In this full report, we provide in-depth coverage of the 27th annual Practical Ways to Achieve Targets in Diabetes Care meeting, colloquially known as “Keystone.” This conference has become an annual favorite for our team, and we imagine for the thought leaders who gather in Keystone as well – each session offers engaging discussions and debates on best practice diabetes care. This year, we were treated to eight packed plenaries, five corporate symposia (sponsored by Medtronic, Dexcom, Insulet, and Novo Nordisk), and two absolutely outstanding keynote lectures: (i) ADA’s Chief Scientific, Medical, and Mission Officer Dr. William Cefalu reviewed notable new data on diabetes therapies from ADA 2017, and shared his view on the “so what?” of each phase 2 or phase 3 readout; (ii) Meanwhile, FDA’s Dr. Courtney Lias continued on her mission to incite the artificial pancreas community to establish a framework for interoperability, presenting an extensive list of arguments in favor of the transition.
Other highlights on the technology front include a rousing talk from Medtronic Diabetes CMO Dr. Fran Kaufman (670G with connectivity “in the future,” clinical trial updates galore, more granular pivotal trial data), Dexcom Medicare reimbursement and pipeline updates, an Insulet panel (featuring Drs. Trang Ly, Bruce Buckingham, plus Ms. Laurel Messer and Mr. Adam Brown) on all things closed loop, and Mr. David Panzirer’s hope that 50% of type 1s in the US will be on CGM by Keystone 2018. In diabetes therapy, Dr. Jay Skyler issued a compelling call-to-action to guideline-writing committees to keep up with the latest clinical evidence (with back-up from Dr. George Grunberger commenting on AACE guidelines and Dr. Simon Heller commenting on ADA/EASD guidelines). In one of his many Keystone presentations, Dr. John Buse spoke to the promise of SGLT-1/2 dual inhibitor sotagliflozin as an adjunct therapy in type 1 diabetes. Cleveland Clinic’s Dr. Steven Nissen delivered two passionate talks on the importance of CVOTs, bringing the cardiologist’s perspective to this diabetes meeting, which we absorbed with rapt attention.
Titles of some of our favorite talks are highlighted in yellow (though this agenda was so filled to the brim with insights that it was nearly impossible to pick!). Titles of talks not included in our daily coverage are highlighted in blue – and you can look back on our top takeaways from each day as well (day #1, day #2, days #3-4).
Detailed Discussion and Commentary
Best of ADA 2017
William Cefalu, MD (ADA, Arlington, VA)
In a rapid-fire overview of the most impressive new data from ADA 2017, Chief Scientific, Medical, and Mission Officer Dr. William Cefalu highlighted many exciting readouts, some of which included SGLT-2 inhibitors (namely, Merck/Pfizer’s candidate ertugliflozin), SGLT-1/2 dual inhibitors for type 1 (Lexicon’s sotagliflozin), the REMOVAL trial on metformin’s CV effects in type 1, biosimilar insulin, nasal glucagon, and Intarcia’s GLP-1 agonist candidate ITCA 650 (exenatide mini-pump). Clearly, the 77th annual Scientific Sessions were packed with exciting results on new therapeutic options, and Dr. Cefalu shared a positive outlook on how these agents will lead to near-term improvements in diabetes care. He articulated the “so what?” of all the clinical trial evidence presented on these therapies.
- ADA 2017 featured several phase 3 readouts from the VERTIS program for Merck/Pfizer’s ertugliflozin. Dr. Cefalu acknowledged the SGLT-2 candidate’s compelling efficacy, but also suggested that due to the fact that other SGLT-2 inhibitors have shown evidence to reduce cardiovascular risk, it will have to show separation from other products in the class given the high hurdle the other products have established. Specifically, he pointed out that Lilly/BI’s Jardiance (empagliflozin) and J&J’s Invokana (canagliflozin) have already shown cardioprotection in the EMPA-REG OUTCOME and CANVAS trials, respectively. The bar for new diabetes drugs is higher than ever, and CV benefits are becoming increasingly important, especially for SGLT-2 inhibitors given speculation over class effects. The DECLARE CVOT for AZ’s Farxiga (dapagliflozin) is scheduled to complete in April 2019. VERTIS CV for ertugliflozin is also ongoing, and is expected to complete in October 2019 (Merck management shared during the company’s 1Q17 earnings call that the CVOT is now fully-enrolled, and is progressing on schedule). We’re excited by the prospect of a four-product SGLT-2 inhibitor class, as we think it will ultimately benefit patients by expanding choice. Moreover, given that canagliflozin was associated with a nearly two-fold risk for lower limb amputations in CANVAS, we’re eager to see continued development of agents in the SGLT-2 class. Additional data on other SGLT-2 inhibitors, including ertugliflozin, will help elucidate this potential safety signal – is it unique to canagliflozin, or does it have anything to do with the mechanism of SGLT-2 inhibition? And, if this amputation finding does negatively impact volume and sales of Invokana, we’ll be glad to see another product from Merck/Pfizer join the class, which has shown strong glycemic and weight loss efficacy overall. Dr. Cefalu noted growing enthusiasm for the SGLT-2 inhibitor class from patients/providers in the field, which was matched by the amount of data on these agents presented at ADA 2017.
