July 17-20, 2014; Keystone, CO; Full Report - Draft

Executive Highlights

In this report, we provide our full coverage of the captivating “Keystone 2014” meeting – more formally known as the Barbara Davis Center Keystone Conference: Practical Ways to Achieve Targets in Diabetes Care (ATDC). Conference directors Dr. Satish Garg (University of Colorado, Denver, CO) and Dr. Jay Skyler (University of Miami, Miami, FL) put together four learning-packed days that included some of the best and brightest key opinion leaders in diabetes. This once-small conference continues to grow wildly in popularity and prominence, with the event sold out weeks in advance – nearly 600 attendees came this year, up ~50% from last year’s ~400.

The program featured 44 talks, along with patient/provider panels and industry-sponsored technology workshops and dinners, up slightly from a year earlier. Rousing discussions touched on the role of biosimilars, cardiovascular disease in diabetes, obesity treatment options, and the payer environment. Keystone’s timing (approximately one month after ADA) and more intimate format provided us with a valuable opportunhity to hear experts’ up close and personal thoughts on the latest topics, trends, and controversies in diabetes. We already look forward to next year’s conference, which will take place July 16-19, 2015 again in Keystone, CO – registration will open in October 2014, so remember to register online early here.

This report organizes our comprehensive coverage into three topic areas: 1) Diabetes Technology; 2) Diabetes Drugs; and 3) Additional Topics. Immediately below, you will find the broad themes that came up throughout the conference:

• Increased costs of diabetes drugs;
• Impact of biosimilar insulins;
• A focus on automating insulin delivery;
• Exciting diabetes technology in companies’ pipelines; and
• Critiques on CVOTs for diabetes drugs.

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.

Themes

Diabetes Technology

• Automated insulin delivery was a major focus of Keystone 2014, and we heard optimism from multiple groups (including the FDA!) on the future of the technology. Most notably, we heard from the FDA’s Dr. Courtney Lias (Director, Division of Chemistry and Toxicology Devices), whose keynote presentation on the artificial pancreas (AP) was perhaps the most optimistic and encouraging we’ve ever seen from the Agency – she commented that approval of closed-loop technologies will happen “sooner than you think” and shared encouraging Agency perspective on device consolidation, mobile technology, and “component artificial pancreas systems” (in which different companies sell different components of an AP system). We continue to view the latter with a degree of skepticism, given the logistical and regulatory challenges that would come with such a system. Nevertheless, her talk was highly encouraging for patients and industry, and provided a positive sign that the Agency is motivated to move automated insulin delivery forward. We also give sincere kudos to the Keystone conference organizers for getting FDA in the building! Meanwhile, Dr. Ed Damiano (Boston University, Boston, MA) outlined tentative plans for final pre-pivotal bionic pancreas studies in 2015, including a chronic glucagon exposure study, a bionic pancreas glycemic set point study, an alcohol tolerance clamp study, and an additional pediatric study. We also heard from Dr. Boris Kovatchev (University of Virginia, Charlottesville, VA), who discussed UVA’s Diabetes Assistant – notably, it has been approved by the FDA for a three-month, at-home, unsupervised pilot study to assess efficacy and safety.
• We also heard multiple perspectives on the pros and cons of bihormonal vs. insulin-only artificial pancreas systems. Drs. Kenneth Ward (OHSU, Portland, OR) and Ed Damiano were among the strong advocates for bihormonal systems, stressing the tighter glycemic control enabled by glucagon dosing; Dr. Ward emphasized that present insulin formulations are unable to mimic physiological insulin, a limitation that glucagon can help overcome. Conversely, the renowned Dr. Fran Kaufman (Chief Medical Officer, Medtronic Diabetes, Los Angeles, CA) provided a more business-like perspective on this issue – while she acknowledged the merits of glucagon, she questioned whether the additional cost and complexity of bihormonal systems will exceed the slightly improved glycemic control. We agree that the cost of glucagon remains a major question, and one that is somewhat unanswerable at the moment until a stabilized glucagon is approved and until it is used over time. The current proxy for glucagon pricing is ~$200 for a 1 mg rescue kit, which is much higher than a stabilized glucagon will likely cost. Dr. Kovatchev also threw his hat into the ring, noting that options for a second hormone are not limited to just glucagon – pramlintide can also help overcome the current limitations of insulin kinetics.
• Industry-sponsored events provided detailed insight into the future of Medtronic and Dexcom’s pipelines – both will be focused on better sensors (Enlite 3, G4AP), while Medtronic will drive towards automated insulin delivery and Dexcom will build towards greater connectivity.
  
  • Though Medtronic’s artificial pancreas progress has been somewhat veiled (“We’ve been secretive about it.”), Dr. Fran Kaufman (Chief Medical Officer, Medtronic Diabetes, Northridge, CA) acknowledged that the company is presently conducting multiple feasibility studies and has met with the FDA to discuss a pathway to US approval. Notably, she said that Medtronic’s plan is to develop a hybrid closed-loop system that features a 24-hour algorithm with manual boluses for food before transitioning to a fully automated system. Dr. Kaufman also implied that the Enlite 3 sensor with intelligent diagnostics is likely to be utilized in the company’s upcoming closed-loop system, and the Medtronic MiniMed 640G predictive low glucose management system may be available by the end of the year (or even “before”!). Dexcom’s pipeline is also very full, including the cloud-based SweetSpot software (no timeline provided, but clearly in the works), ongoing feasibility trials on Gen 6, a reinvigorated integration partnership with Insulet, smaller transmitters, new algorithms to support longer sensor life, accuracy/reliability in non-adjunctive use, and factory calibration. CEO Mr. Terry Gregg said that no decision has been made on whether to make the much improved G4AP algorithm available soon or to wait for Gen 5.

Diabetes Drugs

• A provocative presentation by Dr. Irl Hirsch (University of Washington, Seattle, WA) stimulated much discussion on the soaring cost of diabetes drugs. Dr. Hirsch expressed immense frustration with the rising costs of insulin in particular, which he feels have restricted patient access to the best treatments and discouraged payer investment in insulin analogs (as covering them may actually be more expensive than paying for increased emergency room visits for hypoglycemia, at least according to Dr. Hirsch’s back-of-the-envelope calculations). His talk stimulated an energetic panel discussion on the rising costs of diabetes drugs as a whole. Drs. Hirsch and Matthew Riddle (Oregon Health & Science University, Portland, OR) both defended the use of less expensive therapies like sulfonylureas, TZDs, and human insulin despite the availability of newer drug classes with more favorable clinical profiles. In a separate panel discussion, Dr. Hirsch and Professor Philip Home (Newcastle University, Newcastle upon Tyne, UK) lamented the fact that the US “is being asked to fund all the innovation” in the diabetes pharmaceutical arena, as companies compensate for the strict price limits set by government-run healthcare systems in other countries by raising prices in the US. The audience of HCPs appeared very receptive to complaints about cost, and Dr. Hirsch is correct that rising prices for diabetes drugs cannot continue indefinitely.
• The uncertain impact of biosimilar insulin was also a major topic of discussion. Professor Home gave a comprehensive presentation on what he feels is required for clinical confidence in a biosimilar product, stressing the need for clinicians and regulatory agencies to evaluate the entire data package rather than relying on a single parameter such as clamp studies alone. He predicted that manufacturers’ reputations will serve as a stand-in for quality in many people’s minds, given the lack of access to data on the insulin production process – good news for companies like Lilly that are well-established in the insulin market, though less positive for less well-known biosimilar players like Biocon/Mylan. The net impact of biosimilars on the cost of insulin is unclear – if they are treated as equivalent to generic small-molecule drugs, they could drastically reduce prices and improve access for patients. Drs. Home and Hirsch both speculated that the anticipation of such a price cut is a major reason that insulin companies have raised prices so dramatically in recent years – indeed, our Diabetes Industry financial model suggested that insulin provided a 61% share of the industry’s growth in 2013, up from 37% in 2012 and 33% in 2011 (of course, some of this acceleration also stems from a slowdown in DPP-4 inhibitor growth). Additionally, it remains an open question to what extent clinicians and patients will view biosimilar insulin as a viable alternative to branded formulations like Sanofi’s Lantus (insulin glargine), especially considering the possibility of slight structural differences that could impact the clinical profile.
• Not surprisingly, the issue of cardiovascular outcomes trials (CVOTs) for diabetes drugs came up repeatedly at Keystone. FDA Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) panelist Dr. William Hiatt (University of Colorado, Denver, CO) recounted the controversy over rosiglitazone that led to the FDA’s 2008 CV Guidance and provided some thoughts on the costs and benefits of that policy. While it was difficult to gauge his overall viewpoint, he did express some concern about the enormous cost of running massive CVOTs that have so far produced relatively little valuable data. Dr. Jay Skyler (University of Miami, Miami, FL) expressed more explicit frustration with the design of ongoing CVOTs, arguing that the trials are too short to provide meaningful information about long-term CV outcomes and that they should over-enroll patients with pre-existing cardiovascular disease, given that prevention of cardiovascular complications in patients without CVD is the primary goal of diabetes therapy rather than the mitigation of risk following an event. In Q&A, both Drs. Hiatt and Robert Ratner (ADA, Alexandria, VA) suggested that the FDA may be willing to review the appropriateness of the 2008 Guidance; the open hearing on August 11 regarding the reporting of interim CVOT results was a first step and we hope to see the Agency begin a more comprehensive dialogue on this topic.

Diabetes Technology

Keynote Presentation

FDA Perspective on Closed-Loop Studies

Courtney Lias, PhD (Director, Division of Chemistry and Toxicology Devices, FDA)

The audience was overflowing at Dr. Lias’ keynote talk addressing FDA perspectives on closed-loop devices. Emphasizing the “exciting” progress in this field, she also detailed the “many” challenges that will precede commercialization – her comments drew particular attention to the complex underlying pathophysiology of the disease as a larger hurdle than even device limitations. Looking ahead, Dr. Lias stressed that opportunities for industry growth will abound in the near future, as the FDA is particularly interested in device consolidation and “component artificial pancreas systems” with parts sold from multiple companies. In addition, the FDA anticipates that the growth of mobile technology will play a central role in this consolidation, a sentiment that reflected more openness and less caution than we can recall from past FDA talks. In closing, Dr. Lias dismissed many “common misconceptions” associated with FDA approval, stressing that the FDA is not anticipating or requiring that closed-loop systems be “perfect” solutions. We were very glad to hear this for the sake of patients and providers and society.

• Dr. Lias opened her talk by stressing that “the FDA’s mission is not to squelch innovation”; rather, closed-loop systems fall under the umbrella of “promoting public health.” We were pleased to hear her acknowledge that the FDA recognizes the increased risks and diminished quality of life that are associated with diabetes. Notably, it appeared that the FDA considers the artificial pancreas a practical therapeutic option. This was the most direct response we can recall ever hearing to comments that the FDA is a roadblock to innovation. The device side of the Agency has been much more open, flexible, and responsive in the past 18 months, and it was good to hear Dr. Lias openly responding to these criticisms.
• Noting that artificial pancreas approval will happen “sooner than you think,” Dr. Lias shared particular excitement regarding home and camp studies of closed-loop systems. She applauded clinical trials in camps for “stressing the system” by putting adolescents in novel environments and robustly testing the limits of devices. She also noted that the FDA is looking forward to the findings of upcoming home studies that will test the devices in even more practical, real-world settings.
• The FDA is “100%” behind the growth of mobile technology as a method of facilitating device consolidation. Dr. Lias expressed apprehension that the number of devices (e.g., meter, CGM, pump receiver) in closed-loop systems will contribute to frustration and non-adherence in patients. Given that nearly everyone carries a cell phone, the FDA recognizes that mobile platforms provide a convenient potential solution for consolidation. Notably, Dr. Lias reported that the FDA is working closely with industry on requirements for mobile technology market entry and security, evidenced by their guidance on mobile medical apps issued in September 2013. We consider these comments very encouraging news not only for the future of closed-loop systems, but also for the growth of mobile technology in diabetes self-management more broadly.
• The FDA envisions the future of the closed-loop industry to consist of “component artificial pancreas systems,” in which different companies sell different components of a device. In such a system, a consumer would be able to purchase an algorithm on an app separately from the pump and sensor it communicates with. Such an arrangement would facilitate much greater patient choice and more competition within industry, though it also brings up many tough questions: How would the regulation process work for individual components? Would standards be developed to govern how components interface with each other? Who would develop such standards? How would companies collaborate to develop compatible platforms? Reservations aside, we enthusiastically applaud the FDA’s ambition and vision (as did multiple members of the audience) to foster this innovation.
• Dr. Lias acknowledged that the diabetes population is at risk to begin with, so “it does not make sense” to try and develop a closed-loop device with zero risk. Instead, the approval process is made “in the context of the significant risk people with diabetes face every day.” We were happy to hear this perspective emphasized from the FDA, as the perception for many (incorrectly in our view) is that the Agency often seems to err on the side of “perfection or bust” for many devices and drugs in diabetes. The recent move to flexibility and openness on the device side is welcome for all stakeholders in diabetes, especially industry and patients.

Questions and Answers

Q: I have a question about the Dexcom G4 not being reliable in pediatric populations. Can you share the numbers regarding that?

A: It’s not that it’s unreliable. It’s approved and it’s reliable. However, if you look at the product insert, you’ll be able to see the data yourself. The tables are there with adult and children data, and you can compare it. What happens is that the sensor tends to miss alarms more often in the hypoglycemic range in children. People just need to be aware of that and make a decision that’s appropriate for them.

Dr. Peter Chase: I would add that some of those Dexcom studies have been repeated in children, and it is very similar to data in adults. So the guidelines on the pediatric part will likely be changed in the near future. You were talking about different stages of low glucose suspend. All of us thought that the next stage would be control-at-night, where people don’t have to worry about exercise, stress, eating, and whatnot. Is there anything you can add to the decision of skipping nighttime control and going straight to whole closed-loop?

A: It’s not so much a decision; it’s just not a requirement. FDA wouldn’t be hesitant to allow someone going to full closed loop without doing baby steps. Nighttime control is important. Any closed loop device has to look at performance at night. It’s a matter of looking at both things at once. In device development, you need to assess and mitigate the risks of that device for its intended purpose.

Q: You mentioned that the FDA would try to get companies to cooperate in developing products. How do you plan on doing that?

A: We can’t mandate they work together. We can encourage it, though. We begin by talking with them, often in a large forum, explaining the issues that need to be solved. Sometimes, these companies are starting to work together already and come to us for guidance in how they can interact. In that case, we can help them in planning for these things. However, when people don’t want to work together, it’s difficult to get cooperation. We do have other ways to put pressure on them though. We could even make it a public issue, for example, and make the information regarding cooperation public in order to put pressure on them that way. You have to remember, too, that you – the users – have a lot of leverage as well. Companies depend on consumers, so think about that as well.

Professor Philip Home (Newcastle University, Newcastle upon Tyne, UK): I’m from outside the US. Tell us from within the Agency, what has been a problem in benefit/risk assessment? Sometimes, it seems as if they are maximizing safety issues and minimizing benefit evidence. It ends up feeling like they’ve been working against us. Once you begin to increase risk, it seems like you decrease benefit very quickly. Any comments about how different divisions put input into approvals?

A: Yes, there are different cultures in the FDA and different levels of risk tolerance. Diabetes has been nice in that we have been working with the diabetes community for a long time. A couple years ago, the center did change the approach to regulation of artificial pancreas devices. The Center decided to consolidate under one group so it was more streamlined. This helped manage the process better and helped make it go more smoothly. I do think it has helped. We’ve made a lot of progress in last few years in trying to get the balance better.

Q: Is there a way to link the EMA and FDA guidelines? Because current guidelines for closed-loop systems are very different.

A: You are right – they are very different. We occasionally talk with the EMA, but perhaps not as often as we should. We’re happy to talk with them though. One of the main things is that there are almost no requirements regarding CGMs in the EU – Very few. However, I think once we get to the artificial pancreas, the EU has more requirements. After all, ideally, we don’t want to have totally different requirements for approval in the US and EU. We want to allow companies to do one study and receive approval here and there. In doesn’t make sense to wait three years to bring a device to the US after it’s been approved in the EU.

Plenary: Closed Loop Therapy – State of the Art

Closed Loop Experience in Children and Adolescents

Tadej Battelino, MD (University Medical Center, Ljubljana, Slovenia)

Dr. Tadej Battelino presented on the DREAM consortium’s work on the MD-logic artificial pancreas system, which has demonstrated safety and effective in children and adolescents over thousands of nights. Dr. Battelino reviewed results of the DREAM 3 overnight camp study (published in NEJM), which demonstrated significantly reduced hypoglycemia episodes (from 22 to 7), time spent in hypoglycemia, and median overnight glucose under closed-loop control. He then presented data from the consortium’s six-week home use study, DREAM 4 (presented at ATTD 2014). Results showed a four-fold reduction in hypoglycemic events and a subsequent benefit on hypoglycemia. Ongoing studies include a 24-hour home study, a 24-hour home study without online supervision, and an exercise study. The consortium is currently searching for partners to bring this system to market; more data is expected at ATTD 2015.  Bringing academic systems to the commercial marketplace remains on of the biggest unanswered question in the field of artificial pancreas research – some have proposed the creation of small companies to take academic systems through FDA approval (“The artificial pancreas: current status and future prospects in the management of diabetes.”), though others believe only experienced insulin pump players have the capacity to bring such system to market. There are of course pros and cons to each approach, and we’ll simply have to wait and see what happens.

Wearable Artificial Pancreas

Boris Kovatchev, PhD (University of Virginia, Charlottesville, VA)

Dr. Boris Kovatchev discussed the characteristics that will define the next generation of closed-loop systems. In line with other talks he has given, he asserted that these devices will be “mobile medical networks” and modular systems capable of consolidating the multiple platforms involved (measuring blood glucose levels, computational algorithms, and injecting hormones). Dr. Kovatchev stressed the need for device redundancy and distributed signal processing among the CGM, the pump, and a smartphone – if any component fails, the system needs to “degrade gracefully” and keep the patient safe. He proposed three independent treatment modalities dedicated to different aspects of managing glycemia and keeping patients safe: (i) a continuous algorithm dedicated to preventing hypoglycemia and improving the reliability of the pump; (ii) an algorithm for correcting postprandial hyperglycemia (as needed); and (iii) an overnight basal rate modulator. UVA’s “Diabetes Assistant” (DiAs) employs just such an approach. Notably, we learned in early June that the FDA has approved the DiAs for a three-month, at-home, 24-hour/day pilot study of the DiAs hybrid closed-loop system; the study seeks to collect efficacy and safety data in order to inform a larger, international clinical trial by mid-2015.

• On June 6, the FDA approved an at-home pilot study of the DiAs over a three-month period; the multi-center trial will include locations at UVA, UCSB/Sansum Diabetes Research Institute, Stanford, University of Padova (Italy), University of Montpellier (France), and Schneider Children’s Medical Center of Israel. The study will assess unsupervised daily and overnight use of the DiAs – coupled with manual mealtime bolusing – in adults with type 1 diabetes (n=48). The closed-loop system will consist of a Dexcom G4 Platinum CGM and Roche Accu-Chek insulin pump wirelessly connected to the DiAs algorithm running on a smartphone. The study is partially based on the ongoing five-day home trials of the overnight artificial pancreas (a study we wrote about in diaTribe here). The goal is to collect safety and efficacy data in order to inform a larger, international clinical trial by mid-2015.
  
  • The FDA is currently considering a request to extend this study to six months for a smaller group of select patients.
• Dr. Kovatchev stressed that next-generation closed-loop systems will be modular networks – informed by a “body sensor array” – that enable distributed computing. He described a system in which a smartphone could function as a “System Hub” that includes a control algorithm and graphical user interface interacting with both the cloud and local devices (i.e., sensor, pump). Sensors might consist of multi-unit arrays (e.g., one sensor on your wrist and ankle) in order to improve accuracy and establish redundancy.
• Future closed-loop systems must be designed for redundancy in case one or more components fail. The device should be able to run with a CGM alone; a pump alone; open loop control with SMBG and a pump; “advisory mode” with SMBG, CGM, and a pump; and, of course, closed-loop control. Such varied functionality could also be utilized to enable individualization of care, allowing patients to fluctuate between the various states, if desired. Considering the wide variety of patients that will go on closed-loop, we agree that a spectrum of automation will be critical.
• Dr. Kovatchev stressed the utility of three independent algorithms that he believes are necessary in order to mediate efficient and safe glycemic control:
  
  • Safety First – An algorithm that works continuously to prevent hypoglycemia, the primary objective of any closed-loop system. This algorithm is designed to act as an adjunct to a sensor-augmented pump, supervising the safety of insulin delivery and accuracy of the sensor to detect failures. This algorithm is responsible for alarms and for rescue actions (e.g., glucagon). Notably, Dr. Kovatchev stressed that such a system should be able to intervene and interrupt a bolus, overriding a patient’s discretion if the algorithm calculates that a particular insulin bolus would lead to hypoglycemia.
  • Control-to-Range – A postprandial algorithm that works when needed to correct hyperglycemic excursions. Dr. Kovatchev stressed that this modality, another adjunct to sensor-augmented pump therapy, would be silent if open-loop treatment was optimal. Dr. Kovatchev shared data from his group’s artificial pancreas technology, presented at ATTD 2014, illustrating how such a system might handle a missed meal bolus. The group performed an eight-hour crossover trial of daytime closed-loop control in adolescents (n=16), who ate a 30-g snack at 9 am with no bolus before consuming an “underbolused” lunch. Patients in the closed-loop condition had statistically significantly lower postprandial excursions compared to open-loop control.
  • Overnight Control-to-Target – This basal rate modulation algorithm works continuously to bring patients within a particular range following dinner and sliding to a target glucose level of 120 mg/dl by the morning. Dr. Kovatchev noted that this modality functions as a replacement of sensor-augmented pump therapy and shared additional data from his group evaluating such a system, presented at ADA 2014. This five-day study of overnight closed-loop control improved mean nighttime glucose to 139 mg/dl (vs. 168 mg/dl with open loop), increased nighttime time in target to 85% (vs. 60%), and reduced nocturnal hypoglycemia to 0.6% (vs. 2.1%), while even improving subsequent daytime open-loop glucose control. This study now continues at three centers that include Mount Sinai, Mayo Clinic, and UVA (where it continues at home).
    • Dr. Kovatchev remarked that a similar overnight, 2-month at-home study (n=16) was recently completed in Italy, France, and Holland (Amsterdam Academic Medical Center). A second group of 16 patients is scheduled to begin on September 8.

Bihormonal Bionic Pancreas

Ed Damiano, PhD (Boston University, Boston, MA)

Dr. Ed Damiano presented on the recent progress of his team’s work on the bihormonal bionic pancreas, providing new guidance on plans for the final pre-pivotal studies in 2015. Most notably, Dr. Damiano revealed plans for four 2015 studies under development that would take place before the planned pivotal studies in 2016. These include a chronic glucagon exposure study (which Dr. Damiano stated would likely occupy much of 2015), a bionic pancreas set point study (which he hopes would take place in 1H15), an alcohol tolerance clamp study (which could take place as early as 4Q14), and an additional pediatric study (which would take place in summer of 2015). These studies are not funded at this time, and he and his clinical collaborator, Dr. Steven Russell (Massachusetts General Hospital, Boston, MA), will be seeking funding over the coming months from various foundations to support these studies. The remainder of his presentation was similar to his talk a few weeks ago at CWD/FFL, including a discussion of the Beacon Hill/Summer Camp Studies (covered in detail in our ADA 2014 report and published on June 15, 2014 in NEJM), results from the first two patients in the multicenter study (which were consistent with those of the Beacon Hill Study), and a reminder of the 2014 Summer Camp Study, which began on July 20 and completed on August 15 – this is a similar study to last year’s 2013 Summer Camp Study, but with much less monitoring and much younger participants (ages 6 to 11).

• Dr. Damiano showed results from the first two participants in the team’s recently started 11-day multicenter home study of the bionic pancreas (n=40 at four centers). The first patient had an average glucose level (over 11 days) of 133 mg/dl with <1% of the time <60 mg/dl. The second patient had similar results – an 11-day average of 132 mg/dl and 0% of the time spent <60 mg/dl. These encouraging results are consistent with those observed in the Beacon Hill Study.
• Dr. Damiano did not mention the Bionic Challenge fundraising campaign, first announced at the Children with Diabetes Friends for Life conference earlier this month. The team is currently looking to raise funding with the GO BIONIC Challenge over the 60-day period between July 1 and September 1 to fund the development of the Bionic Pancreas final pivotal device. The fundraising time crunch to build the pivotal device stems from federal funding opportunities over the next nine months – this could support all of the clinical costs of the pivotal study, but for the reviewers to take it seriously, the final pivotal study device will need to be completely built by then. For more details, see our detailed coverage of Friends for Life 2014.

