In this full report, we bring you coverage on one of our favorite conferences: Practical Ways to Achieve Targets in Diabetes Care (ATDC), known to many as simply “Keystone.” Set 9,173 feet above sea level in breathtaking Keystone, Colorado, this year’s meeting drew ~550 attendees from seven countries and 46 states, down slightly from ~600 attendees in 2015. The program featured more than 50 talks, along with patient/provider panels and industry-sponsored workshops and dinners.
It’s timing (~one month after ADA) and intimate format provided the valuable opportunity to hear experts sound off candidly on the latest topics, trends, and controversies in diabetes. On the technology front, Dr. Francine Kaufman (Medtronic Diabetes, Northridge, CA) provided an overview of the evolution of Medtronic’s artificial pancreas, Dr. Ramachandra Naik (J&J, Wayne, PA) shared great detail on the planned pivotal study for J&J’s automated insulin delivery device (a hypoglycemia-hyperglycemia minimizer) with Dexcom’s G5 CGM, and Dr. Courtney Lias (FDA, Silver Spring, MD) picked up where she left off at the NIH Artificial Pancreas Workshop, asking for audience input as to how the FDA can make regulatory processes easier.
On the drug side, ADA’s Dr. Robert Ratner (Alexandria, VA) highlighted results from the ANDIS study that characterize the heterogeneity of type 2 diabetes in terms of five subtypes, Dr. William Herman (University of Michigan, Ann Arbor, MI) rather controversially suggested that the cardioprotective benefits of empagliflozin (Lilly/BI’s Jardiance) and liraglutide (Novo Nordisk’s Victoza) might be replicated more cost-effectively with the intensification of other agents such as aspirin, statins, and sulfonylureas, and Dr. Desmond Schatz (University of Florida, Gainesville, FL) provided an update on the enrollment progress of each of TrialNet’s five type 1 diabetes prevention and intervention studies. Notably, Dr. Schatz also picked up right where he left off in his powerful address at ADA, calling for more urgency in bringing diabetes to “212 degrees.”
We are already looking forward to next year’s conference, which will take place July 13-16, 2017 again in Keystone, CO. Registration will open in October 2016. Remember to register online early as this conference consistently sells out weeks in advance – and for good reason!
Our comprehensive coverage below is organized into three topic areas: (i) Diabetes Technology; (ii) Diabetes Drugs; and (iii) Additional Topics. To help guide you through the report, titles of some of the most memorable presentations are highlighted in yellow, while write-ups that were not included in our daily coverage are highlighted in blue. You can look back at our highlights from day #1 and days #2-4 of Keystone 2016 as well.
- Executive Highlights
- Diabetes Technology
- Keynote Address
- Recent Advances in Diabetes Treatment
- Challenges in Diabetes Management
- Corporate Symposium: Prepare for Closed-Loop Technology (Sponsored by Medtronic)
- Corporate Symposium: Transition of Care from Adolescence to Adulthood (Sponsored by Insulet)
- Corporate Symposium: Partnering to Improve Patient Care: A Technological Evolution in Insulin Delivery (sponsored by J&J)
- Corporate Symposium: Practical Review of Real-Time Continuous Glucose Monitoring in Clinical Practice at the University of Colorado, Barbara Davis Center and the Future of Dexcom Technology (Sponsored by Dexcom)
- Corporate Symposium: Two Ends of the Diabetes Spectrum (Sponsored by Medtronic)
- Diabetes Drugs
- Upcoming Trends in Diabetes Care
- Immunology and Diabetes
- Combination Therapy for Best Diabetes Outcomes
- Macrovascular Disease and Diabetes
- Challenges in Diabetes Management
- Recent Advances in Diabetes Treatment
- Gut and Diabetes
- Patient/Provider Q&A Panels: Pediatric
- Corporate Symposium (Sponsored by Sanofi)
- Additional Topics
- Keynote Address
- Combination Therapy for Best Diabetes Outcomes
- Meet the Peers Sessions
- Hypoglycemia and Diabetes
- Patient/Provider Q&A Panels: Adult
FDA Perspective: Regulatory Promotion of Technology Innovation
Courtney Lias, PhD (FDA, Silver Spring, MD)
In a refreshingly titled talk, “Regulatory Promotion of Technology Innovation,” FDA’s Dr. Courtney Lias picked up where she left off at the NIH Artificial Pancreas Workshop, repeatedly asking for audience input as to how the FDA can make regulatory processes easier. She affirmed that the Agency is prioritizing: (i) device consolidation and convenience via mobile apps; (ii) the optimization of pivotal trial design (namely pre- vs. post-market considerations); and (iii) device interoperability (the FDA announced an internal initiative to encourage interoperability just last week). Touching on the topic of pivotal studies, Dr. Lias reminded the audience that the FDA is flexible and encouraged early communication to ensure that studies have an appropriate balance of pre- and post-market data collection – not just for approval, but also to improve odds of early reimbursement. Medtronic, of course, went with a super-fast single arm, three month trial to demonstrate pre-market safety, to be followed by a planned 1,000-patient post-market outcomes study. While some are worried every company will have to follow this path, the FDA is clearly flexible on this topic. It was great to hear her acknowledge in Q&A that study design can really drive patient access and cost, and the FDA can work with companies to encourage proper design (hopefully with CMS input!). Following her enthusiasm last week, Dr. Lias also continued to preach that device interoperability will actually improve the safety profile of devices and speed up the regulatory process without sacrificing cybersecurity. We will be interested to learn more about the internal initiative, what form it will take, and how that might impact the diabetes device landscape. In Q&A she touched on the OpenAPS movement, noting that as the movement expands beyond personal use, the risk increases and regulation is more likely to be enforced; on the plus side, she highlighted that “these movements apply pressure on the system to approve devices faster, so that we know that the technology that people are using is safe.” We completely agree and recall that the Dexcom G4 Share receiver was approved quickly as the Nightscout community gained steam. We hope the same is true of automated insulin delivery. More highlights from this talk are below!
- Dr. Lias was actually asked to speak about “regulatory challenges in technology approvals”, but she changed the tone and title to be more positive: “Regulatory Promotion of Technology Innovation.” We love it! The FDA has made amazing progress on diabetes devices in the past few years, though there is sometimes still a negative tone associated with the Agency’s work. We applaud Dr. Lias and colleagues for improving FDA’s openness to innovation, and would like to see the FDA more frequently acknowledged for the great and extremely difficult work that they do – particularly given the very under-resourced Agency.
- In her discussion of artificial pancreas pivotal trials, Dr. Lias alluded to Dr. Steve Russell and Dr. Roy Beck’s recently published Diabetes Care paper on the topic – see our ADA coverage here for the highlights. The paper proposed that a “recommended” pivotal trial would be a six-month, parallel group RCT with a representative population (MDIs, high A1c’s, spectrum of ages), a 2:1 randomization (artificial pancreas vs. usual care), and primary outcomes of A1c and time <60 mg/dl.
- Dr. Lias elaborated on some of the mobile app challenges, saying that developers need to consider how the app interacts with the phone’s operating system – How does the app handle updates? What happens to the app’s functioning when the operator receives a phone call? What happens to alarms if the phone is muted? The FDA is “trying to help where they can,” but app developers really have to work with mobile phone companies to address these concerns. This appears to be a big challenge – e.g., Will Apple work with a diabetes device company to help an app override the phone’s mute button when a hypoglycemia alarm comes up?
- Dr. Lias highlighted the FDA’s very rational, tiered approach to regulating mobile apps. At the bottom of the pyramid are wellness apps that don’t require FDA regulation: tracking food consumption, exercise, etc. These are not considered medical devices. The next tier consists of lower risk mobile applications that meet the “device” definition, but are not considered mobile medical applications – patient self management apps and organization/tracking tools fall in this category. At the top of the pyramid are “mobile medical applications,” which are most heavily regulated by the FDA and would do things like communciate with BGMs, CGMs, etc.
- Regarding the pre- vs. post-market balance of data, we recommend reading our take on last week’s JAMA article from FDA’s Drs. Jeffrey Shuren and Robert Califf. The senior FDA officials argued that pre-market trial requirements might be reduced with better post-market data collection. We see high potential for this to be used with automated insulin delivery, particularly for devices that are cloud connected.
Questions and Answers
G. Todd Alonso (Barbara Davis Center, Aurora, Colorado): In September, it will be three years since Medtronic’s threshold suspend was approved. Yet some payers still refuse to pay. We have this peer-to-peer system, but I often find that I’m talking to someone who’s never even thought about treating a patient with diabetes. So we have patients under 16 who do great on the device, but they can’t afford it. What can the FDA do to help us get coverage for them?
A: I agree – the stories I hear of patients fighting for some devices and test strips are frankly terrible. The main thing the FDA can do is talk to manufacturers, basically urging them to consider how they can design their studies so they have the highest chance of achieving reimbursement. We do what we can to try to encourage this kind of thinking. I’d also love to hear your ideas to help with this!
Satish Garg (Barbara Davis Center, Aurora, Colorado): There are two big groups making artificial pancreas devices in their homes – the DIYPS movement and the #WeAreNotWaiting movement. What is the FDA perspective on that?
A: Regardless, they are making a medical device. If they make it for personal use only, the FDA may not get involved. But as the movement grows and the proprietary technologies and algorithms are distributed, the public health risk is increased, the device is not really for personal use, and it is something we would be more likely to engage on. They know that. The other thing to consider is that these movements apply pressure on the system to approve devices faster, so that we know that the technology that people are using is safe.
Q: When I’m outdoors I can’t read my devices, and I feel that’s unsafe. I’ve gotten alarms before and not been able to respond appropriately because I couldn’t see my screen. That should maybe be an FDA issue? Also, if someone loses or misplaces a device, shouldn’t there be a way for whoever finds it to call the manufacturer and have them locate and send it to the owner? Just a thought.
A: See, this is why I love coming to these conferences – those are two suggestions that I’d never heard before. I’ve definitely considered the screen readability issue with my phone before, but never with pumps. Those are human factors issues that I will certainly pass along.
Comment: The FDA used to be a deterrent for getting things done – I’d like to thank Courtney and the FDA for making things move as smoothly and rapidly as they are for the artificial pancreas.
Recent Advances in Diabetes Treatment
Overview of JDRF Role of Closed-Loop in T1D
Aaron Kowalski, PhD (JDRF, New York, NY)
Dr. Aaron Kowalski highlighted JDRF’s instrumental role in the development of the artificial pancreas field, shared some pragmatic thoughts on glucagon, and expressed hope in Q&A that devices will increasingly be used in type 2. Dr. Kowalski discussed the remarkable progress the artificial pancreas field has made in the past ten years, from concept stage to the cusp of commercialization. He noted that JDRF has now contributed nearly $150 million to closing the loop, established the development roadmap, created the artificial pancreas consortium, drove the FDA to release guidance, and is now working on the T1D Outcomes Program (to define better value propositions for all stakeholders beyond A1c). Regarding glucagon, Dr. Kowalski remarked, “I’m not a glucagon skeptic, but a glucagon realist. It’s not as simple as you may think.” The frequently-used analogy, he elaborated, that an insulin-only artificial pancreas is like driving a car without brakes, is not appropriate – “when you drive a car, hopefully the brake works every time you press it.” An occluded glucagon infusion set could be deadly, and Dr. Kowalski argued that glucagon, if included, should only be used as a last-resort rescue. He was careful to point out that he isn’t opposed to the use of glucagon in closed loop devices, but that the health economics aren’t favorable at the moment (the marginal cost is currently greater than the marginal benefit over insulin-only). We look forward to more discussion and data on this topic, not just for glucagon but for other hormones like amylin. How much glycemic/user experience benefit does another hormone have to add relative to additional cost or complexity it brings to the system? How will payers reimburse for a multi-hormone closed-loop and weigh the glycemic and quality of life outcomes?
- During Q&A, Dr. Kowalski commented that type 2s should also use technology (especially CGM) whenever possible. Currently, providers are “dosing all kinds of drugs with no information,” and CGM and closed loop algorithms could drive much more informed treatment (particularly insulin titration). It’s an excellent point, and we see the entire field moving to give type 2s and PCPs more actionable glucose data through better product form factors/cost, clinical decision support, and even behavioral advice (Abbott’s FreeStyle Libre, Dexcom/Verily’s bandage-like CGM, Medtronic/ Qualcomm’s disposable professional CGM, Glooko’s basal insulin dosing system, WellDoc/LifeScan’s partnership, etc.).
- As a person with diabetes himself, Dr. Kowalski expressed right off the bat that it “really gets under [his] skin” to hear people say that people with diabetes aren’t “compliant.” This is a common occurrence, and we agree with Dr. Kowalski – it’s not as if some patients decide to be compliant and others blow diabetes off. Rather, we observe lots of reasons why patients may not be as engaged as others with diabetes: cost of therapy, side effects, real life getting in the way of diabetes, the invisibility of diabetes, the long-term nature of benefits vs. short-term hassles, feeling like a failure, data overwhelm, etc. The most game changing products will help address these issues, since these are likely to be patients running very high A1c’s.
Challenges in Diabetes Management
Challenges (and Opportunities) in Inroducing Closed-Loop Systems
Aaron Kowalski, PhD (JDRF, New York, NY)
In his final talk of the conference, the in-demand Dr. Aaron Kowalski spoke about key upcoming areas of focus in automated insulin delivery: expectation management, learning from CGM’s commercialization, reimbursement, and DIY innovation. To begin, he highlighted the short video shared by Dr. Jeremy Pettus and Dr. Steve Edelman at this year’s ADA – the humorous skit depicts the year 2026, in which closed loop technology has completely solved diabetes, forcing healthcare providers like Dr. Edelman to take up jobs at Starbucks and shutting down organizations like JDRF. This is not how Dr. Kowalski imagines it will work, as the challenges of artificial pancreas implementation will be vast and variable. First, as the technology nears the market, patients must understand that the artificial pancreas is not a cure – it will not restore euglycemia (because of the lag with subcutaneous sensing and insulin infusion). In addition, the systems will require two insertion sites, mealtime bolusing, infusion set and sensor changing, fingerstick calibrations (for now), and a working knowledge of how to manage diabetes in case the system fails. Will patients appreciate the early hassles? Dr. Kowalski wondered if CGM’s commercialization can provide some lessons. The discontinuation rate with early sensors was alarming (no pun intended) – for many patients, the added benefit of using the inaccurate early devices didn’t outweigh their cost and hassles. Dr. Kowalski asserted that healthcare providers should be prepared to hear similar grievances from early artificial pancreas users. [We assume, however, that first-gen AP systems will add more value than first-gen CGM devices, even in early adopters who only use them overnight.] He also touched on reimbursement (“our bugaboo”), expressing slight apprehension because of the lack of a large efficacy trial and appreciation for outcomes beyond A1c. Fortunately, a number of groups – Medtronic, UVA, Cambridge – will all be launching longer efficacy trials soon. Moving forward, Dr. Kowalski highlighted his “Diabetes Scorecard” (Diabetes Care 2015) to judge the value of artificial pancreas systems beyond A1c – scorekeepers are the people with diabetes (& loved ones), clinicians, and payers, and the categories are glycemic control, “burden”, and value.
- “I’m still a big believer in amylin” and JDRF is currently working on use of the hormone with “a number of companies.” Dr. Kowalski noted that pramlintide has not been wild success commercially – adding burden without a dramatic increase in glycemic control or quality of life. However, JDRF has been looking at single cartridge, co-secreted insulin+amylin, and so far, it seems promising for restoring physiology. This echoed Dr. Steve Russell’s comments at the NIH Workshop two weeks ago. Dr. Kowalski remains optimistic for the potential, particularly if insulin and amylin can be co-formulated. He did not discuss cost at length related to the combination.
- Dr. Kowalski asked “What if devices were less ‘medical’?” He pointed to DIY hacking solutions, such as bolusing from an Apple Watch (as we saw from Mark Wilson at the D-Data Exchange), as a great way to minimize the psychosocial burden of diabetes – patients may feel more comfortable managing glycemia from a non-medicalized device. The big unknown we’ve detected is whether industry will harness the innovation in the DIY community and incorporate it into commercial products.
- Dr. Kowalski’s comments on education and expectation management remind us of a poster presented at ADA last month, in which 42% of individuals at a workshop thought that the artificial pancreas was an organ grafting procedure. Worries about provider education were also a clear theme at the NIH AP Workshop two weeks ago. The field must clearly prepare and do a better job of educating those new to technology so they know exactly what to expect from automated insulin delivery. The term “artificial pancreas” is a bit confusing, and we assume many/all commercial products will steer away from it (e.g., MiniMed 670G “hybrid closed loop,” Animas “Hypoglycemia-Hyperglycemia Minimizer,” etc.).
- After the session, a diabetes nurse from Missouri approached Dr. Kowalski and asked him “Why can’t patients talk to their pumps?” What a great idea, particularly as voice recognition becomes more popular and widely used in consumer technology (Amazon Alexa, Apple’s Siri, etc.) A voice-responsive pump would certainly improve the quality of life of visually-impaired patients, and also eliminate pump interface hassle for those who have normal vision. Dr. Kowalski appreciated the suggestion, but had not heard of any companies working on this technology. As diabetes devices move to the smartphone, this seems like a logical foray for the user interface to expand to: “Hey Siri, how much insulin on board do I have?” What may be a challenge is the loftier, “Hey Siri, please give me a three-unit bolus.”
Dr. Satish Garg (Barbara Davis Center, Aurora, CO): Do we have any justification for a rise in the cost of insulin?
Dr. William Herman (University of Michigan, Ann Arbor, MI): Not that I’ve been able to figure out.
Dr. Garg: I don’t understand why our government isn’t able to negotiate the way Europe is.
Dr. Herman: Under Medicare Part D, the government cannot negotiate prices. There is a real lack of transparency surrounding insulin pricing. It’s not well understood and it’s unclear where the money is going, whether it’s to manufacturers, rebates, or something else.
Dr. Aaron Kowalski (JDRF, New York, NY): I’m going to play devil’s advocate a little bit. I remember the first time I went to my college pharmacy, the pharmacist charged me $15. I thought that was egregious! I threw my arms up and stormed out because of my outrage. But the counter-side to this debate, which I think is important, is the incredible cost of drug development. I’m impressed by my experience on Afrezza – there was $2 billion spent on that drug. The company is in dire trenches right now. We say we want better insulin (i.e. glucose-responsive insulin that lowers the risk of hypoglycemia), and that’s going to cost $2.5-$3 billion to bring to market. Drug development is hugely expensive and it’s a high-risk endeavor. I absolutely agree that we need more transparency, and I don’t understand why insulin costs so much, but I empathize with these companies because drug development costs are much too much. Is it the FDA causing drug development costs to be so high?
Dr. Herman: Why was insulin glargine introduced at $40/ vial, which presumably covered R&D, and then made more expensive (it’s now $300/ vial)? I’d also like to point out that the DCCT was done with animal insulin and with human insulin. There is a benefit to newer insulins, but at what cost?
Dr. Garg: The University of Colorado created a foundation that allows patients with type 1 or type 2 diabetes to get any sensor, pump, insulin, or drug they need for free. There is zero co-pay. For the past four years they’ve been coding this experiment, and on average they’re not spending more than $10 million/year. Next year will be the fifth, and we’re planning to analyze this data to answer one critical question: If you take away cost barriers, does it improve patient outcomes? The reason I bring this up is because in Britain as well as Europe, none of these things cost anything. Some of our patients who visit Euorpe, they walk in to a clinic there because they didn’t have enough insulin, and clinics just give them insulin and they’re shocked that it’s free. So I don’t understand.
Dr. Brian Frier (University of Edinburgh, UK): It’s not quite that simple. Patients don’t pay for any drugs in NHS, but the health authorities very carefully watch the budget. If they think drugs are too expensive, they move to strict restrictions on their use. Insulin degludec launched in the UK some time ago but uptake was low because of cost. Now in desperation, Novo Nordisk has dropped the cost by 30%.
Dr. Garg: Artificial pancreas will be available next year, but it is a big deal to start anybody on it. Even in our latest study, there was a lot of handholding. It’s not just something you just slap on. Many patients are confused about the lack of basal rates – there is so much education to do. I could go on and on, we have two pages of comments for Medtronic and the FDA to consider. It’s extremely important, and there needs to be some sort of artificial intelligence so it learns from the last six days how much patients have bolused, and then adjusts the basal/micro-boluses accordingly.
