July 14-17, 2016; Keystone, CO; Day #1 Highlights – Draft

Executive Highlights

Hello down there! We’re in Keystone, CO (9,173 feet above sea level), and tonight marks the beginning of our coverage of one of our favorite conferences, Practical Ways to Achieve Targets in Diabetes Care (ATDC), colloquially known as “Keystone.” With~ 550 attendees hailing from seven countries and 46 states, this is bound to be another terrific year of learning. Dr. Satish Garg kicked off the proceedings with a welcome address full of enthusiasm for the coming sessions, and, notably, reminding attendees to always keep the economic/payer perspective in the backs of their minds: How will all of these amazing drugs and devices that researchers work so hard to make safe and efficacious get into the hands of the people who need them? On this note, ADA Chief Scientific and Medical Officer Dr. Robert Ratner shared insight into the Association’s strategies for combating the ever-increasing prices of insulin. Dr. Ratner also provided commentary on the ANDIS study’s compelling categorization of type 2 diabetes into five distinct subtypes. Discussion of type 1 diabetes staging and intervention, combination therapy in type 1 and type 2 diabetes, and continued buzz for the hybrid closed-loop were also highlights of the day. As a reminder, you can follow this year’s Keystone conference on social media (Twitter #ATDC2016), and we’ll be back soon with our takeaways from days #2-4. See our top 10 highlights from day #1 below, followed by detailed discussion and commentary. Want to know what’s on the agenda for the rest of the meeting? Check out our preview!

Top Ten Highlights

1. Dr. Robert Ratner highlighted results from the ANDIS study that characterize the heterogeneity of type 2 diabetes in terms of five major subtypes: (i) LADA, (ii) severe insulin deficiency, (iii) severe insulin resistance, (iv) obese, and (v) older.

2. Dr. Hertzel Gerstein (McMaster University, Hamilton, Ontario, Canada) introduced the ongoing Canadian REMIT trial of an aggressive short-term combination therapy regimen for type 2 diabetes designed to rapidly bring the patient into diabetes remission. Wow!

3. Continuing the day’s emphasis on combination therapy, Dr. Jay Skyler offered compelling commentary on the promise of combination immunotherapy for type 1 diabetes, a topic currently under investigation in the DIPIT trial.

4. TrialNet Chair Dr. Carla Greenbaum shared that results from the preventive oral insulin trial will be presented at ADA 2017. Both Dr. Ratner and Dr. Greenbaum also highlighted the value of staging type 1 diabetes in the development of preventive therapies.

5. Dr. Francine Kaufman’s pre-recorded address provided an overview of the evolution of Medtronic’s artificial pancreas technology, with many notable updates on the FDA-submitted MiniMed 670G/Enlite 3 hybrid closed loop.

6. In a Sanofi-sponsored corporate symposium, Dr. Bruce Bode (Atlanta Diabetes Association, GA) expressed a very positive view on the potential of basal insulin/GLP-1 agonist combination therapies, going so far as to say we should expect many options in the near future.

7. Not quite finished with his commentary on the future of the field, Dr. Bode also elaborated on the importance of diabetes education and the critical role that technology will play.

8. Dr. Lutz Heinemann critically discussed the value of biosimilar insulin for patients, clinicians, industry, and payers.

9. Several speakers, including Dr. Ratner and Dr. Satish Garg, unflinchingly addressed the cost of diabetes care.

10. Dr. Desmond Schatz covered the difficult area of care transitions and shared valuable insight on the biggest challenge providers may face with the artificial pancreas: understanding context.

Top Ten Highlights

1. Dr. Robert Ratner (ADA, Alexandria, VA) highlighted results from the ANDIS study that characterize the heterogeneity of type 2 diabetes in terms of five major subtypes: (i) LADA, (ii) severe insulin deficiency, (iii) severe insulin resistance, (iv) obese, and (v) older. Patient records for 10,785 newly-diagnosed Swedish patients with type 2 diabetes identified seven major characteristics were sufficient to categorize most patients into one of the subgroups: (i) age, (ii) BMI and waist circumference, (iii) A1c at diagnosis, (iv) liver fat, (v) obstructive sleep apnea, (vi) C-peptide levels, and (vii) presence of anti-GAD antibodies. Records from 5,107 Finnish patients with type 2 diabetes from the DIREVA registry confirmed the results. Patients with LADA are characterized by the presence of anti-GAD antibody and also tended to be younger, have low BMI and waist circumference, very high A1c at diagnosis, and low C-peptide levels. Patients categorized as severely insulin deficient tended to have similar characteristics to patients with LADA but did not have anti-GAD antibodies. Patients with severe insulin resistance were characterized by very high C-peptide levels and the presence of liver fat markers and tended to experience obstructive sleep apnea. These patients also tended to be younger, have a very high A1c at diagnosis, relatively lower BMIs, and higher waist circumference. Patients who fell under the obese subtype, on the other hand, tended to have a high BMI and waist circumference (as expected) high C-peptide levels, presence of liver fat markers and obstructive sleep apnea. These patients were often older and had an elevated but not extremely high A1c at diagnosis. Finally, patients in the older categorization were generally even older than those in the obese subtype, had an elevated BMI and waist circumference, had an elevated but not extremely high A1c at diagnosis, and high levels of C-peptide. These patients may or may not have liver fat or obstructive sleep apnea. We were very interested to hear these specifics; this is the most detail we’ve heard to date from Dr. Ratner on this fascinating topic and clearly, these subtype categorization could offer more accessible individualization of diabetes therapies. If these subtypes are validated and become more established, perhaps diabetes treatment algorithms will stratify their therapeutic recommendation by subtype. For instance, patients with severe insulin deficiency could initiate insulin therapy upon diagnosis while patients with severe insulin resistance might initiate a TZD. Currently, there is little practical guidance for the process of treatment individualization and we imagine the use of type 2 diabetes subtypes could help clinicians determine the right medication for the right patient earlier.