The Role of Glucagon in Closed Loop Treatment for T1D

Kenneth Ward, MD (Oregon Health & Science University, Portland, OR)

Dr. Kenneth Ward discussed the challenges associated with developing a glucagon formulation that could be used for the closed loop (he touched upon this subject during a broader presentation at last year’s ADA. His presentation sought to address concerns that high circulating insulin levels and the depletion of liver glycogen may be associated with glucagon ineffectiveness. He shared data illustrating that, in fasting persons with type 1 diabetes, glucagon doses lose their effectiveness only when plasma insulin concentrations rise above 40 μU/mL. Encouragingly, the depletion of liver glycogen appears to be unlikely in type 1 diabetes patients who are eating “normally” (we’re not clear how this is being defined, since diets among patients with type 1 vary considerably). Based on these findings, Dr. Ward expressed confidence that glucagon dosing can be administered in a consistent and effective manner. However, he stressed that developing a stable, pumpable glucagon remains the biggest challenge to the practicality of a bi-hormonal system. He presented his group’s findings from animal studies with a novel curcumin-ferulic acid stabilized glucagon formulation – Dr. Ward’s “favorite” formulation to date – that prevents fibrillation for seven days while maintaining a consistent pharmacodynamic profile (data was first shared on this at ADA 2014). In closing, Dr. Ward piqued our curiosity with a hint at “sensing catheter” technology in development at his company, Pacific Diabetes Technologies, Inc., that seeks to combine a sensor and infusion set into a single skin penetration – preclinical data on this project was also shared at ADA in late-breaking poster 69-LB.

• Dr. Ward stressed the tighter glycemic control enabled by a bihormonal system relative to an insulin-only system. He emphasized that present insulin formulations are unable to mimic the rapid pharmacodynamic and pharmacokinetic profile of physiological insulin. Not only does glucagon counteract the effects of insulin, but its more rapid pharmacodynamic profile enables much more accurate dosing. During the panel discussion, Dr. Ed Damiano (Boston University, Boston, MA) unsurprisingly agreed with the bihormonal approach, while Dr. Boris Kovatchev (University of Virginia, Charlottesville, VA) noted that the second compound in a bihormonal system does not necessarily need to be glucagon.  
• Though glucagon loses its effectiveness at high circulating insulin levels, Dr. Ward asserted that there is a significant range of “optimal” insulin levels within which glucagon maintains its efficacy. His group has carried out studies in which single doses of glucagon were administered to patients (n=10) at steady state insulin levels under fasting conditions. These results have demonstrated that plasma insulin concentrations less than 40 μU/mL tend to maximize glucagon effectiveness, while glucagon is likely to be less effective when insulin concentrations exceed that level. Noting that glucagon should remain effective at even higher insulin concentrations in the postprandial state, Ward expressed confidence that glucagon can be administered in a consistently effective manner.
• Depletion of liver glycogen is not a concern in type 1 patients who are eating “normally.” Dr. Ward shared unpublished data from his group, in which patients with type 1 diabetes (n=7) were given eight small doses of glucagon (2 ug/kg) in succession under fasting conditions. Even after the eighth dose, patients still seemed to have a good supply of glycogen, and their blood glucose still rose in response to glucagon delivery. This finding is certainly encouraging, but given the potential for inter-individual variability in liver glycogen storage, more data on this front from a larger sample size would certainly be welcome. We also wonder how the results would change in type 1 patients who tend to eat lower carb.
• Commercially available glucagon is too unstable to be used in pumps, though a number of new formulations (including a curcumin-ferulic acid stabilized formulation) hold promise. Dr. Ward reviewed that when glucagon is in solution, it rapidly forms fibril aggregates. However, the Oregon researchers are experimenting with the combination of the polyphenolic compound, curcumin, and ferulic acid. This formulation has shown much lower levels of fibrillation than regular glucagon at seven days and still demonstrates the same rapid kinetics as fresh glucagon, leading Dr. Ward to label it his “favorite” compound to date.
• Consolidation of artificial pancreas platforms will represent the next generation of closed-loop technological improvements. Dr. Ward’s company, Pacific Diabetes Technology, Inc., is in the process of combining a sensor and infusion set into a “sensing catheter.” As opposed to options like the Medtronic MiniMed Duo that involve two skin penetrations, Pacific’s “sensing catheter” appears to wrap the sensor element around the infusion set channel for only one single skin penetration. The slide stated that the “sensing catheter” is currently for research only. Preclinical data on this project was also shared at ADA in late-breaking poster 69-LB.

Panel Discussion

Q: This is a question related to glucagon used in the bihormonal bionic pancreas. Are you using glucagon just off the shelf? Or are you using anything that’s modified?

Dr. Ed Damiano (Boston University, Boston, MA): We’re actually just using off-the-shelf Lilly glucagon – the red kits that we all see in our refrigerators. We’re constituting that every 24 hours. We have an IND exemption from the FDA to use it in our studies for up to 24 hours for each reconstituted vial. Subjects get a bunch of kits and change the cartridge out daily and change insulin every other day. We’ve acknowledged that Lilly glucagon is not chemically stable. We’re looking at this and will look at clamp studies and chronic exposure studies.   

Q: Just to clarify, glucagon is primarily not used for rescue, correct?

Dr. Damiano: Yes, that’s right. We give glucagon in small microdoses. The largest dose we give is 80 micrograms in someone who is 70 kg or larger. However, we can add multiple doses in an hour, so you can receive larger doses than this over several five-minute steps. Our goal is to prevent hypoglycemia, not respond to it. In fact, our device can give glucagon when CGM glucose levels are as high as 180 mg/dl, if it is dropping quickly. And even when the CGM glucose is particularly low, such as around 60 mg/dl, we are still treating hypoglycemia.

Q: When you showed studies of different insulin levels and the effectiveness of glucagon, I noticed that at low doses of glucagon, there was a higher response of glucose output from the liver with the highest insulin infusion. It didn’t go up as you ramped up glucagon, but it was higher than at the medium and low infusion rates. I’m puzzled by that.

Dr. Ken Ward (Oregon Health & Sciences University, Portland, OR): The best way to explain this is that studies with tracers require these non-steady state equations, and there’s always varying glucose. So it’s noisier than we’d like. We have to stand back at look at the big picture. Either way, there were no statistically significant differences.

Q: We’re seeing encouraging results with the insulin-only closed loop. Type 1 diabetes isn’t a disease of insulin deficiency alone. I’d like to hear the panel discuss what will really be the ultimate closed-loop pancreas. Insulin-alone or bihormonal? To me intuitively, bihormonal makes more sense. But I see beautiful results from the insulin-only closed loop.

Dr. Ward: There’s a paper from 2010 with Jessica Castle as the first author. Our system was a PID based system before we added in a glucagon element. We definitely saw improvements in the bihormonal model. Now, there’s an ongoing similar study in Canada. From these two groups, I’d argue you’d need both. Because there’s a marked difference in the PK/PD of glucagon.

Dr. Damiano: I’d like to add that the results we’re seeing in other investigators’ insulin-only systems are encouraging and are far better than conventional treatment. However, what I like about bi-hormonal systems is that they do two things: one, they allow for spontaneity in life. You can’t predict what you’re going to do and what blood glucose levels are going to be one to two hours from now. And two, even if you can dose insulin perfectly, life is going to throw curveballs at you. What happens if you have to run after a bus, for example? The only way to deal with that in insulin-only systems is to eat carbs.

Dr. Boris Kovatchev (University of Virginia, Charlottesville, VA): It is important to note that the second hormone does not have to be glucagon. Insulin and pramlintide seem to be wonderful for blunting postprandial excursions. It suppresses glucagon in the process and allows for rebound after meals, which prevents overshooting with insulin doses. It should be tried as an add-on. It has been looked at, but larger studies are needed.

Dr. Tadej Battelino (University Children's Hospital, Ljubljana, Slovenia): Dr. Jay Skyler told us it’s very difficult to predict the near future. What I see is that there are faster insulins coming out. So if we have a faster insulin, our closed loop system can probably do it. Physiologically, I agree we have glucagon. But it could induce hyperglycemia. We built the algorithm as bihormonal. Our algorithm can immediately add glucagon to it. But our goal is to go to patients.

Q: Dr. Battelino, in most of your studies, you focus on the closed loop at night. In the daytime, you take on open loop. Why do you focus only on night?

Dr. Battelino: We want to see this actually with our patients because we clearly see need. And a sure way to do this was using night. There are 24-hr closed loop systems. But breakfast is the trouble and it’s an issue that we’re working on. It’s a trade-off of building as quickly as possible with getting it into routine clinical use. We’re physicians who are treating young people with diabetes. Our vision is to come to the patients.

Q: With ultra-rapid acting insulin, we may not need glucagon. Where are we with ultra-rapid acting insulins?

Dr. Ward: We have researchers looking at several of these. There is a Biodel group adding EDTA to an ultra-rapid acting formulation to pull out zinc and improve the speed of absorption. But it is not as good as our own physiological insulin. Another group is adding hyaluronidase to increase the dispersion. Several large companies are working on it and not talking about it. I don’t think it’s going to happen in the next couple of years.

Q: I think as a community, we’re knowledgeable about side effects of long-term insulin use. But we don’t know much about long-term glucagon use. So regarding some of the side issues, like glucagon antibodies and other things that may happen in the paracrine system with islets, do we know anything about using glucagon for such a long time?

Dr. Ward: We don’t have good data on this. But there are people who’ve regularly used glucagon on kids with nesidioblastosis. We believe it’s less immunogenic than insulin but haven’t looked at it carefully. We definitely need more studies.

Q: Do we know about antibodies?

Dr. Damiano: I believe most of us don’t measure them.

Dr. Irl Hirsch (University of Washington, Seattle, WA): I think that simple things like glucagon antibodies should be measured in the future.

 Q: The Xeris formulation uses DMSO, which is toxic. How much of that is going to be accumulated with administration over time?

Dr. Damiano: We’re giving minute doses and keeping plasma glucagon levels (and in the normal fasted range most of the time). But I should have mentioned that there are other applications of Xeris glucagon that are being studied in other clinical trials, and our doses are much smaller than those. So we’re confident that it’ll be okay. However, a chronic exposure study before the final pivotal study may be necessary, and that is why we’re looking into that in 2015.

Plenary: Special Issues in Diabetes

The Role of CGM in Achieving Glycemic Targets

Howard Wolpert (Joslin Diabetes Center, Boston, MA)

In an impressively wide-ranging talk, Dr. Wolpert spoke about the utility of CGM and strategies for maximizing the technology’s potential (an update from his presentation at ENDO 2014). Dr. Wolpert acknowledged that the decision to use CGM involves a tradeoff between significantly improving hypoglycemia awareness (“the real benefit of CGM”) and the hassles associated with sensor inaccuracies and nuisance alarms. He expressed confidence that recent technological advances have put the industry at an “inflection point” at which the overwhelming benefits will soon be realized by society. Dr. Wolpert also shared his views on interpreting CGM downloads, emphasizing the utility of “Modal Day Statistics” in identifying frequent trouble spots. In closing, he shared his Joslin group’s approach to alarm optimization, noting that their procedure of trial-and-error replicates many features of setting basal rates on insulin pumps.

• Dr. Wolpert noted that the adoption of CGM entails a trade-off that must be assessed on a per person basis. Indeed, he suggested that the only patients for whom the quality-of-life benefits of CGM tend to significantly outweigh the issues with sensor inaccuracy, burnout, and alarm fatigue are those suffering from significant hypoglycemia unawareness and those with the greatest risk for episodes of severe hypoglycemia. However, he believes that recent technological advances are going to shift this trade-off toward favoring CGM use in the coming years – “We are at an inflection point for accelerated adoption,” he said. We imagine the upcoming move to more automated insulin delivery (e.g., Medtronic’s MiniMed 640G) and sending sensor data to mobile devices (Dexcom’s Share, Gen 5) will play a key role in this shift.
• Dr. Wolpert highlighted the need for data examining sensor adherence, as it is a key predictor of patients that benefit from CGM. Dr. Wolpert noted that the Dexcom G4 Platinum has already made impressive strides on the accuracy and reliability fronts – especially in comparison to the “less accurate” Medtronic Enlite – but that the lack of data on sensor adherence may be limiting clinical adoption of the technology. Dr. Wolpert emphasized that randomized control trials are of little value in predicting real-world adherence, given the issues with subject selection bias and protocol-enforced adherence. We imagine data from the T1D Exchange could help in this regard, though it still has some selection bias.
• Dr. Wolpert stressed that real-world adherence requires a proper conceptualization of the challenges. Patients are often overwhelmed by alarm fatigue and information overload, though these can both be addressed – information overload can be transformed into positive patient self-management through education, while alarm fatigue can be easily minimized. In Dr. Wolpert’s experience, measurements are often seen as a reflection of self-worth, leading patients to feel as though they are “failing.”
  
  • Dr. Wolpert shared Joslin’s approach to CGM alarm optimization and glycemic thresholds. He noted that the clinical challenge in setting these thresholds is to derive benefit from the alarms while minimizing fatigue. Echoing what we have heard from other experts, Dr. Wolpert called for alarms to be set quite widely at the beginning, with tightening over time as patients gain comfort with the system. He stressed the utility of setting high alarms appropriately, a feature that is of particular value during the night when it can prevent patients from trending excessively hyperglycemic. Dr. Wolpert closed by highlighting snooze alarms as an underutilized feature of CGMs, encouraging providers to consider increasing the duration between alarms to minimize nuisance.
• Dr. Wolpert highlighted “Modal Day Statistics” as a particularly helpful way to analyze CGM downloads and identify glycemic trouble spots. Modal day statistics show data from every hour of the day, indicating the typical range of a patient’s blood glucose levels at that time. Dr. Wolpert highlighted this “bird’s-eye” point-of-view as a way of identifying when a patient is having frequent dysglycemia and the variability associated with these excursions. He stressed the clinical utility and simplicity of this information and the ability to actionably treat off this download.

Management of Type 1 Diabetes Using Telemedicine

Paul Wadwa, MD (Barbara Davis Center, Aurora, CO)

Dr. Paul Wadwa discussed the role of telemedicine in diabetes care and presented on the Barbara Davis Center’s (BDC) initial experience. BDC’s telemedicine program started in May 2012 and works with pediatric type 1 diabetes participants (n=52) in four sites (Casper, WY; Cheyenne, WY; Jackson Hole, WY; Durango, CO). BDC’s efforts have provided access to care for rural pediatric type 1 patients and patient/family satisfaction has been relatively high so far, with most participants returning for future visits. Regarding glycemic control, the initial data suggests it is equivalent to standard care, though control remains poor with mean A1c levels at 9.4% - it was surprising to see such high A1c’s and we assume that reflects the challenges of rural pediatric diabetes care. Dr. Wadwa concluded by looking forward, pointing out plans to expand the program (it has already risen from 33 visits in the first year to 120 this year) and to work toward applications such as home use and shared medical appointments.

• Dr. Wadwa defined telemedicine as the delivery of health-related services and information via electronic/telecommunications technologies to improve patients’ health status. He pointed out that telemedicine can be especially effective in diabetes care compared to other medical fields – for example, much of diabetes care involves HCP recommendations that patients implement at home and in daily life.
• There are a number of challenges holding telemedicine back: identifying good partner sites, contracts, coding/billing/reimbursement (CO and Wyoming are good), equipment (connectivity and bandwidth), HIPAA and security (it’s not just as simple as using Skype), interstate licensure (a medical license is needed in both states), credentialing and hospital privileges, and meter/pump/CGM downloads.
• Dr. Wadwa also highlighted some of the barriers to care in rural Wyoming: travel time, cost of travel, geography/weather, and a limited number of pediatric endocrinologists.

Panel Discussion

Q: This links more to the conversation on cost from yesterday, but how much does a bottle of Lantus cost?

Professor Philip Home (Newcastle University, Newcastle upon Tyne, UK): I can’t answer in your terms. In the UK we think about monthly costs, which is about $80 per month.

Comment: Dr. Hirsch, the cost of a bottle of Lantus is around $200. My concern is that pharmaceutical companies are really abusing us. But we’re in bed with them, too. We’re being held hostage. On one hand, they are sponsoring this conference, while some of our patients must give up insulin to eat. How do you justify that?

Dr. Hirsch: The fundamental problem is that this is an international problem, but the US is being asked to fund all the innovation. Other governments around the world are drawing a line in terms of how much they are paying. We don’t have that system where the government sets a price. What happens here is that if we want to see better insulins, less hypoglycemia, more rapid-acting analogs, we’re the ones who are going to pay for it. We need the international community to understand that everyone has to pay for it. I don’t know where this is going to end.

Professor Home: You have a market and they set the market price. In other countries like the UK, there’s no market, there’s an agreement between a monopoly supplier and a monopoly purchaser. The CEO of Novo Nordisk has been hammering the table saying Europe has to pay more because the US can’t go on funding them alone.

Comment: This happened with test strips, they tried to lower the cost and it still doesn’t even matter if you have insurance, the copays keep going up and up.

Dr. Satish Garg (Barbara Davis Center, Aurora, CO): How will pay for performance affect compensation in telehealth? If you only do one visit a year and locals do three visits, what happens?

Dr. Paul Wadwa (Barbara Davis Center, Aurora, CO): That’s a good question, and we don’t know the answer yet. We provide that care even though we’re not seeing the patient in person; we are the clinicians in the pediatric clinic seeing patients. Even if they come to the remote site, our team sees them; we’re still reaching out and making contact. We might only see them in person once a year, but we’re seeing them virtually ideally four times a year.

Q: With the use of telemedicine, did you notice an increase in device usage with your patients? Maybe they were more inclined or had better access?

Dr. Wadwa: We’re analyzing that data now. In the data I showed, we were working with diabetes educators and matching them to patients. We think they were getting better access to technology, more easily. But we’re still analyzing that data.

Q: Dr. Wolpert, your slides on the accuracies and inaccuracies of CGM were older: from 2002-2007. Is there more up to date evidence? And how about SMBG, is there anything that shows the accuracy of that?

Dr. Wolpert: One slide I showed with comparative data of Medtronic and Dexcom was more recent, from 2012-13. I don’t want to overemphasize the issue, I just think it’s important for patients to appreciate that you’re using plasma glucose as a reference for CGM and you’re measuring interstitial glucose, so there’s a physiological challenge in establishing accuracy. People need to appreciate that the discrepancy enters into the accuracy assessment, that there’s a practical limit to what degree you can establish accuracy. We happen to use BGM in terms of self-management because that’s what we have. With improvements in CGM, we will be able – and many patients do – to use interstitial data. There needs to be a shift in the regulatory standpoint; people need to appreciate the nuances of how interstitial glucose changes relative to blood glucose and incorporate that. I’m not focusing on inaccuracy, just on appreciating the difference.

Comment: Well when I started, I was checking my urine and looking at colors on the side of a bottle, so I think CGM is amazing.

Dr. Mohan: Abbott has an average blood glucose profile coming out now. Given the disconnect between blood and interstitial plasma glucose, can we predict or do we have algorithms that can address this difference?

Dr. Wolpert: As you know, there have been recent studies looking at lag. From my studies, in which we’ve had two devices on a patient at the same time, it seems that there’s no consistent lag time, such that it’s going to be hard to come up with consistent recommendations. I think that there are two ways to use CGM. One is that you use it as a synthesis of major trouble spots. I think that what gets lost are the benefits that results from patient insight into self-care habits. That entails getting them to look at details.

Q: I have a question for Dr. Wadwa. When you’re selecting new sites for telemedicine, do you really screen the people or the infrastructure? Do you look for a place that’s already routinely doing A1cs or is it more about finding motivated providers?

Dr. Wadwa: It’s a combination. We get feedback that there’s a need somewhere. We’re focused on Colorado and Wyoming right now; in Durango we use an outpatient pediatric office because they’re eager to work with us, in other places we work with a diabetes center because they have access to tools.

Workshop: Sensor-Augmented Pump Therapy (Sponsored by Medtronic)

Pump and Continuous Glucose Monitoring test-Drive

Linda Burkett, RN, CDE & Kim Larson, RD (Medtronic Diabetes, Northridge, CA)

Ms. Linda Burkett and Ms. Kim Larson led a fascinating hands-on workshop that offered attendees the full experience of using Medtronic’s MiniMed 530G pump with the Enlite sensor. As an unexpected surprise, after being coached on how to insert the sensor and calibrate the pump, audience members were actually allowed to keep the equipment for 48 hours in order to gain a real understanding of the patient experience with the sensor (we’re still wearing ours). A large percentage of the diabetes educators and other health care professionals in the audience said that they had participated in test drives with other CGM or insulin pump systems; however, most were fairly unfamiliar with the low threshold suspend feature of the MiniMed 530G, which was the focus of much of the Q&A (see below). The workshop participants generally agreed that the device was relatively user-friendly – inserting the sensor was painless, according to participants, the menus on the pump were straightforward to navigate, and Medtronic’s instructional video received positive feedback. However, many attendees did require some assistance from the Medtronic representatives during the sensor insertion and calibration process, illustrating how important it is for patients to receive adequate instruction before beginning pump or CGM therapy.

Questions and Answers

Q: People only get a few of these in a box, so there’s little room for error. What should they do if there is an error?

A: This is brand new and people get nervous, so errors do happen. You can have your Medtronic representative give you extra supplies that you can use as demos, and we can support you if there is an error. We also have a 24-hour helpline, so we can get you a new sensor in the mail within 24 hours if something goes wrong.

Q: What happens to glucose during the suspend?

A: We call it the “Dr. Kaufman Nike swoosh.” On average, glucose rises 10-20 mg/dl/hour after suspend begins.

Q: Does it just keep alerting and alerting the patient if they go below the threshold?

A: Yes, the patient has to clear the alert, which is a two-step process.

Q: In your experience, do people just rely on what the sensor says and stop checking their blood glucose with a meter?

A: I would imagine that happens. Sometimes you just can’t check your blood sugar. But the FDA guidance is clear that you can’t rely on the sensor alone.

Q: When people are below threshold, they’ll be eating something, so you don’t really want the pump to suspend for two hours.

A: That’s correct, what you hope they’ll do is check, treat, stop the suspend, and resume basal insulin.

Q: If it’s alerting you for 30 minutes and it takes 45 minutes to correct the low, that would be very annoying.

A: It only alerts every 30 minutes, not continuously, and it only alerts if you’re below threshold, which shouldn’t persist if you’re treating the low.

Q: If someone goes low in the middle of the night when they’re sound asleep, will the alarm wake them up?

A: Some do and some don’t. I slept with it one night and set the target high so it would go off. I didn’t always hear it, but I felt it vibrate and was very aware of it. Sometimes another person in the bed will feel it too (editor’s note – this is probably an understatement).

Q: If you enter the two-hour suspend and at some point check your blood sugar and restart basal insulin, is there any limitation on giving a bolus?

A: No, they certainly can give a bolus. You need to clear the alert and resume basal, and then you can give a bolus if you want to eat a meal. I’ve seen that happen on CareLink, where someone ate a meal and bolused in the middle of the night.

Q: It can be scary to resume basal without treating the low. Shouldn’t the pump ask if they treated before resuming basal?

A: The pump doesn’t ask if you treated, but it does tell you to check blood glucose. It’s the educator’s job to teach people how to treat hypoglycemia. But I love getting feedback, and we’ll take that suggestion back to R&D.

Workshop: Continuous Glucose Monitoring (Sponsored by Dexcom)

Dexcom G4 Platinum Practical Experience & Hands on Workshop

Tomas Walker, CDE; Keri Weindel, MS, RD, CDE (Dexcom, San Diego, CA)

Ms. Keri Weindel and Mr. Tomas Walker educated attendees on the clinical use of CGM, including a hands-on opportunity to insert and operate a Dexcom G4 Platinum for themselves – we are always elated to see device companies do this, since it helps give clinicians much more of a patient perspective. When attendees inserted the sensors, most commented that the process was relatively simple and painless. In explaining the difference between BGMs and CGMs, Ms. Weindel highlighted that “everyone is looking to CGM as the new standard of care” and that CGMs provide trend arrows that allow patients to proactively avoid hypoglycemia or hyperglycemia. Mr. Walker and Ms. Weindel also reviewed Dexcom’s Studio software (we like its simple pattern recognition), including the useful one-page Portrait summary report. The speakers encouraged attendees to use “actionable” alerts rather than “warning” alerts – the goal is to set thresholds at points where patients will respond, thereby avoiding nuisance alarms. We’d note that this has gotten much easier over time as accuracy of CGM has improved from frustrating earlier generations with lots of false alarms. They also recommended calibrating the Dexcom G4 Platinum per the label (twice per day) rather than as frequently as often.

Selected Questions and Answers

Q: Is the sensor affected by sun or sweat?

A: No, but acetaminophen will falsely raise your blood glucose levels. This isn’t just Dexcom. Any similar chemical sensor has this issue. You might see a 25 to 40 point rise.

Q: Why can we not use the arm as a sensor site?

A: The FDA hasn’t given this indication. There is no literature that I’m aware of that explains this, but I believe there are a couple of small trials ongoing. [Editor’s Note: We know that many patients, particularly pediatric patients, wear CGM sensors “off-label” on their arms.]

Reimbursement for CGM

Claudia Graham, PhD (Dexcom, San Diego, CA)

Dr. Claudia Graham’s engaging presentation discussed the current state of CGM reimbursement, the Affordable Care Act’s (ACA) impact on diabetes, and future trends in healthcare reform. Dr. Graham lamented that there is a “significant mismatch” between Medicare and commercial coverage – Medicare provides no coverage for personal use of CGM (though it does reimburse for professional CGM), compared to an impressive 98% of commercial plans that have written coverage for both personal and professional CGM. [There are varieties of efforts to change this, including the Medicare Access Act of 2014, introduced into the Senate on July 30. Dexcom is also working to secure an insulin dosing claim for the G4 Platinum, which would stifle Medicare’s argument that CGM is “adjunctive.”] She also highlighted CGMs’ increasing pharmacy coverage, an encouraging trend for Dexcom’s business and patients. Dr. Graham applauded the ACA’s impact on diabetes in its elimination of pre-existing exclusions and lifetime limits, but pointed out that healthcare reform will continue to evolve with increased pricing pressures and opportunities for innovation.