Dr. Kowalski: A number of the algorithms do adapt over time. Medtronic is a PID controller, which is more calculus-based. Other groups’ algorithms (Cambridge, UVA, bionic) do adapt and can get into activity, meal, and menstrual patterns, and get more sophisticated on a person-to-person basis.
Q: I was thinking about how my CGM and how little reaction it has to the tissue in my body, compared to the pump where you get inflammation, etc. when you leave it in. The main barrier seems to be the subcutaneous administration of insulin. Are any efforts being made to subvert the natural defenses so insulin can be infused in a more physiologic way?
Dr. Kowalski: This is a great question, and a high priority for us at JDRF. The challenge with the implantable is most people don’t want to do it. I know team from Roche is here, but most people don’t want a permanent implantation. So the question is, how small does it need to be for people to adopt it? On the counter side, we know that’s going to take some time, so we’re looking at what we can do right now to improve insulin infusion? Looking at ways to make catheters better, insulin that’s more reliable. I don’t know you’ll get same physiologic benefit as peritoneal delivery, but if we had better ways to infuse insulin right now we could maybe get there.
Dr. Frier: Why is the absorption of short-acting insulin delayed as pregnancy progresses?
Dr. Sarit Polsky (Barbara Davis Center, Aurora, CO): They weren’t able to sort it out in that study. There’s only one I’ve seen that actually looked at that, with closed loop. There’s a question about slight edema in peripheral tissue as pregnancy progresses, and of course increased risk for pre-eclampsia. t’s a great question. Thankfully, at this point, we have data to support that bolusing earlier can help.
Dr. Herman: Are there any issues related to altered GI motility during pregnancy? Earlier bolusing might cause hypoglycemia?
Dr. Polsky: I haven’t seen any data to support that. Early gestation women are hyper motile, later on as pregnancy progresses usually we don’t’ see that. Occasionally if someone has had more advanced diabetes complications going into pregnancy, maybe we’ll see that, but thankfully women tend to be on the lower end and that hasn’t happened.
Dr. Garg: I wonder if some of that has to do with hormones. As pregnancy advances, perhaps the counter-regulatory hormones go up? I agree with Dr. Polsky that some of it must have to do with changes to subcutaneous flow.
Q: We see quite a few women in our clinic with gestational and pre-existing diabetes. We treat our gestationals to targets that you mentioned, but for pre-existing diabetes we treat pre-prandial to <100 as opposed to <90. I’m curious about the difference between pre-prandial targets for gestational and pre-existing diabetes? Why the difference?
Dr. Polsky: There’s actually a lot of controversy in the pregnancy world about what those fasting and pre-prandial levels should be. It’s caused a lot of whiplash, to be honest. A HAPO study looked at different levels of glucose below hyperglycemia ranges and adverse events. What they could see is that 75 mg/dl is a reference range, any level of hyperglycemia above that you see an increased risk in adverse events (c-section, macrosomia, things like that). So the question was, what’s the threshold level, and there was none. There’s lots of groups working on this, international diabetes/pregnancy study group, WHO have their own ideas. We can argue about 90 vs. 100 mg/dl targets but they’re pretty similar for most people and pretty difficult to achieve for every meal regardless. So the question is how low can you go without significant hypoglycemia, and that’s what you should aim for.
Dr. Garg: On the EMPA-REG and LEADER studies – some people are overwhelmingly supporting the use of these drugs based on this data. But contrary to all, Dr. Herman presented that some of these advantages might actually be related to other risk factors. If you can just imagine that Dr. Ratner and Dr. Skyler were here – how would you refute this?
Dr. Herman: With great difficulty – they’re quite persuasive. But again, I don’t think it’s unlikely that a 0.5% reduction in A1c and other benefits could result in a 12-14% reduction in CV outcomes. The question is how easily could this be achieved by titrating the dose of ACE inhibitor or adding sulfonylureas to the existing regimen.
Dr. Garg: Are these CVOTs really needed? We’re adding billions of dollars and enrolling hundreds of thousands of patients in these trials. Some patients said at this conference last year that CVOTs are the best thing that ever happened, but others vehemently disagree.
Dr. Herman: A CVOT would be a useful trial if they signaled increased risk. It’s difficult to interpret a benefit without having equal control of multiple CV risk factors. I think there is going to be an advantage to medications that cause weight loss, improvement in glycemia, blood pressure, and other cardiovascular risk factors.
Dr. Frier: If I understand you correctly Bill, you’re saying that people in these trials were selected to have advanced CV disease, so while there was a tremendous benefit in these groups, if you try and apply the findings to the whole type 2 diabetes population the benefit is not going to be as profound. So we should be cautious about changing algorithms.
Dr. Herman: Absolutely. We have to apply these findings to patient populations included in these trials. But these results should not imply that for those failing metformin three years into the natural history of type 2 diabetes, adding one of these medications is going to have same result.
Dr. Frier: And when you add the economic assessment, it becomes even less compelling.
Comment: I used to work on designing CVOTs. You have to realize that companies are trying to make lemons into lemonade. In order for an NDA to be accepted based on 2008 FDA guidance, companies have to demonstrate the drug is no more than 1.3x more dangerous than placebo in terms of coronary adverse evens. They only have the time from the start of program to finishing efficacy studies, and they have people with a very high rate of CV outcomes who you’re least likely to demonstrate benefit in. CVOTs need 122 MACE events to demonstrate the necessary 1.8 hazard, then the post-approval commitment to demonstrate no more than 1.3 needs about 300 MACE events for that. To demonstrate superiority, or a hazard ratio <1, they need 600 MACE events. For the sponsors to demonstrate safety, they have to go to high-risk people, and then it’s hard to show efficacy. The fact that efficacy has been shown is very, very powerful.
Q: I believe there are biosimilar insulins (glargine) that have been or soon-to-be approved in other parts of the world. What has that done to the brand of glargine?
Dr. Herman: Biosimilars have been slow coming to market. Lutz Heinemann gave a very nice presentation on the limitations and lingering questions as to how similar they really are. The drop in price has been much less in price than one would hope or predict, especially after the experience with generic drugs.
Dr. Frier: It’s about 20-30% reduction in price.
Q: Certainly we need research, but how much actual scientific research is being done by Eli Lilly and Sanofi? How does their research budget actually compare to their marketing budget? Say Dexcom cut the price for CGM in half, but got more insurance companies to agree to cover it. Would that improve things?
Dr. Kowalski: I’m sure marketing budgets are massive, but I know for a fact that research budgets are just huge. Full disclosure: JDRF has partnered with Sanofi and Lilly on glucose-responsive insulin and they’re spending a tremendous amount of dollars on next-generation insulin. You get this tunneling effect into phase 3 costs. My experience with the big three insulin manufacturers is that they’re spending a ton on research. Pricing of sensors is an economics question that I can’t profess to understand. Our JDRF philosophy is that competition can help drive some of this. You could say competition hasn’t worked for insulin, but I hope at some point that it can help.
Dr. Herman: I don’t have a real answer to your question, although I must say I’ve been quite amazed that the cost of U500 human insulin is up to almost $2000/vial.
Corporate Symposium: Prepare for Closed-Loop Technology (Sponsored by Medtronic)
Practical Tools and Applications
Francine Kaufman, MD (Medtronic Diabetes, Northridge, CA)
Dr. Francine Kaufman’s pre-recorded address provided an overview of the evolution of Medtronic’s artificial pancreas technology, with many notable updates on the FDA-submitted MiniMed 670G/Enlite 3 hybrid closed loop. She couldn’t be in Keystone in person this morning because the FDA is currently auditing the company’s pivotal 670G trial (presented at ADA) – a necessary step on the road to approval, and great to see this is happening so rapidly just two weeks post-submission. Timing-wise, she expressed her belief in Q&A that approval should come before ADA 2017, consistent with Medtronic’s plan to launch the 670G by April 2017 (Editor's note: Dr. Fran Kaufman has informed us that she meant to say she can guarantee only that Medtronic will do everything it can to allow their hybrid closed loop to be approved by next summer). She expects minimal lag between approval and launch, and hopes for minimal time between approval and reimbursement – we look forward to seeing how this plays out, particularly how quick payer uptake is, whether the 670G is priced similar to current pump+CGM, and if users will be able to upgrade. Dr. Kaufman noted an ongoing pediatric study is testing the 670G in 7-14 year olds, expanding the indication from the pivotal presented at ADA in 14-75 year olds. The company also just finished 670G feasibility studies in the 2-6-year-old population, and it sounded like discussions are ongoing with the FDA to determine what ages will be considered for approval – a pediatric indication right out of the gate would provide Medtronic with a further leg up on the field. Dr. Kaufman highlighted the positive results from the single-arm, three-month MiniMed 670G pivotal trial (n=124) presented last month: a mean A1c reduction of 0.5% from a low 7.4% baseline; time <70 mg/dl declined 44% (6% to 3%); time <50 mg/dl declined 40% (1% to 0.6%); and a nice tightening of glucose values, particularly overnight and in adolescents. One of the pivotal study participants still on the system was present and commented during Q&A how incredible it is to be able to wake up in range and feel great every morning. Dr. Kaufman also noted that 670G pivotal participants “really ate a lot...pancakes inside waffles, covered with syrup,” and this could explain the slight weight gain (+3 lbs in adults and +2 lbs in adolescents) observed in the study. We look forward to further analysis, since it’s always hard to know how much pivotal trials reflect real world use (either over- or under-reporting the efficacy).
- Following the DreaMed algorithm integration (to give automatic correction boluses), the future of Medtronic’s closed loop is about individualization and adaptation via the IBM Watson partnership. Dr. Kaufman noted that Bluetooth-enabled pumps that send data to the cloud will be critical in this respect. Medtronic’s pre-ADA Analyst Meeting highlighted a next-gen closed-loop product after the 670G that appeared to be a smaller touchscreen pump with smartphone control (!) and “biometric,” “multi-parameter” sensing. Launch was expected after May 2020. We’re not sure if interim products will launch between the next-gen MiniMed 690G and this product.
- As a reminder, the immediate post-670G product, the MiniMed 690G, will add the DreaMed algorithm. We learned last week that it is completing an initial camp study in July. This product will integrate the MD-Logic algorithm to close the loop further – instead of only increasing basal insulin to gradually mitigate highs (670G) and bring blood glucose back to target, the next-gen algorithm will add automatic bolusing to correct highs. That should further improve time-in-range and make the system more aggressive with missed meal boluses.
- Medtronic will present data from a pivotal trial of PLGM (MiniMed 640G) at EASD – we assume this is from the US (before Medtronic moved ahead with the 670G instead), but aren’t positive. “PLGM not only reduces but prevents hypoglycemia by stopping insulin before the threshold is reached,” said Dr. Kaufman, “And with the artificial pancreas, we hope to make hypoglycemia negligible.” Of course, lots of hypoglycemia stems from highs, something the MiniMed 670G and future products will help address.
Questions and Answers
Dr. Grafton Reeves (Nemours Alfred I. DuPont Hospital for Children,
Wilmington, DE): Can you please comment on the advantages/disadvantages of having glucagon as part of the artificial pancreas? And have you used the present iteration of artificial pancreas in children under 11?
A: I’ll start with the second question. We have an ongoing pediatric study with 7-14 year olds. It will be the same as the pivotal trial that we presented at ADA with the 14-75 year olds. We also just finished some feasibility studies in the 2-6-year-old population, and we will be doing a deep dive in that population. I can tell you that the system appears safe and to have the same benefits in that age. If that turns out well, then we’ll ask FDA to include that population. Whether ages 2-75 or 6-75, we’ll know soon.
For your second question, for the hybrid closed loop, the evidence isn’t really compelling that we need a second agent or hormone. And if we do need a second agent, I’m not convinced it should be glucagon. Why not pramlintide, GLP-1, or SGLT-2? It looks like we can protect against hypo pretty well with just insulin – just look at data from Roman Hovorka and Claudio Cobelli. Glucagon adds a lot of complexity and cost to the system, and I don’t think we’ll need it, a least for this first generation of hybrid systems. We also need to consider that we don’t know the long-term risk of chronic glucagon use. But do we need it to get to full closed loop? Maybe – but if we were to add another agent, maybe it wouldn’t be glucagon, some other agent. If we got ultra rapid acting insulin, which seems likely, that might help us enough, save some minutes. We could maybe get to a point where meals don’t have to be announced. There are a other hormones secreted by the islet, other agents that help control glucose, why only focus on glucagon?
Q: In your experience, how long will it take to get this product to market?
A: If I knew the answer, that’d mean I could see the future. I’d leave medicine and go into the stock market. As I can tell, the FDA is incredibly collaborative, helpful and there 24/7 checking all the boxes, and everybody is working really hard to make this happen. I can probably guarantee that it will be before the next ADA meeting (Editor's note: Dr. Fran Kaufman has informed us that she meant to say she can guarantee only that Medtronic will do everything it can to allow their hybrid closed loop to be approved by next summer). All I can tell you is that everyone is working to get this done in a safe, rational, reasonable manner in the proximal future.
Mr. Jason Gessler (Barbara Davis Medical Center, Aurora, CO): I’ve been wearing the 670G for 11 months, my A1c has gone from 8.1 to 6.8, and the system has only kicked me out of closed loop one time. I don’t ever worry about going low, and I always wake up feeling great. I don’t believe glucagon will ever be necessary. Do you see, in future iterations, ways to put in information for proteins and fats, not only carbohydrates? And I’m struggling with the idea that we can’t project artificial pancreas information into cloud – are you considering that for future models?
A: Second question first: Absolutely. We have engineers working on a Bluetooth system. Artificial pancreas connectivity is a little more complex, because there are multiple devices talking (sensor, pump, meter) – it’s not just one connection to the cloud. We do hope to get that all done really soon. I can’t exactly say when because of partners and all that, but our intention is to have it as soon as possible. We can’t envision going much further forward without that – our plan to individualize/personalize is to leverage the partnership with IBM Watson, which can’t be done without cloud connectivity. Watson is the smartest individual anyone has ever met, and real time analytics will be huge, maybe not for the next product, but certainly the one after that. And the next iteration will just have a few changes to user interface without changing the algorithm. Of course, we’re working with DreaMed for the next iteration by adding Fuzzy Logic to our algorithm to enhance meal-handling. The goal is that you won’t have to announce anything about meals – so we may be able to update what you can put in about meal composition, but eventually you won’t have to worry about that at all. As we go forward, we’re going to focus as much as possible on user feedback. We want to be more patient-focused – we have a Chief Patient Officer now – we want feedback on user interface and whatever else the patient wants, as opposed to what we, including our engineers, think people want.
Ms. Rebecca Dennison (Geckle Diabetes and Nutrition Center, Baltimore, MD): I’m curious about your definition of and take on a simple vs. complex carbohydrate breakfast.
A: Simple carbs are tough, even if you pre-bolus. Even people without diabetes respond to simple carbs with increased glucose levels. The other day, I was sitting on a plane and had time to kill, and I was wearing four sensors, so I decided to do an oral glucose tolerance test, using juice – which I always say you should only use if you have a prescription. A lot of juice brought me up to 200 mg/dl! But then I tried complex carbs, which brought me to about 150 mg/dl. The time to normal was longer, but the area under the curve was much less. This gets to the philosophy that most of us should avoid simple carbs unless if we need to recover from hypoglycemia. I try to have my patients remove simple carbs from breakfast and eat more eggs, good fats, yolks, etc. And when eating carbs, to make them complex, particularly around breakfast.
Dr. Glenn Smith (Aurora Two Rivers Clinic, Two Rivers, WI): Agreed, I tell my patients that juice is a dessert, and that they need to treat it that way. With the 670G pivotal trial, A1c went down, but insulin and weight went up. Are you at all concerned about the increase in weight? Would you attribute that to use of more insulin, consumption of more carbs, or what?
A: We’re looking at that in-depth now, but they really ate a lot – there was a significant increase in caloric intake, as measured by carbs entries in the pump in the open loop and closed loop periods. I think that’s driving the need for excess insulin and the increased weight for the most part. They really ate whatever they wanted – pancakes inside waffles, covered with syrup. We also can consider that some of the insulin increase could be from those who were undertreated before the study, and some of weight gain could be because teens naturally gain weight. Our deep dive will help us understand this.
A few parting thoughts: The goal should never be lost that the ultimate end-game is a cure. This is part of that evolution, not a cure, but a better way to treat. We need to support all efforts towards replacing beta cells. That’s one, number two: we’re privileged to be in the developed world, but we can’t forget about all of the people struggling in the developing world – in Haiti, they still use premixed insulin and are limited to two strips a day. The privilege we have needs to extend to those who don’t have it. Beyond that, this is a truly exciting time, we’ve come a really long way and still have some distance to go.
CareLink Pro Therapy Management Software/A Method for Interpreting CGM Data
Kim Larson (Medtronic Diabetes, Jackson, WY)
Ms. Kim Larson showed attendees how to get the most out of Medtronic’s CareLink in little time by using three of the offered reports: the therapy management dashboard, sensor and meter overview, and device settings reports (see samples of all three below). There are nine reports available in total, which can be overwhelming, so this interactive crash-course on navigating the software efficiently was highly appreciated by the providers in the room. The quick methodology to analyze data from the three reports is called “AIM”, meaning assess, identify, and make changes – see the process below. Though not discussed in this talk, we’re looking forward to the launch this summer of Medtronic’s next-gen CareLink Pro reports (shown at ADA), which will help providers optimize pump settings. CareLink will suggest the time of day and direction certain pump settings should change (insulin:carb ratio, insulin sensitivity factor, basal rate – e.g., Increase basal rate from 8am – 12pm. These won’t give exact recommendations like DreaMed/Glooko’s planned system (“change basal rate to 0.75 u/hr from 8am-12 pm”), but will be a clear improvement over the status quo! Clinical decision support has massive potential to drive bigger therapeutic change, and we wonder who which data management platform will nail this in the coming years.
- Providers should begin by looking at the CareLink therapy management dashboard. Here, they can assess from the sensor section the overall control, amount of variability, hypoglycemia, hyperglycemia, and possible glycemic patterns. From the pump section, they can assess the basal rate profile, insulin sensitivity, insulin to carb ratio, active insulin time, and residual/active bolus insulin. At this point, the provider can make an overall basic assessment of the patient’s control regimen.
- Next, providers can assess control during specific periods of interest (i.e. post-prandial) at the bottom of the page, and then scrutinize the statistics panel on the right side of the page to determine how the patient has been using the pump and sensor.
- In the final step of the assessment phase, providers should open the sensor and meter overview report, a graphic that “kind of looks like and EKG” and depicts continuous daily insulin and pump activity, along with carbohydrate input and exercise. On this page, providers can begin to identify issues and their causes – they should look at settings to make sure they are set appropriately. For example, one can tell if the basal rate is appropriate by looking at times when a patient hasn’t bolused, eaten, or exercised for three to four hours.
- After confirming that the detected issues are not anomalies, the provider can go to the device settings report, zero in on one to two aspects to change, and make a follow-up plan
Corporate Symposium: Transition of Care from Adolescence to Adulthood (Sponsored by Insulet)
Addressing the Challenges of Patients, Families, and Providers
Desmond Schatz, MD (University of Florida, Gainesville, FL)
Dr. Desmond Schatz covered the difficult area of care transitions and shared valuable insight on the biggest challenge providers may face with the artificial pancreas: understand context. On the latter, he noted, “Never send me your blood sugar – send me your thoughts on a blood sugar. I find that the biggest problem with AP is the advising – we providers don’t know what a given blood sugar means. Did you just have an argument with mom? Do you play volleyball? Are you a starter or do you come off the bench? We can’t tell. Was it a practice or a game? Because the body responds differently in all of these scenarios. What did you eat? When? The biggest challenge for a provider will be learning the trends of the patient and learning how to advise accordingly without constant patient input.” Good points, and a reminder that the artificial pancreas will fundamentally change what providers do for people with type 1 diabetes – less about insulin changes and more about behavioral context, stress, etc. Most of Dr. Schatz’s talk focused on the keys to a successful adolescent to adult transition, the ‘Three Cs’: “collaborate, communicate, and cooperate, and as a healthcare professional, spend time with patients, colleagues, and families.” These guidelines may seem intuitive, but patients often don’t receive the support that they need, noted Dr. Schatz. Even as attendees were picking at their salads before Dr. Schatz took the podium, we overheard one type 1 in his mid-30s casually mention that he didn’t have any gradual “transition” – he went from no responsibilities until he was 18 to being 100% in charge of his diabetes immediately. And that kind of care is reflected in the concerning data on transitions: Garvey et al. (2012, Diabetes Care) found that transitions yield significant gaps in care, with one in four patients not referred to adult providers and 35% of patients experiencing >6 months without a provider. A separate study reported that patients transferred to a new physician are four times as likely to be hospitalized after transition than those who stayed with the same physician (Nakhla et al., 2009, Pediatrics). Dr. Schatz also referenced a valuable piece co-authored by Drs. Anne Peters and Lori Laffel on diabetes care for emerging adults. We thought the Q&A after this talk was particularly insightful, with several opinions on the challenges and benefits of disclosing “I have diabetes.”