• In terms of prevalence, about 11% of type 2 diabetes patients fell under the category of LADA, about 20% of patients were severely insulin deficient, about 6% of patients were severely insulin resistant, about 20% of patients fell under the obese subtype, and 43% fell into the older category. Remarkably, this breakdown in prevalence in subtype persisted in the Finnish cohort as well. We’d be interested in seeing similar registry analyses for different regions and ethnic groups to determine if these ratios are conserved more broadly.
• Dr. Ratner eloquently outlined a new approach to understanding type 1 and type 2 diabetes pathophysiology, natural history, and prognosis in which a combination of genetic and environmental factors drive either beta cell destruction (in type 1) and beta cell dysfunction (in type 2). Dr. Ratner characterized diabetes – regardless of type 1 or type 2 – as a “fairly internally consistent disorder” and suggested one set of genetic and environmental conditions promote inflammation and autoimmunity, resulting in beta cell destruction and type 1 diabetes, while another set of genetic and environmental conditions drive inflammation and obesity, leading to beta cell dysfunction. In either case, the patient experiences hyperglycemia, some form of diabetes diagnosis, and potentially faces the same downstream complications. Dr. Ratner previously advanced a similar view of diabetes pathophysiology in his AACE 2016 “Meet the Professor” session, though he clarified in Q&A that nobody is suggesting that the categorizations of “type 1” or “type 2” diabetes be abandoned.

2. The most exciting part of day #1 of Keystone was when Dr. Hertzel Gerstein (McMaster University, Hamilton, Ontario, Canada) introduced the ongoing Canadian REMIT trial of an aggressive short-term combination therapy regimen for type 2 diabetes designed to rapidly bring the patient into diabetes remission. REMIT (Remission Evaluation of Metabolic Interventions in Type 2 Diabetes) is an open-label, randomized, parallel design trial (n=100) that compares the effectiveness of an intensive 12-week course of metabolic rehabilitation therapy versus standard type 2 diabetes care after 24 weeks. The metabolic rehabilitation therapy consists of insulin glargine (Sanofi’s Lantus), DPP-4 inhibitor sitagliptin (Merck’s Januvia), metformin, and lifestyle modification. The primary endpoint for the study is the proportion of participants achieving drug-free diabetes remission (defined as A1c<6.5%) after 24 weeks. Secondary endpoints include proportion of patients achieving diabetes remission at 36 weeks and 64 weeks after randomization. According to ClinicalTrials.gov, the study is expected to complete in April 2017. Like others who advocate for an early combination approach, Dr. Gerstein distinguished his remission strategy apart from the current “treat to fail” paradigm, in which patients are prescribed a diabetes treatment regimen only to have it repeatedly intensified after their glucose levels inevitably rise. If the course of the disease could simply be arrested and set into remission, he believes type 2 diabetes patients would be spared the “lifelong, increasingly complex journey of failure and ever-increasing complexity and cost” they suffer under the current standard of care. We’ll be very interested in seeing how the REMIT trial results compare to the STAMPEDE trial for bariatric surgery, in which about one-fifth of patients continued to experience diabetes remission five years after the surgery – it would be a big win if a 12-week intensive medication regimen could produce similar or better results than invasive bariatric surgery. We love the idea of experimenting with patients taking insulin very early on, since then the barriers related to insulin injections that can arise later on (especially related to physician “insulin resistance”) are less likely to occur.

• Insulin glargine (Lantus) has previously shown promise in producing sustained glucose lowering in the ORIGIN trial and even diabetes remission in patients with newly-diagnosed type 2 diabetes, providing support for its inclusion in the REMIT combination approach. By comparison, Dr. Ralph DeFronzo has made a point of not using insulin in his own early, aggressive combination therapy approach. Dr. Ralph DeFronzo’s triple combination therapy (metformin, TZD pioglitazone, and GLP-1 agonist exenatide twice-daily [AZ’s Byetta]) approach in early-stage type 2 diabetes has also shown promise with impressive sustained A1c-lowering efficacy (mean A1c 5.8% in participants treated with triple therapy out to three years). However, patients on the “DeFronzo cocktail” experience a heavy medication burden of two injections and three pills every day, compared to Dr. Gerstein’s ambitious goal of independence from diabetes medications. It would be interesting to know which “sub-type” of patients in Dr. Ratner’s view would be most likely to succeed.

3. Continuing the day’s emphasis on combination therapy, Dr. Jay Skyler (University of Miami, Miami, FL) offered compelling commentary on the promise of combination immunotherapy for type 1 diabetes, a topic currently under investigation in his DIPIT trial. Despite abundant scientific evidence for type 1 diabetes as an immunologically-modulated disease, Dr. Skyler explained that the majority of studies examining the clinical efficacy of antigen-based or other immunomodulatory therapies have shown no or only transient effects. In his view, these therapies “bring in the infantry, but leave the artillery.” That is, beta cell destruction in type 1 diabetes occurs through multiple immune mechanisms, so targeting only one aspect of the immune response is not a very powerful approach. Dr. Skyler believes that the key is a combination of immune therapies, all operating via different mechanisms. Accordingly, his DIPIT (Diabetes Islet Preservation Immune Treatment) trial (n=42) is a randomized, double blind, placebo-controlled study which investigates the effectiveness of a blend of simultaneous immunotherapies at restoring insulin secretion (as measured by C-peptide area under the curve [AUC] four hours after a mixed-meal tolerance test) in early onset type 1 patients after one year. DIPIT’s combination therapy consists of Thymoglobulin (anti-thymocyte globulin, or ATG), Neulasta (pegylated GCSF), Proleukin (IL-2), Enbrel (etanercept), and AZ’s Bydureon (exenatide once-weekly), all of which are FDA approved and have already previously been studied in type 1 patients. The trial has a estimated primary completion date of January 2019 and an estimated final completion date of January 2021, according to ClinicalTrials.gov. This is going to be incredibly interesting to watch – we’ve heard for some time the value of combination therapy in early onset type 1 patients and we’re extremely keen to follow these results.