Dexcom Technology and Future

Jake Leach (Vice President, Research and Development, Dexcom, San Diego, CA)

Mr. Jake Leach wrapped up the morning workshop, explaining the advances with Dexcom’s G4 Platinum and sharing updates on Dexcom’s new ongoing projects. His presentation in Dexcom’s dinner symposium was much more detailed and is covered in depth elsewhere in this report. Regarding the Dexcom G4 Platinum, Mr. Leach pointed out that this CGM “sets new standards” with a new sensor, transmitter, receiver, and software, calling it the “most accurate and easy to use CGM to date,” with a lower MARD and standard deviation compared to other devices. Mr. Leach highlighted Dexcom’s new version of the G4 Platinum, G4AP, which demonstrated an impressive sub-10% MARD in a late-breaking poster 75-LB at ADA 2014. Mr. Leach proclaimed that, “accurate, reliable CGM may be the most important advance since the discovery of insulin,” a comment we’ve heard from some key opinions leaders as well. Moving on to other developments at Dexcom, he stated that the company is working on a new sensor, sensor applicator, and algorithms to support smaller transmitters – our Dexcom 2Q14 report has the latest details on all these fronts. Notably, he mentioned in Q&A that Dexcom is working with a “couple of groups” on insulin infusion set cannulas – we wonder if this would be a combined CGM/insulin infusion set, like Medtronic’s MiniMed Duo. This remains a hugely under-researched area and one with important implications for the artificial pancreas.

Selected Questions and Answers

Q: Is there any progress for visual impairments? Are you working on any modifications like speaking or a larger format? I know we’re trying to get smaller and smaller, but I have one patient who can’t see that well.

A: The goal is to make alternative displays. It’s also going to be on your cell phone or on your watch where you can blow it up. We want to work with the FDA to make these changes.

Q: How about technology-challenged adults?

A: We also have a project working on a receiver with a bigger display. It’s intended to be very simple to use if you don’t want to use a cell phone or watch. We’re also working on a more simplified insertion device, with fewer steps to insert.

Q: I wonder how far away display data on devices is – one of my patients has a Dexcom sensor and can display data on his cell phone and can have it on his watch for his son. How far in the future will that be available to everyone?

A: Not that far off – it’s one of our larger projects. It’s going to go on the iPhone first. We have Dexcom Share, which allows others to follow blood glucose data, which is at the tail end of the FDA. We’re hoping it will be approved soon. That’s our first place in the mobile space.

Q: We all know that the insulin pump’s weakest link is the infusion unit. Will you work on the infusion set?

A: We’re actually working on the infusion cannula. It’s early research, but there are a couple of groups we’re working with. You’re right – the infusion set is usually the weakest link. 

Industry Sponsored Dinner: Animas

Animas

Ramakrishna Venugopalan, PhD (Animas, West Chester, PA)

Dr. Ramakrishna Venugopalan presented on Animas’ predictive control hypo-hyper minimizer (HHM), noting that it has been in collaboration with industry, academia, and JDRF since 2010. He stressed to audience members that they are the “bridge between product manufacturers and patients” in clarifying what the artificial pancreas is and setting appropriate expectations. Dr. Venugopalan commented that the FDA has been especially collaborative and that the clinical evaluation plan following FDA guidance involves feasibility, transitional, and pivotal studies. Dr. Venugopalan asserted that the system provides “promising glucose control,” especially in overnight periods, with similar YSI values and very little hypoglycemia compared to usual care. He looked forward to the next steps of “robustification,” in which efforts will ensure smooth entry/exit from closed loop control, tolerating failures, start-ups, CGM communication errors, infusion set changes, and other system interruptions. Animas has not moved particularly quickly on this project – data from Animas at ADA 2014 on a predictive low glucose suspend controller was very much in the feasibility stage (n=12, 24 hours), and data at ADA 2013 testing the  hypo-hyper minimizer overnight was equally early (n=20, 24 hours). We have been disappointed to see this project advance forward at a slow pace and hope that changes once the Animas Vibe is approved and launched in the US (potentially in 2014, per Dexcom 2Q14); Medtronic, by contrast, has the MiniMed 530G already on the market and MiniMed 640G expected to launch in Europe by April 2015.   

Questions and Answers

Q: Is the system built for available insulins today?

A: Yes, we built the algorithm very ordinarily. So I think we can basically swap any of the insulins. Even in our existing pumps, we have a PK/PD window and that same approach will be deployed with any new insulins.

Q: Giving insulin right before a meal is an example of the system being closed-loop most of the time, but then you would open it up and put in your own data temporarily. On the other hand, it seems as if it should be completely closed and it shouldn’t ask the person to enter in anything. Is it okay to open it temporarily?

A: For me, the value of technology is to democratize outcomes. You have a spectrum of capabilities of people who use these technologies. You see some people who are technologically savvy and others who try their best and just can’t get there. Philosophically, my belief is that we don’t want to cut the patient out of system. You can’t guess everything happening to the patient and you don’t want them so lost or so convinced that the system can do everything. I truly believe we need a hybrid system, which involves interacting with the patient. The amount of time people spend on calculating this is enormous and we have to learn to take the computational chore out to give individuals the bandwidth to focus on things that really matter to them. I want to take away all these chores, so you are engaging on a very meaningful level.

Q: I would like to see instructions on what to do when the pump fails included with every pump.

A: This is part of training. They will start on saline training, where they learn all the basics, emergency pump failure, and go through basal/bolus insulin. We have a program where they can work with a glucose management team that follows them for six weeks. In that same time frame, they get review of acute care management.

Industry Sponsored Dinner: Dexcom

Continuous Glucose Monitoring Technology

Jake Leach (VP, Research and Development, Dexcom, San Diego, CA)

Mr. Jake Leach provided a wide-ranging summary of Dexcom’s pipeline, updating us on the company’s cloud-based SweetSpot software (no timeline provided, but clearly in the works), ongoing feasibility trials on Gen 6, and a mention of the new Dexcom/Insulet collaboration first announced on Day #1 of ADA 2014. Factory calibration of devices was highlighted as an upcoming milestone (“Don’t know when, but it’s coming”) that will facilitate patient convenience and adherence, as will smaller transmitters, new algorithms to support longer sensor life, and accuracy/reliability in non-adjunctive use – great to hear Dexcom is working on all these fronts, and we wonder how the company will prioritize each piece. Mr. Leach also reviewed the company’s current and upcoming products, including the G4 Platinum (adult, pediatric, and professional use all approved); Animas and Tandem pump integrations (no timeline provided; the Animas Vibe has been at the FDA for over a year; the integrated Tandem t:slim was supposed to be submitted in June); Dexcom Share (“available very soon”); the new G4 AP algorithm (data shared at ADA showing nearly comparable accuracy to fingersticks), and Gen 5 mobile platform. Notably, CEO Mr. Terry Gregg said in Q&A that no decision has been made on whether to make the G4 AP algorithm available soon or to wait for Gen 5. He emphasized that Dexcom remains committed to releasing a new product “every 18 months” – the G4 Platinum was originally released in October 2012 (22 months ago), though approvals have recently come for a G4 Platinum pediatric indication and a professional use indication, and Share should be available any time now – as of Dexcom’s 1Q14 call in May, it was characterized as in “the final stages of review.”

• CEO Mr. Terry Gregg said in Q&A that no decision has been made on whether to make the G4 AP algorithm available soon or to wait for the Gen 5. The first study of the G4 AP algorithm was shown in a late-breaking poster #75 at ADA 2014, demonstrating a sub-10% MARD and nearly comparable accuracy to fingerstick meters. There is the possibility that the G4 AP algorithm could be done via a remote web update, though that could only occur after it is approved by the FDA. Given the tentative timeline to launch Gen 5 mobile platform sometime next year, it may make sense to roll the innovations into one FDA submission.
• Dexcom’s cloud-based SweetSpot software will be Mac compatible, solving a gripe of many patients/providers, who are unable to download the G4 Platinum using the Windows-only Studio software. As a reminder, the SweetSpot system will integrate data on blood glucose, CGM, and insulin delivery in an online platform. The last update on this platform came in 3Q12 (!), where Dexcom’s goal was an FDA submission by the end of 2012 – there has been no timing update since. This is an area where Medtronic is definitely ahead of Dexcom with its cloud-based CareLink software, particularly in the minds of providers we’ve heard at recent conferences. We’ve seen previews of some of the sleek SweetSpot reports in conference exhibit halls, and cannot wait to see the advanced features (e.g., pattern recognition, glycemic variability stats). Mr. Leach emphasized that the newest update solves the Mac compatibility issues that has plagued the Windows-only Studio software, a statement that received a rousing round of applause from the audience.
• Ongoing Gen 6 feasibility trials are aggressively testing Dexcom’s next generation sensor membrane system (no timeline provided), and the company is focused on moving toward factory calibration (“Don’t know when, but it’s coming”). The Gen 6 platform will build upon the improvements of Gen 5, including a redesigned phone-compatible transmitter. The combination of a new algorithm and sensor should support longer sensor life, enhanced accuracy and reliability in non-adjunctive use, and entirely mitigate signal responses acetaminophen.
• Dexcom is also hoping to integrate CGM data with the new “HealthKit” feature of Apple’s iOS 8 (release scheduled for Fall 2014). This Apple-developed tool will consolidate data from various health and fitness apps to offer a one-stop-shop for all the data. We love the idea, particularly because it would allow easy pairing of exercise apps with glycemic data. To date, this has only been possible through manual tagging and logging.
• Dexcom is creating an employee-funded foundation that seeks to assist patients who cannot afford its products. Mr. Gregg emphasized that product development at Dexcom is a balance of considering the financial burden on patients (“98% of our patients in US have some type of third-party payers”) and outmaneuvering competitors.

Real Time CGM and Clinical Practice

Jay Skyler, MD (University of Miami, Miami, FL; Board of Directors, Dexcom)

In line with his presentation from Keystone 2013 and AACE 2014, Dr. Jay Skyler reviewed the therapeutic benefits of CGM and commented on the present competitive landscape of the industry. As a reminder, he is on the Board of Directors of Dexcom. He compared the performance of Dexcom’s G4 Platinum to Medtronic’s Enlite and Abbott’s Navigator using multiple clinical studies, including the recently published head-to-head-to-head study from Damiano et al. (Journal of Diabetes Science Technology, 2014). As we’ve come to expect, Dr. Skyler was quite critical of the Medtronic Enlite, provocatively referencing data that its previous Sof-Sensor was actually more accurate than the newer device (Calhoun et al., Diabetes Technology and Therapeutics 2013). That study compared the accuracy of the Enlite (Veo algorithm) to the Sof-Sensor (Guardian Real-Time algorithm), finding that the overall median sensor vs. reference difference was -15 mg/dl for the Enlite and -1 mg/dl for the Sof-Sensor (p<0.001), while the median absolute relative difference was 15% for the Enlite vs. 12% for the Sof-Sensor (p=0.06). Dr. Skyler critically joked, “I’m not sure why Medtronic chooses to go from bad to worse when they allegedly make improvements.” We appreciate Dr. Skyler’s data-driven discussion, though would note that study data is conflicting on the accuracy of the Enlite. The same work from Drs. Ed Damiano and Steven Russell actually suggests the opposite – based on two related studies, Medtronic’s Enlite appeared more accurate than the Sof-Sensor. The group’s 2014 study found an overall MARD of 17.9% for the Enlite (Damiano et al., JDST 2014), while the 2013 study found an MARD of 20.3% for the Sof-Sensor (Damiano et al., Diabetes Care 2013). The later paper notes that these studies are comparable, since the same Navigator sensor was used in both studies and yielded accuracy results that were not significantly different.

• Dr. Skyler was far less critical of Abbott’s technologies relative to Medtronic, which was no surprise considering Abbott’s CGM is no longer available in the US. However, we assume speakers’ talks will increasingly begin mentioning the upcoming launch of FreeStyle Libre in the EU later this year, as the factory calibrated, 14-day wear product certainly merits a role in any competitive landscape discussion of CGM.
• Dr. Skyler noted that Dexcom is working towards broader pharmacy coverage of CGM in an effort to reduce the hassle and paperwork of CGM adoption and “make life easier” on providers. As noted in our AACE 2014 coverage, Dexcom signed a contract with CVS/Caremark in May to have CGM covered as a pharmacy benefit for an impressive ~25 million covered lives. This built on Dexcom’s addition to Express Scripts’ Preferred Drug List in January (pharmacy benefit coverage for ~5 million members). Pharmacy benefit coverage means that patients would only need to pay a copay to get CGM, rather than the average ~20% co-insurance on sensors, transmitters, and receivers. The additional benefit of moving to a pharmacy benefit is it helps patients avoid the high deductibles typically associated with DME.
• As a reminder to the audience, Dr. Skyler summarized the findings from landmark CGM studies: the JDRF CGM trial (JDRF Study Group, Diabetes Care 2009) and SWITCH (Conget et al., Diabetes Technology and Therapeutics 2011). Both studies demonstrated clear relationships between CGM use and reductions in A1c and risk of severe hypoglycemia.  

How Patients with Type 1 Diabetes Translate Continuous Glucose Monitoring Data into Diabetes Management Decisions

Jeremy Pettus, MD (University of California San Diego, San Diego, CA)

Dr. Jeremy Pettus presented intriguing data on how people with type 1 diabetes use continuous glucose monitoring (CGM) trend arrows to make major modifications to their insulin therapy, a follow-up to Dr. Steve Edelman’s initial presentation at ATTD 2014 and two posters at ADA 2014 (836-P and 858-P). Dr. Pettus first highlighted that the current recommendations for adjusting insulin based on real-time CGM data only call for dose changes on the order of 10-20%. His group surveyed CGM users with both type 1 and type 2 diabetes, and this talk discussed the data from the 222 participants with type 1 (very well controlled, with a mean A1c of 6.9%). Respondents filled out an online survey of 70 multiple choice and scenario-based questions that explored their use of real-time CGM data. Results revealed much larger changes in insulin doses than current recommendations suggest – 41% and 48% dose reductions when responding to falling trend arrows (one and two arrows, respectively) and 111% and 140% increases in doses when responding to rising trend arrows. Dr. Pettus’ take home message was that “the rate of change information provided by CGM devices is just as important, if not more important, than the actual glucose value.” He concluded by pushing for more research on the development of dose recommendations based on trend arrows in different clinical situations as well as for this information to be better distributed to patients.

Trend Arrow	Mean Patient Adjustment to Bolus Dose*	Example Bolus Dose*
-->	---	3.0 units
^ (single up arrow)	+111%	6.3 units
^^ (double up arrow)	+140%	7.2 units
v (single down arrow)	-41%	1.8 units
vv (double down arrow)	-48%	1.5 units

*“It has been four hours since your last dose of insulin and meal and your CGM receiver shows a value of 220 mg/dl (matching your fingerstick blood glucose of 220 mg/dl) with an arrow and trend graph that is flat (straight across). If you are not planning on eating or exercising, what dose of insulin would you give yourself to bring your glucose to 120 mg/dl?”

Panel Discussion

Mr. Terry Gregg (CEO, Dexcom, San Diego, CA): I’ve been chasing CGM since I joined MiniMed back in 1994. I’m going to hand over the reigns now to Kevin Sayer. What I’ve realized is that translational information is important. We’ve got to take information and make it actionable. For example, we recently entered into partnership with Joslin to create a database to educate non-diabetes specialists. As we look at the number of diabetes patients that are seen by specialists, it’s only 38% for those over the age of 18. So, the majority of patients are being treated by non-specialists, who we know are only getting something like eight hours of diabetes-related training. So, we’re trying to create a database that educates other doctors so that they can provide more adequate care.

Kevin Sayer and I also hear, “You guys need to do something with big data.” I don’t even know what that term means. When I asked big data specialists, they say, “We don’t have any idea what this is going to do. We just want to collect it and analyze it later on.” Stayed tuned on this idea of translational data. I’m spending a lot of my time on how we can use and share information.

Our CGM is a class III medical device. It’s highly regulated by the FDA. Even though you heard the FDA official earlier today [Dr. Courtney Lias] say, “Go for the endgame,” I will say that going for the endgame is very difficult. Stay tuned, a lot more will come of that. We asked the FDA how fast can we transition into this? They said that if it’s real-time actionable, then it’s a class III medical device, and you have to submit it as such. So hurdles remain. Although we want to do all these things and are capable, we are highly regulated and the regulatory process does have challenges at times. Take Gen 5, for instance. It’s been developed for two years. All companies in this industry have these restrictions. We can only go as fast as the FDA wants us to, but we work in a very close, collaborative relationship with the FDA.

Q: This is a question related to the cloud presentation for CGM. As a parent with multiple children, will there be capabilities to screen child to child? If so, how soon will this be out?

Mr. Jake Leach (Vice President, Research and Development, Dexcom, San Diego, CA): The Dexcom Share app can actually follow up to five people. You can even put pictures next to each person, so you can easily tell them apart. The product was submitted to the FDA last summer, so we do expect it to be available very soon.

Q: So if we’re part of a provider team and we have more than five patients, it doesn’t really leave room for that?

Mr. Leach: It wasn’t really designed for healthcare providers. It was mainly designed for parents or family members. But that’s a future idea.

Dr. Jay Skyler (University of Miami, Miami, FL): As a physician, I wouldn’t want to follow all my patients’ data all the time. [Laughter]

Q: I’m relieved to hear that the Gen 5 receiver will be on the phone. I often lose the receiver. If there was an app on the phone that could make a noise on the receiver so I could find it, I would love that.

Dr. Skyler: That’s awesome feedback. Thank you. But you could lose your phone, too.

Q: Are you guys working towards Medicare approval? I’ve been type 1 for a long time and I will not leave my CGM at home. I’m going to be 65 in three years. It’s a scary thought.

Mr. Gregg: We have an individual who’s working with CMS and she’s working on getting approval. We’re also partnered with Medtronic and with professional societies because we all have a common goal. And that’s greater access to that population. My greatest agony as CEO is to see someone with coverage at 64 and then lose that coverage. I think it’s criminal and we’re doing the best job we can possibly do. I don’t want to candy coat it because I think we’re still looking at two years. There’s a lot of skin in the game but a lot of players.

Dr. Robert Ratner (American Diabetes Association, Alexandria, VA): Non-adjunctive use. That’s the term CMS is focusing on. They categorically turned us down with that saying that therefore, CGM is not necessary. Until you get non-adjunctive use dealt with, and I’d love to hear about that, CMS isn’t going to cover. As soon as you get rid of that, we’ve got all the ammunition in the world to get CMS coverage.

Mr. Gregg: I’ll give you an update on that actually. FDA is well aware that a significant portion of G4 users dose off their CGMs. So we asked them what we have to do to achieve this. We have a close, collaborative relationship with the Agency.

Q: The cloud idea is great from the user’s point-of-view, but from provider’s point-of-view, it would be great if there were more efficient integration with EHR. Have you reached out to major providers regarding this?

Mr. Leach:  Excellent question. Our folks have had a lot of experience with integrating into EMRs. A lot of that integration was unique for each healthcare setting it was developed for. Additionally, one of the things we’ve been looking at is a new feature in Apple’s iOS 8 called the “HealthKit.” It’s a way to share health data on an iPhone. We’re hoping that plugs into EPIC and makes this more feasible. We need to get that data without the effort.

Q: Dr. Pettus, I was interested in the data you collected on hypothetical systems. Were patients making these changes based on hypothetic data without fingersticks? Did you ask them about different situations specifically?

Dr. Jeremy Pettus (University of California San Diego, San Diego, CA): We did ask them what they would do in particular situations. At night, most said they would dose without confirming a CGM reading with a fingerstick. In fact, the majority of people would dose CGM at night without confirming it. Or treat a low without confirming it.

Q: It’s impressive how much more accurate the G4AP algorithm is. You also mentioned how it handles SMBG. Maybe it can detect faulty SMBGs?

Mr. Leach: G4AP is quite a bit smarter than the G4 Platinum algorithm. It looks at the sensor signal and looks at the SMBG reading. It doesn’t believe exactly what the SMBG reading says because of potential error. We’re trusting our CGM sensor more than the SMBG reading. The sensors have gotten so stable that we can do that now.

Q: I have a quick note before my question. Accuracy data gives us confidence as clinicians. I think we get too bogged down in data without thinking about what it means to patients. And improved accuracy leads to more adherence and better outcomes. Ultimately that improves quality of life, which unfortunately is something, as a clinician, that I don’t necessarily get to feel like I’m doing on a day-to-day basis when I’m reminding patients to take insulin, etc. My question is about G4 AP. Will it be available soon? Or will we have to wait till the Gen 5 is available?

Mr. Gregg: No decision has been made. We have approval for downloading software through the Internet. The challenge that Dexcom faces is that we like to iterate quickly. One of the regulatory challenges we have is that when you have the Gen 5 on the horizon, it complicated our decision-making. Which version do you put into which product? It all depends on what’s going to be approved. I can’t answer your question yet. But as soon as we can, we’ll make a statement. It’ll be the Gen 4 Platinum or Gen 5. It’s really based on the timing of approval. We do things concurrently. We don’t wait for things to happen. After all, because of the regulatory challenges at times, we have to be working on things in parallel. Our goal is to get a new product into your hands every 18 months, which requires parallel processing.

Q: I have an application question. You talked about parents watching their kids play sports with their G4s. What kind of sports? Can kids play football with them?

Mr. Leach: I know of two cases of them being used in soccer and basketball. I also know kids play football with them. We even have NASCAR drivers wearing them. They do find places to wear them.

Comment: I have a patient who’s a national BMX racer, and he sports his diabetes paraphernalia with pride.

Q: Dr. Pettus, how has CGM made a difference in your life?

Dr. Pettus: I was just thinking about that. The biggest difference is the feeling of safety. Really feeling like I’ve finally got a handle on my diabetes. I believe that the Gen 4 is the real deal to the point that I really do trust it. In fact, I would rather go back on regular NPH than give up my CGM. My control has always been pretty good, but my ease of achieving that control has changed dramatically. It just means so much to know what your blood glucose is doing all the time. It’s always on your mind to see where you are at. It seems simple, but it’s a big deal.

Q: When you say you’re not happy unless you’re putting out a new product every 18 months, I think it’s important to note that the patient isn’t happy with that. There are financial constraints. Rather than putting out new products that we need to buy, I think it’s more ideal to just update them.

Mr. Gregg: I agree with you completely. I’m probably the most patient-centric CEO on this planet and I’m very sensitive to that subject. I’ll announce here the employees of Dexcom have created a foundation, but not as a company. We’re cash flow positive and we can’t take shareholder money for this. But, we wanted to do something for patients who can’t afford our products. So we are in process of creating an employee-funded foundation that we, including the executives, fund so that we can take care of patients who are needy. That’s kind of the culture of the company. Now there are some things we can’t do when we transition to certain technologies. Ninety-eight percent of our patients in the US have some type of third-party payers. We try to time things appropriately as we can. But at same time, we’re racing. Jake gets told every day that we need to make a replacement for fingersticks. We have to do this in a stepwise fashion and we’re making great strides toward that. I will remind the audience that we spend 30% of our budget on R&D while other companies spend less than 10%. We’ve never taken the position that we do what we do for financial reasons. We do it for patients. I hear your message and it very much resonates to the management team here.

Industry Sponsored Dinner: Medtronic

Medtronic

Francine Kaufman, MD (Chief Medical Officer, Medtronic Diabetes, Los Angeles, CA)

Despite the late hour (8 pm!), Dr. Francine Kaufman addressed a packed auditorium and presented on the promising future of Medtronic CGM, pump, and closed-loop devices. Though Medtronic’s artificial pancreas progress has been veiled (“We’ve been secretive about it.”), Dr. Kaufman acknowledged that the company is presently conducting multiple feasibility studies and has met with the FDA to discuss a pathway to US approval. Notably, she commented that Medtronic’s plan is to develop a hybrid closed-loop system that features a 24-hour algorithm with manual boluses for food before transitioning to a fully automated system. Dr. Kaufman also implied that the Enlite 3 sensor with intelligent diagnostics is likely to be utilized in the company’s upcoming closed-loop system. Regarding the Medtronic MiniMed 640G predictive low glucose management system, Dr. Kaufman shared cautious optimism regarding its EU timeline, suggesting may be available by the end of the year (or even “before”!). The timeline was encouraging to hear, since Medtronic’s F4Q14 call suggested a launch would occur sometime before April 2015. Dr. Kaufman also stressed Medtronic’s focus on device consolidation (e.g., MiniMed Duo combined sensor/infusion set), a common refrain at Keystone 2014. In closing, Dr. Kaufman expressed confidence regarding the road ahead, commenting that the “FDA has been a tremendous partner” and “the agency understands the importance of technology.” In Q&A, Dr. Kaufman shared some astute reservations about dual-hormone delivery, noting that the added benefit may not be justified by the higher complexity and cost.