- Dr. Schatz reiterated his ADA Presidential Address message about bringing diabetes to 212 degrees (the boiling point of water), pushing for a sense of urgency from the community as a whole to bring diabetes issues to the forefront and improve patients’ lives. In this case, that means educating families and providers on how to best implement the “Three Cs”.
- Dr. Schatz referenced a valuable piece co-authored by Drs. Anne Peters and Lori Laffel, which provided the following recommendations for diabetes care for emerging adults: (i) Focus on “having a life” rather than on “having an illness or disability”; (ii) always emphasize the multi-disciplinary team approach – that the patient can’t do it alone; (iii) involve the child in decision-making at an early age; (iv) start the provider transition process as early as possible – absolutely critical; (v) work with the patient and family to create a plan; (vi) identify “champion” adult healthcare teams interested in working with young adults; and (vii) individualize time of transition. In addition, Dr. Schatz recommended looking into NDEP, ADA and other online resources to assist with the transition and advocated for a standardized transitional clinical summary page to make adult providers’ role in easing the transition much more manageable. Dr. Schatz emphasized that, for inexperienced parents and providers, helping adolescents is a challenge, as they are facing constant social pressure, many turning points (graduations, beginning college/career), discomfort with a new adult physician, and other obstacles.
- During the Q&A session, the group agreed that patients benefit from disclosing that they have diabetes, even if it can be difficult. Diabetes is an invisible disease, so patients often have the power to determine who they want to tell about it and when. Disclosing that they have diabetes expands patients’ support networks if they are ever in trouble. Equally important, if patients are taught to talk about and not be ashamed of their diabetes from a young age, stigma is automatically reduced. Dr. Brigitte Frohnert from the Barbara Davis Center suggested that there may be a connection between parents’ willingness to talk about the impact of diabetes and their child’s willingness to talk about it. She proposed a model of early intervention to encourage parents to share more. Dr. Schatz liked this idea and hoped that a study can be done to see if it works.
Questions and Answers
Dr. Brigitte Frohnert (Barbara Davis Medical Center, Aurora, CO): A lot of kids this age come across job problems – they are working at a fast food restaurant, have access to sub-ideal food choices, and are not telling their bosses or coworkers about their diabetes. Are there resources about how to talk to a boss?
A: Yes, it all comes down to communication. Some people don’t want to tell their boss. Why? One, they don’t want them to know, or second, they don’t want to get fired. Take truck drivers – until recently, if they had horribly controlled type 2 diabetes, they could legally drive a truck, even if they were nearly blind. But now, as soon as they go on insulin, they can’t drive. It’s difficult. Does anyone have any solutions?
Q: I’m always worried that kids won’t tell their peers about the disease and I feel strongly that we need to get psychologists involved. You have to tell people around you so that they can save you. Kids often say “I don’t want my friends to know”. Well they will when they’re carrying you because you’ve fainted.
A: I agree – this disease is invisible. Invisible to patients, healthcare providers, to the governments and people who aren’t paying much attention. We have to confront it, expose it. I believe that it is partly through kids who unashamedly say that they have diabetes that change can happen.
Q: I work in Kansas City, Missouri. Neither Kansas not Missouri has expanded Medicaid, so now, kids lose insurance when they turn 19. So now there’s a huge disparity between those kids and those who have traditional insurance. Is ADA lobbying to try to help these kids get insurance?
A: Putting on a different hat here. We are very aware of rising healthcare expenditures and what it means for patients with diabetes. We are tackling the main problem: the huge cost of analog insulin. The cost used to be under $30, now its $300-400 for same volume, same technology. With throughput, it now takes even less to manufacture. And it’s not just the industry’s problem – it’s insurance, it’s the PBMs (pharmacy benefit managers), hospital, healthcare professionals…that’s the trickle-down effect. ADA is grappling with how to deal with the rising cost of insulin, but also other things. Here’s another challenge: a few years ago, Medicare went to competitive bidding – reduce the cost of strips by allowing companies to bid. This move was not bad in intent, which was to reduce overall costs and co-pay, but education was lacking and suddenly patients couldn’t get strips because they and providers didn’t know how to get them. Many of the families just quit doing it. There’s a paper in Diabetes Care that looks at competitive bidding that basically says that it’s great that we make changes, but need to educate. But yes, rising cost of healthcare in diabetes is major focus for ADA – something that, I believe, will need to change at the Washington level before we see significant improvements. Every one of you in the audience needs to be involved –it’s not just the ADA, not just me, not just you – it’s all of us.
Q: I (a type 1 patient) got fired from a job and they made up the excuse that I stole something. Too many people said I took too many breaks. Meanwhile my blood sugar was all over the place and I wasn’t feeling great, so I was taking breaks to check my blood sugar. I annihilated them in court, but I learned that it was my fault for not educating everyone at work and not telling my employer. It sucked, but at my next job, I told my boss right away, and you wouldn’t believe the difference it made – they treated me completely different. A lot of kids don’t want to put it out there because it’s an invisible disease, but it stinks if you don’t confront it.
Ms. Frohnert: The issue of disclosure is something we should really tackle. I wonder if there might be a connection between the way parents disclose diabetes and the way kids disclose diabetes. Maybe we should consider interfering earlier with parents and having them share more with people about the tremendous impact diabetes has had on their lives. I mean, some couples haven’t been on a date in years because they are the only ones who can manage their child’s glucose. That might be helpful.
A: Great question, it’d be a good study to do.
Q: I’m a diabetes nurse educator, and I’ve had diabetes for years. As an educator, I love telling people that I’ve had a good life, I’ve had children, etc... My parents told us, myself and my sister who also has diabetes, that we can’t be ashamed of something we have. My dad would always help us find really cool jobs growing up. But every time, in order for me to interview, my dad would require me to tell the employers right up front that I have diabetes. When I educate patients, I try to make it something that they’re not ashamed of.
A: Thanks for sharing. There are many people who are outgoing, will share with anyone – others are much more personal. For example, I have a colleague from ADA. I asked why he wouldn’t talk about it with other people, he said it’s none of their business. Each person has different preferences.
Comment: Right at diagnosis, I ask my patients “have you told your friends?” These are five year olds, seven year olds – we know right off the bat that we will have to work with them closely if the parents step in and say “oh no, we’re not talking about it with people.”
Corporate Symposium: Partnering to Improve Patient Care: A Technological Evolution in Insulin Delivery (sponsored by J&J)
Predictive Insulin Delivery Devices: Roadmap and Algorithms
Ramachandra G. Naik, MD (J&J, Wayne, PA)
Dr. Ramachandra Naik shared the most detail ever on the planned pivotal study design for J&J’s automated insulin delivery device (a hypoglycemia-hyperglycemia minimizer) with Dexcom’s G5 CGM. Dr. Naik confirmed that the trial will begin in the fourth quarter of this year, will test the device in 200 adults, adolescents, and pediatrics down to two years-old (though children will only be enrolled once it has proven to be safe). The study will include a several-day in-clinic assessment, followed by a three-month home portion, and will take place at 25-30 centers in the US. A post-approval commitment will be necessary, though no details were shared. Animas confirmed with us that, like Medtronic’s MiniMed 670G pivotal study, this will be a single-arm trial. The inclusion of pediatrics in Animas’ pivotal is particularly notable, as the 670G pivotal only went down to age 14 years; Medtronic has already started pediatric studies, but it’s unclear if these will be included in the FDA label out of the gate. These study design details confirm that J&J is IN this field, and could potentially be second to market with a commercial hybrid closed loop system. The timing also confirms what we last heard from Chief Medical Officer Brian Levy at ADA and J&J’s May Medical Device Business Review, which both slated the pivotal to begin later this year. It’s good to see there is now FDA clarity on the path forward. J&J’s Medical Device Business Review called for a US launch of this AID system by November 2017, though J&J updated the expected launch timing at ADA to November 2017-May 2018.
- We haven’t heard many specifics on the Animas hypoglycemia-hyperglycemia minimizer algorithm, but like the MiniMed 670G, it will only modulate basal insulin delivery (not issue automatic correction boluses). Animas’ system will obviously monitor manual boluses and on-board insulin as it makes dosing decisions, and we assume it will work well overnight. Still, there are many questions: How will it initialize? Will the algorithm learn and adapt over time? How will it compare to the MiniMed 670G algorithm in terms of robustness to errors, glycemic target, level of overnight and daytime control, etc.? One comment in Q&A suggested users “must” take a fingerstick for mealtime boluses, as the label for CGM mandates, though we assume many patients will simply enter the CGM value into the bolus calculator. Animas will obviously be closely watching Thursday’s Advisory Committee to see if Dexcom’s G5 will be approved for dosing insulin. Presumably an update there could have implications for this product’s label.
Partnering for a Patient-Centric Approach to Innovation
Damon Tanton, MD (Florida Hospital, Orlando, FL)
Dr. Damon Tanton led a highly interactive session that encouraged attendees to consider diabetes technology from the perspective of patient, provider, family member, educator, and manufacturer. He began by telling the story of his chance encounter with boxer Evander Holyfield near a vending machine filled with cuff links – the important detail of the story, shockingly, has nothing to do with meeting the former boxing champion. Dr. Tanton saw the cuff links and wondered, “What would it be like to have insulin pumps in vending machines?” From a consumer perspective, the idea makes sense, but he pointed out that so much more goes into pump use than simply putting the device on and pressing start. The same goes for the artificial pancreas – even in five years when there are (hopefully) multiple systems on the market, patients and providers will still have to consider sensor changes, communication errors, battery changes, insulin refills, infusion set changes, and other issues. Dr. Tanton remarked that “the technology is here; we just don’t have the cohesion” – presumably, he meant the whole ecosystem surrounding the core devices, including psychosocial factors, usability, device interoperability, prescribing and training hassle, etc. We like this term “cohesion” and believe it could drive adoption more than any clinical or medical factor – Will the average PCP be able to prescribe automated insulin delivery? When will the technology be such a no-brainer than MDI+SMBG users start switching in droves? The progress in algorithms, sensors, and real-world clinical research has been tremendous in the past ten years, but human and patient factors must now be the focus of the field. We really enjoyed the audience responses to this session’s interactive questions – see below.
- In the interactive portion of the session, Dr. Tanton posed four discussion questions to the audience, yielding fascinating responses:
- 1. How would you want a device to interact with friends and family? Audience responses: We want patients, as well as family and friends, to be able to determine what data they get – they might not want all that data.
- 2. What is the role of a diabetes educator? Audience responses: (i) Assess patients’ knowledge and skillset; (ii) Teach families to use the product and empower them to manage child’s diabetes by making adjustments on their own; (iii) “I don’t want anything I prescribe to put more burden on the patient.”
- 3. What is the role of a healthcare provider? Audience responses: (i) Reading downloads and finding out patient’s compliance; (ii) Should be able to provide options to patients; (iii) Ensure patient is capable of learning, testing their own blood sugars, and complying with a regimen.
- 4. What is the role of the manufacturer? Audience responses: (i) Create a safe and reliable product; (ii) “Number one, access. Number two, safety.” (iii) Provide enough manpower in territories: “If you’re going to launch a great product, support us clinicians so we can use it effectively” [applause from audience]; (iv) Work with payers to ensure that products are covered so they can actually be prescribed.
Questions and Answers
Q: Can you give us an update on insulin patch product [OneTouch Via]?
Dr. Naik: So the product is already cleared by the FDA. We are currently doing a clinical outcomes trial. People on MDI tend to miss doses for a number of reasons; this lack of adherence can lead to poorer glycemic control. If they have insulin on demand, they can discreetly dose. We are testing whether or not adherence is better with it, and we hope to have results by early next year on our outcomes trial. We hope to have the product available in a limited manner by the end of this year, and then we will roll it out from there. That’s all I can say about the OneTouch Via. [Per J&J’s update at ADA, the OneTouch Via will launch in limited markets OUS in late 2016, with US launch to follow shortly thereafter.]
Q: How do closed loop insulin systems handle acute illness?
Dr. Naik: We don’t have any data to that effect, but the expectation is that it should work the way it works otherwise. We’re planning to do a CRC assessment. We will induce over- and under- insulinization (giving an extra dose, for example) and see whether the mechanism kicks in for all these extraneous circumstances. Once we’ve tested hypoglycemia, hyperglycemia, and these other extraneous circumstances, then there should be no concern for acute illnesses.
Q: I have no experience with pediatric diabetes patients, but do they require different algorithms for any reason?
Dr. Naik: We’ll test the pediatric population as well, but the algorithm should work the same way. After we show safety in adults, then we’ll move on to efficacy in lower age ranges.
Dr. Argento: All these algorithms learn. Illness is something people deal with all the time. Women on birth control are influencing their hormones every month, and the system should be able to compensate to a new normal. All of these algorithms are built to learn from recent experience.
Dr. Tanton: The same thing is true for Dexcom algorithms. That’s the measure of any good algorithm – it’ll be better on days three, four, and five than it was on days one and two.
Dr. Argento: The FDA requires a dedicated device right now, so forget about your iPhone. It’s a security reason, and some people don’t want their blood glucose controlled through their phone because their phone doesn’t always do what they want it to. [Editor’s Note: This is Dr. Argento’s person opinion, not Animas’ view. As we’ve followed this topic, the FDA has said very clearly that it is open to and excited about moving artificial pancreas devices to phones (see our NIH AP Workshop coverage); however, appropriate safety factors must be designed into the system. We assume the path to market for a dedicated medical device is easier, but it is not a requirement based on what we’ve heard from the Agency at recent meetings.]
Q: In these early devices, how is the pump going to be sensitive enough, or is it going to be too sensitive? What about varied activities, like rowing a boat for an hour?
Dr. Naik: The infusion set issue is real. Studies essentially use saline in healthy volunteers for short durations, so they’re probably not reflecting real world scenarios. We’re looking into innovations for infusion sets alongside our partners. It’s high-time – innovation has to come not only on a systems level, but at the infusion set level.
Dr. Argento: The effect of infusion sets is highly variable. For some people it just won’t work after day three. But the problem isn’t insurmountable. Most of my pump patients do pretty well. What we really need is a sensor that tells us when the set is out, not only when it’s occluded. At least then you’ll have the feedback about blood glucose as an alarm. It’s never going to be “plug it in and forget about it,” at least not for the foreseeable future.
Q: Will there be any more calibrations besides the two per day, as far as the Dexcom sensor goes, with these closed loop systems?
Dr. Naik: For our study, we’re using the Dexcom G5, for which one of the inclusion criteria is two fingersticks per day to calibrate. For closed loop to function well, the sensor must obviously function well. The fingerstick must also still be taken before meals to get mealtime bolus. In the future, we might be able to completely close the loop.
Dr. Argento: Longer term, Dexcom is working on factory calibration too. Also of note, there is an FDA hearing on Thursday on whether Dexcom can get direct dosing, which is what I and half of my patients do, because it works.
Dr. Tanton: One of the hardest talks to have with patients is that their meters are not the gold standard. The Dexcom G4 is probably more accurate than most meters, so if you’re using other CGMs that have higher MARDs, you’re probably actually introducing errors into system.
Dr. Argento: If fingersticks are done properly, they give you a midpoint of a range of possibilities (+/- 15%). The first thing you have to do with a new CGM user is go over fingerstick technique – I have dozens of examples of miscalibrations that led to pretty bad results. We put a lot of weight in fingersticks, but they can be all over the place, even when done well. There should be a system to reevaluate strips that come off the factory shelf – not only what the FDA approved. It’s not like they came down from Mt. Zion – they may be introducing highly deleterious variability into the system. [Editor’s note: Animas Chief Medical Officer Brian Levy emphasized to us that J&J has a rigorous post-market surveillance program to ensure strip accuracy and precision.]
Corporate Symposium: Practical Review of Real-Time Continuous Glucose Monitoring in Clinical Practice at the University of Colorado, Barbara Davis Center and the Future of Dexcom Technology (Sponsored by Dexcom)
Dexcom Technology 2016 & Beyond
Jake Leach (VP of R&D, Dexcom, San Diego, CA)
Dexcom VP of R&D Jake Leach shared several notable pipeline updates in his overview of Dexcom technology: (i) an enhanced G5 app will launch “as soon as possible,” adding backfill of up to three hours of missing data when the phone and transmitter are separated (e.g., when showering) and a mute switch override (e.g., to enable hearing the low alarm when the phone is on silent mode); (ii) the touchscreen receiver was submitted to FDA last month, on par with 1Q16 timing; (iii) an FDA submission of the Android G5 app is expected in the next month or two (making the previous “2016” launch expectation tight but doable); (iv) the Android G5 app will be compatible with Android Wear smartwatches; (v) the next-gen insertion system and 50% smaller transmitter will be filed with the FDA in the “next couple of months” (a 2016 launch was the previous goal, making this timing possible but also tight); (vi) the FDA has approved the IDE for the G6 pivotal trial, which will begin shortly (Dexcom’s largest study ever); and (vii) the Verily partnership is on pace to launch a first-gen product in 2018 (“within two years”). Mr. Leach briefly referred to Thursday’s Advisory Committee meeting on whether G5 should be approved for insulin dosing – though he avoided speculation on potential outcomes, he did comment that the device is extremely accurate and approved for this indication in Europe.
- Dexcom has never had this much going on, and many of these projects will be very meaningful for driving further adoption of CGM – lower cost (Verily), smaller on the body (new transmitter), less painful and intimidating to insert (new applicator), fewer calibrations and better accuracy and alerts (G6), more convenient to view data (Android), etc. Dexcom has blazed a strong trail of product improvements, and we’ll be psyched to see what form factor changes drive the biggest increase in CGM uptake.
Enhanced G5 app with additional features
When near phone after being separated, transmitter will automatically backload three hours of data to the G5 app; mute override on alarms when phone is on silent.
Will launch “as soon as possible”
Submitted to FDA last month, on par with 1Q16 timing
Android G5 app
Compatible with Android Wear smartwatches, available in phone lock screen (analogous to Apple Today view)
FDA submission expected in next month or two (1Q16 called for a launch later this year)
Next-gen insertion system, 50% smaller transmitter
Hoping for FDA submission in next couple months (Was previously expected to launch in 2016, though an update will come on the 2Q16 call)
New sensor and algorithm with 10-day wear, one calibration per day, insulin dosing claim, acetaminophen blocking, predictive alerts
IDE approved, pivotal study starting shortly. The largest Dexcom has ever conducted and including both pediatrics and adults.
Verily [Google Life Sciences] partnership
Simple, low-cost, disposable, 10-14 day sensor system the size of penny integrated into an advanced data analytics platform
On schedule: Goal to launch first product within 2 years, on par with 1Q16 estimate
Corporate Symposium: Two Ends of the Diabetes Spectrum (Sponsored by Medtronic)
from Artificial Pancreas Technology to Insulin Insecurity
Satish Garg (Barbara Davis Center, Aurora, CO)
Dr. Satish Garg announced, for the first time to our knowledge, his hope to publish results from the 670G pivotal trial extension phase by the end of 2016 (>1 year at-home use of the MiniMed 670G). This will be very scrutinized as a follow-up to the three-month results presented at ADA, and it will be interesting to see if the efficacy is sustained in the 80%+ of participants who continued on the device. To our knowledge, this is also the longest and largest group of patients that has continuously worn automated insulin delivery, representing ~99 years of patient exposure by our math (assuming 12 months per user and ~99 users in the extension phase). Many patients have told Dr. Garg that when they see the shield (indicating that the pump is in closed-loop mode), they feel safe – a cool reminder that user interface and icons can really drive psychological satisfaction with a device. A 64-year-old woman told him after the pivotal study “There’s no way I’m giving this back; I need to keep it. My husband travels to Phoenix all the time, I really need this.” She was the first of nearly 100 patients in the pivotal trial to write the FDA and ask for continued access. Dr. Garg expressed gratitude to the FDA and Medtronic (who is funding the extension arm) for allowing the study to continue, both for the sake of collecting data (during the FDA review – a big win!) and for the patients. Medtronic’s Dr. Fran Kaufman expressed high confidence yesterday in the speed of approval, noting, “I can probably guarantee that it will be before the next ADA meeting” – strong optimism from the usually cautious Dr. Kaufman. As a reminder, the MiniMed 670G was submitted to FDA at the end of June, and Medtronic’s pre-ADA Analyst Meeting maintained the expectation to launch in the US by April 2017.