- Dr. Cefalu spoke about the data on sotagliflozin as an adjunct to insulin therapy in type 1 diabetes. He established that results from Lexicon’s inTandem1, inTandem2, and inTandem4 cumulatively support continued development of sotagliflozin. It is particularly exciting that the agent may be one to be considered in the future as an adjunct therapy in individuals with type 1 diabetes.
- In reviewing mixed results from the REMOVAL trial, Dr. Cefalu expressed his view that these findings shouldn’t and won’t meaningfully change clinical practice of using metformin off-label in type 1 diabetes. The study failed to meet its primary endpoint of mean carotid intima media thickness (cIMT), but did meet a tertiary endpoint of maximal cIMT. The significance of these findings on clinical markers aren’t really known as they represent surrogate markers of atherosclerosis. On the other hand, he emphasized that metformin promoted weight loss, reduced lipid levels, and modestly reduced daily insulin requirements, each of which contributes to the “glass half-full” perspective on REMOVAL. We found Dr. Cefalu’s commentary on this study reassuring. In concluding the ADA symposium on REMOVAL, Dr. Peter Rossing mentioned that the results do not support current treatment guidelines suggesting that metformin can improve glycemic control in patients with type 1 diabetes. However, metformin is arguably the most commonly-prescribed (off-label) adjunct therapy for type 1 right now, and we would hate to see this use drop off in a hasty reaction to REMOVAL, since many type 1 patients could still experience clinically-meaningful benefits from metformin therapy.
- Dr. Cefalu underscored how biosimilar insulins offer similar benefits to branded products and the advantage would be a lower price. “It was encouraging to see data on biosimilars being presented.” Given the growing controversy over soaring cost of insulin in the US, we definitely see an important niche for biosimilars to play on the market.
- Dr. Cefalu established that treating severe hypoglycemia outside a hospital setting is a substantial unmet need in diabetes, and then discussed the ADA 2017 presentation on Lilly’s phase 3 nasal glucagon. He described the clunky reconstitution process of current injectable glucagon, which leaves huge room for error. Nasal glucagon offers a more patient/caregiver-friendly solution, and Dr. Cefalu reviewed efficacy data as well as positive feedback from caregivers on ease-of-use and satisfaction.
- Dr. Cefalu captured the advantages of ITCA 650 over current GLP-1 agonist products by explaining how it circumvents the adherence issue (provides continuous, subcutaneous injection via an osmotic mini pump) and delays the need for other therapies. Two posters at ADA 2017 showed this delayed advancement to other diabetes drugs with ITCA 650 from analysis of the current clinical trial data. We’ve heard similar commentary from Intarcia CEO Mr. Kurt Graves, who underscored the added value that ITCA 650 could bring to the class by entirely avoiding the adherence issue that affects twice-daily, once-daily, and once-weekly injectable GLP-1 options. ITCA 650 is currently under FDA review, with a regulatory decision expected by December 2017.
Will Guidelines for Future Artificial Pancreas Approvals be Different?
