensor-augmented insulin-pump therapy with or without the threshold-suspend feature for 3 months. The primary safety outcome was the change in the glycated hemoglobin level. The primary efficacy outcome was the area under the curve (AUC) for nocturnal hypoglycemic events. Two-hour threshold-suspend events were analyzed with respect to subsequent sensor glucose values.

RESULTS

A total of 247 patients were randomly assigned to receive sensor-augmented insulin-pump therapy with the threshold-suspend feature (threshold-suspend group, 121 patients) or standard sensor-augmented insulin-pump therapy (control group, 126 patients). The changes in glycated hemoglobin values were similar in the two groups. The mean AUC for nocturnal hypoglycemic events was 37.5% lower in the threshold-suspend group than in the control group (980±1200 mg per deciliter [54.4±66.6 mmol per liter]×minutes vs. 1568±1995 mg per deciliter [87.0±110.7 mmol per liter]×minutes, P<0.001). Nocturnal hypoglycemic events occurred 31.8% less frequently in the threshold-suspend group than in the control group (1.5±1.0 vs. 2.2±1.3 per patient-week, P<0.001). The percentages of nocturnal sensor glucose values of less than 50 mg per deciliter (2.8 mmol per liter), 50 to less than 60 mg per deciliter (3.3 mmol per liter), and 60 to less than 70 mg per deciliter (3.9 mmol per liter) were significantly reduced in the threshold-suspend group (P<0.001 for each range). After 1438 instances at night in which the pump was stopped for 2 hours, the mean sensor glucose value was 92.6±40.7 mg per deciliter (5.1±2.3 mmol per liter). Four patients (all in the control group) had a severe hypoglycemic event; no patients had diabetic ketoacidosis.

CONCLUSIONS

This study showed that over a 3-month period the use of sensor-augmented insulin-pump therapy with the threshold-suspend feature reduced nocturnal hypoglycemia, without increasing glycated hemoglobin values.

Source: NEJM

Reporting of industry funded study outcome data: comparison of confidential and published data on the safety and effectiveness of rhBMP-2 for spinal fusion.

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Abstract

Objective To investigate whether published results of industry funded trials of recombinant human bone morphogenetic protein 2 (rhBMP-2) in spinal fusion match underlying trial data by comparing three different data sources: individual participant data, internal industry reports, and publicly available journal publications and conference abstracts.

Data collection and synthesis The manufacturer of rhBMP-2 products (Medtronic; Minneapolis, MN) provided complete individual participant data and internal reports for all its studies of rhMBP-2 in spinal fusion. We identified publications and conference abstracts through comprehensive literature searches. We compared outcomes provided in the individual participant data against outcomes reported in publications. For effectiveness outcomes, we compared meta-analyses of randomised controlled trials based on each of the three data sources. For adverse events, meta-analysis of the published aggregate data was not possible and we compared the number and type of adverse events reported between data sources.

Results 32 publications reported outcomes from 11 of the 17 existing manufacturer sponsored studies. For individual randomised controlled trials, 56% (9/16) to 88% (15/17) of effectiveness outcomes known to have been collected were reported in the published literature. Meta-analyses of effectiveness data were almost identical for pain outcomes and similar for fusion across the three data sources. A minority of adverse event data known to have been collected were reported in the published literature. Several journal articles reported only “serious,” “related,” or “unanticipated” adverse events, without defining these terms. Others reported a small proportion of the collected adverse event categories. Around 23% (533/2302) of the total adverse events collected in published randomised controlled trials have been reported in the literature, with randomised controlled trials evaluating the licensed preparation (Infuse) reporting around 11% (122/1108) of collected adverse events.

Conclusions The published literature only partially represents the total data known to have been collected on the effects of rhBMP-2. This did not lead to substantially different results for meta-analysis of effectiveness outcomes. In contrast, reporting of adverse event data in trial publications was inadequate and inconsistent to the extent that any systematic review based solely on the publicly available data would not be able to properly evaluate the safety of rhBMP-2. Analysis of individual participant data enabled the most complete, detailed, and in-depth analysis and was not more resource intensive than extracting, collating, and analysing aggregate data from multiple trial publications and conference abstracts. Confidential internal reports presented considerably more adverse event data than publications, and in the absence of individual participant data access to these reports would support more accurate and reliable investigation, with less time and effort than relying on incomplete published data.

Discussion

Controversy around use of recombinant human bone morphogenetic protein 2 (rhBMP-2) in spinal fusion began with suggestions that inadequate peer review and editorial oversight were responsible for an apparent absence of adverse events from early peer reviewed publications of industry sponsored studies. A subsequent investigation led by the editor in chief of The Spine Journal14 found fewer reported adverse events in academic publications of industry sponsored studies than in related study data available in FDA summaries and public meeting documents. The FDA materials available for that investigation appear to be partial outcome data from a subset of industry funded studies evaluating Infuse/LT-CAGE, Infuse/MASTERGRAFT, and AMPLIFY rhBMP-2 matrix preparations. Our investigation was able to explore this issue in greater depth having individual participant data on all recorded effectiveness and safety outcomes as well as internal reports provided for all Medtronic funded studies of rhBMP-2 for spinal fusion. Given their previous confidentiality, high degree of detail, and availability for all known studies, we consider the combination of individual participant data and internal reports to be the most comprehensive and trustworthy source of Medtronic trial evidence available to date.

Source: BMJ