Upcoming Trends in Diabetes Care
Justification for New Classification for Diabetes
Robert Ratner (ADA, Alexandria, VA)
Dr. Robert Ratner highlighted results from the ANDIS study that characterize the heterogeneity of type 2 diabetes in terms of five major subtypes: (i) LADA, (ii) severe insulin deficiency, (iii) severe insulin resistance, (iv) obese, and (v) older. Patient records for 10,785 newly-diagnosed Swedish patients with type 2 diabetes identified seven major characteristics were sufficient to categorize most patients into one of the subgroups: (i) age, (ii) BMI and waist circumference, (iii) A1c at diagnosis, (iv) liver fat, (v) obstructive sleep apnea, (vi) C-peptide levels, and (vii) presence of anti-GAD antibodies. Records from 5,107 Finnish patients with type 2 diabetes from the DIREVA registry confirmed the results. Patients with LADA are characterized by the presence of anti-GAD antibody and also tended to be younger, have low BMI and waist circumference, very high A1c at diagnosis, and low C-peptide levels. Patients categorized as severely insulin deficient tended to have similar characteristics to patients with LADA but did not have anti-GAD antibodies. Patients with severe insulin resistance were characterized by very high C-peptide levels and the presence of liver fat markers and tended to experience obstructive sleep apnea. These patients also tended to be younger, have a very high A1c at diagnosis, relatively lower BMIs, and higher waist circumference. Patients who fell under the obese subtype, on the other hand, tended to have a high BMI and waist circumference (as expected) high C-peptide levels, presence of liver fat markers and obstructive sleep apnea. These patients were often older and had an elevated but not extremely high A1c at diagnosis. Finally, patients in the older categorization were generally even older than those in the obese subtype, had an elevated BMI and waist circumference, had an elevated but not extremely high A1c at diagnosis, and high levels of C-peptide. These patients may or may not have liver fat or obstructive sleep apnea. We were very interested to hear these specifics; this is the most detail we’ve heard to date from Dr. Ratner on this fascinating topic and clearly, these subtype categorization could offer more accessible individualization of diabetes therapies. If these subtypes are validated and become more established, perhaps diabetes treatment algorithms will stratify their therapeutic recommendation by subtype. For instance, patients with severe insulin deficiency could initiate insulin therapy upon diagnosis while patients with severe insulin resistance might initiate a TZD. Currently, there is little practical guidance for the process of treatment individualization and we imagine the use of type 2 diabetes subtypes could help clinicians determine the right medication for the right patient earlier.
- In terms of prevalence, about 11% of type 2 diabetes patients fell under the category of LADA, about 20% of patients were severely insulin deficient, about 6% of patients were severely insulin resistant, about 20% of patients fell under the obese subtype, and 43% fell into the older category. Remarkably, this breakdown in prevalence in subtype persisted in the Finnish cohort as well. We’d be interested in seeing similar registry analyses for different regions and ethnic groups to determine if these ratios are conserved more broadly.
- Dr. Ratner eloquently outlined a new approach to understanding type 1 and type 2 diabetes pathophysiology, natural history, and prognosis in which a combination of genetic and environmental factors drive either beta cell destruction (in type 1) and beta cell dysfunction (in type 2). Dr. Ratner characterized diabetes – regardless of type 1 or type 2 – as a “fairly internally consistent disorder” and suggested one set of genetic and environmental conditions promote inflammation and autoimmunity, resulting in beta cell destruction and type 1 diabetes, while another set of genetic and environmental conditions drive inflammation and obesity, leading to beta cell dysfunction. In either case, the patient experiences hyperglycemia, some form of diabetes diagnosis, and potentially faces the same downstream complications. Dr. Ratner previously advanced a similar view of diabetes pathophysiology in his AACE 2016 “Meet the Professor” session, though he clarified in Q&A that nobody is suggesting that the categorizations of “type 1” or “type 2” diabetes be abandoned.
Promoting Diabetes Remission in Type 2 Diabetes
Hertzel Gerstein, MD (McMaster University, Hamilton, Ontario, Canada)
The most exciting part of day #1 of Keystone was when Dr. Hertzel Gerstein briefly introduced the ongoing Canadian REMIT trial of an aggressive short-term combination therapy regimen for type 2 diabetes designed to rapidly bring the patient into diabetes remission. REMIT (Remission Evaluation of Metabolic Interventions in Type 2 Diabetes) is an open-label, randomized, parallel design trial (n=100) that compares the effectiveness of an intensive 12-week course of metabolic rehabilitation therapy versus standard type 2 diabetes care after 24 weeks. The metabolic rehabilitation therapy consists of insulin glargine (Sanofi’s Lantus), DPP-4 inhibitor sitagliptin (Merck’s Januvia), metformin, and lifestyle modification. The primary endpoint for the study is the proportion of participants achieving drug-free diabetes remission (defined as A1c<6.5%) after 24 weeks. Secondary endpoints include proportion of patients achieving diabetes remission at 36 weeks and 64 weeks after randomization. According to ClinicalTrials.gov, the study is expected to complete in April 2017. Like others who advocate for an early combination approach, Dr. Gerstein distinguished his remission strategy apart from the current “treat to fail” paradigm, in which patients are prescribed a diabetes treatment regimen only to have it repeatedly intensified after their glucose levels inevitably rise. If the course of the disease could simply be arrested and set into remission, he believes type 2 diabetes patients would be spared the “lifelong, increasingly complex journey of failure and ever-increasing complexity and cost” they suffer under the current standard of care. We’ll be very interested in seeing how the REMIT trial results compare to the STAMPEDE trial for bariatric surgery, in which about one-fifth of patients continued to experience diabetes remission five years after the surgery – it would be a big win if a 12-week intensive medication regimen could produce similar or better results than invasive bariatric surgery. We love the idea of experimenting with patients taking insulin very early on, since then the barriers related to insulin injections that can arise later on (especially related to physician “insulin resistance”) are less likely to occur.
- Insulin glargine (Lantus) has previously shown promise in producing sustained glucose lowering in the ORIGIN trial and even diabetes remission in patients with newly-diagnosed type 2 diabetes, providing support for its inclusion in the REMIT combination approach. By comparison, Dr. Ralph DeFronzo has made a point of not using insulin in his own early, aggressive combination therapy approach. Dr. Ralph DeFronzo’s triple combination therapy (metformin, TZD pioglitazone, and GLP-1 agonist exenatide twice-daily [AZ’s Byetta]) approach in early-stage type 2 diabetes has also shown promise with impressive sustained A1c-lowering efficacy (mean A1c 5.8% in participants treated with triple therapy out to three years). However, patients on the “DeFronzo cocktail” experience a heavy medication burden of two injections and three pills every day, compared to Dr. Gerstein’s ambitious goal of independence from diabetes medications. It would be interesting to know which “sub-type” of patients in Dr. Ratner’s view would be most likely to succeed.
Lutz Heinemann, MD (Profil Institut, Neuss, Germany)
Dr. Lutz Heinemann critically discussed the value of biosimilar insulin for patients, clinicians, industry, and even payers. From a patient and clinician perspective, Dr. Heinemann suggest that the risk/benefit profile of switching patients from Lantus (insulin glargine) to a biosimilar insulin glargine is unclear if the patient is doing well on Lantus. Furthermore, he pointed out that switching between Lantus and a biosimilar could potentially confuse patients and lead to dosing or other errors. From an industry perspective, Dr. Heinemann highlighted the high initial investment needed to develop a biosimilar insulin with an uncertain payoff. Dr. Heinemann noted that the average development cost of a biosimilar is $200 million (varying from $40 million up to $375 million) and it’s difficult for companies to build the technical expertise, manufacturing capabilities, distribution channels, etc. required to bring a biosimilar to market. For comparison, he shared that generic drug development typically costs between $1 million to $4 million. In addition, he drew attention to the challenges presented by the complicated regulatory pathways in the US, EU, and other countries that are not harmonized. Notably, while acknowledging that some payers and healthcare systems might be enticed by the potential cost-savings associated with biosimilars, Dr. Heinemann suggested that the savings might be less than assumed and it’s unclear if biosimilars will help foster greater healthcare efficiency. For instance, he suggested that there may be additional costs associated with training people to use biosimilars and there might be risks involved in switching populations back and forth from originators and biosimilars as payers and countries renegotiate with the drug companies each year. Of course, there are potential risks that we won’t know how should be addressed early on – if at all. Biosimilars have often been positioned as a potential reprieve from rising insulin prices – though Lilly/BI’s biosimilar insulin glargine Abasaglar has been priced at only a 10%-20% discount relative to Lantus thus far – and we were very interested to hear Dr. Heinemann’s opinion.
- Dr. Heinemann presented a fairly critical view of biosimilar insulins overall, suggesting that the safety profile of biosimilars cannot be assured. Dr. Heinemann emphasized that biologic manufacturing is much more complex than small molecule manufacturing and the biosimilar manufacturing process involves many steps that can introduce differences between the biosimilar molecule and the originator biologic. Dr. Heinemann repeatedly emphasized that, as a result, biosimilar cannot be considered identical to the originator, despite similar clinical profiles. He pointed to data from analytical comparisons using reverse HPLC of three biosimilar insulin glargines against Sanofi’s Lantus (insulin glargine) indicating that the similar have a different analytical fingerprint than Lantus. While this may not affect A1c efficacy, Dr. Heinemann suggested that differences in manufacturing processes between biosimilars and orginators can lead to differences in immunogenicity. That said, Dr. Heinemann acknowledged that no clinical studies of biosimilar insulins thus far have identified an increase risk of neutralizing cross-reactive antibodies – the main concern associated with immunogenicity – and that studies monitoring this risk are ongoing. While there has not yet been extensive discussion from others on the profile overall of biosimilars, Dr. Heinemann’s presentation served as an important reminder of the nuances of biosimilars compared to the more familiar oral generics and that the use of biosimilars is relatively uncharted territory within the diabetes field. We await broader use – it also may be that the complexity is high but also is possible to address. To be sure, there is no question that biosimilar manufacturing is far more complicated than oral drug manufacturing – we would also love to know more about insulin manufacturing within the broader biosimilar world.
Q: I admit I’m not totally objective because I work for a company developing an SGLT-2 inhibitor. An FDA Advisory Committee on inhaled insulin suggested that the decrease in hypoglycemia may have been due to the insulin itself being less efficacious. The committee also noted an increase in DKA. Can you interpret?
Dr. Stephen Davis (University of Maryland, Baltimore, MD): No one is going to comment on the wisdom of the FDA. If you have short-acting insulin, I think that does open up the opportunity to control plasma glucose very nicely, but then as things progress during the day, glucose can increase. Your point is very well taken. It’s still very early on in this story.
Dr. Garg: If you really want to use inhaled insulin, you have to take it more often. It makes sense – the duration of action is only a few hours. But we did present a study about eight years ago showing that if you take two inhalations before a meal and two after a meal, you achieve a much better drop in A1c.
Dr. Davis: I absolutely agree.
Q: Dr. Ratner, where do you see the classification fitting in for antibody-negative type 1 diabetes, or what we’re now calling type 1b?
Dr. Ratner: Or is it what we call type 2 diabetes with significant insulin deficiency? Or is it antibody-negative only because we haven’t found the right antigen? We don’t understand enough about these diseases, and there are so many unknowns in this area. As we move forward, the increased classifications give us the opportunity to better understand pathophysiology and therapeutics. If we can more specifically identify responders and non-responders, we can guide their treatment more effectively.
Dr. Garg: Should you take into account Dr. Ratner’s hypothesis that there are these new ways to classify diabetes when identifying and stratifying patients who could be treated for diabetes remission?
Dr. Gerstein: There is not yet data to suggest which types of patients will go into diabetes remission. This is a new area! The most important thing is to collect data, and that’s what we’ve started to do in a few small trials. Who is the best person for such a study? You might say someone with newly-diagnosed diabetes, and we’re doing that. You might also argue that we need to study this in obese patients, which we are very interested in. Of course there will be responders and non-responders to the therapy. Again, it is a new area.
Q: Diabetes type 1.5 – is it real? If so, what is it, and should we care?
Dr. Ratner: When you characterize insulin deficiency vs. insulin resistance, the bottom line is that you can always overcome any degree of insulin resistance by giving enough insulin. If you look at DCCT, where participants were on intensive insulin therapy and experienced profound weight gain and became profoundly insulin-resistant, how would you categorize this? I would call it insulin resistance on top of type 1 diabetes. The other common understanding of type 1.5 are patients who phenotypically look like they have type 2 diabetes, but they need insulin. These are not patients who are purely insulin-resistant or who have the obesity- or age-related disease. Rather, what we’re talking about is a subset of type 2 diabetes that also presents with beta cell problems, some of which may be genetic. Most of the genes associated with diabetes are beta cell genes.
Dr. Gerstein: Somewhere around 10% of your patients with type 1 diabetes would have gotten type 2 if they didn’t get type 1. There are a lot of patients with type 1 diabetes who really have both, but their absence of insulin is what we’re primarily dealing with.
Q: Dr. Ratner, a lot of weight is being put on antibody measurement for diabetes diagnosis. This is often done on the basis of a single antibody, and the tests aren’t perfect. It is very limited. The simplest way around it is to measure antibodies more than once to confirm, but I don’t think this is currently the standard of care. We’ve observed in studies that have followed high-risk kids who have fluctuated between being positive and negative for these antibodies before coming down with type 1. Is it true that the expert committee is going to suggest that we forget about type 1 and type 2 diabetes and now have one diabetes with subtypes?
Dr. Ratner: No! There was never any truth at all to the suggestion that we were going to get rid of the differentiation between type 1 and type 2. In response to your previous comment, I’d like to point out that there is a difference between retrospective and prospective antibody analysis. We are currently trying to convince CMS, JDFR, ACE, and the Endocrine Society that the retrospective utilization of antibodies to distinguish type 1 and type 2 patients should be abolished. We are actively trying to get rid of this retrospective use of antibodies (applause). For the prospective use of antibodies, keep in mind that my talk was only 25 minutes long! The idea of coming up with thresholds is going to important, as is repetitive testing. How that ultimately feeds into a classification system remains to be seen.
Q: I’m confused because we’re discussing the distinguishing factors between type 1 diabetes and type 2 diabetes, but in the last talk on biosimilars this was presented as a complex situation. There are different properties. You can’t replace the origin of the duplicate. Where should I go with that? If it would be you to decide what kind of insulin to use in the future, what…
Dr. Heinemann: The reality is that you’re not selecting the insulin. It’s selected for you, by the Ministry of Health or some equivalent organization, simply for cost reasons. The people in these institutions are only interested in money, and so money will be the driving force affecting biosimilar insulins. This is definitely one of my main concerns, because it reduces regulation and evaluation of biosimilars in clinical contexts. If we don’t have careful evaluation of what’s going on, problems may arise that we aren’t able to detect. Biosimilar insulins are a hot topic and going forward, we will have to discuss the complex details surrounding their use.
This will be the driving force, and it’s also one of my concerns, because I believe regulatory processes are okay, but quality is something we have no good understanding of. The quality of the batches used for approval might be good; however, I’m concerned about what will happen in the long-term. By chance a French nephrologist had 3 patients who developed pure red cell aplasia and he was strong enough to report it. This final report made it into NEJM. If we don’t have careful evaluation of what’s going on, potentially we might not be able to detect it. I’m pretty sure that biosimilar insulins are a hot topic and we will have to discuss the complex details in the future over and over again.
Q: Dr. Gerstein, we always say that patients fail lifestyle modification, but what is it about lifestyle modification that will bring glucose levels toward normal? How are we supposed to outline this in terms of the actual benefits of lifestyle modification instead of just saying that “patients fail”?
Dr. Gerstein: I don’t think I said that patients fail. Treating diabetes is complicated, just like treating cancer is complicated. Not all treatments work for cancer, just like not all treatments are going to work for type 2 diabetes. We do know that things tend to get worse with time over the course of diabetes. We’ve never tried an algorithm that instead of chronic treatment tries to reverse the disease! And we won’t get there unless we try. When we see the large rates of diabetes remission with bariatric surgeries, it suggests that there is hope for remission therapies.
Comment: But how do we outline that? Is it 2 steps, or 20 million?
Dr. Gerstein: We don’t know the answer to that question. We do know that lifestyle modification will need to be a package of changes we make, never just one thing.
Immunology and Diabetes
Update on Autoimmunity of Type 1 Diabetes
Carla Greenbaum, MD (Benaroya Research Institute, Seattle, WA)
TrialNet Chair Dr. Carla Greenbaum (Benaroya Research Institute, Seattle, WA) shared that results from the preventive oral insulin trial will be presented at ADA 2017 in San Diego. The trial – eight years in the making according to Dr. Greenbaum – is investigating oral insulin’s potential to prevent or delay progression to type 1 diabetes in people with multiple autoantibodies but normal glycemia. Dr. Greenbaum previously shared in November 2015 that enrollment in the trial was nearing completion. According to ClinicalTrials.gov, the estimated enrollment of 400 participants is complete and the study is expected to complete in January 2017. We’ll certainly be looking forward to the results at ADA 2017 next year! Dr. Carla Greenbaum also briefly mentioned but provided no updates on TrialNet’s other ongoing preventive trials in type 1 diabetes: abatacept for people with multiple autoantibodies and normal glycemia and teplizumab for individuals with multiple autoantibodies and dysglycemia.
- Both ADA Chief Medical Officer Dr. Ratner and Dr. Greenbaum highlighted the value of staging type 1 diabetes in the development of preventive therapies. Under the staging system – developed at a JDRF/ADA workshop – individuals with multiple autoantibodies and normal glycemia are considered to have stage 1 type 1 diabetes, those with multiple autoantibodies and dysglycemia but no symptoms are considered to have stage 2, and those with symptomatic hyperglycemia are considered to have stage 3. Both Dr. Ratner and Dr. Greenbaum emphasized the preventive opportunity by recognizing and diagnosing early stages of type 1 diabetes, considering that 80%-85% of individuals with multiple antibodies will progress to symptomatic type 1 diabetes within 15 years and staging offers a formal point for earlier, pre-emptive intervention. Dr. Ratner suggested that type 1 diabetes therapies need to move beyond the framework of solely managing hyperglycemia and aim to actually address the natural history of the disease. Hear hear! Similarly, Dr. Greenbaum applauded advancements in closed-loop, but likened improvements in diabetes management tools to improvements in wheelchairs for children with rheumatoid arthritis and argued for the need for immunomodulatory therapies in type 1 diabetes to provide the same level of transformative impact they had in rheumatoid arthritis. Furthermore, both Dr. Ratner and Dr. Greenbaum emphasized the benefits of screening high-risk individuals for type 1 diabetes to lower the risk of the individual experiencing diagnosis due to hospitalization with diabetic ketoacidosis. As Dr. Ratner put it in a panel discussion: “The goal of defining type 1 diabetes is to make sure nobody presents with ketoacidosis.” This was music to the ears of so many patients who presented with type 1 and DKA “in the old days.”
Rationale for Combination Immunotherapy for Type 1 Diabetes
Jay Skyler, MD (University of Miami, Miami, FL)
Dr. Jay Skyler offered compelling commentary on the promise of combination immunotherapy for type 1 diabetes, a topic currently under investigation in his DIPIT trial. Despite abundant scientific evidence for type 1 diabetes as an immunologically-modulated disease, Dr. Skyler explained that the majority of studies examining the clinical efficacy of antigen-based or other immunomodulatory therapies have shown no or only transient effects. In his view, these therapies “bring in the infantry, but leave the artillery.” That is, beta cell destruction in type 1 diabetes occurs through multiple immune mechanisms, so targeting only one aspect of the immune response is not a very powerful approach. Dr. Skyler believes that the key is a combination of immune therapies, all operating via different mechanisms. Accordingly, his DIPIT (Diabetes Islet Preservation Immune Treatment) trial (n=42) is a randomized, double blind, placebo-controlled study which investigates the effectiveness of a blend of simultaneous immunotherapies at restoring insulin secretion (as measured by C-peptide area under the curve [AUC] four hours after a mixed-meal tolerance test) in early onset type 1 patients after one year. DIPIT’s combination therapy consists of Thymoglobulin (anti-thymocyte globulin, or ATG), Neulasta (pegylated GCSF), Proleukin (IL-2), Enbrel (etanercept), and AZ’s Bydureon (exenatide once-weekly), all of which are FDA approved and have already previously been studied in type 1 patients. The trial has a estimated primary completion date of January 2019 and an estimated final completion date of January 2021, according to ClinicalTrials.gov. This is going to be incredibly interesting to watch – we’ve heard for some time the value of combination therapy in early onset type 1 patients and we’re extremely keen to follow these results.