• Dr. Kaufman reviewed the OpT2mise trial – recently published in the Lancet – which showed that pumps are superior to multiple daily injections (MDI) in patients with poorly controlled type 2 diabetes. As noted in our coverage of the trial previously covered, the trial compared insulin pump therapy to MDI in 431 type 2 patients in poor glycemic control (baseline A1c: 9.0%); A1c declined by 1.1% in those on an insulin pump compared to 0.4% in the MDI group (p<0.001) after 27 weeks. The data speaks to the value of insulin pump therapy in type 2 diabetes, an area that has suffered from a dearth of data compared to pumps in type 1 diabetes. Dr. Kaufman stressed the important role pumps can play in improving outcomes for type 2 patients in poor control, an assertion that aligns with Medtronic’s recent commitment to type 2 diabetes (first expressed in its 2014 Analyst Day in June, as well as with the ADA 2014 announcement of a partnership with Sanofi).
• Notably, Dr. Kaufman commented that Medtronic’s plan is to develop a hybrid closed-loop system that features a 24-hour algorithm with manual boluses for food before transitioning to a fully automated system. In the company’s 2014 Analyst Day, the MiniMed 670G was characterized as a “hybrid closed-loop system” and a “big step towards the ultimate goal of an artificial pancreas” – no timeline was presented at the time, though Dr. Kaufman’s remarks suggested that commercialization is not too far away. She acknowledged that multiple feasibility studies are ongoing and the company has met with the FDA to discuss the path to approving an artificial pancreas.
• Dr. Kaufman hinted that the Enlite 3 sensor will be utilized in Medtronic’s upcoming artificial pancreas technology. As a reminder, we were told at the company’s 2014 Analyst Meeting that this sensor will incorporate “intelligent diagnostics” and “improved accuracy and comfort”; The sensor is currently being evaluated as part of a 64-patient, eight-center in-clinic US study of the MiniMed 640G (ClinicalTrials.gov Identifier: NCT02130284). Per Dr. Kaufman’s remarks in Q&A, the intelligent diagnostics will include smart calibration algorithms that reject questionable fingerstick values.
• Dr. Kaufman shared cautious optimism regarding the EU timeline for the MiniMed 640G, suggesting that the predictive low glucose suspend system may be available in the EU by the end of the year (or even “before”!). The timeline was encouraging to hear, since Medtronic’s F4Q14 call suggested a launch would occur sometime before April 2015. As a reminder, the 640G is currently undergoing user evaluations at six centers in Europe, and as noted above, is under evaluation in a US in-clinic trial (ClinicalTrials.gov Identifier: NCT02130284). Unfortunately, Dr. Kaufman did not comment on the US timeline for a launch of the device; we heard during the FQ14 call that management was working “collaboratively with the FDA” in order to expedite the US approval process.
• Dr. Kaufman commented that the “FDA has been a tremendous partner to us” and “understands the importance of technology.” This sense of collaboration between the FDA and industry has definitely been a key theme of Keystone 2014. In particular, Dr. Ed Damiano shared similar thoughts on his team’s collaborative relationship with the FDA; these statements complemented the Saturday morning Keynote address from the FDA’s Courtney Lias (Director, Division of Chemistry and Toxicology Devices, FDA), who highlighted the “exciting” progress of closed-loop technologies; she even stated that artificial pancreas approval will happen “sooner than you think.”

Questions and Answers

Q: Have any studies looked at the efficacy of the MiniMed 530G in children younger than 16 years old?

A: We’re in the process of doing those studies now in the US. In Germany, it has been done. The results are essentially the same as in adults.

Q: When blood sugars go down, where do you set the threshold? Does it pay attention to the rate of drop? Is it one set number that you put in there or does it look at rate?

A: The threshold suspend of 530G is a threshold. It doesn’t matter what rate you got to reach that. In the next generation, the rate of changes makes all the change in the world. Because it’s predicting when you’ll hit the threshold.

Q: Do you set the rate of change or is that preset?

A: It is preset. There is an algorithm that predicts when you’re going to get to threshold.

Q: Any thoughts on the dual hormone system?

A: Well first I think the research is great. My personal stance is that it’s going to be complicated enough to move the world to the artificial pancreas, in particular, the move with the payers. They’re not thrilled about this concept until we show benefit. We need to show cost savings through less hypoglycemia or higher quality of life or some measure. I think the bar is set high for any system. Now you start adding complexity and cost. If glucagon doesn’t change cost structure, it’s $200 a bottle. That’s $60,000 more a year. I don’t think insurers are going to be thrilled about that unless it’s that much incrementally better than insulin alone. Are we going to totally normalize glucose with the closed loop? No one is until we get faster insulin. I think we’ve done enough studies. Others have done enough studies. We can do a really good and safe job with insulin alone. So why the complexity? I don’t know what the regulatory people will say. But we have never given glucagon to people every day. We know very little about its daily delivery. What can the artificial pancreas do? It’ll lead to no severe hypoglycemia and no opportunity to get DKA. At an A1c less than seven, there are no long-term complications. I don’t know what can be better than that other than just a cell that takes the entire burden off.

Q: Is your hope that the artificial pancreas is going to be an out-of-the-box product?

A: Our goal is that it’s an out-of-the-box system. There would be learning algorithms preset. The thing that drives the algorithm is how a patient responds to a particular insulin dose. If it gives a particular dose and observes a big drop, then it won’t give that dose again. After each delivery, it’s assessing the patient’s sensitivity. Importantly, I just want to note that I would not recommend that patients go from MDI to this system. You’d need to step up gradually. First a pump; then a sensor and pump; and then the artificial pancreas.

Q: Does the Enlite 3 still require twice-daily calibration?

A: Yes. The thing is that normal calibration can screw up a sensor. However, this sensor will be able to exclude a bad calibration. If a glucose fingerstick gives you value of 300 mg/dl, it will tell you to go wash your hands. If the second time it’s still a large value, it will accept it. And if it doesn’t see itself getting fixed, it will shut itself down.

Q: Is there any movement toward an internal pump?

A: We have an internal pump. It has been under investigation in the EU for some time. We had been in studies with the implanted pump in the US, but the program was stopped here while it continues in the EU – there is now a new motor for the pump and Sanofi is our partner on the insulin side. The insulin was evaluated in the implanted pump in the EU – it’s a concentrated insulin. So there are a number of patients with implanted pumps in the EU. We haven’t done much about the form factor though – it’s still not near to a final version. However, people on intraperitoneal delivery don’t want to stop getting their insulin delivered through that route, and those on it have failed to reach glycemic control with subcutaneous insulin.

Diabetes Drugs

Plenary: Controversies in Diabetes

Should We Count Protein and Fat for Bolus Insulin Dose?

Howard Wolpert, MD (Joslin Diabetes Center, Boston, MA)

Dr. Howard Wolpert discussed the importance of thinking beyond carbohydrates when calculating mealtime insulin doses, presenting evidence demonstrating the significant effects that large amounts of fat and protein can have on postprandial glycemic control. He mentioned two studies he is currently involved in: one that aims to develop and validate a “fat bolus” and to identify characteristics that can predict an individual’s “fat sensitivity,” and another that will investigate the glycemic effects of different types of fat – some types seem to exert large effects on gastric emptying, others on insulin sensitivity.

• In addition to his thoughts on his core topic, Dr. Wolpert also offered several insights into his views on CGM. He said that the introduction of CGM was his original impetus for thinking about how different macronutrients affect postprandial glucose, as CGM data provides a much more complete picture of a patient’s postprandial glycemic profile than was previously possible. He highlighted the benefits of high glucose alarms, one of the less-celebrated features of CGM, saying that it is helpful in alerting patients to the profound hyperglycemia that can occur overnight after a high fat meal. In response to a question about the use of CGM trend arrows in developing algorithms for mealtime insulin, he said he was “actually quite skeptical” of their usefulness in this context, as only retrospective studies have been done and there are far too many factors influencing the rate of change to effectively incorporate it into a bolus calculation.
• Dr. Wolpert quite plaintively stated that more meal planning was needed. We agree with this – we think the move to pumping has taken our attention away from what we do and don’t eat as patients and believe some of the discipline has to strengthen for some patients.

Do Postprandial Glycemic Excursions Impact Cardiovascular Risk?

Viswanathan Mohan, MD, PhD (Diabetes Specialties Centre, Chennai, India)

Dr. Viswanathan Mohan gave a compelling presentation on the particular importance of addressing postprandial hyperglycemia, arguing that it may be a key component of reducing cardiovascular risk in patients with diabetes. A body of evidence suggests a link between postprandial blood glucose elevations and both microvascular and macrovascular adverse outcomes (Hurel & Mohan, JAPI 2006). In addition to contributing to elevations in A1c (although usually more modestly compared to fasting glucose), glycemic variability itself can induce oxidative stress and further damage. Dr. Mohan emphasized that while the height of postprandial glucose excursions is widely appreciated as a metric of glycemic control, the duration of the excursion is also a major contributor to elevated A1c levels. Given the ability of postprandial excursions to forecast cardiovascular health, Dr. Mohan emphasized the utility of agents with more pronounced effects on postprandial glucose as a necessary strategy in the prevention and management of complications in diabetes patients – the list of agents he suggested (including GLP-1 agonists and rapid-acting insulins but also alpha-glucosidase inhibitors and glinides) was perhaps more aligned with the choices of physicians in India.

• The duration of postprandial excursions contributes to chronic sustained hyperglycemia, while the magnitude of the spike contributes to glycemic variability. Dr. Mohan believes that the contributions specifically of postprandial glucose excursions merits further study, although it was pointed out during Q&A that designing a study that compared differences in glycemic variability while holding A1c constant is quite difficult. The ongoing FLAT SUGAR is attempting to do exactly that, and during Q&A Dr. Irl Hirsch (University of Washington, Seattle, WA) noted that data collection from the trial is almost complete.   
• “Postprandial glucose levels seem to determine cardiovascular mortality better than fasting plasma glucose levels do,” emphasized Dr. Mohan. Citing the DECODE study (n=15,388), among others, Dr. Mohan noted that postprandial glucose levels (as measured by OGTT) were shown to be better predictors of all cause mortality and cardiovascular death than fasting plasma glucose levels (DECODE Study Group, Lancet 1999).
• Given that most patients spend the majority of their day in a postprandial state, Dr. Mohan expressed concern that the vast majority of metabolic studies are done in the fasting state. He stressed that effective pharmacotherapeutic strategies exist to blunt postprandial excursions, from GLP-1 analogs and rapid-acting insulins to amylin analogs and alpha-glucosidase inhibitors. SGLT-2 inhibitors did not make it onto the list, but Dr. Mohan hails from India (where he runs the world’s largest diabetes center) and as a result his list was reflective of the drug classes available there. Dr. Mohan proposed that correcting these spikes should form part of the strategy for the prevention and management of cardiovascular disease in diabetes patients.

Role of Pramlintide in Diabetes Care

Matthew Riddle, MD (Oregon Health & Science University, Portland, OR)

Dr. Matthew Riddle argued that pramlintide (AZ’s [originally Amylin’s] Symlin) is underutilized as a treatment for type 1 and type 2 diabetes, chiefly due to the requirements for multiple daily injections, frequent blood glucose testing, and strict medical supervision under current regulatory guidelines. With a different paradigm, Dr. Riddle believes that Symlin could be a useful alternative to rapid-acting insulin for patients with type 2 diabetes and that a fixed-ratio combination of pramlintide and insulin could be a very effective therapy for type 1 diabetes. He provided an overview of the PICOS study, a phase 1 clinical trial (ClinicalTrials.gov Identifier: NCT01708044) sponsored by Amylin and the JDRF that investigated the effects of several Symlin/insulin ratios on postprandial glucose. The study enrolled 19 patients with type 1 diabetes (average baseline A1c was 7.8%) who received injections of three different fixed-ratio combinations ranging from six mcg Symlin/unit of regular insulin to 12 mcg Symlin/unit of insulin, or placebo (insulin alone), with breakfast in a random order on four separate days. All ratios led to significant reductions in postprandial glucose compared to placebo. Interestingly, the effect was similar with all three ratios, though the higher doses did have a greater duration of action. All ratios also led to a reduction in postprandial glucagon. With regard to adverse events, no hypoglycemia and very little nausea was observed. Dr. Riddle said that a follow-up study is planned to investigate the effects of a continuous infusion of one of these ratios. We hope that researchers are able to identify an effective ratio that would allow for a single mealtime injection of the two hormones, as the difficulties currently associated with dosing of Symlin are likely a major obstacle to its wider use.

Panel Discussion

Q: Dr. Mohan, clinical trials don’t seem to say that postprandial hyperglycemia is important for cardiovascular outcomes. How can you explain that?

Dr. Viswanathan Mohan (Dr. Mohan’s Diabetes Specialties Center, Chennai, India): The problem is that the division of postprandial and fasting glucose is a bit artificial because one depends on the other. Few trials look just at postprandial lowering without looking at fasting and vice versa. When you lower fasting glucose, postprandial comes down, and the same is true in reverse; most drugs we use affect both.

Dr. Robert Ratner (ADA, Alexandria, VA): Shouldn’t the study design be two groups with identical A1cs at the end, but one group is only treated for postprandial glucose?

Dr. Mohan: That’s very difficult to achieve.

Dr. Ratner: HEART2D tried and found no effects; NAVIGATOR was not successful.

Dr. Matthew Riddle (OHSU, Portland, OR): There is a trial underway and several investigators are in the room: the FLAT SUGAR study, where people are randomized to receive rapid-acting insulin or exenatide and the goal is to achieve equal A1c values.

Dr. Irl Hirsch (University of Washington, Seattle, WA): We’re almost done with the actual data collection and we’re excited about what we’ll see. I should point out that this is a proof-of-concept trial to show we can do something extremely difficult, namely keeping A1c the same but with different variability. We’re talking about variability not just from the postprandial spike but from hypoglycemia, which also leads to inflammatory activation and oxidative stress. So we’re looking at all variability, at the obvious endpoints like weight and hypoglycemia and some less obvious ones. We’re excited; we’ll have a lot of data, probably more than one manuscript of data. It should lead to more definitive trials, but it won’t give the final answer.

Dr. Ratner: Will the data be ready for ADA?

Dr. Hirsch: That’s an interesting topic. It may be ready earlier.

Q: Dr. Wolpert, in your study, will you use CGM and introduce the use of trend arrows for titration of insulin?

Dr. Howard Wolpert (Joslin Diabetes Center, Boston, MA): There’s no easy answer. I’m actually quite skeptical of the utility of arrows. There’s a divide in pediatrics vs. adults. Parents want something definitive, but when you look at all the factors that account for the rate of change in the context of a meal, it’s difficult to come up with anything emphatic. The studies are all retrospective, so there’s bias there, and it’s the people who are more engaged that use these rate of change indicators. I would say one area we tend to overlook is shutting off hepatic glucose production in advance of absorption, people being able to get insulin in 30-40 minutes before a meal to turn off the liver and blunt that spike; that’s a really key issue. You have to consider all factors accounting for the rate of change, and it’s impossible to model that with insulin adjustments.

Dr. Riddle: We all have lots of enthusiasm for guidelines and algorithms; all business managers like them and everyone wants their own. Some things are not amenable to guidelines, and this is one of them. You can set targets for glucose control, but guidelines for tactics are much harder. With management of insulin dosing or mealtime glucose regulation, the starting assumption is to try something with each person and revise the plan based on what you see.

Dr. Wolpert: What we’re doing is giving insight. We believe that protein has a significant effect, and if you keep food records and CGM logs, we can help you decide what to do, whether it’s giving a 50% dose or an extended bolus or insulin delivery ahead of time? People can gain ground on their own management.

Q: If somebody eats only protein and fat, do you require insulin?

Dr. Wolpert: I don’t want to get into a debate about high fat vs. low fat. The important insight is that if there’s variability in people’s fat intake, that could impact their postprandial and overnight glucose control. It’s more about finding those insights to optimize postprandial control rather than getting into a polemical argument about the optimal diet.

Q: With closed-loop therapy, will we need to count protein and fat or will counting carbs be enough? Maybe the basal rate will take care of it?

Dr. Wolpert: We’ll have a metabolic model for dosing; if that doesn’t incorporate these considerations and adjust insulin dosing, the system won’t come out with the right dose.

Dr. Tadej Battelino (University Children’s Hospital, Ljubljana, Slovenia): Recent data has shown that eating basically induces oxidative stress. Several natural compounds prevent this. Is there any evidence that pramlintide reduces oxidative stress induced by food?

Dr. Riddle: In early studies with pramlintide, that effect was not really apparent. But there are studies underway now, and I would expect them to be favorable, since pramlintide blunts the postprandial effects.

Q: Dr. Riddle, you showed compelling data about satiety effects and weight loss with amylin. Though the obesity epidemic affects type 1 patients, we still have lean patients. Among those, does it still have the same effects? If so, maybe the amylin/insulin ratio should be different?

Dr. Riddle: We don’t know from good cross-sectional data in a broad population whether there’s a ratio difference between subgroups. We do have data on weight loss in less obese people. In published studies of pramlintide, there was weight loss in obese people, but normal weight people did not lose weight.

Dr. Hirsch: I want to preface my comment by saying that I certainly do not want to see pramlintide go away. But there are two major burdens associated with the drug: first, all the additional work associated with taking a mealtime injection, leading a lot of patients to get burned out very quickly, and second, people on the drug claim to experience tachyphylaxis. My hope is that the co-formulation in a pump would resolve that. The data are very interesting and exciting, but my concern is that the drug stops having the same effect over time.

Dr. Riddle: Tachyphylaxis is specifically a pharmacological term, but what you’re describing is a waning of the effect. I don’t think we can distinguish between the two. The only way to answer the question is to have a standard protocol and do a long-term study. 

Q: I’m a type 1 patient, and I’ve been using pramlintide for years and loving it. What I’ve found most useful about pramlintide is the postprandial effect of the drug. In fact, I’m able to figure out how many carbohydrates I ate during the meal and cover myself with rapid insulin later. It’s giving me that flatter postprandial effect, and I find that very useful.

Dr. Riddle: Thank you for the comment. I think that what I said before I truly believe to be true: Most endocrinologists have a few patients who have wonderful results with pramlintide. It tends to be people with type 1 who have had weight gain when attempting intensive therapy. So I think it’s a subgroup of better responders. May I ask you, have you had any tachyphylaxis?

Comment: I did increase dosing on it. It didn’t appear to be as effective over time. I went from below 60 mcg to 60 mcg. I found I had to take it a little sooner before the meal to get the same effect. I’ve taken it for seven to eight years now and it still has a wonderful postprandial effect.

Q: I want to address the first comment on whether we need to know fat and protein content for closed-loop. As Howard mentioned, the answer is probably no because the model always has a component that embeds the effect of protein and fat into the equations for insulin action, and that’s estimated every five minutes. Dr. Riddle, thanks for mentioning the PICOS studies; I’m excited to hear results from the trial. That would mean we have a decent mathematical model of co-formulation of insulin and pramlintide, that we’re capable of modeling the kinetics of co-formulation. My suggestion would be to use that model for closed-loop solutions that use co-formulations. Would a PICOS artificial pancreas trial be possible?

Dr. Riddle: Yes, it depends on the people who might pay for it. I like the suggestion but I think with continuous delivery, some of the kinetics may change, so we may need to alter the model. It should be tried so we’ll know.

Plenary: Diabetes Management Issues

Hypoglycemia Unawareness: (Impaired Awareness of Hypoglycemia)

Professor Philip Home (Newcastle University, Newcastle upon Tyne, UK)

Professor Philip Home shed light on the significant problem of hypoglycemia unawareness, in which patients do not experience symptoms of hypoglycemia until their blood glucose has dropped to dangerously low levels. He noted that hypoglycemia unawareness is estimated to affect 20-25% of adult patients with type 1 diabetes, with elderly patients at particularly high risk. The problem is especially acute at night, as the typical counterregulatory adrenaline response to hypoglycemia is reduced during sleep, even in people without diabetes. Additionally, Dr. Home shared that the response is attenuated for some time after a hypoglycemic event, creating a vicious cycle in which patients with recent hypoglycemia are at greater risk for a future episode – the concept that “hypoglycemia begets hypoglycemia,” demonstrated most recently in the ASPIRE in-clinic study of the MiniMed 530G. Dr. Home mentioned several questionnaires, such as the Gold, Clarke, and Ryan scoring systems, that can be used to measure hypoglycemia awareness, and he stressed the importance of a thorough clinical assessment that includes an evaluation of CGM data and a detailed history from the patient and observers.

• Patient education and careful avoidance of hypoglycemia has been shown in multiple studies to be effective in improving awareness and reducing the risk of severe events; for example, in the HypoCOMPaSS study of 96 people with type 1 diabetes and impaired hypoglycemia awareness, undergoing an educational program reduced the amount of time spent with a blood glucose level <54 mg/dl from an average of 53.3 minutes per day to 24.5 minutes/day and decreased the percentage of people experiencing severe hypoglycemia from 77% at baseline to 19% during the trial.

Explanation for the ACCORD Outcomes?

Matthew Riddle, MD (Oregon Health & Science University, Portland, OR)

Dr. Matthew Riddle explored different explanations for the cardiovascular death signal that led to the termination of the ACCORD study, ultimately proposing a unifying hypothesis regarding hypoglycemia and CVD. Dr. Riddle spent a majority of the presentation exploring the complexities of the available data, also touched on by Dr. Mark Feinglos (Duke University, Durham, NC) at this year’s ADA. The evidence suggests that CVD risk is associated with severe hypoglycemia, but the association may not be causative. Although it is hard to make specific conclusions on the results of ACCORD (follow-up analyses are still ongoing), Dr. Riddle did put forth a more general hypothesis on the connection between hypoglycemia and CV death. Evidence suggests that CV events following severe hypoglycemia are mediated by catecholamine secretion and resultant arrhythmias. An isolated severe event provokes maximal response to catecholamines, while prior mild hypoglycemia is protective since these events blunt the catecholamine response. If true, postulated Dr. Riddle, the greatest risk of CVD is in those with intermittent adherence to treatment, who experience isolated severe hypoglycemic events following prolonged periods of hyperglycemia.

• Explanations for the safety signal observed in ACCORD include the high-risk population, the rapid reductions in A1c, and the increase in severe hypoglycemia seen with intensive treatment. Dr. Riddle demonstrated support for the vulnerable, high-risk population hypothesis, but data does not support the rapid-A1c-lowering hypothesis – the opposite is actually true, as risk was highest for those that saw little reduction in A1c.
• Dr. Riddle presented on the various benefits and risks seen in ACCORD, pointing out that the study population consisted of people at very high risk for CVD. Some benefits included reduction of non-fatal myocardial infarction, albuminuria, retinopathy, and decline of brain volume. However, he highlighted that CVD developed over time, with the increased all-cause mortality seen at 3.4 years leading to the trial’s cessation.
• Dr. Riddle presented evidence suggesting that the high-risk population contributed to the mortality signal. A subgroup analysis (Calles-Escandon et al, Diabetes Care 2010) showed an association between the high baseline A1c characteristics and complications.
• Discussing severe hypoglycemia as a possible factor mediating the connection between intensive therapy in ACCORD and an increase in all-cause mortality, Dr. Riddle discussed the somewhat contradictory results from the trial. For example, although the intensive arm had more hypoglycemic events, the association between hypoglycemia and death was much stronger in the standard arm compared to the intensive arm (which was also seen in ORIGIN). Furthermore, mortality risk and severe hypoglycemia were both greater at higher A1c levels. Non-severe hypoglycemic events also showed to be a somewhat protective factor against mortality.

How to Well Manage T1DM in the Cheapest Way Possible?

Irl Hirsch, MD (University of Washington, Seattle, WA)

Dr. Irl Hirsch opened a provocative talk on the skyrocketing cost of insulin by warning anyone in the audience from an insulin company to “stand back!” The numbers as he presented them were stark – the cost of a vial of Lantus (insulin glargine) has increased 243% over the past nine years and 84% over the past two. The majority of attendees responded with an emphatic “yes” when asked if they were aware of the rising cost of insulin. Much of the presentation was devoted to a set of tips to help clinicians safely reduce costs for their patients. The list included buying test strips from Amazon (most attendees were not aware that this was possible) to using Goodrx.com to look for the best prices in your zip code. Though Dr. Hirsch praised the impact of insulin analogs (“the single biggest advance in type 1 diabetes in the 1990s”) on reducing hypoglycemia, he was blunt about the mindset of payers, who might not feel sufficient pressure to invest in better insulins to reduce hypoglycemia when the cost of those products is so high (almost $5,000 per year per patient by Dr. Hirsch’s back of the envelope calculation). He predicted that if insulin remains unaffordable to this extent, it is “only a matter of time” before government will intervene, and he suggested that an act of Congress might be the only realistic way to bring prices down. Dr. Hirsch’s presentation fell upon very receptive ears, and it stimulated an energetic discussion during the subsequent panel discussion (see below). 

• Over the past seven years, the cost of insulin products has increased from 84%-547% compared to an overall inflation rate of 11%-15%. Dr. Hirsch said that “these numbers are difficult to really appreciate unless you’re buying them yourself,” but there was no lack of appreciation among the audience members, as demonstrated through a show of hands. He did not speculate in detail about industry’s reasons for elevating prices, but he did suggest that the approaching wave of biosimilars might be a cause. We would also assume the rising cost of developing diabetes drugs – particularly the requirement for CVOTs following 2008 – has contributed as well.
• Dr. Hirsch shared a few compelling patient examples to illustrate the real life consequences of skyrocketing insulin costs. Dr. Hirsch told the story of a patient who faced an amputation of her dominant arm due to cancer that made operating a syringe impossible; she was unable to convince Medicaid to cover the cost of an insulin pen. Dr. Hirsch also mentioned that several of his patients use regular insulin or a mixture of regular and analog insulin in their pumps due to rising copays for analogs. He described an insurance company that would only dispense a new vial of insulin within 48 hours of the end of the previous vial, even if the patient would be traveling; almost 100% of the audience raised their hands when asked if they had encountered a similar experience.
• Dr. Hirsch suggested several “workarounds” that HCPs can use to reduce costs for their patients. He encouraged providers to shop around for the best prices on insulin and other equipment – insulin at Walmart and Costco is significantly cheaper than elsewhere, and it is possible to order test strips on Amazon.com (only 25% of the audience was aware of that). Alongside his recommended strategies, he listed some cost-saving tactics that should be avoided, like using infusion sets for longer than recommended or reducing the frequency of blood glucose testing.
  