4. TrialNet Chair Dr. Carla Greenbaum (Benaroya Research Institute, Seattle, WA) shared that results from the preventive oral insulin trial will be presented at ADA 2017 in San Diego. The trial – eight years in the making according to Dr. Greenbaum – is investigating oral insulin’s potential to prevent or delay progression to type 1 diabetes in people with multiple autoantibodies but normal glycemia. Dr. Greenbaum previously shared in November 2015 that enrollment in the trial was nearing completion. According to ClinicalTrials.gov, the estimated enrollment of 400 participants is complete and the study is expected to complete in January 2017. We’ll certainly be looking forward to the results at ADA 2017 next year! Dr. Carla Greenbaum also briefly mentioned but provided no updates on TrialNet’s other ongoing preventive trials in type 1 diabetes: abatacept for people with multiple autoantibodies and normal glycemia and teplizumab for individuals with multiple autoantibodies and dysglycemia.

• Both ADA Chief Medical Officer Dr. Ratner and Dr. Greenbaum highlighted the value of staging type 1 diabetes in the development of preventive therapies. Under the staging system – developed at a JDRF/ADA workshop – individuals with multiple autoantibodies and normal glycemia are considered to have stage 1 type 1 diabetes, those with multiple autoantibodies and dysglycemia but no symptoms are considered to have stage 2, and those with symptomatic hyperglycemia are considered to have stage 3. Both Dr. Ratner and Dr. Greenbaum emphasized the preventive opportunity by recognizing and diagnosing early stages of type 1 diabetes, considering that 80%-85% of individuals with multiple antibodies will progress to symptomatic type 1 diabetes within 15 years and staging offers a formal point for earlier, pre-emptive intervention. Dr. Ratner suggested that type 1 diabetes therapies need to move beyond the framework of solely managing hyperglycemia and aim to actually address the natural history of the disease. Hear hear! Similarly, Dr. Greenbaum applauded advancements in closed-loop, but likened improvements in diabetes management tools to improvements in wheelchairs for children with rheumatoid arthritis and argued for the need for immunomodulatory therapies in type 1 diabetes to provide the same level of transformative impact they had in rheumatoid arthritis. Furthermore, both Dr. Ratner and Dr. Greenbaum emphasized the benefits of screening high-risk individuals for type 1 diabetes to lower the risk of the individual experiencing diagnosis due to hospitalization with diabetic ketoacidosis. As Dr. Ratner put it in a panel discussion: “The goal of defining type 1 diabetes is to make sure nobody presents with ketoacidosis.” This was music to the ears of so many patients who presented with type 1 and DKA “in the old days.”

5. Dr. Francine Kaufman’s pre-recorded address provided an overview of the evolution of Medtronic’s artificial pancreas technology, with many notable updates on the FDA-submitted MiniMed 670G/Enlite 3 hybrid closed loop. She couldn’t be in Keystone in person yesterday because the FDA is currently auditing the company’s pivotal 670G trial (presented at ADA) – a necessary step on the road to approval, and terrific to see this is happening so rapidly just two weeks post-submission. Timing-wise, she expressed her belief in Q&A that approval should come before ADA 2017, consistent with Medtronic’s plan to launch the 670G by April 2017 (Editor's note: Dr. Fran Kaufman has informed us that she meant to say she can guarantee only that Medtronic will do everything it can to allow their hybrid closed loop to be approved by next summer). As expected, she said that there should be minimal lag between approval and launch, and hopes for minimal time between approval and reimbursement – we look forward to seeing how this plays out, particularly how quick payer uptake is, whether the 670G is priced similar to current pump+CGM, and if users will be able to upgrade easily – there certainly should be demand for this. Dr. Kaufman noted an ongoing pediatric study is testing the 670G in 7-14 year olds, expanding the indication from the pivotal presented at ADA in 14-75 year olds. The company also just finished 670G feasibility studies in the 2-6-year-old population, and it sounded like discussions are ongoing with the FDA to determine what ages will be considered for approval – a pediatric indication right out of the gate would provide Medtronic with a further leg up on the field. Dr. Kaufman highlighted the positive results from the single-arm, three-month MiniMed 670G pivotal trial (n=124) presented last month: a mean A1c reduction of 0.5% from a low 7.4% baseline; time <70 mg/dl declined 44% (6% to 3%); time <50 mg/dl declined 40% (1% to 0.6%); and a “nice tightening of glucose values”, particularly overnight and in adolescents. One of the pivotal study participants still on the system was present and commented during Q&A how incredible it is to be able to wake up in range and feel great every morning. Dr. Kaufman also noted that 670G pivotal participants “really ate a lot ... pancakes inside waffles, covered with syrup,” and this could explain the slight weight gain (+3 lbs in adults and +2 lbs in adolescents) observed in the study. We look forward to further analysis, since it’s always hard to know how much pivotal trials reflect real world use (either over- or under-reporting the efficacy).

6. Dr. Bruce Bode (Atlanta Diabetes Association, GA) expressed a very positive view on the potential of basal insulin/GLP-1 agonist combination therapies, going so far as to suggest that as many as 80% of patients with type 2 diabetes can be completely adequately managed with basal insulin and GLP-1 agonists alone. Dr. Bode positioned GLP-1 agonists or basal insulin/GLP-1 agonist combinations as good alternatives to rapid-acting insulin for patients in need of basal insulin intensification. Dr. Bode pointed out that taking both drugs together allows patients to take a lower dose of each – less insulin translates to a reduced risk of hypoglycemia, while less GLP-1 agonist means fewer side effects, including nausea. He also spoke to the possibility that a combination basal insulin/GLP-1 agonist might decrease BeAM scores (difference in blood glucose at bedtime vs. morning), a sometimes-overlooked indicator of when a patient has maxed out on basal insulin according to Dr. Bode. This suggests that basal insulin/GLP-1 agonists could delay progression to a rapid-acting mealtime insulin, thus delaying the associated weight gain and increased risk of hypoglycemia. Basal insulin/GLP-1 agonist combinations from Novo Nordisk (Xultophy [insulin degludec/liraglutide]) and Sanofi (LixiLan [insulin glargine/lixisenatide]) are on the horizon – both products received positive FDA Advisory Committee votes in May. We’re certainly looking forward to the final FDA decisions and to their respective US launches. While we are excited for patients to have therapies that are easier to use and that work better, we’re also very keen for doctors to be able to access and prescribe these therapies.