Autoimmune Co-morbidities in T1D
Marian Rewers, MD (Barbara Davis Center, Aurora, CO)
Davis Center Executive Director Dr. Marian Rewers recommended early screening in type 1 diabetes patients for antibodies associated with other autoimmune diseases. He noted that 30%-40% of patients with type 1 diabetes are affected by at least one additional autoimmune process and that there are at least 11 autoimmune diseases associated with type 1 diabetes, including hypothyroidism (2x higher risk for type 1 patients), Addison’s disease (750x higher risk for type 1 patients) and celiac disease (10x the risk). Interestingly, celiac disease, hypothyroidism, and Addison’s disease are linked to the same HLA DR-DQ haplotype as type 1 diabetes. Celiac disease is caused by maladaptive processing of gluten-containing grains and an autoimmune response, leading to GI problems, abnormal growth, and a number of other deleterious symptoms. Furthermore, it has also been suggested that A1c and overall glycemic control is poorer in patients who have both type 1 diabetes and celiac – this is bad news for the many (~3%; up to 6% for ages 5-9) type 1 patients who test “strongly positive” for the celiac-related autoantibodies. In 20%-40% of autoantibody-positive cases, the patient requires immediate treatment and effective treatment is easily available. With all of this in mind, Dr. Rewers strongly advocated for screening at type 1 diagnosis, and then biannually until the age of 10, or if the patient is symptomatic.
Dr. Ralph DeFronzo (University of Texas, San Antonio, TX): Dr. Skyler, in terms of your combination therapy approach, at what stage do you want to initiate this?
Dr. Skyler: From a practical standpoint, they need to have stage 3, clinical type 1 diabetes. That’s what I’m proposing in a five-year study.
Dr. DeFronzo: But there’s no turning back at that point. Why not start at an earlier stage?
Dr. Greenbaum: I used to think we should only study people who have clinically overt disease. But if you’re taking people at stage 1, and you’re preventing them from getting type 1 diabetes, that’s a huge and pretty obvious benefit for those individuals. The risk/benefit protocol is better prior to clinical diagnosis, although it all must be done in stepwise fashion.
Q: Is the thinking now, with respect to immunotherapy, that this is going to be a lifelong therapy? Are you changing some underlying immune surveillance or function so the therapy could be stopped? Or will it be lifelong?
Dr. Greenbaum: We’re excited about animal studies suggesting that one can induce tolerance, but that has not been seen in humans. But we can get smart. Like in so many other autoimmune diseases, we can treat with intermittent therapies in response to flare-ups. We are looking forward to the sequential therapeutic approach and studies with intermittent therapies from TrialNet.
Dr. Rewers: We have to be careful not to ‘bombard’ patients with a combination of 5 drugs that each showed no lasting effect on diabetes and has potentially severe adverse effects.
Dr. Skyler: I think it’s a matter of perspective. I gave a similar talk arguing in favor of combination therapy on two separate occasions: one group with immunologists and transplant surgeons in Geneva said that I’m not giving enough immunomodulation, but the next week at ATTD, many said “how dare you give any of that to patients?” You have to balance all these things. Marian, you’re a pediatrician, so you’re against it, but many in the room are for it.
Dr. Bellin: I’m a pediatrician too, and I see patients do very well on islet transplant. Not only with autoimmunity, but with alloimmunity too. It’s not risk-free. Rarely do we see patients who have minor side effects that have impacts on quality of life. As always, we have to balance benefits and risk.
Dr. Satish Garg (University of Colorado, Aurora, CO): Do we know the long-term safety of the drugs before we start exposing these young adults to it?
Dr. Greenbaum: We are not reckless people. This is, in a way, a mis-statement about risk. Think about it – insulin is a lethal drug with a narrow therapeutic window. I think we need to learn how to use these therapies judiciously and safely to attack the disease. Yes, we don’t understand the full aspects of the disease, but in medicine we use therapies every single day that are beneficial despite the fact that we don’t understand their mechanisms fully. It would be a mistake if we waited until we understood diabetes fully to develop new therapies.
Dr. Rewers: I’m more skeptical of immunotherapy. If you don’t do immunotherapy in leukemia the patient will die. In type 1 diabetes this is not the case, the patient will still live and in most cases do very well with our existing therapies.
Q: Dr. Bellin, may there be a role for GLP-1 agonists to preserve survival and function of islet cells during transplantation?
Dr. Bellin: GLP-1 agonists have been used in transplantation centers, but there hasn’t been a randomized trial looking at the effectiveness this. We tried testing DPP-4 inhibitors in a randomized population, but they were not effective. So there is potential for GLP-1 therapy and it is being explored at multiple centers.
Q: How much is the improved glycemic control that you’re seeing post-transplant mediated by beta cell vs alpha cell restoration?
Dr. Bellin: That’s a really interesting question. There are a couple of theories on that. We think that a large component is from the restoration of beta cell function, but studies on alpha cell function have been performed. Basically, we probably do see partial improvement in alpha function, but not a total rescue. One thing to point out is that patients do get back some symptom awareness – probably some component of that is counter-regulatory in nature.
Combination Therapy for Best Diabetes Outcomes
For Type 1 Diabetes
Desmond Schatz, MD (University of Florida, Gainesville, FL)
Dr. Desmond Schatz picked up right where he left off in his address at ADA, calling for more urgency in bringing diabetes to “212 degrees” and suggesting that one reason for our inertia is the heterogeneity of the condition, focusing particularly on type 1 diabetes. Not only does type 1 diabetes manifest distinctly in adults vs. children and in unique individuals, but the disease itself presents differently today than it did 20 years ago – “the changing face of type 1 diabetes” as Dr. Schatz put it. Only 67% of organ donors with type 1 diabetes aged 1-14 and 29% aged 15-36 present with insulitis today, compared to what used to be 100%. Patients positive for insulitis also have greater beta cell mass. Interpreting these findings, Dr. Schatz posed a contentious question: “Is it possible that insulitis is not destructive, but in fact, may be protective?” He shared type 1 diabetes incidence data from the TEDDY cohort to demonstrate a divergence in the first autoantibody that appears (41% GADA only, 39% insulin only, 13% both GADA and insulin autoantibodies) and asked, does a different “first” autoantibody suggest a different disease? Dr. Schatz urged the audience to confront questions like this as the heterogeneity of type 1 diabetes becomes too powerful to ignore. He made the case that acknowledging this heterogeneity would improve the way we understand, prevent, and treat type 1 diabetes, pushing us toward personalized medicine. Dr. Schatz warned that, while big data may lead us to the “coalescence of factors” that cause type 1 diabetes, healthcare providers must continue to approach each patient as a unique case in order to achieve the best possible outcomes in diabetes care. Dr. Schatz emphasis on the heterogeneity of the type 1 diabetes echoed Dr. Ratner’s presentation on the heterogeneity of type 2 diabetes on the first day of the conference – we hope that greater attention to this topic can lead to practical approaches for truly individualized and personalized medicine in both type 1 and type 2 diabetes.
Dr. Aaron Kowalski (JDRF, New York, NY): I’m fascinated by the elucidation of type 1 diabetes heterogeneity and the complex biochemistry underlying it – this seems to be a theme from these first two days. But I am concerned by lack of information we have about glycemia. Why the focus on A1c rather than variance in glycemic profiles? When we have the potential for continuous glucose monitoring, why are we driving drug treatments with such a limited picture of glycemia?
Dr. DeFronzo: I’m a big advocate of CGM. Excluding expense, everyone with type 1 diabetes should be doing CGM. I also recommend it for type 2 patients on insulin, although I think the data are less compelling for type 2 patients on exclusively oral agents which don’t cause hypoglycemia. Expense is a big problem which is holding things up. There are data on spikes in glucose throughout the day, but I don’t think any of this data suggests that these spikes affect micro or macrovascular complications in humans, though there is suggestive evidence that this may be important.
Dr. Kowalski: What I’m getting at is that we’re prescribing drugs to people on the basis of A1c – a three-month plus check in. We have the potential (though it’s only utilized by 11% of type 1 patients) to continuously measure glucose – the hallmark of diabetes. In addition to A1c, we should look at how different drugs affect time in range and daily glycemic patterns.
Q: For patients with type 2 diabetes, are you suggesting that triple therapy be initiated right away or at a later point?
Dr. DeFronzo: In newly-diagnosed patients, we start triple therapy at first visit. If I personally had type 2 diabetes, I would want to be on triple therapy from my time of diagnosis. I think the ADA has been a major impediment to moving forward. We would never do this in cancer chemotherapy, and yet in diabetes we still have not learned. There are just too many abnormalities in diabetes to expect one drug to take care of it all.
Dr. Ratner: There will be an FDA workshop on outcomes beyond A1c on August 29 in the Great Room at the FDA facility in Silver Spring. There will be the opportunity for 1,500 people to call in and participate. I would encourage you to participate if you truly believe – which you should – that there are meaningful outcomes beyond A1c.
Now, my response to Ralph: Data are clearly becoming to come in about combination therapy. We are very conscious of that. I suggest you turn to your immediate left and speak to the chair of our Professional Practice Committee (Dr. Cryer). Our job at the ADA is to make evidence-based recommendations. The evidence base right now really doesn’t support combination therapy. Yes, the hypothesis is very strong and new data are coming out. I wouldn’t be surprised at all if this evidence base changes in the near future.
Dr. DeFronzo: The evidence is very, very clear. If your A1c is <6.5, as I’ve shown you, you do not develop microvascular complications. If you keep A1c low, it’s reasonable to expect that you won’t develop macrovascular complications. The problem is that the ADA is in an archaic mode, and you’re not going to see the results you say you need unless the NIH or someone else funds it. I can give you a study that shows the science behind it though. If you don’t believe that maintaining A1c below 6.5-7 prevents microvascular complications, you shouldn’t be in diabetes.
Dr. Ratner: In fact, we do have those standards, and we recommend initial combination therapy in patients who present with an A1c >9. In that case, the data definitely suggests that you need to initially go to combination therapy.
Q: In all the long-term studies on weight loss, you almost always see weight re-gain. The biology is becoming more clear – we have homeostatic mechanisms in place that return you to a set point weight. At what point do you believe that pharmacologic or even surgical therapy should be instituted?
Dr. Herman: Your points are well-taken, and we’re beginning to address these issues. Pharmacotherapy for weight loss maintenance may make more sense than pharmacotherapy for weight loss. The ADA has also changed its position on bariatric surgery, recommending that it be considered as a treatment option at lower BMI thresholds.
Q: Independent of very important evidence-based guidance, in the real world if we don’t have patients enrolled in clinical trials, what insurance out there will let us prescribe combination therapy out of the gate for type 2 diabetes?
Dr. DeFronzo: Metformin is very cheap. A GLP-1 agonist outside the context of a government program requires a co-pay of $25/month, which is expensive for some but affordable for others. Tomorrow I’m going to show you the most remarkable data in the world on GLP-1 agonists. To me, this combination therapy is really quite effective.
Comment: And cost-effective?
Dr. DeFronzo: That’s a study that should be undertaken by the NIH. I can’t tell you the answer to that. We really need to get an answer in terms of long-term outcomes and complications.
Dr. Satish Garg (University of Colorado, Aurora, CO): What is the FDA doing to promote standardization of CGM reports? As you know, most of the devices on the market have their own type of display, and most physicians are confused by how to download the data. Shouldn’t there be a mandate for some standardization to this meter and the download reports?
Dr. Courtney Harper Lias (FDA, Silver Spring, MD): We spoke about a standardized report that could be easily downloaded. I first want to say that the needle has moved with respect to technology companies and their attentiveness to this issue. Companies are focused less on unique displays as being something that will drive people to their product and are shifting perspective to realize that it is user friendly for physicians as well as patients. We can try to use our bully pulpit to push toward things in the market that will add value. We want to make these communication protocols a priority, and by consequence hopefully the pyramid of development will move toward the best type of display. Will we mandate standardization? Probably not, but we want to help.
Q: Since government agencies may have a little more say in making payers pay for these new devices, technology, and treatment options, are there any incentives or things being done by regulators to help in that?
Dr. Harper Lias: I think you overestimate our say in coverage decisions. We develop relationships with CMS and talk to them about things, including CGM. They’re feeling the heat, I will say that. We’ll do what we can, but we don’t have the ability to convince CMS toward certain coverage decisions. At conferences like this, I almost never see payers engaged in conversation and learning. Efforts need to be made in the healthcare community to engage the payers and help them understand why it should be a priority to be at meetings like this, because if they don’t care about these issues they’re not going to understand our arguments.
Dr. Cryer: That strikes me as a really good idea.
Comment: We all know that anybody can out-eat any anti-diabetic medication. So rather than focus on A1c and so on, what can we take home with us? The responsibility that each patient with diabetes has to him or herself. How can we achieve this? Maybe with simple glucose monitoring. This will show patients the effect of that last meal – where was your blood sugar before and after? I think fostering more personal responsibility is priority #1. This will reduce diabetes medications; it will reduce A1c.
Q: Patients in Wisconsin tend to drink a lot of juice, soda, and beer. The problem with intense behavior modification is that we have trouble getting behavioral educators to come out to our area, and getting behavioral therapy paid for. Do you have any recommendations for mini behavior therapy measures in the office or at home?
Dr. Herman: I think it requires a more comprehensive approach than that. The good news is that the ACA has provided the opportunity to get behavioral therapy covered, and we should take advantage of this. There are also societal interventions that could be pivotal, like the soda tax. Eliminating sugar-sweetened beverages – especially at the policy level – might have a large impact.
Macrovascular Disease and Diabetes
Do We Need CVOT Trials?
Jay Skyler, MD (University of Miami, FL)
In his presentation on cardiovascular outcomes trials (CVOTs) in diabetes, Dr. Jay Skyler expressed surprise that the SUSTAIN 6 CVOT topline results were able to claim a statistically significant reduction in cardiovascular risk for Novo Nordisk’s once-weekly GLP-1 agonist semaglutide with just 250 events. He noted that it is difficult to determine statistical superiority with a low number of events because the confidence intervals are usually too narrow – he pointed out that intensive therapy just missed statistical significance for cardiovascular risk reduction in the UKPDS trial and the beneficial effect was only evident after many years of follow-up during which more events accumulated. The SUSTAIN 6 trial accumulated 250 MACE events (cardiovascular death, non-fatal MI, and non-fatal stroke) in 3,300 subjects over a little over three years and two years of treatment with semaglutide. Dr. Skyler suggested that he would prefer a p-value of 0.025 or less, as a result with the traditional p<0.05 threshold for significance only has a 50% probability of being replicated in a second study. We do think conventional acceptance is the traditional p<0.05 though we are always eager to hear various opinions on statistical results. Dr. Skyler noted that to demonstrate a hazard ratio with an upper bound of the 95% confidence interval of 1.3 or less with 80% power and achieve a p<0.025, 456 primary cardiovascular events are needed. For 90% power, 611 events would be needed to demonstrate non-inferiority with a hazard ratio with an upper bound of the 95% confidence interval of 1.3. To demonstrate superiority, even more events would likely be needed. As we understand it, a number of others would agree that SUSTAIN 6 trial results would not support a label indication for cardioprotection and we expect Novo Nordisk will have to conduct a larger CVOT powered for superiority – indeed, of course, they are developing an oral once-weekly version of the drug. We’re certainly looking forward to EASD in Munich in September hear more about the full results for this trial. Dr. Skyler indicated that we will need to wait until the full presentation and the paper to understand what was meant by the press release.
- Dr. Jay Skyler suggested that it’s “probably an overreach” for the FDA to continue to require CVOTs for all diabetes drugs. He suggested that, instead, CVOTs should be selectively conducted for certain drugs and focus on specific questions that need to be addressed for the specific drug rather than uniformly required for all new diabetes compounds. Furthermore, Dr. Skyler argued that CVOT design should be more focused, aimed at demonstrating a preventive benefit in people who don’t have acute coronary syndrome or pre-existing cardiac disease, as this is the population that would benefit most from cardioprotection. Dr. Skyler suggested the neutral results of ELIXA study for Sanofi’s GLP-1 agonist Lyxumia (lixisenatide) were the results of a less than optimal study design that enrolled patients with acute coronary syndrome. He then suggested the study organizers may have been seeking a short trial with a fast event accumulation rate, rather than an opportunity to demonstrate a potential meaningful cardioprotective benefit for the drug – this was effectively pointing out in our view that this was a trial to prove safety rather than cardioprotection, which seemed reasonable.
- Dr. Jay Skyler also bluntly stated his distaste for the cost argument for the use of sulfonylureas and even metformin. As he put it, sulfonylureas are known to increase the risk of hypoglycemia, cause weight gain, and increase cardiovascular risk, so “why the hell are we using any sulfonylureas?” Dr. Skyler considered the argument for their use on the basis of cost and accessibility to be a “cop-out” and characterized it as “irresponsible” to prescribe sulfonylureas. More controversially, Dr. Skyler also suggested that the evidence to justify use of metformin is “slim to nonexistent” and its A1c-lowering efficacy is fairly low at -0.4%, so he personally doesn’t use metformin in his own practice. Dr. Skyler felt similarly about DPP-4 inhibitors, noting that the class is much weaker than GLP-1 agonists and three CVOTs thus far has demonstrated a decidedly neutral effect of the class on cardiovascular outcomes. On the other hand, Dr. Skyler supported the use of the TZD pioglitazone, the SGLT-2 empagliflozin, and GLP-1 agonists based on their antihyperglycemic and cardioprotective potential. Overall, Dr. Skyler advocated for a shift toward a value-based reimbursement system that will provide coverage for drugs with proven benefits.
Challenges in Diabetes Management
Rising Costs: Diabetes Drugs
William Herman, MD (University of Michigan, Ann Arbor, MI)
Dr. Herman rather controversially suggested that the cardioprotective benefits of empagliflozin (Lilly/BI’s Jardiance) and liraglutide (Novo Nordisk’s Victoza) might be replicated more cost-effectively with the intensification of cardiovascular and/or glucose-lowering agents such as aspirin, statins, and even sulfonylureas. He argued that if the cardiovascular benefits of empagliflozin in the EMPA-REG OUTCOME trial and liraglutide in the LEADER trial were due to a combination of their small improvements in A1c, weight, and cardiovascular risk factors rather than off-target effects, these risk factors can be addressed through cheaper, older medications. This would imply in our view that patients would be engaged with these compounds and take them! Dr. Herman noted that the absolute risk reduction of the composite three-point MACE outcome (cardiovascular death, non-fatal MI, or non-fatal stroke) was relatively small in these trials with a high number needed to treat and high cost to prevent one primary event. In the case of empagliflozin, with a number needed to treat of 143 and an average wholesale price of $470 per person per month, it would cost $700,000 to prevent one primary event. In the case of liraglutide, with a number needed to treat of 200 and an average wholesale price $928 per person per month, it would cost $2 million to prevent one primary event. Others would argue with this math (given the costs vary globally, etc.) – still, Dr. Herman argued that the participants in both trials were not optimally managed in terms of their glucose and various cardiovascular risk factors (we can’t imagine those who designed/executed the trial would not disagree). In the EMPA-REG OUTCOME trial, mean baseline systolic blood pressure was 135 mmHg while mean baseline LDL cholesterol was 86 mg/dl. In the LEADER trial, mean baseline systolic blood pressure was 136 mmHg. Dr. Herman pointed out that this indicates a substantial portion of participants had blood pressure and cholesterol levels that were significantly higher than the mean and that these averages are already rather high for patients with pre-existing cardiovascular disease. He also felt that cardiovascular therapies such as aspirin, beta blockers, anti-platelet agents, ACE inhibitors, and statins could be further intensified in these patients. For example, only about 71%-77% of participants in EMPA-REG OUTCOME and LEADER were on statins at baseline. He asserted that almost all of the participants eligible for these trials should have already been on high-dose statins at baseline. Furthermore, in an ensuing panel discussion, Dr. Herman went so far as to suggest that the 0.5% A1c difference at the end of EMPA-REG OUTCOME and LEADER could account for the cardioprotective effect and that the addition of sulfonylureas to achieve comparable glycemia could achieve a similar result. He also commented that sulfonylureas were shown to be safe and effective in the UKPDS.