  • Dr. Hirsch provided a list of “OK places to try to save money”– use of CGM sensors past their label date, repeated use of pen needles, syringe needles, and lancets, reducing physician visits as much as possible, use of NPH insulin for obese and insulin resistant patients, and a reduction in the frequency of certain tests (retinal exams and albumin-creatinine ratio labs). He made it clear that he did not necessarily support the strategies in this list, but that the extremes of patients’ inability to pay might merit their consideration.
• Dr. Hirsch presented some back of the envelope calculations to explain why payers might not currently be incentivized to invest in insulin analogs. He suggested that it may simply be more expensive to cover insulin analogs (cost differential of ~$4,920 per patient per year compared to human insulin) than to pay for the increase in emergency room visits for hypoglycemia (~$102 per patient per year). In Dr. Hirsch’s view, government intervention is inevitable if insulin remains unaffordable for many patients.
  
  • We would note that the data on the costs of hypoglycemia is quite variable, and that many estimates would place the per-episode cost of hypoglycemia hospitalization much higher than the value Dr. Hirsch used ($1,186 per visit) – as an extreme example, a study presented at last year’s ADA estimated the cost at over $46,000 per hospitalization, while Quilliam et al., AJMC 2011 estimated it at ~$17,654. For more on this topic, see our coverage of a JAMA Internal Medicine’s paper on hypoglycemia-related emergency department visits.

Panel Discussion

Q: Dr. Hirsch, has anyone ever given you an explanation for the dramatic cost of increase for insulin analogs?

Dr. Irl Hirsch: The short answer is no. The usual response is R&D and so forth. I personally don’t think it’s a coincidence that biosimilars are around the corner. Looking at the real reasons, when looking at inflation and looking at the bigger denominator in type 1 and 2 diabetes using insulin, this brings up that we know that it’s $10 a vial in India. I don’t have a good explanation. To be fair to insulin companies, almost every person I’ve talked to, they’re on our side. Many of them are physicians or patients themselves, so they understand it.

Q: Are any of the professional societies taking this on?

Dr. Hirsch: I have heard a rumor that a letter is going to The New York Times from the former ADA presidents. This does really need to become a national outcry.

Dr. Riddle: This is a distinctively American problem. In other parts of world, there’s less of a differential over time. It’s our problem, and we have to figure out what can possibly be done. It’s not just insulin for type 1, but medications for type 2 as well.

Dr. Hirsch: Don’t get me started on that.

Dr. Riddle: It takes me back to one of my personal rants that we shouldn’t be throwing old well-tested drugs under the bus. NPH, regular insulin, metformin, SFUs, and TZDs look pretty good when you look at price, and you can get good control even in type 1 with NPH and regular insulin.

Dr. Hirsch: I agree, especially with the issue of starting insulin using human insulin. If you look critically at the data for prandial insulin in type 2, there’s not much difference at all. You do see a difference with type 1 but not type 2.

Professor Philip Home: Think about the components of price. If you take aspart or glargine, the development costs were written off a long time ago. Now companies are only faced with production costs, and those are no different for analogs than for NPH – it’s the same process to produce them. What determines price is what the market will bear, and the market has been prepared to bear it. Screaming is important; pressure has to be applied. It’s not going to change otherwise.

Dr. Satish Garg: What’s the real cost of making insulin?

Dr. Hirsch: I honestly don’t know, but I know you know, so why don’t you tell us?

Dr. Garg: So I recently looked into this. These are actual facts because I’m involved with companies that make insulin. They can make 1,000 units of insulin for 25 cents. Now, let’s give companies the benefit of the doubt. Their cost is probably five times that. That’s why anywhere in the world, it costs $1-4 per vial. By 2018, the market that Irl showed was going to be less than a billion dollars. It was going to swell up to $8 billion just for insulin worldwide. It’s unbelievable numbers.

Q: I have two short questions. For Irl, do you feel that everyone with type 1 should have an unexpired vial of glucagon?

Dr. Hirsch: Let’s first talk about type 2. I do prescribe glucagon if there’s any history of severe hypoglycemia and go through the same stuff with the family. In type 1 patients, everyone gets a vial of glucagon. I don’t know what it costs anymore, but there are huge, huge issues and it’s gone up in price. Decades ago, you could take a kit in when it expired and replace it for no charge. Those days are long gone. It is a significant cost, and we want everyone to obviously have it. Look it up and let us know.

Comment: I looked up the price of glucagon. At pharmacies in this area, it’s $195-$201 with a discount or coupon.

Q: Dr. Riddle, in your review of ACCORD and increased death with intensive treatment, you didn’t go into different medications and increased doses. What are your thoughts on that as a cause?

Dr. Matthew Riddle: I didn’t mention it because we haven’t published analyses. It’s difficult to do analyses of on-treatment drug prescriptive records, let alone what people actually were taking because the database is less secure. There was lots of confounding between arms of the study and in other ways related to physician preferences and strategies and beliefs, so it’s a difficult analysis. That said, there’s no smoking gun in the data we have. For example, it doesn’t look like TZDs frequently cause lots of heart failure. There’s an analysis that was reported as an abstract but not published – a sophisticated analysis, the best we have at the moment – looking at the risks of insulin use. The short version of the conclusion was that there was no relationship between use, dosage, or time of insulin to a difference between outcomes. That was particularly true for basal; it was less secure for prandial, where there might be weak signal but not statistically strong. That’s where we are, it’s hard to know what to make of it, but it’s an important question.

Q: What about just the people who died, there was no difference?

Dr. Riddle: We haven’t done a subgroup analysis of those who died. That’s even more difficult and confounded. It’s the right question; we just don’t have the answer.

Q: Regarding prevalence of hypoglycemia unawareness, you said numbers between 20-25%. I’ve had experience asking people with type 1 if they recognize when they have low blood sugar. And they say, “yeah, I do all the time.” But when I download their data, I sometimes see some real lows like in the 30s. Do you think we are overestimating some peoples’ abilities?

Professor Home: Yeah, there is a nighttime problem. People also do go down in the daytime. Even you and I, we sometimes go down to surprisingly low levels without noticing it. So it does occur. The phenomenon that you have to watch out for is if you’re unaware, you can destroy your short-term memory. So you end up not even remembering going low. That’s what makes it really hard.

Plenary: Special Issues in Diabetes

Biosimilars in Diabetes Care

Philip Home, DM, DPhil (Newcastle University, Newcastle upon Tyne, UK)

Professor Philip Home shared his thoughts on what should be required for clinical confidence in a biosimilar insulin, stressing that current regulatory guidelines may not be sufficient to ensure the safety and efficacy of these products. “Biosimilars are coming our way” due to the patent expiry of Sanofi’s Lantus (insulin glargine), Professor Home noted, and there is currently a lack of clear regulatory guidelines surrounding their approval. The EU has the most detailed guidelines specific to biosimilar insulins, but Professor Home critiqued several aspects of that guidance, saying that the confidence intervals of 20-25% for pharmacokinetic (PK) and pharmacodynamics (PD) studies are too wide and expressing strong disagreement with the EU’s statement that randomized controlled trials for efficacy will likely not be necessary. He believes that it is essential to study biosimilar insulins in the most sensitive clinical population (in this case, C-peptide negative patients) and to review a totality of clinical outcomes rather than focusing on a single measure (PK, PD, A1c, pre-injection glucose, hypoglycemia, immunogenicity). He expressed concern about the lack of access to manufacturing quality data (differences in manufacturing techniques could significantly affect biosimilar performance), saying that a company’s reputation will likely be the best indication of quality for many clinicians. Professor Home closed by reviewing data presented at ADA on Lilly’s biosimilar insulin glargine LY2963016, pointing out that while the studies appeared to be well run, the erratic PK data in type 1 patients and the wide confidence intervals for many of the efficacy measures might not individually confirm biosimilarity conclusively.

• A review of the current regulatory guidelines on biosimilar insulins illustrated the high degree of variability in this area. The EU has been somewhat of a pioneer, with a set of guidelines for general biosimilars since 2005 and guidelines specific to biosimilar insulins more recently. However, Professor Home sharply critiqued some of those guidelines, saying that the required confidence intervals of 20-25% for PK/PD studies were far too wide and that he fundamentally disagreed with the statement that there was “no anticipated need” for randomized controlled clinical trials for efficacy. Elsewhere in the world, the guidance is even less clear – the US and Canada have only general guidelines for biosimilar approval, and, concerningly, in many other countries like Mexico, the requirements for approval are extremely lax.
• Professor Home believes that reviewing a “package of clinical outcomes” is the best way to ensure the clinical safety and efficacy of a biosimilar insulin. He outlined several outcomes that should be part of such a package, including PK and PD studies, A1c, pre-injection glucose, hypoglycemia, and immunogenicity, cautioning that focusing on any of those outcomes alone will not be sufficiently powered to demonstrate biosimilarity. He emphasized the need for clinical studies in the most sensitive population possible, such as C-peptide-negative type 1 diabetes patient, as any endogenous insulin secretion could buffer out any difference between a biosimilar and its reference product.
• It will be difficult to monitor and evaluate the quality of the manufacturing process for biosimilar insulins. Slight differences in the manufacturing process compared to the reference product are inevitable due to the complexity of insulin production, but it is essential to ensure that those alterations do not change the product’s clinical profile or lead to adverse effects like antibody production. Professor Home lamented the lack of access to data on the quality and consistency of the manufacturing process and predicted that clinicians will most likely rely on the manufacturer’s reputation to assess the quality of the product – this would work to the advantage of companies like Lilly that are well-established in the insulin market, whereas Asia-based companies such as Biocon may have a larger perception barrier to overcome.
• Professor Home offered a mixed assessment of LY2963016, Lilly’s biosimilar insulin glargine, emphasizing that the current data package is fairly strong but that there are issues about the strength of individual parts of the data. He praised some aspects of the comparative data presented at last month’s ADA against Sanofi’s Lantus – the PK profiles of two different doses of LY2963016 in healthy subjects gave him “some confidence” that the two insulin glargines have similar absorption profiles, and he was satisfied with the data showing no significant difference in clinical outcomes between the two glargines. However, he characterized the PK data in patients with type 1 diabetes as “all over the place” and criticized the wide confidence intervals in the efficacy trials.

Plenary: Cardiovascular Disease and Diabetes

Is CVD Outcome for Diabetes Drugs Appropriate?

William Hiatt, MD (University of Colorado, Denver, CO)

Cardiologist Dr. William Hiatt offered a thorough and perhaps somewhat ambivalent perspective on the much-debated topic of diabetes drugs and cardiovascular risk – we were listening closely, as Dr. Hiatt is a member of the FDA Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC). He began by suggesting that A1c does not represent a useful biomarker for cardiovascular risk, based on results from ACCORD and ADVANCE that indicate that the most intensive control may increase the risk of mortality. Dr. Hiatt said little about the value of ongoing outcomes trials except to express his disappointment that trials on newer diabetes drug classes have not yet demonstrated any cardiovascular benefit, though he is hopeful about the potential of SGLT-2 inhibitors due to their beneficial effects on blood pressure and weight (there is also great hope in the field that GLP-1 agonists may prove to be cardioprotective). Much of Dr. Hiatt’s talk was devoted to recounting the controversy over rosiglitazone that led to the FDA’s 2008 CV Guidance. It was hard to gauge his overall viewpoint on the saga: he disparaged some elements of the RECORD trial, but also acknowledged that the Duke Clinical Research Institute (which ran the re-adjudication that ultimately exonerated the drug) performs excellent work. He concluded his presentation by suggesting that the TZDs and the DPP-4 inhibitors that have had CVOTs completed likely do not posed increased CV risk.

• During the panel discussion, Dr. Hiatt more forthrightly expressed his concern and ambivalence over the appropriateness of the FDA’s CV Guidance (see below). He acknowledged that SAVOR and EXAMINE (the CVOTs for AZ’s Onglyza and Takeda’s Nesina) cost a great deal and provided relatively little notable data. Ultimately, should the FDA choose to review the appropriateness of the 2008 CV Guidance, EMDAC voices such as Dr. Hiatt that are neither bluntly for or against the policy might be key tiebreakers in the discussion.
• As a reminder, the FDA is holding an open hearing on August 11 regarding the reporting of interim CVOT results - it should provide some insight into the FDA’s current views on the current CVOT paradigm.

Recent and Ongoing Cardiovascular Outcomes Trials with Diabetes Drugs

Jay Skyler, MD (University of Miami, Miami, FL)

Dr. Jay Skyler reviewed four of the biggest recent cardiovascular outcomes trials (CVOTs) with diabetes drugs and highlighted ongoing trials, expressing frustration with the way the trials are being designed. He emphasized that current CVOTs are too short to prove much about long-term CV outcomes – this has been disappointing. He also argued that trials should not rely on enrolling patients with pre-existing CVD, given that the primary goal of diabetes therapy is to prevent CVD in the first place. Dr. Skyler thoroughly reviewed results of SAVOR, EXAMINE, AleCardio, and ORIGIN, whose results have all been previously presented in detail at other meetings. Looking ahead, he presented a slide with the large number of ongoing CVOTs, emphasizing that these studies will require large pools of patients as well as money. He also pointed out that MannKind’s inhalable insulin Afrezza will not be required to do a CVOT in the classic sense, but that the FDA-mandated pulmonary safety study will provide good long-term data on CV safety – a CVD trial in disguise!  To conclude, Dr. Skyler emphasized that he is concerned with the design of these CVOTs, stating that longer studies enrolling people without cardiovascular disease are in order to assess risk reduction, not just neutrality.

• When reviewing the results from SAVOR, Dr. Skyler paused to consider the slight (5-to-12) asymmetry in pancreatic cancer rates that trended towards favoring Onglyza. He argued that if the imbalance had gone the other way, even though the difference would not have been statistically significant, the news headlines would have been completely alarmist. Both here and at other moments during the conference, Dr. Skyler suggested that the mainstream media has done a poor job of framing the results of major trials, causing far-reaching shockwaves.
• During the panel discussion, Dr. Skyler noted that many of the individuals behind the CV guidance (which direct large amounts of research funding towards academic institutions) were from the institutions that now run many CVOTs. He characterized this as a major conflict of interest, and questioned why industry-linked conflicts of interest were weeded out whereas academic conflicts of interest were not.

Rationale for ADA Treatment Guidelines for CVD Prevention

Robert Ratner, MD (American Diabetes Association, Alexandria, VA)

Dr. Robert Ratner offered his take on why it has been so difficult to establish a link between improved glycemic control and reduced cardiovascular risk in patients with diabetes. He pointed out that the absolute risk of macrovascular complications has been declining in recent years (the absolute MI risk in patients with diabetes has dropped to 1.5% per year), which makes it more difficult to elucidate the specific effects of individual treatments and A1c targets on cardiovascular outcomes. The main obstacle facing investigators is the massive investment required to produce a sufficiently powered study: given the relatively low baseline event rates, thousands of subjects must be followed for many years and a number of confounding variables must be accounted for. To illustrate the statistical impact of study length, Dr. Ratner explained that in UKPDS it took over 15 years for the improvement in the incidence of macrovascular outcomes became statistically significant.  Dr. Ratner speculated that glycemic control may have a more pronounced effect on cardiovascular health earlier in the progression of diabetes, a hypothesis that is not being tested by current CVOTs that enroll patients with more advanced CVD. In a cautious conclusion, reflective of the lack of conclusive data connecting improved glycemic control and CV outcomes, Dr. Ratner said it was possible that we simply have not yet invented a therapy that can both lower blood glucose and reduce CV risk.

• Dr. Ratner disagreed with Dr. William Hiatt’s (University of Colorado, Denver, CO) conclusion during his earlier presentation that the takeaway from the ACCORD trial is that intensive control is linked to cardiovascular harm. If intensive control actually caused harm, one would expect the increased risk to be greatest in those with the lowest A1cs during the trial. However, as Dr. Ratner pointed out, the higher all-cause mortality in the intensive treatment group occurred in the people with the highest A1cs, and patients who reached the more stringent A1c target actually had a decreased risk of mortality.

2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults

Robert Eckel (University of Colorado, Aurora, CO)

Dr. Robert Eckel defended the evidence-based approach used to create the 2013 ACC/AHA lipid guidelines for the use of cholesterol-lowering drugs in the treatment of atherosclerotic cardiovascular disease. The presentation echoed many of his sentiments from ADA 2014 when he and Dr. Henry Ginsberg debated the suitability of the guidelines. As a reminder, the ACC/ADA guidelines encourage statin therapy in four groups proven to experience benefit from the treatment: (i) people with existing atherosclerotic cardiovascular disease (ASCVD – e.g., stroke, coronary disease, aortic aneurysm, peripheral vascular disease, etc.); (ii) LDL ≥190 mg/dl and age ≥21 years; (iii) primary prevention in diabetes patients aged 40-75 years and LDL 70-189 mg/dl; (iv) primary prevention in patients without diabetes but with 10-year risk score of ≥7.5% (using the new risk calculator), aged 40-75 years, LDL 70-189 mg/dl. The new guidelines have been somewhat controversial, especially because they significantly de-emphasize LDL cholesterol targets for many patients. However, Dr. Eckel emphasized that the new guidelines should not be seen as strict rules, recognizing that individualization of therapy is often necessary to accommodate different factors. In fact, he encouraged providers to value a patient-centered approach over strict adherence the guidelines, assuming there is good reason for the deviation. Dr. Eckel’s discussion of other “major controversies” related to the guidelines is highlighted below.

• Dr. Eckel argued against the notion that the ACC/AHA-developed risk-assessment calculator used in the guideline overestimates patient risk, referencing recently-published data (Muntner et al., JAMA, 2014). This retrospective analysis of patients enrolled in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study using the ACC/AHA risk estimator found that observed and predicted five-year incidence of adverse CV outcomes coincided well.
• Statin therapy based on a threshold of 7.5% 10-year estimated cardiovascular disease (CVD) event risk does not lead to overtreatment – a common critique of the guidance – according to Dr. Eckel. Sharing data from Lancet and NEJM, Dr. Eckel noted that statin therapy has been shown to benefit patients with even a 5% 10-year estimated CVD event risk. However, Dr. Eckel “repeatedly emphasized” that the decision to use statin therapy is informed by clinical judgment and patient choice as much as it is by risk factors and other clinical evidence.
• Dr. Eckel was surprised by accusations of bias among committee members. Given that the majority of statins recommended were generics (for all but one potent statin), he argued that the claims were unfounded. He also reminded the audience that the process of guideline development incorporated many different organizations in which conflicts of interest were addressed up front.

Dr. Eckel stressed that the lack of LDL and HDL cholesterol goals does not preclude goal-setting or lipid-lowering treatment; however, targets are not fully evidence-based. Dr. Eckel noted that the committee found no evidence of the benefit of specific targets for the population as a whole; however, he continued to emphasize that individual clinicians “treat people not populations” and therefore, have much latitude in employing their personal judgment in prescribing medications.

Panel Discussion

Q: Following this session, how many of you feel better prepared to deal with cardiovascular disease?

[Only a few people raised their hands]

Q: How many of you feel more confused?

[Sheepish laughter]

Q: What do we do about these unnecessary CVOTs? Do we complain to senators?

Dr. Robert Ratner (ADA, Alexandria, VA): The FDA is clearly starting to look at this issue again. At the last rosiglitazone meeting, the one that took away the black box with the restrictions, one panel member said, ‘There’s the elephant in the room that we’re not talking about. With the removal of restrictions on rosiglitazone, does that mean we’re going to stop requiring CV outcomes trials?’ And Bob Temple’s response to that was, ‘That’s not why we’re meeting today.” On the other hand, in August, they are going to talk about opening up interim data from the CVOTs for review for the approval of drugs. So I think the discussion is coming back. Do you see that happening, Will?      

Dr. Will Hiatt (University of Colorado School of Medicine, Denver, CO): I do. I must say. I’ve really wrestled hard with the diabetes guidance. It extended to drugs such as sibutramine that clearly caused harm. And I think that thinking about it is okay, but the problem is that you need enough events to rule out a certain amount of risk, so these tend to be low-risk populations, particularly with obesity drugs, and you don’t necessarily require a lot of events. And so you have these really high upper bounds on the confidence intervals driven by the lack of events. So what triggered the 2008 guidance and what was in the public discussion was the rosiglitazone meta-analysis. That’s what triggered it – it was that big. Looking back now and thinking about the saxagliptin and sitagliptin publications, I say to myself that we spent a lot of money to learn not a whole lot. So I worry about that exact same issue. Going forward, if you have a drug with a mechanism that you think actually might reduce cardiovascular disease, by all means go for it [the CVOT]. But the fact that we require every drug in the world … is it overdone? I don’t want to sit and do too much judging, but I am concerned about the same issue.

Dr. Jay Skyler (University of Miami, Miami, FL): Regarding the 2008 Advisory Committee meeting, if you go back and look at the minutes of the meeting, there are people with conflicts of interest who were not allowed to participate because they’re involved in industry. And then the people who are allowed to participate and who are giving recommendations happen to be from the Cleveland Clinic, Oxford, Duke, and other institutions. They suggest that trials should be done and conducted by independent academic groups, the same groups that they represent! How is that not a conflict of interest? They’ve created their own machines and they’re driving them themselves.

Q: The cost of all these outcomes studies and getting the medications in front of the FDA are huge. These medications aren’t even supposed to affect cardiovascular disease. They’re for diabetes. These drugs lead to relatively small reductions in A1c. Is it really worth it? I propose a brand new medication – its name is one less slice of bread a day. We could probably get more significant reductions at much lower cost.

Dr. Jay Skyler: I agree with you. I think it would have been nice for the people to have planned the meals for this conference to have taken that into consideration.

Dr. Satish Garg (Barbara Davis Center, Aurora, CO): Now I have to step in here. Every year, we take these comments into account. We got rid of the pizza from last year! [Laughter]

Q: I didn’t hear any mention of Cycloset? Can you comment on cardiovascular safety trials? 

Dr. Skyler: Trials were actually initiated prior to the time that the FDA put the new guidelines into effect and it wasn’t powered in the same kind of way. The results were actually quite surprising and showed a dramatic decrease in cardiovascular events with Cycloset. And the FDA let them put it in the label under side effects. But, there weren’t any. They were concerned it was going to be an increased risk, but actually, there was a 50% reduction, which is really dramatic. The explanations for this were not entirely clear.

Dr. Ratner: Cycloset is a perfect example of the danger of small numbers. When you have a small number of events, chance alone is going to have a positive p value of one in 20. That’s essentially what happened. There is another example of cardiovascular benefit from low numbers, in which acarbose had a dramatic effect in reducing myocardial infarctions. But no one really believes it because it wasn’t really validated in other studies. I think that’s the situation with Cycloset. Small numbers become difficult to replicate.

Dr. Skyler: But with a 50% reduction in cardiovascular events, I think the data still says something [about Cycloset]. If it were 10-20%, I might dismiss it. I think what it says is that we need another bigger trial to understand it better.

Q: I’m on the hospital side and in a lot of my consults, I see people with chest pain post-myocardial-infarction, a new diabetes diagnosis, and no health insurance. I would love to use a DPP-4 inhibitor but I have no choice but to use cheap things like metformin and sulfonylureas. We all have that love/hate relationship with sulfonylureas but they are inexpensive. I’ve heard a lot about the ischemic preconditioning problems with glyburide. Can you elaborate more on sulfonylurea therapy in people who have just had a coronary event? Once, I was told that I’m endangering their lives by prescribing sulfonylureas and that they need to come up with the money to get more expensive therapies.

Dr. Hiatt: We have gotten a lot better at treating heart disease and diabetes outcomes because background therapy has gotten a lot better. I’m not a complete nihilist around the A1c. I do think any drug you can use that can adequately manage their metabolic problems to some appropriate level is absolutely appropriate. We’re not advocating bad therapy. We have drugs that do that and you should use them. I too am concerned that we’re adding lots of new expensive drugs with small A1c benefits, where I’m not convinced that it helps the patient that much. In your case, you’re not just worried about sulfonylurea isolation. You can use good blood pressure medications that are generic as well as good statins that are generic. You can do all the things that Dr. Eckel referred to that have a huge impact and feel good about that.

Professor Philip Home (Newcastle University, Newcastle upon Tyne, UK): I’ve been looking at sulfonylureas for years and have published reassuring papers. More importantly, there is a supportive paper from the Diabetes Care editor’s forum, in press. These are serious people who are respected who have concluded that there are no issues of safety. From outside the US, I just wonder why you cannot get generic sulfonylureas. We pay $5 a month for gliclazide, which is a perfectly acceptable alternative.  

Q: We can use gliclazide and glimepiride for fairly inexpensive prices. And I usually do use glimepiride because you can titrate it much better. But again, those are all the choices we have. If patients get that, we’re also getting prescriptions for statins and all these other things, etc. so we have more co-pays. Sometimes we really have no choice but to use sulfonylureas. I’m just really concerned that I’m increasing their cardiovascular risk.

Professor Home: If I can bring up another point that arises here, Jay showed us all those twenty studies on CVOTs. These studies cost five or ten billion US dollars – who’s going to pay for these? It’s going to be the person with diabetes and health insurance. I don’t offer thanks to FDA’s inappropriate attitude in driving costs of future therapies up. Patients and insurers are ultimately going to have to pay.

Q: For those of us who practice exclusively in the pediatric world, what is your take-home message for us?