7. In a talk filled with a variety of learnings on treatment and support, Dr. Bode elaborated on the importance of diabetes education and the critical role that technology will play. He emphasized the urgent need for smart programs that connect insulin dosing to the cloud, especially for older patients or patients with severe hypoglycemia unawareness who require rigorous external monitoring. He especially suggested that BeAM measurements – an indicator of when basal insulin is no longer sufficient and intensification is required – will be a key piece of data to incorporate into these smart programs. We had not heard before of BeAM and found this a particularly interesting idea for how to quantify whether a therapy is working. Dr. Bode also championed the Glucommander software (presented in an exciting poster at ADA), which he mentioned will be launched later this year. He asserted that automated systems will allow providers to efficiently manage high numbers of patients who need to titrate their insulin and to select optimal medications for a patient based on factors like age, weight, duration of diabetes, creatinine, etc. On the topic of diabetes self-management, Dr. Bode enthusiastically praised patient support programs like Sanofi’s COACH program that provides one-on-one diabetes education for all patients taking Toujeo. He noted that this support will be particularly critical for patients with hypoglycemia unawareness. We’re certainly in agreement with Dr. Bode on the pressing need for digital health to fill in the gaps of insulin therapy, and were happy to hear his optimism on this front

8. Dr. Lutz Heinemann ((Science & Co GmbH, Düsseldorf, Germany) critically discussed the value of biosimilar insulin for patients, clinicians, industry, and payers. From a patient and clinician perspective, Dr. Heinemann suggest that the risk/benefit profile of switching patients from Lantus (insulin glargine) to a biosimilar insulin glargine is unclear if the patient is doing well on Lantus. Furthermore, he pointed out that switching between Lantus and a biosimilar could potentially confuse patients and lead to dosing or other errors. From an industry perspective, Dr. Heinemann highlighted the high initial investment needed to develop a biosimilar insulin with an uncertain payoff. Dr. Heinemann noted that the average development cost of a biosimilar is $200 million (varying from $40 million up to $375 million) and it’s difficult for companies to build the technical expertise, manufacturing capabilities, distribution channels, etc. required to bring a biosimilar to market. For comparison, he shared that generic drug development typically costs between $1 million to $4 million. In addition, he drew attention to the challenges presented by the complicated regulatory pathways in the US, EU, and other countries that are not harmonized. Notably, while acknowledging that some payers and healthcare systems might be enticed by the potential cost-savings associated with biosimilars, Dr. Heinemann suggested that the savings might be less than assumed and it’s unclear if biosimilars will help foster greater healthcare efficiency. For instance, he suggested that there may be additional costs associated with training people to use biosimilars and there might be risks involved in switching populations back and forth from originators and biosimilars as payers and countries renegotiate with the drug companies each year.  Of course, there are potential risks that we won’t know how should be addressed early on – if at all. Biosimilars have often been positioned as a potential reprieve from rising insulin prices – though Lilly/BI’s biosimilar insulin glargine Abasaglar has been priced at only a 10%-20% discount relative to Lantus thus far – and we were very interested to hear Dr. Heinemann’s opinion.

• Dr. Heinemann presented a fairly critical view of biosimilar insulins overall, suggesting that the safety profile of biosimilars cannot be assured. Dr. Heinemann emphasized that biologic manufacturing is much more complex than small molecule manufacturing and the biosimilar manufacturing process involves many steps that can introduce differences between the biosimilar molecule and the originator biologic. Dr. Heinemann repeatedly emphasized that, as a result, biosimilar cannot be considered identical to the originator, despite similar clinical profiles. He pointed to data from analytical comparisons using reverse HPLC of three biosimilar insulin glargines against Sanofi’s Lantus (insulin glargine) indicating that the similar have a different analytical fingerprint than Lantus. While this may not affect A1c efficacy, Dr. Heinemann suggested that differences in manufacturing processes between biosimilars and orginators can lead to differences in immunogenicity. That said, Dr. Heinemann acknowledged that no clinical studies of biosimilar insulins thus far have identified an increase risk of neutralizing cross-reactive antibodies – the main concern associated with immunogenicity – and that studies monitoring this risk are ongoing. While there has not yet been extensive discussion from others on the profile overall of biosimilars, Dr. Heinemann’s presentation served as an important reminder of the nuances of biosimilars compared to the more familiar oral generics and that the use of biosimilars is relatively uncharted territory within the diabetes field. We await broader use – it also may be that the complexity is high but also is possible to address. To be sure, there is no question that biosimilar manufacturing is far more complicated than oral drug manufacturing – we would also love to know more about insulin manufacturing within the broader biosimilar world.

9. Several speakers, including Dr. Ratner and Dr. Satish Garg (University of Colorado, Aurora, CO), addressed the cost of diabetes care. Dr. Garg set the tone during his opening remarks, during which he highlighted President Barack Obama’s recent JAMA paper on the positive impact of the Affordable Care Act (ACA) to-date on reducing major drivers of healthcare costs, such as hospital readmissions. Dr. Garg expressed his support for the ACA and emphasized that we must continue to invest in innovative health reform strategies now to see future cost-savings. He urged attendees to keep the costs of diabetes care to the system in mind throughout the conference and predicted that the cost theme would frame many of the discussions happening over the next four days, including Dr. Ratner’s Saturday morning keynote. While we were very happy to hear about some positive impacts of the ACA, we believe quite a negative impact has been cost-shifting from employers – higher deductibles and co-pays are elements we believe should also be addressed. Dr. Ratner spoke to rising insulin prices during a panel discussion, acknowledging the criticism that the ADA has received from Dr. Irl Hirsch and others for the organization’s inertia in responding. He assured the room that the ADA has not been ignoring this cost issue. In fact, the ADA has called for (i) full transparency in where insulin prices are marked up, whether at the pharmacy benefits manager (PBM) level or elsewhere; (ii) off-patent insulin and diabetes drugs to be supplied at tier one; and (iii) legislature to make Medicare Part D negotiable in terms of drug-pricing. In the same panel, both Dr. Ratner and Dr. Heinemann called out pharmacy benefits managers as an opaque contributor to rising insulin costs. We appreciated this nuanced recognition that insulin list prices have increased in lockstep with rising rebate levels and we’re looking forward to more detailed discussion on this topic throughout the rest of the conference.