- This statement doesn’t, of course, adequately reflect sulonylureas’ well-characterized negative impact on increasing hypoglycemia risk and weight gain (to say nothing of beta cell burnout), which have a negative impact on cardiovascular health. In the LEADER trial, participants in the placebo group were significantly more likely to initiate sulfonylurea therapy during the trial (p<0.001) (and were also more likely to initiate other antihyperglycemic agents), yet the liraglutide-treated group was still able to achieve a lower mean A1c and experienced a significant reduction in risk for the primary MACE outcome and cardiovascular death. In fact, Dr. Anne Peters (USC, Los Angeles, CA) previously interpreted the LEADER results as further evidence against the use of sulfonylureas. Furthermore, we imagine the intensification of therapy through the addition of numerous cardiovascular and antihyperglycemic agents could have negative consequences on patient medication burden and adherence. There are a variety of factors to consider regarding empagliflozin and liraglutide use; for example, patients are able to achieve the combination of improvements in A1c, weight, and cardiovascular risk factors without the addition of multiple new agents they would otherwise need. Some of these new agents could be low-cost, although then the problems associated with low adherence may prompt other problems that are more costly (i.e., patients not taking medicine so going onto dialysis, having preventable heart disease etc).
Health Economics and Diabetes
Robert Ratner, MD (Chief Medical Officer, ADA, Alexandria, VA)
Dr. Robert Ratner expressed concern over the high direct and indirect economic costs of diabetes and advocated for the prevention of diabetes and diabetes-related hospitalizations through better outpatient management. He shared that the ADA’s 2012 economic analysis of diabetes costs found that $76 billion of the total $176 billion direct medical costs of diabetes was attributable to hospital inpatient care, by far the largest category of direct diabetes costs. For comparison, the cost of diabetes medications and supplies at $21 billion was less than one-third of the cost of diabetes-related hospitalizations – some argue this figure should be higher given the impact on long-term outcomes, though this is very hard to prove without decade-long trials etc. Physician office visits tied with nursing/residential facility stays for the lowest spending category, accounting for only $15 billion of costs each. He persuasively argued that reducing hospitalizations would have a remarkable beneficial health economic impact. For instance, he noted that the cost savings of keeping a single patient out of the ER for a single day could pay for a year of CGM for that patient. Keeping one patient out of the ICU would pay for all of the insulins and other diabetes-related medications for 10 people for a year. In an afternoon session on diabetes in the elderly, Dr. Ratner noted that the prevention of one sulfonylurea-induced hypoglycemia-related ER visit would pay for five years of DPP-4 inhibitor therapy for that patient. Ultimately, Dr. Ratner supported the reduction of diabetes-related hospitalizations through (i) improving outpatient management through diabetes medications and prescriptions for diabetes complications; (ii) increasing access to and use of outpatient diabetes diagnosis and care through Medicaid expansion under the ACA; and (iii) preventing diabetes through widespread reimbursement of the Diabetes Prevention Program (DPP). To reduce diabetes medication spending, rather than advocate use of sulfonylureas, Dr. Ratner called for Medicare Part D to have the ability to directly negotiate drug prices with manufacturers, in place of the current system in which the for-profit pharmacy benefits managers (PBMs) for individual commercial sponsors for Part D plans negotiate with the pharmaceutical companies. We appreciated Dr. Ratner’s candid take on rising diabetes costs and his proposal of solutions that don’t involve limiting patient access to medications that significant benefits in terms of safety and quality of life as well as A1c efficacy.
Recent Advances in Diabetes Treatment
Rationale for New Targets in T1D Children
Desmond Schatz, MD (University of Florida, Gainesville, FL)
Dr. Desmond Schatz (University of Florida, Gainesville, FL) offered a balanced discussion of the differing views on whether we should be setting lower A1c targets in pediatric patients with type 1 diabetes, ultimately emphasizing the need for better strategies to help more pediatric patients achieve A1c targets, whatever they may be. On the one hand, he acknowledged that the 10-year follow-up to the Diabetes Control and Complications Trial (DCCT) found that A1c had merged for adolescents in the intensive therapy and control groups and that the beneficial effect of intensive glucose control on slower progression of retinopathy had disappeared. Dr. Schatz suggested that such evidence leads some to argue against lower targets for children, especially when coupled with fear of hypoglycemia and its long-term neurocognitive consequences. The correlation between hypoglycemia and neurocognitive damage is also contentious, according to Dr. Schatz. He noted that some studies show that frequent, severe hypoglycemia events at a young age decrease an individual’s long-term spatial memory, verbal ability, and problem solving skills. On the other hand, he pointed out that other studies have found no relationship or a detrimental impact of too much hyperglycemia. Further, Dr. Schatz notably pointed out that the risk of hypoglycemia associated with a lower A1c goal has declined substantially since the initial publication of the DCCT due to vast improvements in insulin dosing devices. Moreover, a more recent 30-year follow-up to the DCCT found significantly reduced all-cause mortality for the intensive therapy group, which encourages lower A1c targets. We hope further research provides more clarity on how A1c targets impact short- and long-term health outcomes for young patients with type 1 diabetes. We’d also like to see an acceleration toward individualized care and patient-centric diabetes management on this front. With mixed evidence on A1c goal-setting, providers should have the flexibility to set nuanced targets based on a patient’s lifestyle and preferences.
- Dr. Schatz highlighted international differences in the achievement of pediatric A1c goals. He shared US data suggesting that lower targets result in fewer patients meeting their goal (only 27% of patients age 1-6 achieved the new, lower ADA target of 7.5% according to the T1D exchange vs. 64% achieved the prior, higher 8.5% target). On the other hand, data from the DPV registry in Germany and Austria show that pediatric patients <6 years-old met their lower A1c target of 7.5% more often than pediatric patients in the US met a higher target of 8.5%. Dr. Schatz remarked that in the German/Austrian population, expecting more from patients helps them achieve their A1c goals, even when those goals are more challenging. Dr. Schatz previously elaborated on this topic in an editorial co-authored with Drs. Irl Hirsch (University of Washington, Seattle, WA), Bimota Nambam (University of Florida, Gainesville, FL), and Thomas Danne (Centre for Children and Adolescents with Diabetes, Hannover, Germany).
- “We need to do better.” Putting the debate over low vs. high A1c goals aside, Dr. Schatz emphasized how much work remains in getting patients to target. He presented data that only 13% of patients under the age of 6, 18% of patients age 6-13, and 9% of children age 13-20 are meeting ADA-supported A1c targets. Dr. Schatz referred back to his remarkable address at ADA in arguing that we are falling short in our treatment of type 1 diabetes, and he once again expertly conveyed the sense of urgency that we need to speed up progress in this field.
Q: We’re required to screen for retinopathy every year, but most centers have cut. Our center screens maybe 50% of children. The argument is that it’s excessive and we can cut costs. Can you comment on that?
Dr. Schatz: I agree with you. We have data emerging from the exchange and other resources to show that there’s such a low frequency of retinopathy that we probably don’t need to screen so stringently. At the ADA we’ll be honest again based on new data. Is it time to change? I personally agree with you. In terms of cost-benefit analysis, it’s probably not worth it.
Dr. Gregory Forlenza (Barbara Davis Center, Aurora, CO): I want to first focus on our ski camp study with UVA – it took a lot of work from our team to get the university to approve it. We just took a look last week, and the data so far were very encouraging. There was a significant decrease in hypoglycemia during exercise, and we have some data to indicate that we can actually use sensors to detect exercise so that patients won’t have to input it. We actually saw a huge altitude effect that we haven’t published yet. We dropped the kids’ insulin doses by 25% coming in the door, and all kids had significant hypoglycemia – we had 35 hypoglycemia interventions in 16 kids in one night going just from Denver to Breckenridge.
Q: Dr. Ratner, the data shows a nice decrease in acute MI, stroke, etc. But we’re seeing a huge increase in hospital costs and that’s driving the cost of diabetes. Is that because we have so many more people with the disease? Do we need to focus on different types of prevention?
Dr. Ratner: Data from the CDC is incidence data. You’re looking at risk of developing MI or stroke per 10,000 patients, but the denominator has skyrocketed. That’s what’s driving increased prevalence of these events. The risk for any individual patient is going down, but the total number of events is going up.
Comment: And are your referring to MI and stroke more so than DKA?
Dr. Ratner: The CDC data would suggest that blood glucose-related emergencies are staying the same or going down, and are substantially fewer in number than micro or macrovascular complications. The most profound effects on stroke and MI are probably due to things other than glucose control (i.e. statins). What’s demonstrated by the data on end-stage renal disease is improved overall management of diabetes, and that’s important. We simply need to get to all the people who are developing diabetes.
Q: I have some patients in whom NSAIDs are completely contraindicated, opioids are not desired or practical, and they have pretty severe pain – are there any practical ways of dealing with this concern?
Dr. Hovorka: I think there are some other options, but it really depends on comorbidities with other treatments. However, acetaminophen effects last about six hours, so maybe just avoid making therapeutic judgements during that period.
Dr. Kowalski: We’ve been working with companies to try to minimize the interference problem – I know that doesn’t help us today, but hopefully it will in the future.
Q: Dr. Ratner, what are your thoughts on increased utilization of neuropathy scans? This is a fairly costly test.
Dr. Ratner: I’m not sure exactly what you’re describing, but the standpoint of the ADA is that the most effective way to diagnose diabetic neuropathy is a physical examination with a monofilament. And that’s real cheap. It’s just as effect as nerve conduction velocity. One of the biggest controversies now is autonomic nervous system testing – there are debates ongoing as to whether or not testing is worth it. The simplest way to assess autonomic neuropathy is to check someone’s pulse while they’re in a supine position. That one’s cheap, too.
Dr. Satish Garg (University of Colorado, Aurora, CO: We know of many meters and sensors that do not perform that well at high altitudes and different levels of humidity – does anyone have any ideas regarding whether these sensors and pumps and artificial pancreas devices be checked out before going to market? Because patients are going to ski. What is the safety of these devices when patients go higher?
Dr. Kowalski: We’ve been discussing this with the FDA, that miscalibration with the meter can cause serious issues. Roman can talk about maximizing calibration, but as far as calibration at different altitudes, I’m not sure how that works.
Dr. Hovorka: One of the reasons we see the problem is because of reduced oxygen pressure. So in the future, when oxygen is not needed for glucose detection (as in the FreeStyle Libre), altitude will be less of a concern.
Dr. Kowalski: I do hope we can get to a point where these are calibration-free, because having a mismatch between sensor and SBGM is a pretty serious risk.
Dr. Hovorka: In altitude, there is a risk for bubble formation in pumps as well. So patients need to be really careful with sensors, but also with pumps when changing altitude.
Q: What are you going to have from a device company to help type 2 diabetes patients?
Dr. Kowalski: I’m absolutely a huge believer in this. I’m shocked that we’re dosing all these different drugs with almost no information. It’s crazy to me. Patients come in to see their provider every three months, if that, and we’re monitoring on a monthly or almost bi-yearly basis even though we can get data much more often than that. The reason we see companies like Google coming into diabetes is not for type 1, it’s for type 2. There’s a tremendous opportunity to use devices in treating anybody with diabetes, whether it’s type 1, type 2, gestational. I’ll be shocked if in five years, CGM is not the standard of care.
Dr. Hovorka: The potential is great, but the cost is probably too high right now. That’s the economic argument. There’s a great drive to improve in-patient glucose management and dosing with closed loop in hospitals, which I see as a step forward in demonstrating how devices will lead to better outcomes. Once we use these tools in hospitals, then maybe we can move from inpatient to outpatient settings.
Q: Every month, I see patients with increased renal secretion and end-stage renal disease hospitalized for hypoglycemia. I think a closed loop system is a great alternative, but how does the system deal with altered insulin clearance?
Dr. Hovorka: About 80% of insulin is actually cleared by the liver, so I don’t think that’s a major issue. But the kidney is also involved and it needs to be studied. I generally don’t think it’s a huge concern.
Dr. Hovorka: We’ve talked about the ADA A1c guidelines for type 1 diabetes, but what does the panel think about guidelines for minimum hypoglycemia? What’s the acceptable level and how much time can you spend in that range?
Dr. Frier: We’ve widely agreed that 70 mg/dL (3.9 mmol/l) is a good alert level, whether or not that represents true hypoglycemia.
Dr. Ratner: We have not looked at timing or time below range for standards of care because that’s such new data. What’s acceptable and what’s not is still unknown for these circumstances. Going back a great many years, we advised that a patient needs to aim for the lowest A1c achievable without unacceptable hypoglycemia. Of course that level of “unacceptable” varies from patient to patient. So the critical piece here is really the idea of individualizing care – patient-centric management.
Gut and Diabetes
Gut Hormones: Regulation of Glucose Homeostasis and Energy Balance
Ralph DeFronzo, MD (UT Health Science Center, San Antonio, TX)
Dr. Ralph DeFronzo discussed what he characterizes as the GLP-1 agonist class’ “miraculous” effect on the beta cell, highlighting two past GLP-1 studies he regards as “great breakthroughs in diabetes” that, he asserted, the “majority of endocrinologists are not familiar with.” Dr. DeFronzo suggested that GLP-1 agonists “saves the beta cell,” promoting weight loss and reducing A1c. It is well-understood that GLP-1 agonists increase insulin gene transcription (Pdx-1) and inhibit beta cell apoptosis, but two lesser-known studies demonstrate that GLP-1 agonists do so almost instantaneously, and for a long period of time. A 2003 study in Diabetes – which DeFronzo hailed as “the most important study in diabetes literature in the last 15 years” – demonstrates that a single dose of liraglutide (7.5 ug/kg) restores type 2 diabetes patients’ beta cell insulin response to normal in just eight hours. To complement this, Dr. DeFronzo pointed to data from a three-year study that demonstrated that patients treated with exenatide present normal insulin secretion in response to a 15mM clamp – a 319% improvement over insulin glargine (p<0.0001). Dr. DeFronzo concluded his talk by passionately underscoring the critical importance of the GLP-1 agonist drug class. “If you understand what’s in the literature, there is no excuse why this wouldn’t be first-line therapy for type 2 diabetes.”
- Dr. DeFronzo also highlighted the promise of emerging combination approaches that merge GLP-1 agonism with action on other gut hormones. Among these are GLP-1/glucagon, GLP-1/PYY, GLP-1/GIP, and GLP-1/oxyntomodulin. The most advanced GLP-1 combination approach is the GLP-1/glucagon dual agonist class, which has been shown to reduce body weight, increase energy expenditure, and improve glucose tolerance better than GLP-1 alone. According to Dr. DeFronzo, such combinations have the greatest potential to “outthink the gut hormones” to treat both diabetes and obesity. We’ve seen significant and increasing interest in GLP-1/glucagon dual agonists over the last year, including plenty of buzz surrounding gut hormone dual agonism at this year’s ADA.
Bariatric Surgery: The ROle in Diabetes
Jonathan Schoen, MD (University of Colorado, Aurora, CO)
Dr. Jonathan Schoen discussed the use of bariatric surgery in both patients with type 1 and type 2 diabetes. Dr. Schoen began his talk by highlighting the “historic” ADA position statement released this spring, which for the first time recommends bariatric surgery as a treatment option specifically for type 2 diabetes, a testament to the impact of bariatric surgery on metabolic control. Dr. Schoen also drew attention to several less-often-considered issues surrounding such procedures – most notably, the need for more information about the effectiveness of bariatric surgery for type 1 diabetes and the importance of surgery-related psychological counseling. Dr. Schoen explained that our understanding of bariatric surgery with respect to type 1 diabetes is limited, with only a total of 17 studies examining the effects of bariatric surgery in only 107 patients. Overall these surgeries have resulted in significant reductions in BMI (down to 31 kg/m2 from 42 kg/m2 on average), A1c (down to 7.9% from 8.4% on average), and insulin requirements. Despite these promising results, there is very little information regarding the mechanisms underlying these effects in people with type 1 diabetes. To better understand this, Dr. Schoen issued a call for more scrutiny of post-surgery changes in gut hormones such as ghrelin, GLP-1, GIP, and PYY. Furthermore, he reviewed evidence (largely in type 2 populations) describing long-term trends in weight loss following surgery, the key takeaway being that patients have different responses to bariatric surgery and some maintain their weight loss better than others. Dr. Schoen highlighted the need for surgery to be paired with psychological counseling in order to prepare patients for this possibility and in order to facilitate behavioral strategies to promote healthy lifestyle changes to promote the surgery’s long-term success.
Q: Dr. Schoen, you presented the 3 year data, but what would you say about safety and benefit of bariatric surgery 5 years later?
Dr. Schoen: The long-term data shows not many surgical complications, but there is definitely some relapse in weight and diabetes. We need to keep looking at this specifically.
Dr. Satish Garg (University of Colorado, Aurora, CO): Do we have data on the GLP-1 levels in normal individuals who graze versus those who eat discrete meals? Or early stage type 2 patients? This is important for how we recommend treatment options.
Dr. DeFronzo: For your first question, no. For your second question, GLP-1 has been examined in the fasting state and after meals in type 2 patients. It was all reviewed very nicely in an article that came out in Diabetologia last year. Basically there is no deficiency of GLP-1 or GIP in type 2 diabetes patients. The problem is two-fold: (i) there is resistance to those hormones and (ii) there are not enough beta cells to respond to the hormones.
Q: We are nervous to recommend bariatric surgery to our type 1 patients because of the risk of hypoglycemia.
Dr. Schoen: No doubt, hypoglycemia was a risk for those patients. We don’t have much experience with type 1 diabetics to speak to, unfortunately. It comes down to diet and very careful insulin adjustments. We try to break it with diet first; we tell patients not to eat any more than 4g of simple sugar per meal.
Q: I realize there’s limited to no data on this, but what medications would we use for type 2 patients after gastric bypass or sleeve gastrectomy? I used to not use GLP-1s because I thought these hormones were upregulated post-bypass. Now I’m starting to think we should have those hormones on board.
Dr. DeFronzo: There is not a single study to my awareness that has examined this. People have made the argument that because GLP-1 levels are high after bariatric surgery it doesn’t make sense to use a GLP-1 agonist. That may be true, but I don’t know. Others like DPP-4 inhibitors – again, I don’t know. I’m not aware of any study that has consistently looked at this.
Dr. Schoen: I don’t either. We typically start with metformin, and we like that because there is less hypoglycemia with it after bypass.
C: I started using more SGLT-2s, probably because they don’t have GI symptoms like metformin and GLP-1s do.
Dr. DeFronzo: The most important thing is to follow the patient. Listen to them – if it works, it works!
Q: When we see new patients in the hospital, we typically see them with high A1cs and put them on basal bolus insulin. Dr. DeFronzo, would you take them off basal bolus insulin and put them on GLP-1 and your combination therapy, or wait until they are less toxic?
Dr. DeFronzo: In the old days, people would be put on basal bolus insulin to reduce glucose toxicity and then put on a drug regimen. I’ve shown that you don’t have to do that! I showed you that we took every single person – A1c’s above 10 even – and 1.5 years later after a GLP-1 agonist plus pioglitazone they are well-controlled. This is a viable option. In our trial, we didn’t see a single person fail! Although patients with the TCF7L2 mutations will be unresponsive to GLP-1 antagonists, so it is important to be closely following the patients.
Q: Can you speak to the age criteria for bariatric surgery?
Schoen: There really is no lower or upper age criteria. In the world there are case reports of operations on 3 and 4 year olds – this happened in Saudi Arabia with kids whose legs are already bowing under their weight. Our requirement at the University of Colorado is that the patients have skeletal maturity. We check hand x-rays if there is any question. In my practice, the youngest I’ve operated on is a 15 year old, and I would hesitate to go below that.
Dr. Robert Ratner: There has been lots of talk lately about hind gut versus fore gut. DeFronzo from pathophysiology and Schoen from surgery, what’s your take on that?
Dr. DeFronzo: The EndoBarrier procedure produces only modest weight loss but has significant effects to improve glycemic control. If you just denude the duodenal epithelium, and we’ve seen this in some studies in South America, you dramatically improve diabetes control. On this basis, we believe that there are factors coming out of the duodenum that are inhibiting beta cell function, and once these factors are removed there are vast improvements in glucose tolerance. We’re looking into this. We have prepared extracts and we are looking at cultured beta cells and hepatocytes to see which genes are over or under expressed in this duodenal, gut effect.
Dr. Schoen: Initially there were two camps in the surgical field, “hind gut” versus “fore gut.” For me I think it is “all gut.” We just don’t know! I think we will find important factors in the duodenum.