Dr. Skyler: I don’t have any data on this. As Bob pointed out, there’s not adequate cardiovascular data, so you make individual recommendations to try to deal with it.

Professor Home: The simplest answer, I think, is that in the absence of clinical trial data coming from the pediatric population. We do have clear data that you can manage CV and arterial risk. Because we do know that it is associated. The message is that within the limits of your individual track, good blood glucose control with our current therapies and good education and support groups should minimize cardiovascular risk.

Dr. Robert Eckel (University of Colorado, Aurora, CO): We are making a lot of assumption about atherosclerosis in type 1. Many people think that it’s just like type 2, but happens earlier. We’ll be having a workshop on basic science on this in the fall. I’m entering with a bias that there is more calcification and more fibrous processes. But this has never been specifically studied in type 1. We don’t have enough science in type 1 to know what to do. In adults with type 1, we really need science. Type 1 has been ignored, and many assumptions have been made.

Dr. Ratner: The ADA just recently came out with type 1 diabetes specific guidelines. And we do have some data on adolescents, but we have very little on children. With adolescents, we have the subgroup from DCCT with 25 years of follow-up. So the glycemic guidelines have been brought down to 7.5%, even for small children. We know the blood pressure benefits, even in those adolescents. But we have no data on lipids.

Dr. Marian Rewers (University of Colorado School of Medicine, Denver, CO): Regarding the clinical trial data, there’s a lot of observation from DCCT. Let me add one more bias in terms of cardiovascular disease in type 1. A major uncontrolled risk factor is peripheral hyperlipidemia – in an effort to control A1c in these patients, we’re giving way too much insulin in the peripheral system. Cardiac data show that there is insulin resistance in all of the target organs. So I think the several sessions here about the artificial pancreas should look at minimizing the dose of insulin in type 1 patients by optimization of timing. Part of the delivery is going to help tremendously down the line in terms of cardiovascular risk in this population.

Dr. Eckel: However if you think about insulin resistance, which we’ve clearly documented in type 1, ultimately, cholesterol is high and triglycerides are lower in type 1. Why is that? In general, the lipid protein abnormalities that were deemed appropriate for atherosclerosis just don’t appear to be there in type 1. The hypothesis is that this may be a different process in terms of the arterial wall.

Dr. Ratner: I would also look at the ORIGIN data to suggest peripheral hyperinsulinemia probably can’t be blamed.

Professor Home: The associations are relatively poor between peripheral hyperinsulinemia and atherosclerosis. In terms of giving insulin, you’re improving insulin insensitivity and if you measure insulin levels, they fall in type 2 diabetes. We have to be very careful in interpreting that data. I personally don’t believe the peripheral hyperinsulinemia and atherosclerosis story.

Comment: [Dr. Rewers] We’re mixing type 1 and type 2. What we call it in type 2, insulin levels are in ranges of 20-40 units per milligram. In type 1s, it’s insulin levels after injections of short-acting or long-acting insulins at three or four times that level. I suggest that we have a separate session next year on this issue.

Dr. Skyler: The hyperinsulinemia question goes back to three papers in the 1970s that studied non-diabetic populations. A bunch of studies found that circulating levels of insulin were correlated with increased coronary risk. But when we looked at it later, it wasn’t insulin. It was insulin resistance at those tissues that’s really the culprit. Hyperinsulinemia reflects insulin resistance in those organs.

Q: We’ve talked a lot about cardiac events this morning. At the 2013 meeting of EASD, Dr. John McMurray stated that we need to make heart failure more important and that it is the most important complication of diabetes. What is your response?

Professor Home: I know Dr. John McMurray well and he is a heart failure guy. But honestly, who is saying that heart failure is more important than cardiovascular death or myocardial infarction? In most studies these days, we do adjudicate data regarding heart failure. So that data is there already. But I would go against saying that cardiovascular death, stroke, and heart failure should be consider equally important complications of diabetes. That’s not a very intelligent way to approach that.

Dr. Hiatt: I think that the number of deaths that occur from ischemic heart disease overwhelms the number from heart failure. We should still prevent heart failure – After all, there is evidence that people with diabetes have stiff left ventricles. Other than that, you want to keep things in perspective.

Additional Topics

Keynote Presentation

Delivery of Quality Care in the Evolving Payer Landscape

Robert Ratner, MD (American Diabetes Association, Alexandria, VA)

Dr. Robert Ratner presented on how a critical trend in the overall healthcare system – the rise of patient centered medical homes (PCMH) and accountable care organizations (ACOs) – can be seen as an opportunity to improve diabetes treatment. He reviewed several studies on the effects of PCMH implementation on diabetes outcomes and costs: by emphasizing integrated, team-based care and quality-based reimbursement, organizations (in many cases) were able to significantly reduce ER visits and inpatient hospitalizations, improve achievement of treatment goals, and save substantial amounts of money ($161 million annually, in the case of Community Care of NC). Dr. Ratner also discussed several ACO pilot projects, including the Medicare Shared Savings Program, which will eventually involve 360 Medicare ACOs in 47 states and Washington, DC. Out of the 114 organizations that have participated thus far, 54 spent less than their budget benchmarks and 29 qualified for shared savings (an average $126 million savings to the healthcare systems and $128 million for the Medicare Trust Fund). Dr. Ratner believes that ACOs will grow rapidly in prevalence, and he encouraged the diabetes community to take the lead as a “chronic disease model” for providing high quality care at a reasonable cost.

• Citing the fact that preventing one hospitalization pays for a pump for a year (at least!), Dr. Ratner stressed the importance of keeping patients out of the hospital. The Affordable Care Act is one of many factors driving a transition from a fee-for-service reimbursement model to one that better aligns provider incentives with improved outcomes. PCMHs and ACOs are two of the proposed strategies to fundamentally change the way care delivery is structured, and Dr. Ratner suggested that the two new care delivery models could be an opportunity to greatly improve diabetes care.
• Dr. Ratner listed the seven key components of the PCMH:
  
  • Coordination and integration of care
  • Decision supports for quality and safety
  • Whole-person orientation
  • Each patient is associated with a “personal physician”
  • The personal physician is the director of patients’ care
  • Enhanced access to care
  • Quality-based reimbursement
• Dr. Ratner defined ACOs in a easy-to-understand manner, characterizing them as an update on the theme of capitated care. A group of 32 “pioneer” ACOs covering nearly 700,000 Medicare beneficiaries are early implementers of the ACO model; 25 of them have reduced risk-adjusted hospital readmission rates below their benchmarks, and 30 of them have made money, suggesting that this model could be an effective means of bending the healthcare cost curve.

Questions and Answers

Q: Medicare restricts the thing that costs the least: test strips. If a cop pulls you over and asks how fast you’re going and you say, “I looked yesterday,” you get a ticket.

Dr. Ratner: That’s traditional Medicare. In an ACO, you give them as many strips as it takes.

Comment: I hope that Medicare will provide smarter reimbursement in the future, because it is not right now.

Dr. Ratner: This is where we are in an evolution. What does it take to keep people out of the ED? That’s what’s ultimately going to win. Penny wise and pound foolish, that’s what Medicare is right now.

Q: This was a great overview, but I didn’t see any emphasis on personal responsibility. No health care system will survive unless patients are personally responsible

Dr. Ratner: You’re right but we need to be very careful. We provide education and support to do all of that. To throw a person with diabetes under the bus if they can’t do everything because they don’t understand or they don’t have the finances is unfair. We should not use pay for performance on selected individuals or a percentage of individuals; that’s not a patient centered approach. Shared decision-making and decision support is how you get buy-in.

Comment: With car insurance, having a bad record means you pay more money. Why can’t we put that concept into health insurance? You’re overweight, you don’t take care of yourself, you pay more.

Dr. Ratner: We have to differentiate car insurance from health insurance. You have 100% of the responsibility for driving; that’s not true for your health.

Q: I work for a PCMH and ACO. The biggest problem is that patients aren’t interested. We give them behavioral health and diabetes education, but they don’t want to do it, so my data’s not as good. The administration understands for now, but in the future, if I don’t meet their guidelines, I may have to drop patients.

Dr. Ratner: The idea of cherry picking is what killed capitated care. The issue is that given the Affordable Care Act, you can’t deny someone coverage based on a previous diagnosis or previous expenditures. People won’t be able to cherry pick. We’ll have to learn to accommodate people. Not everyone will have an A1c under 7% and stay out of the hospital. The question is, do you shift the distribution curve? Everything is a normal distribution: if you can shift it to the left so the vast majority are doing better, you’ll have outliers who don’t get there, but you’re saving money for the system.

Q: Can you comment on the very high reimbursement for procedures relative to the type of care we endocrinologists do? It is a real challenge if the salaries of other disciplines keep going up compared to us endos.

Dr. Ratner: That’s the past. Radiologists are in trouble. Increased procedures (radiology, scoping folks who don’t need it) will cut into an ACO’s ability to provide care, so they’ll get penalized. There will be increased reimbursement for keeping people out of the hospital and keeping costs down, not high cost procedures that defeat the purpose.

Dr. Satish Garg (Barbara Davis Center, Aurora, CO): Costs are so overinflated. How do we account for that? In many countries, you can get a CT scan for $40.

Dr. Ratner: That’s the past. What we’ve done is pay for individual procedures. That’s changing. With bundled care, if you get charged $3,000 for MRIs, you’ll stop doing $3,000 MRIs. It will be $200 or it won’t be done.

Q: There was recently an editorial in NEJM on what’s preventing us from preventing type 2 diabetes. What are we doing to expand on environmental factors, personal responsibility, etc. to prevent costs?

Dr. Ratner: Do I have another hour and a half? The Diabetes Prevention Program is very active and expanding. Social determinants of diabetes and obesity were reviewed by the prevention committee at ADA and a piece was published in 2013 about what the environmental influences are. The difficulty is that we don’t have good data on changing determinants. We need those. We need the public will to consider diabetes a public health problem. Mayor Bloomberg tried to do that and he got shot down. It’s an evolving situation. We managed to come up with the public will to get rid of lead in paint and gasoline, and that’s had a major impact on kids and lead poisoning. Do we have public will to change issues around sugar-sweetened beverages and high-calorie, low-density food? I don’t know that we do yet but that’s where we have to go.

Plenary: Improving Diabetes Outcomes

How Diabetes Outcomes Have Changed Over the Past 30 Years

Philip Home, DM, DPhil (Newcastle University, Newcastle upon Tyne, UK)

Professor Philip Home began the first plenary session of the meeting by discussing the extent to which diabetes outcomes have changed over the past 30 years. There has been evidence of improvements in diabetes surrogate and actual outcomes, but the crucial “how” (i.e.: the interpretation of the exact changes that yielded the improvements) is harder to elucidate. The overall increase in diabetes incidence/prevalence and changes in the incidence and treatment of other health conditions complicates the arithmetic on the incidence of adverse diabetes-related outcomes, even in landmark studies like the DCCT. The “intensive control” tested in the DCCT involved a number of factors, including more aggressive and customized insulin titration, improved patient education, and perhaps even increased patient motivation. It is therefore difficult to distinguish which combination of these factors contributed to the results of the DCCT. In Professor Home’s view, the only conclusion that can convincingly be drawn from the DCCT is that some aspects of intensive diabetes management, combined in unknown proportions, prevent microvascular complications. In this sense, he noted that it is “clinicians who have made a difference,” emphasizing that their commitment to engaging with patients, implementing monitoring tools, and accepting new educational approaches has made a significant difference in improving patient outcomes.

• Professor Home noted that the interpretation of diabetes outcome data is quite complex. For example, he highlighted CDC data illustrating that the number of individuals with high A1c (>8.0%) has fallen over the past 25 years, but noted that this data might simply reflect an earlier average diagnosis. Overall, although Professor Home was certainly enthusiastic about the observed improvements in outcomes, his presentation’s theme was caution against conflating correlation and causation.
  
  • “Certainly something good is happening with respect to our treatment of hyperglycemia,” Dr. Home emphasized. He noted that diabetes-related age-adjusted rates of death due to hyperglycemia have decreased significantly over the past 29 years.  
  • Conversely, Professor Home stressed that our understanding of hypoglycemia is limited. Data are much harder to come by, such that statistics reported by the CDC only report the incidence of hypoglycemia-related emergency room visits in the US over the past four years. However, this statistic has held steady at 1.5 visits per 1000 diabetes individuals, leading Professor Home to suggest that “we’re doing okay.”
• Professor Home emphasized that the difficulties with interpreting data even plague our understanding of landmark trials, such as the DCCT. The intensive treatment group of this study could have been positively influenced by a number of factors, including education, telephone advice, increased motivation, and glycated hemoglobin targeting, such that it is difficult to distinguish which combination of these factors contributed to the results of the DCCT. Ultimately, all that can be interpreted from the DCCT is that some or all of the aspects of “intensive diabetes management,” combined in some unknown proportion, prevented microvascular complications.
• In closing, Professor Home noted that it is too soon to observe the likely benefits of recent therapeutic tools, especially given the continued rise in diabetes prevalence. He expressed hope that the implementation of these novel monitoring tools (e.g., CGM) and educational approaches (e.g., patient-centered care) will improve outcomes in coming years.

Why Obese People Are Unable to Keep Weight Off After Losing It

Robert Ratner, MD (American Diabetes Association, Alexandria, VA)

Dr. Robert Ratner provided an instructive and thorough presentation on how complex biological mechanisms drive weight regain, explaining the roles of epigenetics, leptin, energy efficiency, and the microbiota. He emphasized that it does patients a disservice to say that their obesity is due to poor lifestyle or dietary choices alone, given the complexity of weight regulation with its many hormonal and neural signals. He explained how formerly obese individuals have lower non-resting energy expenditure, making it easier to gain weight. Dr. Ratner also noted that leptin sensitivity is reduced with obesity, and that this reduction may not be easily reversed with weight loss. Although he admittedly is “not a large advocate for bariatric surgery for clinical purposes,” Dr. Ratner did credit bariatric surgery for illuminating some of the mechanisms and hormones that can help patients achieve weight loss through pharmacotherapy (such as GLP-1). Providing a window into the ADA’s current areas of interest, Dr. Ratner dedicated a large portion of his presentation to the effect of the gut microbiome on obesity. He pointed to several studies that showed changes in bile acid concentrations and the microbiome after vertical sleeve gastrectomy as well as after Roux-en-Y gastric bypass (RYGB). In recognizing the microbiome as an exciting new topic in obesity, Dr. Ratner concluded by inviting the audience to attend ADA’s and JDRF’s research symposium, Diabetes and the Microbiome in Chicago on October 27-29.

What Should be the Therapeutic Glycemic Target in Intensive Care Units?

Irl Hirsch, MD (University of Washington, Seattle, WA)

Dr. Irl Hirsch discussed the potential benefits of intensive glycemic control in intensive care units, a topic that continues to be controversial given the nuances of interpreting the literature. He addressed the “confusion” associated with the counterintuitive findings of NICE-SUGAR trial (read our report on the initial results and the 2012 NEJM follow-up on hypoglycemia). In explaining these results, Dr. Hirsch noted that “standard control” in all of the randomized controlled trials maintained blood glucose levels around 150 mg/dl, which in his view is significantly better than the ~200 mg/dl levels more commonly achieved in the real world. In light of this personal experience, Dr. Hirsch was adamant that we have “no evidence to keep blood glucose levels in the hospital above 200 mg/dl,” a statement that received a rousing round of applause from the audience. More recent data (including Okabayashi et al., Diabetes Care, 2014) indicate that closed loop systems (or at least CGM) might be the key to achieving lower glycemic targets safely in the ICU. The overriding hypothesis is that hypoglycemia is the culprit to bad outcomes, according to Dr. Hirsch.

• Our current understanding of inpatient glycemic targets is plagued by reliance on retrospective data that are complex and paradoxical. For example, multiple studies (including Umpierrez et al., Journal of Clinical Endocrinology and Metabolism 2002) have demonstrated that hyperglycemia is more strongly linked to mortality in individuals without diabetes relative to those with diabetes (16% in-hospital mortality rate vs. 3%; p<0.01). Notably, Dr. Hirsch highlighted a more recent analysis (Kotagal, Symons & Hirsch, Annals of Surgery 2014, in press) that corroborates these findings; this study demonstrated that hyperglycemia did not impact the risk of adverse events in patients with diabetes, though progressive hyperglycemia resulted in increased risk of each adverse event in the non-diabetic cohorts.
• The counterintuitive findings of the NICE-SUGAR trials contribute to the confusion regarding ICU glycemic targets. Though the study appeared to show that intensive insulin therapy could increase mortality, Dr. Hirsch noted that “standard control” in all of the randomized controlled trials maintained blood glucose levels around 150 mg/dl, an unrealistic standard that would be a vast improvement over how hyperglycemia is generally managed in US hospitals.
  
  • “I don’t want to see another NICE-SUGAR study without CGM. I’m tired of it,” Dr. Hirsch stated emphatically. His suggestion implied that hypoglycemia from intensive treatment was a major reason for bad outcomes in the majority of these studies, and avoiding dangerous lows may show the true benefits of tight glycemic control. While some may argue that RCT protocols could simply be replicated with more efficient monitoring, Dr. Hirsch was adamant that “it is difficult to imagine many hospitals doing better” than the frequent blood glucose measurements of the NICE-SUGAR trial (every 2.5 hours).
• Recent data suggest that closed loop systems and CGM might be the key to achieving lower glycemic targets safely in the ICU. Dr. Hirsch highlighted data from Okabayashi et al. (Diabetes Care 2014), which compared closed-loop control in surgical ICU patients randomized to intensive (80-110 mg/dl) or intermediate (140-180 mg/dl) targets. Patients in the intensive cohort were less likely to suffer from surgical site infections (9.8% vs. 4.1%, p= 0.03) and spent a shorter duration in the hospital (23 days vs. 18 days; p=0.02). Notably, the closed-loop device allowed patients to entire avoid hypoglycemia.
• Epidemiological data consistently show that hyperglycemia is associated with increased mortality. As such, maintaining “intermediate” blood glucose levels (140-180 mg/dl) is reasonable, but the use of more conservative targets is “unacceptable” and must be “abandoned.” He expects evidence of the therapeutic benefits of intensive targets to become apparent once closed-loop systems (or CGM) are used in the ICU population.

Contemporary Pediatric Diabetes Care

Tadej Battelino, MD (University Medical Center, Ljubljana, Slovenia)

With his valuable experience in pediatric care, Dr. Tadej Battelino presented on the benefits of using insulin pump therapy and CGM in pediatrics. To start, he showed data on the increasing rate of pediatric type 1 diabetes in Europe – an 8% annual rise in the last ten years. Interestingly, he also pointed out that the average age at diagnosis has decreased by three years from 12 to nine from 2000-2012. Delving into tools specifically, Dr. Battelino first discussed insulin pump therapy. He shared a study from Sulmont et al, (Journal of Pediatrics 2010) that started pumps in children below age six and followed them for up to eight years afterwards – notably, pumps improved A1c levels by about 0.7% vs. MDI, an effect that was sustained throughout the long-term follow-up. He concluded that pumps are the preferred treatment modality, even in very young type 1 patients. Regarding barriers to broader use of pumps, Dr. Battelino pointed to different attitudes and insufficient HCP training as reasons for its inadequate use. He then supported the use of CGM in pediatrics, given its ability to reduce A1c levels and time spent in hypoglycemia. Dr. Battelino asserted that CGM isn’t used as much in Europe, as Europeans believe the technology is difficult to use – we believe this perception will change over time with next-gen systems, but it will take time as the shadow of previous generation systems wears off. Additionally, we believe reimbursement continues to be a challenge, particularly in Europe, where patients are not used to paying out of pocket.

• Dr. Battelino supported lower pediatric A1c targets, sharing that the previous ADA goal was rooted in a fear of hypoglycemia. Dr. Battelino emphasized that both hypoglycemia and hyperglycemia can permanently damage the brain in pediatric patients – in particular, high A1c levels can even damage gray matter. As a reminder, the ADA recently changed its guideline to drop the A1c target to 7.5% for all pediatric patients (now harmonizing the standard with ISPAD).

Panel Discussion

Q: Is there any evidence that certain foods support or inhibit the gut microbiome?

Dr. Robert Ratner (American Diabetes Association, Alexandria, VA): There is no substantive data that probiotics or any other nutritional supplement changes the microbiome. Diet-induced weight loss can make some changes, but not nearly as much as what you see following bariatric surgery. However, data is coming soon on this question.

Q: My question has to do with the problem of achieving and maintaining weight loss without diabetes vs. those with glucose intolerance. People with diabetes seem to have greater difficulty. Why is that and what should we do about it?

Dr. Ratner: I don’t know if anyone who has a firm answer. The issue may have to do with the medications for diabetes, such as sulfonylureas, insulin, and TZDs, which increase weight. In my own clinical experience, the fear of hypoglycemia in individuals on insulin makes them overeat – it’s a pure calorie issue in that they’re afraid that they’re going to drop. There’s no question that people with diabetes have a harder time losing weight. There is new data on GLP-1 analogs that suggest that they still can.

Q: Dr. Ratner, you recommended women to lose weight before they get pregnant. Do women who are less obese tend to have better outcomes relative to women with higher BMIs?

Dr. Ratner: I don’t think anyone has done a good analysis of that. One of the particularly interesting issues though is that gestational weight gain isn’t the only important consideration. We’ve looked, 20 years ago now, at the average weight gain of obese women who went through pregnancy, and it turned out that obese women tend not to gain excess weight during pregnancy.

Dr. Ratner: Irl, you say that you don’t want to see another NICE-sugar trial without CGM. Can you tell us about the reliability of CGM in ICU patients who may be hypotensive and who clearly don’t have normal blood flow?

Dr. Irl Hirsch (University of Washington, Seattle, WA): I’m hoping by next year, I’ll have data to show you. I don’t have any data as of now. Although it’s been off my radar for now, we’re seeing more visibility for intravascular sensors. We acknowledge that initial sensors for outpatients were less accurate than what we needed in that situation. The issue is that as sensors become more accurate, and as we learn how current and future sensors do, the other part of this is what is going to be allowed in sensors by regulatory agencies. It’s a separate topic, but related. If nothing else, look at trends and look at the rate of trends and do glucose measurements. The key is avoiding hypoglycemia. If we can avoid hypoglycemia, we’re going to see what the NICE-sugar folks wanted to see.

Q: In Ljubljana, do you have pre-determined protocols for basal insulin settings? How about protocols for the treatment of hyperglycemia?

Dr. Tadej Battelino (University Children's Hospital, Ljubljana, Slovenia): We have exactly the same protocols as you have in the US. Sometimes, we use it; sometimes we modify it. We tend to start with a lower dose of insulin to try to avoid hypoglycemia in first few days. It’s very simple and we learned it at Yale; we don’t do it any differently.

Dr. Satish Garg (University of Colorado, Denver, CO): Have we ever looked at the cost efficiency of pumps and sensors? We keep talking about costs. How are the providers and payers going to deal with it? Can we show that costs are going to get taken care of?

Professor Philip Home (Newcastle University, Newcastle Upon Tyne, UK): We’ve just decided to re-analyze this in the UK. For adult and pediatric patients, we’re doing it. So one answer is: Wait and see.

Dr. Matthew Riddle (Oregon Health & Science University, Portland, OR): If you’d like to do a cost analysis of your country, we’d give it a good look.

Dr. Hirsch: We’re not consistent with our evaluation or the metrics. We’re not consistent region to region or even payer to payer within the same region of the US in terms of what’s cost-effective and not. Whether you’re a payer or provider or vendor or pharma company, we tend to cherry pick, which is another part of problem. It’s very complex. We can look at different parts of management of type 1 and type 2 diabetes. When we hit the ceiling, it’s important what happens afterwards. Look at what’s happened with competitive bidding. The real issue to me is not what’s happening until we get to this breaking point with pumps and sensors. Sensors aren’t mainstream yet so it’s a different discussion. The real issue to me is insulin. A breaking point is going to happen and I don’t know when that breaking point is going to be. But, we can’t go down this trajectory anymore.

Dr. Riddle: Professor Home, can you speak about the improved management of diabetes before, during, and after pregnancy in the past 30 years?

Professor Home: The interpretation of this data suffers from the fact that the problem has changed a lot in the past 20 years. There’s been an increase in the number of women with gestational diabetes. We have also seen an improvement in our ability to gather data on this. But if you actually ask me what’s happened, there’s no good data. There’s no doubt at all that management of data regarding pregnancy has improved dramatically; the centralization of care has been critical to this. However, it’s been dreadfully patchy; there’s still not enough news in that area.

Q: Are hypoglycemic events going to hurt adolescents permanently in terms of grey matter/white matter changes?

Dr. Battelino: Most studies regarding this question have been done in pre-pubertal populations, while brains are still developing. However, there have been documented cases of patients 70 years old or older, who show changes in the brain as a result of lows. Hypoglycemia is toxic! I strongly suggest that if we can treat and avoid hypoglycemia in adolescent patients, then that’s ideal.