10. Dr. Desmond Schatz (University of Florida, Gainesville, FL) covered the difficult area of care transitions and shared valuable insight on the biggest challenge providers may face with the artificial pancreas: understanding context. On the latter, he noted, “Never send me your blood sugar – send me your thoughts on a blood sugar. I find that the biggest problem with AP is the advising – we providers don’t know what a given blood sugar means. Did you just have an argument with mom? Do you play volleyball? Are you a starter or do you come off the bench? We can’t tell. Was it a practice or a game? Because the body responds differently in all of these scenarios. What did you eat? When? The biggest challenge for a provider will be learning the trends of the patient and learning how to advise accordingly without constant patient input.” Dr. Schatz’s remarks were such a valuable reminder that the artificial pancreas will fundamentally change what providers do for people with type 1 diabetes – less about insulin changes and more about behavioral context, stress, etc. Most of Dr. Schatz’s talk focused on the keys to a successful adolescent to adult transition, the ‘Three Cs’: “collaborate, communicate, and cooperate, and as a healthcare professional, spend time with patients, colleagues, and families.” These guidelines may seem intuitive, but patients often don’t receive the support that they need, noted Dr. Schatz. Even as attendees were picking at their salads before Dr. Schatz took the podium, we overheard one type 1 in his mid-30s casually mention that he didn’t have any gradual “transition” – he went from no responsibilities until he was 18 to being 100% in charge of his diabetes immediately (we were also surprised to hear of a teenager who had no responsibilities). And that kind of care is reflected in the concerning data on transitions: Garvey et al. (2012, Diabetes Care) found that transitions yield significant gaps in care, with one in four patients not referred to adult providers and 35% of patients experiencing >6 months without a provider. A separate study reported that patients transferred to a new physician are four times as likely to be hospitalized after transition than those who stayed with the same physician (Nakhla et al., 2009, Pediatrics). Dr. Schatz also referenced a valuable piece co-authored by Drs. Anne Peters and Lori Laffel on diabetes care for emerging adults. We thought the Q&A after this talk was particularly insightful, with several opinions on the challenges and benefits of disclosing “I have diabetes.”

• Insulet’s Alex Nguyen discussed the company’s growing patient education efforts, including an upcoming pre-pod training portal (September/October launch), a new educational iPad app for kids (launched at Friends for Life), and an app for OmniPod reordering and support (launched in May with the new branding). The pre-pod training will ensure that patients get proper education when they start on the OmniPod, and it will only take 30 minutes and cover pre-pump basics – this will be key for retaining new users and helping them maximize use of the pump. The new management team has talked about these efforts for several quarters, and we’re glad to see continued investment in Digital Insulet – this work will pave the way for the very important OmniPod app to communicate with the next-gen Bluetooth enabled PDM. Per 1Q16, this is slated for an FDA filing later this year.

Detailed Discussion and Commentary

Corporate Symposium: Prepare for Closed-Loop Technology (Sponsored by Medtronic)

Practical Tools and Applications

Francine Kaufman, MD (Medtronic Diabetes, Northridge, CA)

Dr. Francine Kaufman’s pre-recorded address provided an overview of the evolution of Medtronic’s artificial pancreas technology, with many notable updates on the FDA-submitted MiniMed 670G/Enlite 3 hybrid closed loop. She couldn’t be in Keystone in person this morning because the FDA is currently auditing the company’s pivotal 670G trial (presented at ADA) – a necessary step on the road to approval, and great to see this is happening so rapidly just two weeks post-submission. Timing-wise, she expressed her belief in Q&A that approval should come before ADA 2017, consistent with Medtronic’s plan to launch the 670G by April 2017 (Editor's note: Dr. Fran Kaufman has informed us that she meant to say she can guarantee only that Medtronic will do everything it can to allow their hybrid closed loop to be approved by next summer). She expects minimal lag between approval and launch, and hopes for minimal time between approval and reimbursement – we look forward to seeing how this plays out, particularly how quick payer uptake is, whether the 670G is priced similar to current pump+CGM, and if users will be able to upgrade. Dr. Kaufman noted an ongoing pediatric study is testing the 670G in 7-14 year olds, expanding the indication from the pivotal presented at ADA in 14-75 year olds. The company also just finished 670G feasibility studies in the 2-6-year-old population, and it sounded like discussions are ongoing with the FDA to determine what ages will be considered for approval – a pediatric indication right out of the gate would provide Medtronic with a further leg up on the field. Dr. Kaufman highlighted the positive results from the single-arm, three-month MiniMed 670G pivotal trial (n=124) presented last month: a mean A1c reduction of 0.5% from a low 7.4% baseline; time <70 mg/dl declined 44% (6% to 3%); time <50 mg/dl declined 40% (1% to 0.6%); and a nice tightening of glucose values, particularly overnight and in adolescents. One of the pivotal study participants still on the system was present and commented during Q&A how incredible it is to be able to wake up in range and feel great every morning. Dr. Kaufman also noted that 670G pivotal participants “really ate a lot...pancakes inside waffles, covered with syrup,” and this could explain the slight weight gain (+3 lbs in adults and +2 lbs in adolescents) observed in the study. We look forward to further analysis, since it’s always hard to know how much pivotal trials reflect real world use (either over- or under-reporting the efficacy).

• Following the DreaMed algorithm integration (to give automatic correction boluses), the future of Medtronic’s closed loop is about individualization and adaptation via the IBM Watson partnership. Dr. Kaufman noted that Bluetooth-enabled pumps that send data to the cloud will be critical in this respect. Medtronic’s pre-ADA Analyst Meeting highlighted a next-gen closed-loop product after the 670G that appeared to be a smaller touchscreen pump with smartphone control (!) and “biometric,” “multi-parameter” sensing. Launch was expected after May 2020. We’re not sure if interim products will launch between the next-gen MiniMed 690G and this product.
  