Patient/Provider Q&A Panels: Pediatric
TrialNet Ongoing Trials: An Update
Desmond Schatz, MD (University of Florida, Gainesville, FL)
Dr. Desmond Schatz provided an update on the enrollment progress of each of TrialNet’s five type 1 diabetes prevention and intervention trials: the two oral insulin trials, the abatacept trial, the teplizumab anti-CD3 trial, and the ATG/GCSF combination trial. He repeated TrialNet chair Dr. Carla Greenbaum’s update from the first day of the conference that the TN07 trial of oral insulin is fully enrolled and the results will be presented at ADA 2017 in San Diego. Furthermore, he also noted that the final enrollment of the trial was 562 participants, significantly exceeding the estimated enrollment of 400 on ClinicalTrials.gov. In addition, he shared that a second oral insulin trial, TN20, will initiate soon. This trial will be a mechanistic study similarly aimed at patients with stage 1 type 1 diabetes (with the presence of multiple autoantibodies and normal glycemia). The study hopes to determine how different doses and dosing intervals of oral insulin might impact immune response. In particular, the trial is evaluating 75 mg of oral insulin daily and 500 mg oral insulin every other week. TrialNet hopes to complete enrollment by the end of December 2016 and enroll up to 80 participants from the US and 20 from Canada, Europe, or Australia. Enrollment began in March and has already exceeded expectations thus far with 56 participants enrolled by June. The trial is expected to complete in December 2017 (primary completion expected September 2017) according to ClinicalTrials.gov. On the other hand, enrollment for the TN18 abatacept trial similarly aimed at participants with stage 1 type 1 diabetes has progressed slower than expected. That said, Dr. Shatz shared that as of May 2016, the trial had enrolled 114 of the total 206 expected participants (compared to a target of 130 participants enrolled by May 2016). The trial is expected to complete in February 2018 according to ClinicalTrials.gov. Enrollment for the TN10 anti-CD3 teplizumab trial is slightly ahead of schedule and had enrolled 58 of the total 71 expected participants by May 2016 (compared to a target of 54 participants enrolled by May 2016). This study is aimed at participants with stage 2 type 1 diabetes (with the presence of multiple autoantibodies and abnormal glucose tolerance) and is expected to complete in January 2022 (primary completion expected January 2021) according to ClinicalTrials.gov. Finally, the TN19 trial of ATG/GCSF in patients with new-onset type 1 diabetes just reached its target enrollment goal of 84 participants, significantly exceeding enrollment expectations. ClinicalTrials.gov lists the estimated primary completion date of this trial as October 2016 and Dr. Schatz expressed his optimism that results would be available next year. It’s encouraging to hear that that most of these trials, except TN18 abatacept, have reached or are nearing complete enrollment. Dr. Schatz noted that it’s important to begin thinking about the next generation of TrialNet trials and potential immune and therapeutic agents that will build on the insights from these trials. In the meantime, see our coverage of Dr. Greenbaum’s TrialNet update from November 2015 to learn more about the aims behind each trial.
Corporate Symposium (Sponsored by Sanofi)
Changing to Toujeo From Other Basal Insulins in Adults with Diabetes
Bruce Bode, MD (Atlanta Diabetes Association, GA)
In a talk filled with a variety of learnings on treatment and support, Dr. Bruce Bode elaborated on the importance of diabetes education and the critical role that technology will play. He emphasized the urgent need for smart programs that connect insulin dosing to the cloud, especially for older patients or patients with severe hypoglycemia unawareness who require rigorous external monitoring. He especially suggested that BeAM measurements – an indicator of when basal insulin is no longer sufficient and intensification is required – will be a key piece of data to incorporate into these smart programs. We had not heard before of BeAM and found this a particularly interesting idea for how to quantify whether a therapy is working. Dr. Bode also championed the Glucommander software (presented in an exciting poster at ADA), which he mentioned will be launched later this year. He asserted that automated systems will allow providers to efficiently manage high numbers of patients who need to titrate their insulin and to select optimal medications for a patient based on factors like age, weight, duration of diabetes, creatinine, etc. On the topic of diabetes self-management, Dr. Bode enthusiastically praised Sanofi’s COACH program which provides one-on-one diabetes education for all patients with a new Toujeo prescription. He suggested that all patients will eventually be served by a similar coach program and again noted that this support will be particularly critical for patients with hypoglycemia unawareness. He suggested that while smart program technology develops (and hopefully reaches its finish line soon), COACH is a cost-effective solution, improving a patient’s chances of getting to target for just a $15 co-pay. We’re certainly in agreement with Dr. Bode on the pressing need for digital health to fill in the gaps of insulin therapy, and were happy to hear his optimism on this front.
- Dr. Bruce Bode expressed a very positive view on the potential of basal insulin/GLP-1 agonist combination therapies, going so far as to suggest that as many as 80% of patients with type 2 diabetes can be completely adequately management with basal insulin and GLP-1 agonists alone. Dr. Bode positioned GLP-1 agonists or basal insulin/GLP-1 agonist combinations has good alternatives to rapid-acting insulin for patients in need of basal insulin intensification. Dr. Bode pointed out that taking both drugs together allows patients to take a lower dose of each – less insulin translates to a reduced risk of hypoglycemia, while less GLP-1 agonist means fewer side effects, including nausea. He also spoke to the possibility that a combination basal insulin/GLP-1 agonist might decrease BeAM scores (difference in blood glucose at bedtime vs. morning), a sometimes-overlooked indicator of when a patient has maxed out on basal insulin according to Dr. Bode. This suggests that basal insulin/GLP-1 agonists could delay progression to a rapid-acting mealtime insulin, thus delaying the associated weight gain and increased risk of hypoglycemia. Basal insulin/GLP-1 agonist combinations from Novo Nordisk (Xultophy [insulin degludec/liraglutide]) and Sanofi (LixiLan [insulin glargine/lixisenatide]) are on the horizon – both products received positive FDA Advisory Committee votes in May – we’re certainly looking forward to the final FDA decisions and to their respective US launches. While we are excited for patients to have therapies that are easier to use and work better, we’re also very keen for doctors to be able to access easier to prescribe therapies.
Questions and Answers
Q: Is there a patient you would start on Lantus instead Toujeo?
A: The issue here is the payer system – many payers won’t cover Toujeo over Lantus. I just write a prescription and fight it later. If I lose, then I put the patient back on Lantus. But we should recognize that 10-14% of the time, patients on Lantus don’t show any improvement. Then again, Lantus is cheaper (maybe $15 instead of $25). We always have samples in the refrigerator for reps, who only care about saving money, so I advised not to put Lantus in our refrigerators because Toujeo’s a better insulin. No one changes their habits unless you force them to. They keep doing the same thing, writing the same prescriptions, and even if a patient is still going low they don’t change anything – they just say “try harder.” The way to change is not having the lesser option there. Everyone on Toujeo says it’s better, smoother, causes less hypoglycemia. I like to force change in patients. That’s how I pick it right now.
Q: Have you seen Toujeo used twice a day?
A: No. But have people done it? Yes. Other doctors have told me they use it twice a day and it works. Every individual’s a little different.
Q: Can you explain the BeAM factor again?
A: When you consider all the Lantus titration trials and look at who did or didn’t get to goal, individuals who experience a change in blood sugar >55 mg/dL overnight don’t reach their target and are at increased risk for hypoglycemia. That’s how the results came out. I think this was one of the most important papers ever published on basal insulin. If a patient’s blood glucose differs by >55 mg/dL between bedtime and the AM, you know you’ve maxed out on basal insulin and have to turn to something else. We have tools coming out for basal insulin combined with GLP-1 agonists that will solve this problem automatically. You need less basal insulin because of the GLP-1 which means less hypoglycemia, and you need less GLP-1 because of the basal which means fewer side-effects like nausea. For advances like this, we’re going to need BeAM information.
Q: You mentioned a 1:1 conversion, but most people require 10-20% more Toujeo compared to Lantus.
A: It’s very much true that you need more, but you start with a 1:1 ratio because that’s what we did in the trial. I always tell patients upfront that they’ll need 10-20% more. I warn them that the first four or five days, they’re going to feel the need for a dose correction, but don’t worry about it because we’ll titrate.
Q: Why do they need 4-5 days? What’s the science behind that?
A: At three days you have about 85% of patients on board. At four days it’s about 95%. It’s such a small surface area, 50% less to be exact, which changes things. Some people will want to quit immediately when they don’t feel better – I had a mother who stopped Toujeo in her six-year-old after the first day because she didn’t think it was working. But you have to keep going. Another option is to keep a low dose of Lantus going for a while until Toujeo kicks in.
Comment: Mother knows best.
Comment: I’ve often found when switching a patient from twice-a-day Levemir to Toujeo (an attractive option because of only having to take insulin once per day) that they have a higher A1c, which usually means they were missing some of their doses beforehand. In that case, you don’t necessarily have to increase the total insulin dose.
Q: What’s your opinion on the comparison between Toujeo and Tresiba? Are there some people who would benefit from one vs. the other?
A: Both products are longer-acting insulins with a smoother, more predictable PK/PD profile and less subsequent hypoglycemia. Tresiba has slightly less insulin than Lantus; Tresiba has slightly more. We’re not sure why. The method of action for Tresiba is that it forms long chains of multi-hexamers, and then as zinc leaches out, monomers also come out slowly. In this sense, it’s a completely different insulin from Toujeo. There are no head-to-head studies on the books right now. I believe there’s an ongoing PK/PD blinded study going on in Germany right now – maybe that will be at ADA next year. I’ve also heard about a clinicaltrials.gov study of Toujeo vs. Tresiba in Europe, but I’m not sure who the sponsor is. There’s a study in type 2 diabetes patients planned for 2017 by one company. But to sum up, there is no clinical data to draw from right now. Instead, the distinction between these two insulins is based on what you see in your patients. Tresiba also takes a few days to get to a steady state, so you see the same delay. Because Tresiba involved a totally new compound, Novo Nordisk had a much bigger research program surrounding its development and did many more trials to get things on the label.
Q: Could someone with type 2 diabetes take Tresiba every other day?
A: We tried it on Mondays, Wednesdays, and Fridays for Tresiba. We doubled the dose and still didn’t see much hypoglycemia because it’s so slow release. However, when we tried this in type 1 patients they were ketotic on Monday morning. Novo Nordisk decided that if you can’t take it every other day for type 1 diabetes, we can’t prescribe it for type 2 diabetes either because no one knows the difference. So they kept it at once a day. It probably wasn’t going to work for patients anyway, because how many people are aware of it being Monday, Wednesday, and Friday? That’s not how habits work. If you’re going to take your insulin regularly, you’re going to do it daily or you won’t do it.
Comment: I’m really hard-pressed to determine a superior option for my patients between Tresiba and Toujeo. Patients ask me what I would do, but I don’t know. It depends on the patients, but it’s difficult for them to decide when they want their doctor’s input. Also, it comes down to insurance.
A: Absolutely, researchers at both companies would like this to be studied. We could do an investigator-initiated trial, but we’d need to find a sponsor. Hopefully we do get a sponsor so we can look at this more closely. Looking at a CGM would be a smart approach – we can determine whether there’s a difference among insulin glargine U100, glargine U300, and Tresiba, and then predict what would happen three months ahead and do a dedicated three-month trial. The issue is that I’m not sure if everyone wants to take the risk. If it’s equivalent, it’s all based on the payer. If one is better but the payer doesn’t pay for it, that’s no good either. But I think this study does need to be done, in pediatrics as well as adults.
Q: When a patient misses a dose, what do you recommend?
A: I tell them to take it right then when they realize. If they don’t have access (i.e. at work), I tell them to make up for it at mealtime if they’re on mealtime insulin, which gets them by. But if a patient can take it when they realize they’ve missed a dose, it’s nothing to worry about. Everything that does well in diabetes has to be simple. For example, with a Verizon meter, a patient’s reading goes right to the cloud and then comes right back down to a computer so we can see what everyone’s doing. Go caps are in development, where every time someone doses and puts the cap back on their insulin, it’ll tell us how much they dosed. Then, we’ll know their insulin dose and their blood glucose.
Q: When you start type 2 diabetes patients on basal insulin, it can be hard to titrate them based on how they’re eating. It’s also hard to have them come back to see you again and again.
A: That’s why we do this in the hospital. Once patients know insulin is their friend, they know they can always go back to it. We keep them on insulin until their illness is over. Then, if they’re okay, we put them on metformin or a GLP-1, etc. But they know that if they get into trouble again they can go back to four shots/day. If you use insulin off-physiologic, dosing too much basal or causing too much eating, then the treatment doesn’t work and insulin doesn’t seem like your friend. You’re also going to see technology come through rapidly in this space. We did a poster on our automatic titration tool, Glucommander, a hospital-based computer system. It worked well, and we’ll start launching later this year. How do you charge people for a Glucommander? I have no idea. But I do know that patients love the idea of being connected – they love the feeling they get every time they get a text message that says they’re doing great or gives them advice on how to adjust their treatment regimen. It feels like you’re talking to someone, even if it’s computer-generated (“Mary, you’re doing great!” or “Mary, you’re taking too much insulin here and we recommend taking a higher supper dose instead; please verify that you did that.”).
Comment: I remember when I transitioned my first patient from twice-a-day Lantus to once-a-day Toujeo, he came back to me and said he’s never felt this good before with how smooth everything is going.
A: Definitely. What matters most is the patient experience. Why was Lantus so successful? It was much better for the patient experience than NPH. Doctors aren’t going to re-prescribe something that a patient hated.
Welcome and Introductory Remarks
Satish Garg, MD (University of Colorado, Aurora, CO)
During day 1 of the symposium, several speakers, including Dr. Ratner and Dr. Satish Garg (University of Colorado, Aurora, CO), addressed the cost of diabetes care. Dr. Garg set the tone during his opening remarks, during which he highlighted President Barack Obama’s recent JAMA paper on the positive impact of the Affordable Care Act (ACA) to-date on reducing major drivers of healthcare costs, such as hospital readmissions. Dr. Garg expressed his support for the ACA and emphasized that we must continue to invest in innovative health reform strategies now to see future cost-savings. He urged attendees to keep the costs of diabetes care to the system in mind throughout the conference and predicted that the cost theme would frame many of the discussions happening over the next four days, including Dr. Ratner’s Saturday morning keynote. While we were very happy to hear about some positive impacts of the ACA, we believe quite a negative impact has been cost-shifting from employers – higher deductibles and co-pays are elements we believe should also be addressed. Dr. Ratner spoke to rising insulin prices during a panel discussion, acknowledging the criticism that the ADA has received from Dr. Irl Hirsch and others for the organization’s inertia in responding. He assured the room that the ADA has not been ignoring this cost issue. In fact, the ADA has called for (i) full transparency in where insulin prices are marked up, whether at the pharmacy benefits manager (PBM) level or elsewhere; (ii) off-patent insulin and diabetes drugs to be supplied at tier one; and (iii) legislature to make Medicare Part D negotiable in terms of drug-pricing. In the same panel, both Dr. Ratner and Dr. Heinemann called out pharmacy benefits managers as an opaque contributor to rising insulin costs. We appreciated this nuanced recognition that insulin list prices have increased in lockstep with rising rebate levels and we’re looking forward to more detailed discussion on this topic throughout the rest of the conference.
Combination Therapy for Best Diabetes Outcomes
Role of Exercise and Diet in Management of Diabetes
William Herman, MD (University of Michigan, Ann Arbor, MI)
Dr. William Herman emphasized lifestyle modification as an essential component of successful diabetes combination therapy – particularly in the case of type 2 diabetes. Dr. Herman acknowledged the difficulty of eating healthily and maintaining an active lifestyle in today’s increasingly sedentary culture (even pointing out that conferences like this one force people to stay seated all day – and inviting the audience in the middle of his presentation to stand up and move). The key to making lasting behavioral changes, he argued, is structured and intensive lifestyle management programs that offer long-term counseling – citing evidence from Look AHEAD, a randomized controlled trial in which intensive lifestyle intervention produced lasting weight loss and partial remission of diabetes in obese subjects with type 2 diabetes (n=5,145) over 11.5 years. Acknowledging the inaccessibility of such programs for many people with diabetes, Dr. Herman expressed enthusiasm that reimbursement for lifestyle interventions is not far away: under the Affordable Care Act, interventions with an evidence grade of B or above are mandated for coverage, and behavioral interventions for diabetes and obesity management meet this bar.
- Dr. Herman’s talk comes on the heels of a recent announcement that Medicare reimbursement for the Diabetes Prevention Program (DPP) will begin in January 2018. We are excited to (finally!) see this policy-level support for the importance of lifestyle modification programs for people with diabetes and prediabetes alike. We will be curious to see how these now more-accessible programs will scale in the coming years, and whether they will be utilized widely enough to make an impact on our nation’s diabetes incidence.
Meet the Peers Sessions
Meet the Peers: Pediatric Educators
Kimberly Driscoll, PhD (Barbara Davis Center, Aurora, CO); Gail Spiegel (Barbara Davis Center, Aurora, CO); Laurel Messer (Barbara Davis Center, Aurora, CO)
In this intimate gathering of pediatric diabetes educators, the Barbara Davis Center’s Dr. Kimberly Driscoll, Ms. Gail Spiegel, and Ms. Laurel Messer focused on practical solutions to common problems we encounter in pediatric diabetes. Dr. Driscoll emphasized the crucial transition that occurs when a patient goes from child to adolescent. She explained that too often, parents and providers assume that patients diagnosed young understand their diabetes by their teenage years. Instead, Dr. Driscoll called for a re-education of patients as they enter adolescence and have to take more responsibility for their own diabetes care. In addition, she emphasized key components of behavioral interventions: small, realistic, and achievable goals using positive reinforcement as a means to increase desired behaviors related to diabetes care and adherence. Ms. Spiegel’s talk covered nutritional challenges for children with diabetes. She highlighted data to show that children with diabetes are not meeting basic nutrition goals and outlined overarching guidelines for the timing and amount of insulin needed for large amounts of fat and protein. Ms. Spiegel emphasized, however, that there are vast individual differences in insulin needs from patient to patient. Ms. Messer concluded the session with an overview of available technology for use in pediatric patients with diabetes, focusing on insulin pumps, CGMs, remote monitoring, and the prospect of the artificial pancreas as they apply to a child with type 1 diabetes. Notably, an overwhelming majority of people in the room said they use devices to treat children and teenagers with diabetes, but only a scattering of hands went up when Ms. Messer asked how many people are fully comfortable differentiating between the variety of devices currently on the market. During Q&A, several members of the audience expressed their frustration at poor payer coverage for CGMs. In response, panelists encouraged educators to keep talking about patient needs, which they agreed is the only way to push the needle toward broader coverage. Some audience members also expressed frustration with “Dr. Google:” when parents of pediatric patients trust bloggers over doctors. As a whole, this session underscored the tremendous need for increased literacy surrounding best practices in diabetes care, from drugs to devices to insurance. The conference’s “meet the peers” sessions were a step in the right direction, sparking productive conversations about the latest diabetes knowledge among healthcare providers and educators.
Hypoglycemia and Diabetes
Definition of Hypoglycemia
Phil Cryer, MD (Washington University, St. Louis, MO)
On the topic of the ongoing debate over how to define hypoglycemia, Dr. Phil Cryer proposed the addition to the definition of severe hypoglycemia of a criterion of a plasma glucose <50 mg/dl. Currently, the ADA defines severe hypoglycemia as an event requiring the assistance of another person and defines documented symptomatic and asymptomatic hypoglycemia as a plasma glucose <70 mg/dl with or without symptoms. He suggested that the definition of severe hypoglycemia be expanded to include hypoglycemic events with a self-monitored plasma glucose, CGM, or lab measurement of plasma glucose <50 mg/dl, along with the previously-defined hypoglycemic events requiring assistance from another person. Dr. Cryer prefers <50 mg/dl as the plasma glucose threshold for hypoglycemia because it is unambiguously dangerous, should be scrupulously avoided, and is a clear marker of severe hypoglycemia even if assistance from another person is not required. He did not propose changes to the current consensus on non-severe documented hypoglycemic events, which we appreciate as plasma glucose values <70 mg/dl can still often negatively impact a patient’s quality of life. Dr. Cryer did note that only the plasma glucose criterion of <50 mg/dl should be used to diagnose severe hypoglycemia in children, since pediatric patients typically require assistance no matter the severity of the event. Furthermore, he pointed out that there is tremendous variation in how different individuals experience hypoglycemia and that plasma glucose <70 mg/dl is not necessarily dangerous for all patients. As Dr. Cryer put it, “it’s not possible to cite a specific plasma glucose concentration that ‘defines’ hypoglycemia in diabetes, because the critical glucose concentration varies within and among individuals based on frequency of hypoglycemia, A1c, and other factors.” We imagine it’s possible that, using a stricter <70 mg/dl definition, the FDA has underestimated the benefit of drugs like Novo Nordisk’s Tresiba (insulin degludec) in reducing the risk of more unambiguously dangerous severe hypoglycemia (Novo Nordisk used a confirmed hypoglycemia plasma glucose threshold of <56 mg/dl in its trials for Tresiba). Hard-set or inappropriate hypoglycemia thresholds may oversimplify patient diversity and restrict our full understanding of new medications. We’d love to hear more consensus on different levels of hypoglycemia from key opinion leaders in the field, and for the FDA to consider this heterogeneity when evaluating new drugs and proposed label updates. We do have a growing sense that what payers care the most about is patients avoiding hospital visits and ambulance calls, not particularly avoiding hypoglycemia (however defined).