Plenary: Obesity and Type 2 Diabetes

Role of Lifestyle Modifications

James Hill, PhD (University of Colorado, Denver, CO)

In an attempt to uncover the secrets of “successful losers” (of weight), Dr. James Hill examined data from the National Weight Control Registry, a database of ~10,000 people who have maintained substantial weight loss (~73 pounds or 11 BMI units on average) for an average of 5.7 years. Interestingly, the initial weight loss method appeared to have little impact on long-term maintenance; the participants in the registry used a wide variety of approaches, and the only common factor was that all involved both diet and exercise. There were, however, a number of important similarities in how the participants maintained weight loss; almost all reported consistently following a low-fat, low-calorie diet while eating breakfast seven days a week, weighing themselves frequently, and implementing specific changes when they exceeded their target weight. They also engaged in high levels of physical activity, which can help restore metabolic flexibility and counter the natural biological drive to gain weight. Long-term weight loss maintenance is clearly not for the faint of heart – many registry participants said they still had to consciously work to keep the weight off even 20-30 years after the initial loss. Dr. Hill emphasized the importance of psychological factors, saying that people need to link new behaviors to important aspects of their lives and create the most favorable environment possible for a healthy lifestyle (“nothing good happens in the chip aisle”).

Pharmacological Approaches to Weight loss

Daniel Bessesen, MD (University of Colorado Denver, Denver, CO)

Dr. Daniel Bessesen gave an engaging presentation on weight loss medications and the role of weight management in diabetes. He emphasized that although weight loss medications are often not discussed with patients, pharmacotherapy of obesity is “mainstream,” and many professional societies (NHLBI, ACP, AACE, Endocrine Society) have now included weight loss drugs as part of their guidelines. Dr. Bessesen referred to NHANES data showing that weight loss medications do help people lose weight, but noted that the use of the old generation of weight loss medications actually fell from 2008 to 2010. Regarding specific pharmacotherapies, he provided an overview of the new generation of agents, including Vivus’ Qsymia (phentermine/topiramate) and Arena/Eisai’s Belviq (lorcaserin) noting that Qsymia comes out ahead of Belviq with regards to weight loss. He brought up the idea of prescribing phentermine along with Belviq, but noted that the safety and efficacy of this approach is unclear. Dr. Bessesen also mentioned Novo Nordisk’s liraglutide 3.0 mg (which will be discussed during its FDA AdComm on September 11) and Orexigen’s Contrave (naltrexone/bupropion) as potential new medications. Dr. Bessesen emphasized the importance of providing weight loss medication information to people with diabetes honestly and accurately, concluding that he hopes he has made attendees “feel more comfortable discussing the risks and benefits” of weight loss medications with their patients.

Role of Bariatric Surgery in Obesity & Diabetes

Phillip Schauer, MD (Cleveland Clinic, Cleveland, OH)

Bariatric surgery proponent Dr. Phillip Schauer presented data showing that surgery results in superior clinical outcomes compared to medical treatment – read our coverage of an Ethicon product theater at AACE for another recent presentation on this topic from Dr. Schauer. He first reminded us of the Look AHEAD study results, in which intensive lifestyle intervention led to weight loss initially but most of the weight was regained within ten years and no reduction in cardiovascular events was observed. From this, Dr. Schauer stressed that greater, longer sustained weight loss is necessary to produce clinical benefits, claiming that bariatric surgery is the principal way to achieve this. He presented background data showing that bariatric surgery results in improvements or resolution in hypertension, diabetes, and hyperlipidemia – drawing from the STAMPEDE trial (which we covered in-depth at ACC 2014). Dr. Schauer concluded that the evidence behind bariatric surgery is making it more mainstream, promoting it as a worthy option for people with uncontrolled diabetes and obesity.

Novel Approaches to Weight Loss

Robert Eckel, MD (University of Colorado, Denver, CO)

Dr. Robert Eckel highlighted several new approaches to weight loss beyond the standard set of lifestyle, surgical, and pharmacological options. He began by discussing Aspire Bariatrics’ AspireAssist technology, which allows patients to “aspirate” (drain) a portion of their stomach contents through an endoscopically-implanted tube. Results from a small proof-of-concept study (n=18) demonstrated that the AspireAssist removed 25-30% of the calories from each meal and led to ~20% average weight loss over 52 weeks (“that beats all pharmacotherapy”) as well as higher self-reported quality of life. Though Dr. Eckel said that he personally finds the idea of gastric aspiration “kind of unappealing myself,” survey results suggest that a large majority of patients find the procedure acceptable. An ongoing 10-center pivotal trial involving 175 patients is expected to complete in April 2015 (ClinicalTrials.gov Identifier: NCT01766037).

• Dr. Eckel also expressed cautious interest in the endoluminal barrier approach (which GI Dynamics is developing as the EndoBarrier), which attempts to mimic the physiology of gastric bypass surgery in a less invasive manner by inserting a sleeve into the small intestine to block nutrient absorption. This method has not yet been studied in humans, but it has been shown to lead to modest weight loss and substantial improvements in glucose tolerance in rodents.  He also briefly evaluated the gastric balloon approach (he is skeptical of its ability to truly alter body weight regulation) and transoral gastric suturing, which limits stomach volume by tying together regions of the mucosal lining (preliminary data suggests it may be effective).

Panel Discussion

Dr. Satish Garg (University of Colorado, Denver, CO): I’m intrigued with your data, Dr. Schauer, though it was three-year data and mostly in type 2 diabetes. Could there be a role in type 1 since many of those patients are getting bigger than the type 2 patients?

Dr. Philip Schauer (Cleveland Clinic, Cleveland, OH): The data was strictly in type 2 – 100% of the folks had type 2 diabetes. There’s limited data on the effect of surgery on type 1 patients with severe obesity. There was a small study this year in Diabetes Care of 12 patients with type 1 diabetes and an average BMI near 50 kg/m²; presumably the insulin they were taking increased their body weight. We obviously didn’t cure any diabetes in that group, but we did see significant weight loss, similar to what we saw in type 2 diabetes, plus improvements in blood pressure, cholesterol, and glycemic control. Those patients are more difficult to manage post-operatively – one had to be readmitted for “mild DKA,” whatever that is. So you have to be careful about major swings and the stress of surgery.

Q: When people regain weight, they think they’ve failed. Can you comment on the biology of weight regain after losing weight? Why are people more biologically driven to eat more after losing weight?

Dr. James Hill (University of Colorado, Denver, CO): We have good data that suggests that when people lose weight, the body compensates in many ways – for example, a lower metabolic rate. The resting energy expenditures (REE) goes down and the hormones change to make you more likely to overeat. Now, we don’t know how much of that pre-existed before becoming obese and how much is a consequence after becoming obese. But when you lose weight, you’re fighting very strong biology to keep weight up. It’s not all willpower, but to overcome that biology, you must do it with behavior.

Dr. Daniel Bessesen (University of Colorado, Denver, CO): In animal models, the tendency to regain weight doesn’t go away; the biological forces stay there. We need a new-worn path, with behavioral adaptations that allow long-term success.

Dr. Hill: The message for patients is that it won’t suddenly become okay. You can’t work hard for two years and suddenly you’re like your neighbor who’s never been obese. I’ve seen many people who work hard and say it’s worth it. It may not be fair, but this is what it takes.

Comment: I’m just so amazed with gastric aspiration [e.g., Aspire Bariatrics]. It’s like bulimia with a tube. Aren’t we going to end up with the same problems as bulimics with nutrition factors and malnutrition and whatnot? Except I guess you won’t get dental problems.

Q: If any of you have great post-op programs, can you speak to those of us at rural centers? Our patients go to larger centers and get lost to follow-up, and the onus ends up on us to deal with complications.

Dr. Robert Eckel (University of Colorado, Denver, CO): The qualifications of the surgeon are important.

Dr. Schauer: Beyond surgeon qualifications, we’re moving to the idea of a bariatric center that involves an ancillary team with psychologists, dieticians, medical doctors, etc. I didn’t have much time to go into that but it’s important. It takes three to six months to prepare someone for surgery, and the post-operative phase is important as well. Surgery has grown over the last decade and several centers have achieved center of excellence status. There are 550 or so around the country and every state has ten or so. We also have lots of information for primary care physicians and nurse practitioners on standard management strategies.

Q: Dr. Eckel, in terms of aspiration therapy, did you say these patients were self-aspirating? Do they go to the lavatory of the restaurant? You did say they’re aspirating roughly 2,000 grams, right?

Dr. Eckel: Yes, that’s with a higher caloric intake. But yes, that’s grams. The food was a mixture of carbs, fats, and proteins. The calories were estimated based on composition of food aspirated. So presumably, they did bomb calorimetry and did nutrient analysis. Yes, hopefully they did excuse themselves.

Q: Dr. Hill, you stated that most patients who lost weight and maintained it ate breakfast. Do you have thoughts on the caloric content of the breakfast?

Dr. Hill: That was not in the study but it’s a good question. Breakfast is a marker of a healthier lifestyle; we look at factors individually but it’s really the combination of lifestyle that makes the difference. We didn’t look at composition; there’s been some recent work on high protein and how it makes you less hungry, but more work needs to be done.

Comment: There’s really no good history of breakfast, but it’s a good story.

Q: This is a two-fold question. The evolution of bariatric surgical procedures is interesting to me. Vertical banded gastroplasty  (VBG) seemed to have gone out of favor and to me, was replaced by adjustable gastric banding. Now that we have sleeve gastrectomy, it seems to be that that is becoming more popular. So I wanted to know that first, will we see adjustable gastric banding go away? And second, are there new surgical procedures on the horizon?

Dr. Schauer: So today, we’ve definitely learned that losing weight is hard and keeping it off is harder, even with surgery. So it takes a cycle of ten to fifteen years before we really know the long-term benefit. With gastric bypass, I think that’s the procedure that we have the most knowledge on and it seems to be the most durable. VBG had its heyday of ten to fifteen years and then we started seeing problems with that. It’s unclear if sleeve gastrectomy is going to be superior to VBG in the long run. It does seem like it’ll have fewer complications, because VBG required a very tight band, which caused a lot of problems. So we’ll have to see. The gastric band had its heyday for a while and it’s gone out of favor, so we have to look at these long-term.

Dr. Bessesen: We’ve said this amongst ourselves. These unusual procedures give us clues as to how the basic biology of weight regulation works. I think gastric bypass is the gold standard operation. It has a twenty-year track record. But on the other hand, it’s a big deal for people and it’s a lot for them to think about. Despite the mortality data, for a person, it’s a big deal for them to think about. People want something more modest. That’s what we’re struggling with. Can we even get close to that with these other things? So, gastric bypass is the gold standard. Everything else is trying to live up to that and hasn’t reached that bar yet.

Dr. Schauer: There has been a lot of work in the past couple decades trying to mimic these procedures endoscopically to reduce costs and potential complications. It’s been a struggle – even with these endoscopic stitches, although they lose weight pretty well initially, those stitches can fall out and then weight regain happens. So durability is a key factor. It’s the same with this internal sleeve. We have to make that durable and make the sleeve stay. So a foreign body in the GI tract is not a proven concept yet.

Q: My compliments to all four of you for talking about treatment, but I want to talk about prevention. This epidemic is 30 years old; could you address some of the environmental issues and prevent obesity instead of backtracking?

Dr. Hill: I can speculate, though we have been talking about some treatments – we think surgery and pharmacology are treatments to look at – but we’re trying to fix physiology that isn’t broken. Obesity is a response to our physiology being in an environment that’s different from the environment for most of human evolution. I don’t think obesity results from broken physiology but from normal physiology. When we’re talking about prevention, if the physiology isn’t broken, the environment is. We have a physiology that says eat and rest; when you put that in this environment, overeating and weight gain are normal responses. We’re responding appropriately to today’s environment. We need to look at environmental factors; that’s where the action is. Now, that’s easy to say. We created the environment we’ve got because we like it. From an environmental point of view, what do we change? People say put taxes on sugar, get rid of fast food, but we have little evidence that we can succeed with those. In the long run, we’re more likely to be effective preventing than treating, so we have to focus on different areas. It will be hard but that’s where we need to put effort. We need to change the environment so that given our physiology, we can maintain a healthier weight.

Q: If we can blame the environment from the perspective of the food supply and availability or physical activity, which is more important in terms of the epidemic we’re experiencing, particularly in childhood obesity?

Dr. Hill: I don’t think we can answer that question. I think it has got to be both. We fail when we look at food activity. People look at food and have the wrong perspective. They think they eat a burger and have to walk several blocks to burn it off. That’s totally the wrong idea. You have to have a working physiology, which means you have to be active and you have to focus on food. We have gotten here because of thousands of little things going on and we’re trying to fix it by changing big things and it’s not going to work.

Dr. Schauer: Epidemiologically, both have worsened over the last thirty years. I would ponder over calorie intake rather than a reduction of exercise over time. That’s what I would lean towards.

Dr. Bessesen: So, is the problem driven by calorie intake or lack of physical activity? I think another way to look at this is what we can fix here. Maybe we can be more successful with physical activity. Because where’s the dose response? Maybe it doesn’t take too much activity. Maybe we just have to get off our butts a little bit and maybe it’ll do something.

Q: Dr. Schauer, what is your opinion so far on the data of patients with diabetic gastroparesis and obesity having gastric bypass surgery?

Dr. Schauer: There’s not a lot of data, just a handful of small studies with no comparators. For folks with obesity, diabetes, and gastroparesis, gastric bypass is probably the better option, since it bypasses the damaged organ, and there’s a benefit in terms of weight and diabetes.

Plenary: Type 1 Diabetes – Immunology and Cell Therapy

Knowledge Gains in Type 1 Diabetes Pathogenesis – New Opportunities for the Next Generation of Disease Biomarkers

Mark Atkinson, PhD (University of Florida, Gainesville, FL)

Dr. Mark Atkinson expressed optimism about the potential of using new biomarkers to more effectively diagnose and treat type 1 diabetes.  He began by acknowledging that type 1 diabetes biomarkers face a significant implementation gap – out of every 100 biomarkers discovered, only a very few make it through clinical validation. He believes that the areas of greatest unmet need are: (i) prediction of who is at highest risk of developing type 1 diabetes, (ii) stratification of patients’ response to treatments (both conventional insulin therapy as well as experimental attempts to reverse the disease), and (iii) more broadly accounting for the heterogeneity of the disease. He identified five approaches that could potentially lead to the discovery of useful biomarkers: (i) finding direct markers of beta cell health (rather than relying on insulitis, which is turning out to be less pronounced in humans than once thought), (ii) examining other pancreatic abnormalities, such as size, exocrine insufficiency, or leaky vasculature, (iii) more accurate staging of type 1 diabetes based on evaluating test results in the context of genetic markers for disease risk, (iv) quantifying beta cell mass, which is variable between individuals and may be related to the risk of developing diabetes, and (v) evaluating the clinical significance of residual C-peptide production in long-standing type 1 diabetes, as recently suggested with improved C-peptide assays. Dr. Atkinson said that the NIH and other entities are increasingly aware of the need for better biomarkers in type 1 diabetes and are working to improve the process; indeed, the recently launched second phase of the European Innovative Medicines Initiative (IMI2) has listed biomarker development as a priority for diabetes research, and we hope that other organizations will follow suit. In addition, we’d note a recent publication (Feldman et al., Nature Medicine 2014) that demonstrated potential to diagnose type 1 diabetes using a microchip.

Is Primary Prevention a Realistic Expectation?

Marian Rewers, MD, PhD (Barbara Davis Center, Aurora, CO)

Dr. Marian Rewers asserted that primary prevention of type 1 diabetes is still a realistic expectation, despite the inconclusiveness of much recent research in this area. An important goal is to identify the environmental triggers responsible for the increasing incidence of type 1 diabetes (a rise of 3-5% per year in children under 15 since the 1960s) so that it will be possible to prevent islet autoimmunity from developing. Because islet autoimmunity typically begins very early in life, many primary prevention studies have focused on potential triggers in the infant diet. However, the large number of trials in this area has not led to a consensus in the field about the best approaches; Dr. Rewers noted that every expert would come up with a different list of likely environmental triggers if asked. A review of several of the larger studies, including TEDDY, TRIGR, and BABYDIET, served to emphasize the level of uncertainty in this area and the difficulty of identifying one trigger that significantly increases a child’s risk of developing diabetes. In Dr. Rewers’ view, there is little evidence that childhood obesity, cow’s milk formula, or routine immunizations are risk factors for type 1 diabetes. Evidence is slightly stronger (though far for conclusive) for the introduction of cereal outside of the ideal age range (four to six months) or exposure to enteroviruses. Additionally, there is evidence that omega three fatty acids may be somewhat protective against developing islet autoantibodies. These conclusions are far from definitive, and Dr. Rewers stressed that much more work will be needed to identify environmental triggers and translate findings into clinical practice.

Immunomodulatory Trials: What Will Work?

Peter Gottlieb, MD (Barbara Davis Center, Aurora, CO)

The highly regarded Dr. Peter Gottlieb provided an overview of the state of the science on immunomodulation as a therapy for type 1 diabetes. Three years ago, Dr. Gottlieb presented on the same topic (read our coverage) – it was somewhat sobering to see the relatively modest updates from that presentation to his current one, although he did give us some reasons to be optimistic. The two main immunomodulatory strategies for type 1 diabetes involve changing the balance of harmful autoreactive T cells vs. more protective regulatory T cells. Moving through time from 1980 to the present, Dr. Gottlieb compiled a massive list of the immunomodulatory therapies that have been tried, marking those that showed promise and those that did not yield positive results. He expressed reservations about myeloablation with stem cells (the “Voltarelli cocktail”), which in his view effectively constitutes a bone marrow transplant and comes with a very high level of risk. He shared a more positive outlook on the ATG/GCSF combination therapy presented at this past ADA (read our coverage), which showed preservation of C-peptide and improvements in T cell balance. A common theme over the course of the presentation was the need to identify responders to particular therapies and to use better biomarkers to tailor a package of therapies for different patients.

• Dr. Gottlieb touched upon his own group’s work investigating alpha-1 antitrypsin (AAT), an anti-inflammatory serum protein. In a recently published study of 12 newly diagnosed type 1 diabetes patients, AAT was shown to preserve or increase C-peptide levels in four of the patients. Dr. Gottlieb interpreted the results with a glass-half-empty/glass-half-full mentality – the improvements seen in the four patients were certainly intriguing, and potentially merit further study in a larger randomized trials, but as he tells patients frequently in response to their phone calls, there is not enough data yet to support the use of AAT off-label.

Targeting the Trimolecular Complex for Immune Intervention

Aaron Michels, MD (Barbara Davis Center, Aurora, CO)

Dr. Aaron Michels outlined two immunologic approaches – small-molecule pharmacotherapy and an insulin vaccine – that he believes could eventually lead to prevention of type 1 diabetes. He used the analogy of a hot dog to describe the trimolecular complex that stimulates the autoimmune attack in type 1 diabetes: if the insulin peptide is the hot dog, the T cell receptor and the antigen presenting cell are the bun and condiments that surround it. Dr. Michels believes that the right small molecule may be able to separate the “hot dog” from the “bun” by inserting itself into crucial binding sites. He highlighted the hypertension drug methyldopa (Aldomet) as a candidate that has been shown to block the immune response to insulin in preclinical studies; a phase 1b clinical trial investigating the compound in patients with recent onset type 1 diabetes is currently enrolling (ClinicalTrial.gov Identifier: NCT01883804). Another approach, based on an insulin vaccine, aims to alter the balance of helpful vs. harmful immune cells and stimulate a protective immune response. Dr. Michels’ lab has developed a novel insulin peptide with a mutation in the B chain, which successfully induced a protective immune response and delayed the development of islet autoantibodies and type 1 diabetes in non-obese diabetic (NOD) mice. Early clinical studies have demonstrated that both patients with recent onset type 1 diabetes and healthy control subjects have a similar protective response to this peptide. Although the project is still at a relatively early stage, Dr. Michels is hopeful that by exposing immune cells to a constant, low concentration of the peptide, it may be possible to alter the balance of helpful and harmful immune responses and prevent progression to type 1 diabetes.

Beta Cell Regeneration or Replacement – Hype or Hope?

Jay Skyler, MD (University of Miami, Miami, FL)

Dr. Jay Skyler asserted that despite excessive hype in the last several decades, there is still a great deal of hope that effective cell-based therapies for type 1 diabetes can be developed. The procedure for islet cell transplantation is improving (recent data has shown that the new CIT07 protocol enables the majority of patients to remain insulin independent for at least two years), though there are still concerns about recurrent autoimmunity as well as a shortage of islet cells that can be used for transplantation. Dr. Skyler identified four potential methods for obtaining new beta cells: (i) stimulating the proliferation of existing cells, (ii) neogenesis of beta cells from ducts, (iii) differentiation of stem cells, or (iv) transdifferentiation of acinar or alpha cells. Several agents have been shown to impact proliferation and/or neogenesis in animal models, including betatrophin, gastrin, and GLP-1 agonists, but none have been successful in humans as of yet. Dr. Skyler was somewhat more optimistic about the prospects of differentiation-based therapies, such as programming embryonic stem cells to develop into islets or converting hepatocytes to insulin-producing cells (Orgenesis recently demonstrated promising preclinical results with the latter approach and is moving towards clinical trials). Dr. Skyler also highlighted encapsulated pro-islet grafts, which he said would be moving to clinical trials at UCSD in the near future, as well as bioactive scaffolds that can facilitate insulin production when inserted near islets. He acknowledged that many of these ideas are not new, but expressed hope that at least some of them will be able to be translated into clinical practice in the future.

• See our ADA 2014 Type 1 Diabetes Therapies (Cure Related) Report for some of the latest data on cell-based therapies, including refinements of the relatively harsh “Brazil cocktail” to find a more tolerable “Brazil lite.”

Panel Discussion

Q: I was most interested, Marian, in your slides on cereal. I can see with the immature gut why you would not introduce cereal before four months, but why is it a problem after six months?

Dr. Marian Rewers (Barbara Davis Center, Aurora, CO): I have no good answer – I can only tell you that the problem was found so far in just one study. TEDDY has not looked at that yet. It’s interesting why babies tolerate new antigens best around that age. There was additional information published in JAMA Pediatrics about a year ago showing that the best course of action in terms of lowering the risk of islet autoimmunity is when there is a combination of some breastfeeding and the introduction of foreign antigens at low doses. The worst-case scenario is when you delay the introduction of new foods and expose the child to huge amounts of those antigens – that was the cause of a huge epidemic of Celiac disease in Sweden.

Q: I have a question for Dr. Rewers – you mentioned microbiota as a potential determinant of type 1 diabetes. We know microbiota have a role in the development of the gut immune system. What is known about their role in type 1 diabetes?

Dr. Rewers: We’re in an early stage of investigation. You have to keep in mind that what we’re studying are stool samples, which give a late picture of what’s happening in the intestine. The action may be in the small intestine, which is the closest part to the pancreas, but what we’re studying is stool, which is less than optimal. There are some studies suggesting that decreased diversity of gut microbiota is a risk factor for autoimmunity and diabetes. You get diverse microbiota from not using antibiotics, introducing foods at regular intervals, early on by having babies delivered vaginally, not by C-section. The opposite reduces diversity and may be a risk factor. Mark is the expert in this area.

Dr. Mark Atkinson (University of Florida, Gainesville, FL): Good job, I agree with your first statement. The role of the microbiome in type 1 diabetes and type 2 is an early field. Diversity of microbiota in type 1 patients vs. controls is a major factor, and certain genus and species are different between the two, there’s a different ratio. The answers you get in Finland may not work in Sweden or Colorado, so there will be differences as people publish data. Tying it all together, the thought is that types of foods influence the types of bacteria; there are differences in butyrate producing bacteria. Type 1 patients have leaky intestines, so the frequency of butyrate producers could tie into that. Everything is early and hypothetical; people are collecting better samples, so we’ll know more.

Q: I was fascinated, Mark, by your work on the “imaging biomarker” of the size of the pancreas in type 1 diabetes. It appears that this data goes in the opposite direction in type 2 diabetes. Is there some sort of imaging marker that could help us in TrialNet to identify patients at the highest risk?

Dr. Atkinson: The notion about the smaller pancreas size dates back a few decades to subjects with type 1 diabetes that had the disease for decades and ended up with a smaller pancreas. Studies that have come out in the past few years using MRI show that at the time of onset, the pancreata are smaller, but we’re not sure when in the natural history it starts. Closely after birth? Is it a step model? We’re not yet sure, but we are working at Vanderbilt to get 100 children studied to define the size of the pancreas in normal individuals. Then in TrialNet we have a protocol where we are doing ultrasounds in 300 people, and we will use MRI in a subgroup of those. 

Dr. Peter Gottlieb (Barbara Davis Center, Aurora, CO): I think another important part of what Mark said is that we could use another assay that would allow us to look at beta cell death. We’re starting to appreciate that if we can correlate size by MRI with beta cell death, you generate a stronger finding.

Q: I have a question for Dr. Rewers. You talked about environmental factors. There was work done in the 1990s by Dr. Classen about a relationship between vaccines and a statistically significant increase in diabetes in Finland and New Zealand. What are your thoughts on that?

Dr. Rewers: I have ethical problems with that work. Dr. Classen did one small study in an animal model and immediately applied for a patent in 100 countries so he could benefit from a change in immunization schedules in any one of those countries. It was worthless work in my opinion and not confirmed by large studies. He misused data form Finland – that’s my opinion. I hope that answers your question. However, there is a problem with vaccines. They can cause autoimmune diseases. The best example is an epidemic of narcolepsy that swept Scandinavia. Scandinavian countries are organized and compliant because the government says to vaccinate kids.  For a new agent like H1N1, they vaccinated almost everyone, then you saw an epidemic of narcolepsy, which is an autoimmune disease liked to HLA-DQ. So that’s a proof of concept that vaccines can cause autoimmune disease, but there’s no evidence for type 1.

Dr. Jay Skyler (University of Miami, Miami, FL): You were remarkably restrained and polite about Dr. Classen.