  • As a reminder, the immediate post-670G product, the MiniMed 690G, will add the DreaMed algorithm. We learned last week that it is completing an initial camp study in July. This product will integrate the MD-Logic algorithm to close the loop further – instead of only increasing basal insulin to gradually mitigate highs (670G) and bring blood glucose back to target, the next-gen algorithm will add automatic bolusing to correct highs. That should further improve time-in-range and make the system more aggressive with missed meal boluses.
• Medtronic will present data from a pivotal trial of PLGM (MiniMed 640G) at EASD – we assume this is from the US (before Medtronic moved ahead with the 670G instead), but aren’t positive. “PLGM not only reduces but prevents hypoglycemia by stopping insulin before the threshold is reached,” said Dr. Kaufman, “And with the artificial pancreas, we hope to make hypoglycemia negligible.” Of course, lots of hypoglycemia stems from highs, something the MiniMed 670G and future products will help address.

Questions and Answers

Dr. Grafton Reeves (Nemours Alfred I. DuPont Hospital for Children,
Wilmington, DE): Can you please comment on the advantages/disadvantages of having glucagon as part of the artificial pancreas? And have you used the present iteration of artificial pancreas in children under 11?

A: I’ll start with the second question. We have an ongoing pediatric study with 7-14 year olds. It will be the same as the pivotal trial that we presented at ADA with the 14-75 year olds. We also just finished some feasibility studies in the 2-6-year-old population, and we will be doing a deep dive in that population. I can tell you that the system appears safe and to have the same benefits in that age. If that turns out well, then we’ll ask FDA to include that population. Whether ages 2-75 or 6-75, we’ll know soon.

For your second question, for the hybrid closed loop, the evidence isn’t really compelling that we need a second agent or hormone. And if we do need a second agent, I’m not convinced it should be glucagon. Why not pramlintide, GLP-1, or SGLT-2? It looks like we can protect against hypo pretty well with just insulin – just look at data from Roman Hovorka and Claudio Cobelli. Glucagon adds a lot of complexity and cost to the system, and I don’t think we’ll need it, a least for this first generation of hybrid systems. We also need to consider that we don’t know the long-term risk of chronic glucagon use. But do we need it to get to full closed loop? Maybe – but if we were to add another agent, maybe it wouldn’t be glucagon, some other agent. If we got ultra rapid acting insulin, which seems likely, that might help us enough, save some minutes. We could maybe get to a point where meals don’t have to be announced.  There are a other hormones secreted by the islet, other agents that help control glucose, why only focus on glucagon?

Q: In your experience, how long will it take to get this product to market?

A: If I knew the answer, that’d mean I could see the future. I’d leave medicine and go into the stock market. As I can tell, the FDA is incredibly collaborative, helpful and there 24/7 checking all the boxes, and everybody is working really hard to make this happen. I can probably guarantee that it will be before the next ADA meeting (Editor's note: Dr. Fran Kaufman has informed us that she meant to say she can guarantee only that Medtronic will do everything it can to allow their hybrid closed loop to be approved by next summer). All I can tell you is that everyone is working to get this done in a safe, rational, reasonable manner in the proximal future. 

Mr. Jason Gessler (Barbara Davis Medical Center, Aurora, CO): I’ve been wearing the 670G for 11 months, my A1c has gone from 8.1 to 6.8, and the system has only kicked me out of closed loop one time. I don’t ever worry about going low, and I always wake up feeling great. I don’t believe glucagon will ever be necessary. Do you see, in future iterations, ways to put in information for proteins and fats, not only carbohydrates? And I’m struggling with the idea that we can’t project artificial pancreas information into cloud – are you considering that for future models?

A: Second question first: Absolutely. We have engineers working on a Bluetooth system. Artificial pancreas connectivity is a little more complex, because there are multiple devices talking (sensor, pump, meter) – it’s not just one connection to the cloud. We do hope to get that all done really soon. I can’t exactly say when because of partners and all that, but our intention is to have it as soon as possible. We can’t envision going much further forward without that – our plan to individualize/personalize is to leverage the partnership with IBM Watson, which can’t be done without cloud connectivity. Watson is the smartest individual anyone has ever met, and real time analytics will be huge, maybe not for the next product, but certainly the one after that. And the next iteration will just have a few changes to user interface without changing the algorithm. Of course, we’re working with DreaMed for the next iteration by adding Fuzzy Logic to our algorithm to enhance meal-handling. The goal is that you won’t have to announce anything about meals – so we may be able to update what you can put in about meal composition, but eventually you won’t have to worry about that at all. As we go forward, we’re going to focus as much as possible on user feedback. We want to be more patient-focused – we have a Chief Patient Officer now – we want feedback on user interface and whatever else the patient wants, as opposed to what we, including our engineers, think people want.

Ms. Rebecca Dennison (Geckle Diabetes and Nutrition Center, Baltimore, MD): I’m curious about your definition of and take on a simple vs. complex carbohydrate breakfast.

A: Simple carbs are tough, even if you pre-bolus. Even people without diabetes respond to simple carbs with increased glucose levels. The other day, I was sitting on a plane and had time to kill, and I was wearing four sensors, so I decided to do an oral glucose tolerance test, using juice – which I always say you should only use if you have a prescription. A lot of juice brought me up to 200 mg/dl! But then I tried complex carbs, which brought me to about 150 mg/dl. The time to normal was longer, but the area under the curve was much less. This gets to the philosophy that most of us should avoid simple carbs unless if we need to recover from hypoglycemia. I try to have my patients remove simple carbs from breakfast and eat more eggs, good fats, yolks, etc. And when eating carbs, to make them complex, particularly around breakfast.