Hypoglycemia Morbidtity, Mortality, and Cost
Brian Frier, MD (University of Edinburgh, Edinburgh, Scotland)
Dr. Brian Frier offered compelling commentary on the cost of hypoglycemia, from both a physiological and an economic standpoint. The acute morbidities of hypoglycemia – falls, accidents, cardiovascular complications, seizure, cognitive dysfunction, etc. – are well-known, but Dr. Frier pointed out that this is just the tip of the iceberg. We must rethink our view of hypoglycemia and its associated risks, he urged the audience, because hypoglycemia comes associated with a host of other surprisingly long-lasting pathophysiological consequences. Among these are: (i) inflammation, involving elevated levels of CRP, VEGF, and IL-6 for at least two days; (ii) blood coagulation abnormalities, involving elevated platelet, neutrophil, and factor VII activation for up to seven days; (iii) endothelial dysfunction, including decreased vasodilatation; and (iv) neurological issues, including cognitive impairment that can persist for an hour or more after blood glucose has returned to normal and unpleasant changes in mood that can last for hours. Economically, hypoglycemia can involve the direct cost of medical treatment, emergency medical treatment, and sometimes inpatient care, as well as the indirect cost of lost productivity and inability to work. According to a Canadian survey from 2003, the average annual total cost of hypoglycemia to patients was $129 per patient for type 1 diabetes and $78 per patient for type 2 diabetes, with glucagon being the biggest expense.
- Dr. Frier pointed out that there is a bidirectional relationship between cognitive decline and hypoglycemia. Episodes of severe hypoglycemia can provoke cognitive decline and dementia, but those who are already cognitively impaired have a risk of developing severe hypoglycemia. This is an increasingly relevant issue as life expectancy increases and the population of people with diabetes ages and encounters a greater risk of dementia associated with aging.
Q: I’m a pediatric diabetes educator at the University of Minnesota, and I have a child with type 1 diabetes. I’ve noticed through social media and podcasts that a lot of parents feel that our fear of low blood sugar is compromising a child’s long-term health. I see some young patients aiming for very low A1c targets, and I’m torn. If you keep blood sugar too high the long-term effects may be much greater, but you risk short-term effects of low blood sugar. Some people are so fearful of lows that they keep their child high. Others want to be more aggressive with insulin because they’re afraid of the long-term health effects of hyperglycemia.
Dr. Cryer: I’m going to say something pretty strong here – hypoglycemia can kill. The range of reported mortality is in the 4-10% range. That’s over a lifetime, so it’s not terribly frequent. But ladies and gentlemen, you only die once. Severe hypoglycemia can be lethal, so it’s reasonable to worry about it.
Q: What I’m struggling with is if you have a CGM and you can avoid severe lows below 50 mg/dL, but you’re having frequent lows into the 60s because you’re aiming for an A1c below 6%, would this have a long-term effect on children?
Dr. Cryer: The bad thing about plasma glucose in the 60s is not that value in itself, but whether it’s going down or up. If you have CGM that can tell you the trend, maybe you can just watch and see what happens. I don’t think that 60 is going to hurt anyone, but the risk comes if it progresses to 50 or 40 mg/dL.
Dr. Frier: The real concern at that level is not so much sudden death, but impaired awareness of hypoglycemia. This problem may result from exposure to unrecognized nocturnal hypoglycemia over a period of time. One-fourth of patients with type 1 diabetes have some degree of impaired awareness, so I think this is the real complication we should be talking about. For this reason, we have to be very careful in setting targets for A1c.
Dr. Hovorka: To determine the long-term effect of A1c, we need stronger data. You can also look at treatment for different groups, because there are major differences in how different countries approach pediatric diabetes treatment. The Germans and Austrians keep their children much tighter than the US does. This is also one of the reasons CGMs can be helpful. Parents on social media are expressing that they like CGM, but they’re still keeping their children at the same A1c level as they would have without CGM. So there needs to be support from the clinical community, and there need to be tighter guidelines to see A1cs even lower.
Dr. Davis: I empathize with the position you’re in. I’ll tell you that there is a group of patients with type 1 diabetes that absolutely wants to drive A1c down to normal, which is a little bit like jumping off the Empire State Building – you’re subjecting yourself to hypoglycemia unawareness, you’ll see weight gain, and you can expect changes in mood when you become an adult. If you exercise, you see gross problems with hypoglycemia and driving problems. These are the conversations you should kick-start with your pediatric patients.
Comment: That’s precisely my concern over tighter control for very young children. I worry about them keeping their A1c tight with blood glucose in the 60-range. I worry about how they’ll do in school. I don’t know that we have the data that says they’ll be harmed being a little high over a period of time, but we do have data to show that if their blood sugar is low they might experience cognitive impairment.
Dr. Hovorka: It’s a balance between hypo and hyperglycemia. One thing parents are doing is using mobile phones to monitor their children’s blood glucose, which can help ease worries and help parents make a more informed decision between hypo and hyper risks. This is one way to think about things for the future.
Q: With hypoglycemia, our current treatment is glucose, glucagon if necessary, and monitoring. Are there other things that we can do? Is there any discussion on that?
Dr. Davis: It’s a good point. Yes, if you give any anti-thrombolytics you increase blood glucose through the night.
Dr. Cryer: Those studies, we’ve done them. They’re interesting but not terribly important because glucose levels are best controlled by the two hormones insulin and glucagon.
Larry Hirsch (BD, Franklin Lakes, NJ): Looking at the data, I got pretty concerned about long-term effects of hypoglycemia from a cognitive-performance perspective. I’ve been taking insulin for 58.5 years now and I’ve had my share of blows. I’m trying to reconcile what you presented with the follow-up of the DCCT where there were probably 15 tests of cognitive function, and you saw a three-fold difference in severe hypoglycemia between groups, but no difference in cognitive performance. Were those instruments just insensitive? Were those patients immune to adverse effects on cognitive function?
Dr. Cryer: You’re right, the data were convincing that recurrent hypoglycemia had no effects on cognitive function. Dr. Frier spoke to that in his talk, that the vulnerable time is really when the patients are young.
Dr. Frier: Yes, the DCCT data are reassuring, but the DCCT cohort is not typical – they were recruited because they were at low risk for hypoglycemia. There were retrospective studies showing that type 1 patients with five or more episodes of severe hypoglycemia had a small reduction in cognitive function. The data I presented was for type 2 diabetes. I wouldn’t start getting worried – data for type 1 diabetes in older populations are just not there yet because people haven’t lived long enough. We did one study in type 2 diabetes that showed that there was a link between previous severe hypoglycemia and subsequent cognitive decline. This is a worry when treating the geriatric population – if we go for strict glycemic control, which I’m not sure we have to do in this group, we may accelerate dementia. We have to keep in mind the difference between what we know about the effects of hypoglycemia on cognitive function in type 1 and type 2 diabetes.
Dr. Aaron Kowalski (JDRF, New York, NY): Roman, can you apply any learnings from closed loop to open loop?
Dr. Hovorka: People are looking to optimize open loop by looking at closed loop. One big thing you can take from closed loop is that you can’t beat yourself up if you don’t get control on open loop. It’s extremely difficult and there is just so much variability to consider. But to answer your question, I think that’s really something for the individual to assess, not something that can be addressed on a population level.
Q: I appreciate the information on cardiovascular changes during hypoglycemia. Now that we have access to the trend data from CGMs, is anything known about the rate of change? I know that it’s better to keep blood glucose levels as constant as possible and avoid the “roller coaster” – can you speak more about that?
Dr. Hovorka: That is a complicated story. Should we reduce glucose variability? Yes. Without the closed loop, another way to do that is with drugs, such as GLP-1 receptor agonists.
Patient/Provider Q&A Panels: Adult
In this patient-centric panel, a beloved and highly-anticipated tradition at Keystone, four of Dr. Satish Garg’s (University of Colorado, Aurora, CO) patients took the stage to discuss their unique stories of life with diabetes. Their testimonies provoked laughs, tears, and a standing ovation from a packed audience, and this emotional session concluded with a thoughtful and illuminating Q&A session between Courtney, Kimberly, Patricia, and Troy and the audience of providers.
Patient Testimony: Courtney
I had just turned 14 when I was diagnosed with type 1 diabetes – this was in the early 80’s. I started to notice a difference in my moods in late teens and early 20s. I had no idea what it was – in those days, mental illness was never talked about or suggested. By the time I reached college, I was extremely depressed and was sleeping 12-14 hours/day. Everything was centered around that. I also experienced extreme highs where I hardly ever slept, and was always awake with rapid and racing thoughts. My mood went along with my diabetes, and my A1c was very affected by my bipolar illness. My numbers went high especially in periods of depression, because depression slows you down. You don’t test and you miss shots because you’re in your own world.
I couldn’t finish college because of the lack of motivation that came with my depression, so I moved back home. I was in and out of jobs, and bipolar kept me in those patterns. I was lucky to have very supportive parents, but they didn’t know what to do or how to help me. Eventually I was hospitalized, and they misdiagnosed me with major depressive disorder. The antidepressants made things worse, and I was finally diagnosed with bipolar in my early 30’s. Diabetes alone, much less a mood disorder, can be very difficult on marriage. It has been difficult at points, but my husband is my advocate and my provider, and he’s very aware of my symptoms that take place.
2.5 years ago I became completely nonfunctional and was hospitalized again. I started electroconvulsive therapy (ECT) and it saved my life. Urge your patients to do this if it fits for their particular situation. I hadn’t felt that good, that normal, since I was a little girl, and it was amazing. Having that kind of stability in moods – oh my gosh! It helps control your diabetes a lot better. My diabetes made ECT treatment complicated since it requires anesthesia, so I started transcranial magnetic stimulation (TMS), which is an amazing thing, because treatment for mental illness used to be only talk therapy and meds. The fact that other options exist, gives me hope in and of itself, and that’s a wonderful thing.
My diabetes and my bipolar are the two worst things that I deal with, because you don’t know if the ups and downs in blood sugar are causing ups and downs in mood or the other way around. You don’t know what came first. When I am in depressive or manic episodes, it is difficult to keep diabetes right there in front of you, since diabetes changes every minute of every day. Diabetes is manageable but it is affected by so many things, it’s not in a box. I’ve had many surgeries and hospitalizations, and all of these things contribute to messing with my diabetes. I am very blessed to have help with the medical teams I do. Dr. Garg and his staff are amazing, and I’m thankful for my family and friends to get me through it day by day.
Patient Testimony: Kimberly
I’m 46 years old and I’ve had type 1 diabetes for 40 years. In the early days, when I was diagnosed, we did urine testing and my insulin was derived from beef cattle. My A1c was 10, and that was considered good! Over my teen years, and in college, human insulin was developed. This opened the door to control blood sugar better. My A1c went down to between 8 and 9, and that was considered pretty good.
Dr. Garg became my doctor when I was 16, so we’ve worked together for a long time! In college I didn’t take care of myself as well; I wasn’t good about blood sugar testing. I got married at 21, and pregnant at 22. I went in for a checkup and my A1c was 13 – that was quite the wakeup call. We worked very strictly to get my blood sugar down to 7 in just a few months, which was amazing. But at 20 weeks of the pregnancy I became preeclampsic and gained about 40 pounds. Two years later, I was pregnant again. I actually found out because I had to take a pregnancy test before starting pump therapy! During that pregnancy my A1c was in the 5s, and I was told it was almost too low. Despite trying traditional methods of diet and exercise I gained another 20 pounds.
I had a cardiac event at age 38 – a 95% blockage in my right coronary artery. I went to cardiac rehab for several weeks, and learned about diet and exercise. I lost about 40 pounds with the diet and exercise I learned on the cardiac rehabilitation program. But I’ve gained 20 pounds since then, so I’ve vacillated back and forth.
Many of the concerns people with diabetes have is about weight and how to manage it best with diet and exercise. The other thing we deal with is nighttime lows. Midnight comes around, your blood sugar is super low, and you eat everything in the refrigerator – I’m tired of eating those glucose tablets! The other thing that’s concerning is getting support from people who know what you’re going through. People with diabetes are not an equation, and all of our bodies are different.
Patient Testimony: Patricia
I’m a physical therapist and I was diagnosed with diabetes in 1996 at age 26 (you can do the math to see how old I am!). In high school I was heavy but not obese. Gradually, when I decided not to go to college, I gained a lot of weight because I was eating a lot of fast food. I decided I needed to go to college after I began charging groceries to my credit card. And in college I actually lost weight…and was thirsty as all get-out. One of my roommates was a nursing student and she had just studied the chapter on diabetes and the warning signs. I heeded her advice, got tested, and my A1c was 11.6. I was sent immediately to diabetes education classes. My doctors told the diabetes educators – but not me – that I might be type 1 and not type 2, but to still do the classes anyway. I was spilling ketones in my urine, so I began doing injections. Insulin made me gain back 20 pounds – which I was not happy about – but after the dehydration and the fatigue, you get that first insulin injection and you feel like you got your life back.
That was amazing, but the weight gain wasn’t. I gained more weight and my insulin doses increased to 200 units of per day between long-acting and short-acting. I weighed 263 pounds and made the decision to have the lap band procedure. I quickly lost 33lbs, but then plateaued. I kept very strictly with the program, but nothing got me out of that plateau, and I slowly gained all of that that weight back. A proper lady would never tell you what she weighs, but luckily for you, I’m not a proper lady! (Laughs). I weigh 270 pounds today. Because of my weight I had to get a knee replacement, and I know that my other knee will need it at some point too. You think that would be enough motivation: ‘just eat and exercise and the weight will come right off!’ But I failed at every diet out there. I decided that I’m never going to be thin. This is how I am and I have to come to terms with that.
Today I take 145-160 units a day through my insulin pump. With that much insulin I find it very difficult to lose weight. It’s a vicious cycle: insulin makes you gain weight and that makes diabetes more difficult, and then you need more insulin again. Hopefully with a bit more time and two good knees I can start exercising again. And enjoying it like I used to.
Patient Testimony: Troy
Before I begin, I just want to say that before I came up here I was taking care of my low blood sugar. We deal with this 24 hours a day, 7 days a week. Diabetes is a constant struggle.
I didn’t start off overweight. When I was younger I was very athletic; I played football at Texas Tech. I’m just an eater! My problem is that I like to eat. Looking back, I was 35 when I was diagnosed and met Dr. Garg, who I call “The Hammer!” (Laughs). Every time I went in for a visit it was a screaming match! (Laughs.) He’s my hero but what he was trying to tell me was that I had to lose weight. After about 2 years of him banging on me, I decided to get bariatric surgery. It was the best decision. There’s two real key things to know if you have a patient get bariatric surgery. For one thing, at first Dr. Garg wasn’t allowed to come in and help me get my blood sugar down post-surgery. The second thing is to make the patient get up and walk immediately following the surgery. Get active immediately!
I was always in shape, and even went into body building for a time, but as soon as I was diagnosed with diabetes the weight came on and wouldn’t stop. For everybody that’s overweight, bariatric surgery saved my life. I used to weigh 450 pounds. I’ve lost over 100 pounds with the surgery and I’ve kept it all off.
Dr. Satish Garg: I don’t often say this, but I was so scared about how to manage his diabetes after bariatric surgery. The surgeon and I worked together to figure it out, and the outcome has been amazing.
Q: Courtney, can you give us some insight into how the ECT and TMS impacted your blood sugars? During the days, acutely.
Courtney: My A1c runs from 6.8-7.2, but right before ECT I was at 8.6 because I was so depressed. That was 2.5 years ago, and it was done under general anesthetic which is a mess with type 1 diabetes. I typically ran high going into the procedure, but it was mostly out of my hands.
Dr. SatishGarg: Being in a psychiatric hospital, you’re taken away from your insulin so it’s very difficult. Troy, how did you manage your diabetes when you were in the hospital for your bariatric surgery?
Troy: I monitored myself very closely with my Dexcom. It was a constant hassle.
Dr. Satish Garg: He managed it because the surgeon and I talked and decided to let Troy manage himself.
Troy: The hospital folks were very resistant to that! They tried to take away my Lantus. Without Dr. Garg intervening it would have been terrible.
Q: Troy and Patricia, I find it interesting that both of you tried the lap band first. How did you make the decision about which procedure to undergo? And if you were talking to someone with type 1 diabetes and considering surgery, what would you say?
Patricia: I chose the lap band because I work in the hospital and have seen a lot of bad outcomes – infection, feeding tubes – from RYGB. At the time that I did it, all the research said that the weight loss is the same between the two procedures, but just takes longer from the lap band. Going into the surgery, I didn’t have a handle on what an emotional eater I was. The guy giving me the psychological exam was clearly reading the questions the insurance company wanted to have asked. You’d have to be an idiot not to know what answers he wanted! So I told him what he wanted to hear. I wish there had been a better pre-surgery psychological exam. And more than one of them.
Troy: I would go straight to the Roux-en-Y. I don’t know why I wasted my time with the lap band for 6 years!
Q: Did anyone try the weight loss-aiding diabetes medications, like GLP-1 agonists? And what do each of you think is the most important diabetes technology you have – what would you bring with you to a dessert island?
Patricia: I had tried metformin and phentermine and I saw only minimal success with those. Atkins got me to lose about 20-30 pounds but I couldn’t go much beyond that. For technology, I would bring my insulin pump and CGM combo, it is amazing. Dr. Garg has promised me the closed loop system once it’s ready!
Kimberly: I’m on metformin and have been for 15 years. I lost a lot of weight initially, but that was probably from all of the nausea the drug gave me! It’s good for my blood sugar but I haven’t experienced much weight loss. In terms of technology, I’m old school so I would bring my syringes and my insulin. And my glucometer. I don’t like tapes – they pull out, they itch, they give me scar tissue, and the beeping alarms drive me crazy.
Troy: I would take every electronic deal I could possibly have! And in terms of drugs, I tried all those things – all the diets, all the drugs. I’ve lost 100lbs several times and always gained it back. The only thing that stuck was the Roux-en-Y.
Q: I’m wondering if you have any sort of observations about which kind of insulin therapy made you gain or lose weight.
Troy: The pump has helped me regulate things better. I used to be always over-injecting and under-injecting, it was a mess. With the pump it has been easier to keep the weight off.
Kimberly: For myself, when I was on the pump I experienced by lowest lows, which are really scary. For a while I was scared just to bolus because crashing is such a scary thing. I’m on Tresiba now and that’s pretty good; my blood sugar has been very consistent. But certainly with better control you will gain weight.
Q: We have a glucose management service at our hospital and we keep statistics to see how well we’re doing. In other hospitals glycemic control is very poor for patients coming in for other procedures, and we need to fix this.
Dr. Satish Garg: Hospitals tend to put type 1 and type 2 diabetes in the same boat; type 1’s tend to get lost. At the Barbara Davis Center we tell the hospital the diabetes treatment guidelines we want the surgeons to do.
Patricia: I work in a hospital as well. We have on-site diabetes educators. If you’ve had diabetes for a long time – 16 years for me – they should leave you alone and let you take care of it yourself. I can do this better than you can, so just go away with your stuff! (Laughs, applause). But I do think they’re an excellent resource for the newly-diagnosed and the very poorly-controlled.
Comment: I work at a hospital and we work really hard to let patients stay on their pumps throughout their stay. We understand that you want to stay on your pump and we’re trying to work on that!
-- by Abigail Dove, Helen Gao, Brian Levine, Payal Marathe, Lisa Rotenstein, Adam Brown, and Kelly Close