Q: With some interventions, what you see in animals may not predict what you see in humans. Is there a risk that you might enhance the autoimmune response with what you’re trying?

Dr. Aaron Michels (Barbara Davis Center, Aurora, CO): We’ve tried giving many types of insulin and we’ve never once accelerated the disease process. I don’t think that antigen-specific therapy is going to worsen patients’ diabetes.

Dr. Rewers: The US government created a massive fund which now has $15-20 billion in the bank to cover adverse reactions to vaccinations. This fund was created to encourage vaccine manufacturers to keep making them. Otherwise, those manufacturers were scared that lawsuits that their vaccines were causing autism or diabetes would destroy them. The last time I looked, there were more than 10,000 lawsuits filed in over 40 states to claim money from this fund. There is a huge legal machinery monitoring problems with vaccines. Additionally, the CDC has a mandatory reporting system for which all pediatricians are supposed to report adverse reactions to vaccines. On a small scale, all the studies like BABYDIET did look at the effect of early vaccines, and now we’re following those kids.

Q: About increasing beta cell mass, we have data showing that you can get good regeneration of beta cells early on in fetuses and perhaps infants and toddlers. In Denver we had the case of a kid with IPEX syndrome who was treated effectively with a bone marrow transplant. After the transplant he entered complete remission and was insulin free for a year and a half. The kid has definitely regenerated some islets.

Dr. Skyler: You saw the graph that it is possible to get cell generation early in life. It’s later in life when you don’t get it. It sounds like a very special circumstance with this child, but I think that all these things are possible and we just have to figure out how to do it. Nature has lots of checks and balances, and we need to overcome those checks and balances when manipulating things in one way or the other.

Professor Philip Home (Newcastle University, Newcastle upon Tyne, UK): What do you think about combining regenerative approaches with immune approaches?

Dr. Skyler: Absolutely, most people on the podium have heard me talk about that. We need to pay attention to that kind of combination with multiple components. Peter showed that early on, IL1 activation occurs. We gave anti-IL1 and it didn’t work, but it might not have been enough. If you add it to anti-CD3, or another antigen-specific approach, and something to help the beta cell, that could be a viable approach. Convincing regulators of that is an interesting dilemma. People did a study of GCSF alone, the START study looked at ATG alone, and they didn’t work. Now there’s a study looking at the combination that shows great promise, but individually they didn’t. The regulatory paradigm is that you can’t put 2 drugs together unless each one has an effect and you want more than an additive effect. That paradigm doesn’t work in type 1; things we’ve rejected may work if put together in the right combination. We need to think out of the box and change the regulatory paradigm. It won’t happen easily – the  current group of regulators is pretty rigid, but regulators can undergo education (at least I hope so).

Dr. Satish Garg (Barbara Davis Center, Aurora, CO): Dr. Skyler, the title of your talk was about hype and hope. The main issue is that hype generally overtakes hope, and people want to have something new as quickly as possible. How do we monitor this and bring policy back to reality? For example, thirty years ago at the Barbara Davis Center back when I started seeing patients, everyone was told that in ten years they would not have to deal with the disease. George Eisenbarth would say the same thing in the hallways. How do we put checks and balances on that? Should the ADA or JDRF put it in real perspective?

Dr. Skyler: I think that we as an overall scientific and medical community need to react to the information that is not so prevalent on blogs and the Internet. There is more misinformation than information, and people use anecdotal statements that lead to people calling us asking for AAT because it’s supposed to be the best thing since sliced bread. What the actual data says is that there needs to be a full-scale randomized control trial to answer the question definitively. There is enough promise to merit doing that, but until we do there is not enough evidence to support using that therapy. As a community, we need to rely on randomized control trials and rigorous scientific evidence. That is how we will move things ahead. Anecdotes and pilot studies can give us hints about future RCTs, and we’re getting better at doing that to select potential responders, but we also need to verify that the biomarkers we used to select responders are in fact negative in non-responders. It’s a complicated issue, but we need to be persistent in not letting anecdotes and noise on the Internet get in the way of reality.

Professor Home: Still, we all have to have hope. Clearly, we’ve said “ten years” too many times and have been wrong. Some of these things are going to take longer than ten years. But my grandchildren are at risk, and there is some hope out there. Hype can help a bit to carry hope into the media. 

Meet the Peers

Adult Providers

This informal discussion among adult providers (conference faculty and attendees) covered a number of topics, including comparisons between the US and UK healthcare systems, the best agents to achieve weight loss, frustration with payer-mandated switching between insulin brands, and how to obtain more affordable glucose testing strips.

• On SMBG and test strips: Dr. Irl Hirsch (University of Washington, Seattle, WA) started his answer to an audience question on “offshore strips” by drawing a distinction between US-produced low-cost strips and strips that are produced internationally, generally in Asia. Quality issues plague the latter category of strips, and Dr. Hirsch pointed out that the FDA does not police these strips once they have been approved. Regarding the lower cost domestic options, Dr. Hirsch suggested that Nipro’s TrueTrack and TrueTest strips are to be avoided, and shared that he prefers the Agametrix Presto brand. Dr. Satish Garg (Barbara Davis Center, Aurora, CO) pointed out that competitive bidding has brought down prices significantly, and that testing strips are in the process of becoming more of a commodity than before.
• On HMO-mandated switches from one insulin brand to another: Dr. Garg suggested that these changes, such as payer-mandated switches from Lantus to Levemir (or vice versa), are a waste of providers’ valuable time. Dr. Hirsch followed by noting that sometimes the switches are between products that are not clinically identical – he cited the example that patients generally need a higher dose of Levemir than Lantus – and that continued switching stands to cause problems in the community.
• On the use of GLP-1 agonists in type 1 diabetes: Dr. Hirsch shared the story of a type 1 diabetes patient who was placed on a GLP-1 agonist four years ago due to an incorrect diagnosis, and who has since not seen a drop of insulin. He is interested to see more clinical trials on this application of the GLP-1 class, as he cannot recommend the option on-label to his type 1 diabetes patients at the moment. As a reminder, Novo Nordisk’s phase 3 trials testing liraglutide in type 1 diabetes began in 4Q13, and management is “hoping” for a 2015 launch.
• On weight loss medications: Regarding the newest generation of obesity therapeutics, Dr. Sarit Polsky (Barbara Davis Center, Aurora, CO) expressed a strong preference for Vivus’ Qsymia (phentermine/topiramate) over Arena/Eisai’s Belviq (lorcaserin). She stated that she never prescribes Belviq due to a “huge” side effect profile and very modest weight loss. Although she acknowledged that Qsymia is also associated with some risks and (like Belviq) can be expensive, she expressed satisfaction with the 10% weight loss possible with the agent.
• On differences in diabetes care between the US and UK: UK representative Professor Philip Home (Newcastle University, Newcastle upon Tyne, UK) noted that more patients are seen in primary care in the UK, and that sulfonylureas and NPH are used to a greater extent. Dr. Matthew Riddle (OHSU, Portland, OR) suggested that the UK treatment paradigm does a good job of doing a lot with old tools, but Dr. Hirsch countered that the patients he sees who have come from the UK have a higher prevalence of retinopathy and other complications.

Adult Educators

This open-ended session with a panel of adult diabetes educators quickly turned into a passionate discussion of the need for Medicare coverage of CGM. The consensus opinion in the room was well articulated by one panelist: “we all feel like we’re screaming at the wall.” Many of the educators had written numerous letters to their senators or to the Center for Medicare & Medicaid Services (CMS) telling stories of patients who had successfully managed their diabetes for years with CGM only to rack up ER visits after transitioning to Medicare and losing CGM reimbursement (“my patient has a stack of ambulance bills this high”). Disappointingly, none could cite a single case in which the government was willing to provide coverage. Much of the discussion centered on the most effective tactics for changing the current policy; a Medtronic representative in the room mentioned the company’s joint lobbying effort with Dexcom but cautioned that industry “can only fight one end” of the battle. Many participants agreed that personal letters from patients would be the most effective way to convince CMS of the importance of CGM coverage, though one educator described a conversation she had with a CMS official that convinced her that proving cost effectiveness is ultimately the best solution.

Pediatric Providers

The Meet the Peers Session for pediatric providers featured a heated discussion regarding the recently revised ADA A1c target of 7.5% for pediatric type 1 diabetes patients (read our report on the Position Statement presented at ADA 2014). Notably, a poll of the 60-person audience demonstrated that only 50% were satisfied with the new recommendations. The well-respected Dr. Fran Kaufman (Medtronic Diabetes, Northridge, CA), speaking on behalf of those with reservations, acknowledged the importance of the new Position Statement, but stressed that there are too many “caveats” in the real-world to apply a single target for all patients. In order to personalize care, she emphasized that recommendations need to be adjusted based on the patient, such that appropriate A1c targets could range a great deal. Dr. Tadej Battelino (University Children's Hospital, Ljubljana, Slovenia) suggested that the ADA recommendations were not strict enough, although he did acknowledge that hyperglycemia is relatively unlikely to lead to permanent brain damage in most pediatric patients. Later in the session, pediatric providers also expressed great frustration regarding the legal and reimbursement challenges that have handcuffed their ability to use social media to interact with patients. Although the entire audience (60 persons) felt that social media would improve patient outcomes, only two clinicians reported using such technology. Multiple attendees reported running into legal trouble upon attempting to use Facebook, Twitter or mobile technology to distribute information. However, providers stressed that these policies could not prevent third-party sources from attempting to provide information – often misleading –and insisted that there must be a way to communicate with and monitor patients outside the clinic.

• Dr. Battelino on hyperglycemia and brain damage: “Who is really afraid of hyperglycemia? Parents. It’s the worst fear they can get.”
• Dr. Battelino on the power of social media: “I had a patient with an A1c of 6.7%. She asked me if she can have a piece of chocolate. I said, ‘Sure!’ Within minutes, this was on Facebook. ‘Battelino allows chocolate.’ I had everyone asking me for chocolate. This never could have happened without social media. This is the power of social media. We need to do something – I just don’t know how.”
• An attendee speaking on social media and reimbursement: “Insurance companies would love it if we interacted with patients over Facebook. But we still have to be paid.”
• Dr. Battelino on reimbursement in Europe: “What I want you to say is that physicians are cheap in Europe all over. That’s why we can afford more nurses and more physicians. It’s a social system. How else would a heart surgeon or brain surgeon make exactly the same salary as me. We’re cheap. For me, a young physician costs me approximately $45,000. It’s cheap labor.”

Concurrent Sessions: Pediatric Diabetes Challenges

Diabetes Management in Toddlers/Preschoolers Under Age Six

Peter Chase, MD (Barbara Davis Center, Aurora, CO)

Dr. Peter Chase focused his presentation on the ADA’s updated pediatric A1c guidelines, presenting data from the Diabetologia study that compared the impact of previously different A1c guidelines in the US and Germany/Austria. As background, Dr. Chase explained that ISPAD has recommended an A1c target of <7.5% for all children for many years, while the ADA has recently lowered guidelines from an A1c <8.5% to A1c <7.5%. As highlighted in our past report, data from the T1D Exchange in the US and from the Prospective Diabetes Follow-Up Registry (DPV) in Germany/Austria were collected and compared. The analysis found that T1DX participants had a higher mean A1c than DPV participants (8.2% vs. 7.4%) and that the percentage of patients using an insulin pump was significantly lower in the T1DX than in the DPV (50% vs. 74%). Notably, Dr. Chase emphasized that DKA frequency was twice as high in the T1DX (6% vs. 3%), which was shown to clearly relate to A1c levels. On the other hand, there were no significant differences in hypoglycemia rates. From these results, Dr. Chase concluded that an A1c target of <7.5% can be achieved in young children reasonably safely, with reductions in DKA risk without large corresponding increases in severe hypoglycemia. While it has been proposed that sub-optimal control in the T1DX participants may be due to less insulin pump use, the data does seem to support lower A1c targets in this age group. Dr. Chase concluded on a cautious note, saying that the pediatric guideline change will take significant effort from families and providers and that only time will tell if this change will lead to improved clinical outcomes in the US and other geographies that use the ADA guidelines. 

Care of Adolescents with Type 1 Diabetes

Darcy Owen, MS, RD, CDE (Barbara Davis Center, Aurora, CO)

Ms. Owen presented on how the Barbara Davis Center is changing the approach to caring for the adolescent and teenage diabetes patient population by offering what the center calls the “team clinic.” This approach involves a multi-disciplinary team and focuses on development using a positive psychology framework, motivational interviewing techniques, self-advocacy, and social support. During center visits, both teenagers are parents are given the opportunity to attend separate team clinics, which involve icebreakers and patient-driven, facilitator-mediated discussion. The approach focuses on peer interactions and respects the teenager’s independence and autonomy. Concluding, Ms. Owen showed that responses from both teenagers and parents have been positive, with the majority of both groups saying they have felt more comfortable and would attend again. The psychology of diabetes care is an important, often neglected area that has the power to improve adherence to therapy and quality-of-life for patients, and the stress felt by parents of diabetes patients is not always apparent from a provider perspective – we were glad to see these topics being addressed by this team at the Barbara Davis Center.  

Type 2 Diabetes in Youth

Tadej Battelino, MD (University Children's Hospital, Ljubljana, Slovenia)

Dr. Tadej Battelino presented on the complexity of pediatric type 2 diabetes, pushing for more resources and research for this growing patient population. He explained how prevalence of the condition varies among Slovenian ethnic groups, with Caucasians more protected against it while Eastern Europeans are at much higher risk. However, overall prevalence has been increasing with increases in obesity prevalence. Dr. Battelino highlighted how the etiology of pediatric type 2 diabetes is complex, with social, behavioral, and environmental factors interacting with genetic susceptibility. For example, he demonstrated gene-diet interactions with FTO and MC4R gene variants that appeared to contribute to childhood obesity. In addition, while admitting that he would not address bariatric surgery in children “because it’s controversial,” he brought up EndoBarrier therapy as an option for youth who are severely obese. Concluding, Dr. Battelino highlighted that type 2 diabetes in youth is escalating and underdiagnosed, and that any treatment approaches must take into account differences in etiology, social background, ethnicity, and other factors.

Panel Discussion

Q: On the numbers for DKA in the US vs. Austria and Germany, do you have any comments on this? Do you think the new ADA guideline is the answer?

Dr. Chase: Well, the most common deficiency we see at the Barbara Davis Center is families not having ketone strips or having not had any training on them. There needs to be more education on this at each clinic visit.

Dr. Battelino: We use blood ketone measurements and I know Germans always use them. So this may be a factor. We don’t get a lot of strips because it’s expensive but we do look at it so we can probably see DKA earlier.

Q: Regarding screening, ADA has recommended using A1c. What do you think of that as a screening tool?

Dr. Battelino: You need some time before A1c goes up. It’s an interesting decision actually. I’m not against it. It may very well be that A1c is enough, but I also see OGT as an alternative.

Dr. Chase: By the time we see two OGT tests that are abnormal, we document them as type 1 diabetes. Sometimes in these situations, some still have normal A1c levels. A1c for early type 1 diabetes is not reliable.

Dr. Paul Wadwa (Barbara Davis Center, Aurora, CO): The ADA’s guideline is focused on adults. In pediatrics, we see lots of false positives.

Concurrent Sessions: Challenges with Diabetes Complications

Microvascular Complications

Jay Skyler, MD (University of Miami, Miami, FL)

Dr. Jay Skyler stressed the progress that has been made in the treatment of the microvascular complications of type 1 diabetes, especially retinopathy and nephropathy, in the past few decades. His presentation covered many of the same topics and data he discussed in a talk at the 2013 Cardiometabolic Health Congress. Highlighting data from the Diabetic Retinopathy Study (the “most important” study done in the 1970-80s), he noted that the study’s greatest contribution was the identification of high-risk criteria that define the need for pan-retinal photocoagulation. He emphasized that patients with diabetes should be seen by retinal subspecialists to a greater extent than is currently practiced today. That said, Dr. Skyler shared promising data from the FinnDiane study, which found that the incidence of retinopathy 20 years post-diagnosis was 30-40% in those diagnosed before 1980, compared to 5-10% in those diagnosed since 1985. For both retinopathy and nephropathy, Dr. Skyler cited data from DCCT/EDIC to show that the benefits of even transiently improving glycemic control can last for many years.

Macrovascular disease in Diabetes

William Hiatt, MD (University of Colorado, Denver, CO)

Dr. William Hiatt tackled the challenging topic of cardiovascular risk in diabetes, emphasizing that while glycemic control likely has some impact on macrovascular complications, it is one of many other factors, including obesity, cholesterol, and blood pressure. He cited data from LookAHEAD and UKPDS, which were unable to conclusively demonstrate a relationship between intensive glycemic control or lifestyle intervention and cardiovascular risk reduction (at least in the timeframe of a few years), to illustrate the uncertainty in this area. The UKPDS did provide early evidence of the long-term cardioprotective impact of metformin, but Dr. Hiatt lamented the fact that newer diabetes drug classes have thus far not demonstrated reductions in cardiovascular risk. Based on the available evidence, he recommended a multifaceted approach to preventing macrovascular complications in diabetes patients: an A1c target of <7% preferably achieved with metformin (a realistic goal with metformin alone works only for part of the type 2 diabetes patient population), a blood pressure target of <140/80 mm Hg, and treatment with a statin to reduce dyslipidemia. 

Neuropathy

Daniel Bessesen, MD (University of Colorado, Denver, CO)

Dr. Daniel Bessesen acknowledged that despite immense progress in developing glucose-lowering agents and preventing microvascular complications in recent years, treating diabetic neuropathy remains incredibly frustrating. Because there are currently no available treatments that address the underlying pathophysiology of the condition, clinicians are reduced to treating the pain and hoping that good glycemic control will stave off the progression of neuropathy for as long as possible. Even in the realm of pain relief, there is no clear treatment algorithm; Dr. Bessesen reviewed guidelines from several organizations that recommend various combinations of drugs including anticonvulsants, tricyclic antidepressants, and opiates. Neuropathy is clearly an area of great unmet need in diabetes research, and we hope that new mechanistic therapies and a continued emphasis on prevention will be able to reduce this significant burden for patients in the future. In the meantime, new technology-based solutions such as NeuroMetrix’s Sensus transcutaneous electrical nerve stimulation (TENS) device and certain drugs can offer patients a modicum of relief from pain and the resulting loss in quality of life.

Panel Discussion

Q: I see lots of patients, many have neuropathy, and aspartame comes up a lot. Do you have any opinions on that?

Dr. Daniel Bessesen (University of Colorado, Denver, CO): Aspartame is the most studied chemical in the universe. What most people learn off the Internet is craziness. Many organizations around the world have looked very carefully and don’t interpret it as showing evidence of harm.

Dr. Jay Skyler (University of Miami, Miami, FL): I fully agree; this is part of the condemnation of the nonsense on the Internet.

Dr. Satish Garg (Barbara Davis Center, Aurora, CO): Could all the improvement in retinopathy and neuropathy be attributed to the improvement in A1c?

Dr. Skyler (University of Miami, Miami, FL): I think it is.

Dr. Garg: How about the treatments themselves? Like MDI? Have better treatments made a difference?

Dr. Skyler: They’re related. I don’t know how you separate those out.

Q: Dr. Hiatt, you alluded to the cardiovascular risk calculator from the new guidelines. I use it in practice; it’s a great tool. There are some limitations: it was based on studies with patients age 40-75. Lots of us treat patients with type 1 diabetes, and if someone young comes in who has had diabetes for up to 30 years with variable control, their LDL is not great, I find that challenging. Should I start statin, at what dose, do I wait? If it’s a woman of reproductive age, that makes me nervous. Let me ask the audience – do you find those cases challenging? I don’t think I’m alone? (some nods in agreement)

Dr. William Hiatt (University of Colorado, Denver, CO): I couldn’t agree more. The calculator takes adults, mostly without diabetes, and tells you what to do. At my age, I should be on a statin because I’m a guy and I’m 64, and I haven’t decided to do that yet. Evoke a conversation with the patient. In your situation, I would calculate the absolute risk and base the decision on that. If you have a young woman who has type 1 diabetes with an LDL of 120 or 130, her absolute cardiovascular risk is extremely low, driven by her age and gender. I wouldn’t start her on a statin; I would reevaluate at 30 or 40. Others may have different opinions.

Dr. Skyler: I’m an aggressive statin user. I would give it to almost everyone.

Dr. Hiatt: What about a reproductive age woman with an LDL of 120?

Dr. Skyler: I would be more cautious. I recommend planned pregnancies, and when she’s planning the pregnancy, I would stop the statin and the ACE inhibitor. In general, I give statins. If you look at the pre-2013 guidelines, everyone with diabetes is at risk.

Dr. Bessesen: Cardiovascular risk develops over a long time, so that’s an argument for staring earlier. It’s important to note that we don’t have great data, so you should involve the patient. Some want to take aggressive action, others are more cautious. I would express the absolute and relative risk and let them decide.

Q: If you take someone who has diabetes, but is type 1 and is otherwise healthy, do you give them statins? I play with risk calculators all the time to try to figure this out.

Dr. Hiatt: Risk calculators have been criticized by a number of people. If you really want to talk about statins, one question I would ask is: Do you give statins to patients who are 5 years old?

Dr. Skyler: There’s not a lot of evidence for that. We know statins work when you are 90. But we don’t know whether they work when patients are 10. It’s all about your clinical perspective as a provider. With the new guideline – the paradigm shift here – it’s about your perspective as a clinician. I think it’s a situation that doesn’t have evidence to support one side or the other. In my view, it’s perfectly fine to be aggressive with statins.

Dr. Bessesen: There is another tool that can be helpful. The Mayo Clinic has a stain decision-making aid that can be really helpful. I hear some doctors tell their patients that “you’re going to die of a heart attack and statins will stop that.” They say that the risk of such an event goes down 30% with statins. But that’s not accurate. How do you convey the idea of absolute risk? With this decision aid, there are 100 balls of three colors – green (low risk), red (high risk), and yellow (moderate risk) – and as a doctor you can say that we don’t know whether you’re a member of the green, red, or yellow group. The tool shows a patient visually that if you take a statin you might move from the red to the green group. But we don’t know. Maybe you take a statin and you weren’t going to have a heart attack in the first place.

Dr. Skyler: What I will add to that is that the safety of stains has been well documented. Most decisions involve a risk-benefit tradeoff and in this case, the risk is very low and the potential benefit is very high.

Q: Do you change the insulin dose when you start statins in type 1?

Dr. Skyler: This whole discussion of statins in diabetes is overplayed. I’d just watch people because it doesn’t affect everyone. It may shift metabolic control sharply, but I wouldn’t do anything prospective.

Dr. Bessesen: I agree.

Dr. Hiatt: Me too.

Patient/Provider Panel: Question & Answer Session

Adult

In one of the most moving and inspiring sessions of the conference, several patients with type 1 diabetes joined Drs. Satish Garg, Peter Gottlieb, Irl Hirsch, Aaron Michels, Jay Skyler, and Howard Wolpert onstage to share their stories and discuss pertinent issues in diabetes management. The audience of HCPs was blown away by the patients’ experiences – one patient said he had recently celebrated his 80^th birthday after living through 66 years of type 1 diabetes and over 500 seizures due to hypoglycemia; another described how he fell in love with exercise and lost almost 200 pounds after struggling with his weight for years. The conversation eventually turned to the urgent need for Medicare coverage of CGM – both patients and providers expressed immense frustration with the futility of their efforts to obtain coverage, though one patient had succeeded after going through a lengthy appeals process and writing multiple letters explaining that he could quite literally die without the device. One audience member expressed hope that change could be possible if enough doctors and patients “were to start screaming and hollering at these people to get a move on,” but Dr. Hirsch predicted that Medicare would want to see a specific clinical trial showing a difference in outcomes between CGM and non-CGM users in Medicare patients before changing the policy. Dr. Satish Garg said that when Medicare turns down CGM coverage, patients’ secondary insurance may pay for the technology – while not a perfect solution, this could be a useful workaround for some patients.

• The session concluded with an informal poll of the panelists’ interest in an artificial pancreas device – five of the eight panelists said yes, they would take it in a heartbeat; two said they would potentially be interested but would need more information, and Dr. Robert Eckel said that he would turn it down for the same reason he turned down the Medtronic MiniMed 530G (“if it’s working, don’t break it”).

Pediatric

Several families from the Barbara Davis Center (BDC) were gracious enough to share their experiences on a variety of topics including what gives support and strength to parents, how to communicate with a teen patient, and what to tell newly diagnosed families. Dr. Paul Wadwa (University of Colorado School of Medicine, Aurora, CO) accurately concluded the session saying, “We’ve all learned something, laughed some, and have been moved to tears.” Below, we have highlighted several of our favorite quotes from the session.

• “There’s no guilt – your child’s going to be okay and diabetes can be controlled.” – Parent panelist on what to tell newly diagnosed families
• “Family support and a tight-knit community are huge. We have grandparents who log everything when we’re away. BDC has a grandparents’ workshop, which is amazing. Diabetes is really a whole group effort.” – Parent panelist
• “I feel like my most important teachers were people with diabetes and their parents. I learned from them that it’s important to split up duties and have the father’s involvement.” – Parent panelist
• “We don’t like being told what to do. We like to have some degree of control, so the patient and provider should be on the same page.” – Teenage panelist with diabetes
• “Providers are also human. Families and patients should see physicians as humans who also sometimes need to mature.” – Dr. Tadej Battelino (University Children’s Hospital, Ljubljana, Slovenia)

 

-- by Melissa An,  Adam Brown, Varun Iyengar, Nina Ran, Emily Regier, Manu Venkat, and Kelly Close