Dr. Glenn Smith (Aurora Two Rivers Clinic, Two Rivers, WI): Agreed, I tell my patients that juice is a dessert, and that they need to treat it that way. With the 670G pivotal trial, A1c went down, but insulin and weight went up. Are you at all concerned about the increase in weight? Would you attribute that to use of more insulin, consumption of more carbs, or what?

A: We’re looking at that in-depth now, but they really ate a lot – there was a significant increase in caloric intake, as measured by carbs entries in the pump in the open loop and closed loop periods. I think that’s driving the need for excess insulin and the increased weight for the most part. They really ate whatever they wanted – pancakes inside waffles, covered with syrup. We also can consider that some of the insulin increase could be from those who were undertreated before the study, and some of weight gain could be because teens naturally gain weight. Our deep dive will help us understand this.

A few parting thoughts: The goal should never be lost that the ultimate end-game is a cure. This is part of that evolution, not a cure, but a better way to treat. We need to support all efforts towards replacing beta cells. That’s one, number two: we’re privileged to be in the developed world, but we can’t forget about all of the people struggling in the developing world – in Haiti, they still use premixed insulin and are limited to two strips a day. The privilege we have needs to extend to those who don’t have it. Beyond that, this is a truly exciting time, we’ve come a really long way and still have some distance to go.

CareLink Pro Therapy Management Software/A Method for Interpreting CGM Data

Kim Larson (Medtronic Diabetes, Jackson, WY)

Ms. Kim Larson showed attendees how to get the most out of Medtronic’s CareLink in little time by using three of the offered reports: the therapy management dashboard, sensor and meter overview, and device settings reports (see samples of all three below). There are nine reports available in total, which can be overwhelming, so this interactive crash-course on navigating the software efficiently was highly appreciated by the providers in the room. The quick methodology to analyze data from the three reports is called “AIM”, meaning assess, identify, and make changes – see the process below. Though not discussed in this talk, we’re looking forward to the launch this summer of Medtronic’s next-gen CareLink Pro reports (shown at ADA), which will help providers optimize pump settings. CareLink will suggest the time of day and direction certain pump settings should change (insulin:carb ratio, insulin sensitivity factor, basal rate – e.g., Increase basal rate from 8am – 12pm. These won’t give exact recommendations like DreaMed/Glooko’s planned system (“change basal rate to 0.75 u/hr from 8am-12 pm”), but will be a clear improvement over the status quo! Clinical decision support has massive potential to drive bigger therapeutic change, and we wonder who which data management platform will nail this in the coming years. 

• Providers should begin by looking at the CareLink therapy management dashboard. Here, they can assess from the sensor section the overall control, amount of variability, hypoglycemia, hyperglycemia, and possible glycemic patterns. From the pump section, they can assess the basal rate profile, insulin sensitivity, insulin to carb ratio, active insulin time, and residual/active bolus insulin. At this point, the provider can make an overall basic assessment of the patient’s control regimen.
• Next, providers can assess control during specific periods of interest (i.e. post-prandial) at the bottom of the page, and then scrutinize the statistics panel on the right side of the page to determine how the patient has been using the pump and sensor.
• In the final step of the assessment phase, providers should open the sensor and meter overview report, a graphic that “kind of looks like and EKG” and depicts continuous daily insulin and pump activity, along with carbohydrate input and exercise. On this page, providers can begin to identify issues and their causes – they should look at settings to make sure they are set appropriately. For example, one can tell if the basal rate is appropriate by looking at times when a patient hasn’t bolused, eaten, or exercised for three to four hours.
• After confirming that the detected issues are not anomalies, the provider can go to the device settings report, zero in on one to two aspects to change, and make a follow-up plan.

Corporate Symposium: Transition of Care from Adolescence to Adulthood (Sponsored by Insulet)

Addressing the Challenges of Patients, Families, and Providers

Desmond Schatz, MD (University of Florida, Gainesville, FL)

Dr. Desmond Schatz covered the difficult area of care transitions and shared valuable insight on the biggest challenge providers may face with the artificial pancreas: understand context. On the latter, he noted, “Never send me your blood sugar – send me your thoughts on a blood sugar. I find that the biggest problem with AP is the advising – we providers don’t know what a given blood sugar means. Did you just have an argument with mom? Do you play volleyball? Are you a starter or do you come off the bench? We can’t tell. Was it a practice or a game? Because the body responds differently in all of these scenarios. What did you eat? When? The biggest challenge for a provider will be learning the trends of the patient and learning how to advise accordingly without constant patient input.” Good points, and a reminder that the artificial pancreas will fundamentally change what providers do for people with type 1 diabetes – less about insulin changes and more about behavioral context, stress, etc. Most of Dr. Schatz’s talk focused on the keys to a successful adolescent to adult transition, the ‘Three Cs’: “collaborate, communicate, and cooperate, and as a healthcare professional, spend time with patients, colleagues, and families.” These guidelines may seem intuitive, but patients often don’t receive the support that they need, noted Dr. Schatz. Even as attendees were picking at their salads before Dr. Schatz took the podium, we overheard one type 1 in his mid-30s casually mention that he didn’t have any gradual “transition” – he went from no responsibilities until he was 18 to being 100% in charge of his diabetes immediately. And that kind of care is reflected in the concerning data on transitions: Garvey et al. (2012, Diabetes Care) found that transitions yield significant gaps in care, with one in four patients not referred to adult providers and 35% of patients experiencing >6 months without a provider. A separate study reported that patients transferred to a new physician are four times as likely to be hospitalized after transition than those who stayed with the same physician (Nakhla et al., 2009, Pediatrics). Dr. Schatz also referenced a valuable piece co-authored by Drs. Anne Peters and Lori Laffel on diabetes care for emerging adults. We thought the Q&A after this talk was particularly insightful, with several opinions on the challenges and benefits of disclosing “I have diabetes.”

• Dr. Schatz reiterated his ADA Presidential Address message about bringing diabetes to 212 degrees (the boiling point of water), pushing for a sense of urgency from the community as a whole to bring diabetes issues to the forefront and improve patients’ lives. In this case, that means educating families and providers on how to best implement the “Three Cs”.
• Dr. Schatz referenced a valuable piece co-authored by Drs. Anne Peters and Lori Laffel, which provided the following recommendations for diabetes care for emerging adults: (i) Focus on “having a life” rather than on “having an illness or disability”; (ii) always emphasize the multi-disciplinary team approach – that the patient can’t do it alone; (iii) involve the child in decision-making at an early age; (iv) start the provider transition process as early as possible – absolutely critical; (v) work with the patient and family to create a plan; (vi) identify “champion” adult healthcare teams interested in working with young adults; and (vii) individualize time of transition. In addition, Dr. Schatz recommended looking into NDEP, ADA and other online resources to assist with the transition and advocated for a standardized transitional clinical summary page to make adult providers’ role in easing the transition much more manageable. Dr. Schatz emphasized that, for inexperienced parents and providers, helping adolescents is a challenge, as they are facing constant social pressure, many turning points (graduations, beginning college/career), discomfort with a new adult physician, and other obstacles.
• During the Q&A session, the group agreed that patients benefit from disclosing that they have diabetes, even if it can be difficult. Diabetes is an invisible disease, so patients often have the power to determine who they want to tell about it and when. Disclosing that they have diabetes expands patients’ support networks if they are ever in trouble. Equally important, if patients are taught to talk about and not be ashamed of their diabetes from a young age, stigma is automatically reduced. Dr. Brigitte Frohnert from the Barbara Davis Center suggested that there may be a connection between parents’ willingness to talk about the impact of diabetes and their child’s willingness to talk about it. She proposed a model of early intervention to encourage parents to share more. Dr. Schatz liked this idea and hoped that a study can be done to see if it works.

Questions and Answers

Dr. Brigitte Frohnert (Barbara Davis Medical Center, Aurora, CO): A lot of kids this age come across job problems – they are working at a fast food restaurant, have access to sub-ideal food choices, and are not telling their bosses or coworkers about their diabetes. Are there resources about how to talk to a boss?

A: Yes, it all comes down to communication. Some people don’t want to tell their boss. Why? One, they don’t want them to know, or second, they don’t want to get fired. Take truck drivers – until recently, if they had horribly controlled type 2 diabetes, they could legally drive a truck, even if they were nearly blind. But now, as soon as they go on insulin, they can’t drive. It’s difficult. Does anyone have any solutions?

Q: I’m always worried that kids won’t tell their peers about the disease and I feel strongly that we need to get psychologists involved. You have to tell people around you so that they can save you. Kids often say “I don’t want my friends to know”. Well they will when they’re carrying you because you’ve fainted.

A: I agree – this disease is invisible. Invisible to patients, healthcare providers, to the governments and people who aren’t paying much attention. We have to confront it, expose it. I believe that it is partly through kids who unashamedly say that they have diabetes that change can happen.

Q: I work in Kansas City, Missouri. Neither Kansas not Missouri has expanded Medicaid, so now, kids lose insurance when they turn 19. So now there’s a huge disparity between those kids and those who have traditional insurance. Is ADA lobbying to try to help these kids get insurance?

A: Putting on a different hat here. We are very aware of rising healthcare expenditures and what it means for patients with diabetes. We are tackling the main problem: the huge cost of analog insulin. The cost used to be under $30, now its $300-400 for same volume, same technology. With throughput, it now takes even less to manufacture. And it’s not just the industry’s problem – it’s insurance, it’s the PBMs (pharmacy benefit managers), hospital, healthcare professionals…that’s the trickle-down effect. ADA is grappling with how to deal with the rising cost of insulin, but also other things. Here’s another challenge: a few years ago, Medicare went to competitive bidding – reduce the cost of strips by allowing companies to bid. This move was not bad in intent, which was to reduce overall costs and co-pay, but education was lacking and suddenly patients couldn’t get strips because they and providers didn’t know how to get them. Many of the families just quit doing it. There’s a paper in Diabetes Care that looks at competitive bidding that basically says that it’s great that we make changes, but need to educate. But yes, rising cost of healthcare in diabetes is major focus for ADA – something that, I believe, will need to change at the Washington level before we see significant improvements. Every one of you in the audience needs to be involved –it’s not just the ADA, not just me, not just you – it’s all of us.

Q: I (a type 1 patient) got fired from a job and they made up the excuse that I stole something. Too many people said I took too many breaks. Meanwhile my blood sugar was all over the place and I wasn’t feeling great, so I was taking breaks to check my blood sugar. I annihilated them in court, but I learned that it was my fault for not educating everyone at work and not telling my employer. It sucked, but at my next job, I told my boss right away, and you wouldn’t believe the difference it made – they treated me completely different. A lot of kids don’t want to put it out there because it’s an invisible disease, but it stinks if you don’t confront it.

Ms. Frohnert: The issue of disclosure is something we should really tackle. I wonder if there might be a connection between the way parents disclose diabetes and the way kids disclose diabetes. Maybe we should consider interfering earlier with parents and having them share more with people about the tremendous impact diabetes has had on their lives. I mean, some couples haven’t been on a date in years because they are the only ones who can manage their child’s glucose. That might be helpful.

A: Great question, it’d be a good study to do.

Q: I’m a diabetes nurse educator, and I’ve had diabetes for years. As an educator, I love telling people that I’ve had a good life, I’ve had children, etc... My parents told us, myself and my sister who also has diabetes, that we can’t be ashamed of something we have. My dad would always help us find really cool jobs growing up.  But every time, in order for me to interview, my dad would require me to tell the employers right up front that I have diabetes. When I educate patients, I try to make it something that they’re not ashamed of.

A: Thanks for sharing. There are many people who are outgoing, will share with anyone – others are much more personal. For example, I have a colleague from ADA. I asked why he wouldn’t talk about it with other people, he said it’s none of their business. Each person has different preferences.

Q: Right at diagnosis, I ask my patients “have you told your friends?” These are five year olds, seven year olds – we know right off the bat that we will have to work with them closely if the parents step in and say “oh no, we’re not talking about it with people.”

--by Abigail Dove, Helen Gao, Brian Levine, Payal Marathe, Adam Brown, and Kelly Close