Courtney Harper Lias, PhD (FDA, Silver Spring, MD)
FDA’s Dr. Courtney Lias proclaimed with an emphatic “Spoiler Alert!” that clinical trials are not chiefly responsible for slowing the commercialization of automated insulin delivery systems; rather, a lack of a framework for interoperability, and all that it entails, has slowed the field. We’re glad to see her continuing to hammer this message home, which we’ve heard from her at a number of conferences in the past year (e.g., ADA 2017, NIH Workshop, AADE 2016, ADA 2016). Number one on Dr. Lias’ list of things that bog down progress toward launch is contracting – she noted that some companies may have to work with three to four others to put together a closed loop system (e.g., CGM, pump, BGM), and the requisite effort put into determining and finalizing who is responsible for what in every scenario, what modifications need to be made in the future, postmarket responsibilities, and performance requirements are astronomical. In her experience, contracts can slow things down by months to years at a time: “I only have an impression, which is that there’s a vastly larger sum of time and money spent developing and maintaining contracts than spent dealing with us.” She’s under no illusion that we can expect for every company to develop or acquire their own sensor, pump, algorithm, and BGM (for sensor calibration, if necessary) – on the contrary, she would rather see the development of communication/interoperability specifications for automated insulin delivery components. Such a framework would make empirical design and testing – the process of developing a system and iterating through tweaks after small studies – a thing of the past. This kind of interoperability would enable safer, more nimble automated insulin delivery innovation, diminish regulatory and clinical study burden, and create a thriving ecosystem of component parts. In essence, devices must be optimized to work together, not in silos. The creation of transparent performance and communication specifications – something she asked for the community’s input on, perhaps with an eye on updating the 2012 AP guidance – “may allow for open development and open approval of automated insulin delivery systems. I can’t tell you how many submissions that would eliminate.” She later mentioned that FDA is working to facilitate open discussion toward solving these challenges – we look forward to this discussion moving to tangible specifics, as the vision and benefits seem obvious for all stakeholders. She concluded her talk by explaining the urgency for a mindset shift in artificial pancreas development: “Companies are struggling and peering over the edge of the cliff – there’s no market for pumps, and people are not using devices because of real resource challenges. We don’t want regulatory burden or contracts to be the reason they fall off the cliff. We need to bridge the gap and have resources be put to what matters the most.” So, in simple answer to her speaking charge: “Will guidelines for artificial pancreas approvals be different in the future? It has to be yes. We will make these changes because if we don’t, we won’t see these systems become available.” Dr. Lias, our hats go off to you, and we hope interoperability moves forward in a meaningful way. By the way, please vote for Dr. Lias, Beck, and the FDA AP team here – they deserve to win a Service to America Medal!
- Dr. Lias emphasized that interoperability standards would not mandate open system design, transmissions of proprietary data, or prevent secure data access, but could involve the specification of defined mandatory and optional input and output data elements. The upside of interoperability is undeniable, as it could expand and simplify collaboration, streamline commercialization following component updates for single-manufacturer systems (e.g., if Medtronic wanted to use a next-gen CGM for 670G), and effectively promote innovation.
- To give some examples, Dr. Lias said that the specifications CGM manufacturers currently use do not optimally enable interchangeable use because there is no way to know how different parameters of performance change across patient populations or device generations, and CGM developers don’t often think beyond MARD in understanding performance. Similarly, CGM manufacturers don’t currently consider how accurate a BGM needs to be for optimal performance – instead, they have to back-calculate, which creates a delay in selecting BGM partners (the threshold Dr. Lias frequently hears for BGM accuracy is “if it’s cleared,” but she’s the first to point out that there are sadly a lot of cleared meters that aren’t accurate).
- She also mentioned that not all pumps are created equal in terms of automated insulin delivery adaptability – some have existing suspension/predictive algorithms (how will external algorithms interact with this software?), and the fundamental properties of pumps (dosing precision, bolus delivery speed, etc.) are not well understood.
- Dr. Lias acknowledged that there are different challenges for unique paths to market. Systems can be developed fully within one company, making things relatively easy (e.g., MiniMed 670G, though it relies on a partnered Ascensia BGM); a pump company can buy an algorithm and license a CGM (e.g., Insulet, Tandem); an academic investigator can use a commercially available CGM and pump (e.g., Dr. Roman Hovorka’s Cambridge group); or an algorithm can make a new pump and license the CGM (e.g., Beta Bionics, Bigfoot). Within many of these paths, there are unique challenges, but each must nail down BGM, CGM, pump, post-market responsibilities, performance requirements, clinical investigators, right of reference, and device modifications/updates. It’s clear how a hiccup in one of these areas can severely delay progress!
- Solving the challenges laid out by Dr. Lias will streamline clinical evaluation of new devices. Doing so could eliminate the need for new studies using different CGMs, as well as the need for clinical evaluation of modular or updated automated insulin delivery systems. At the end of the day, a more comprehensive understanding across AID algorithms and how they interact with component devices will reduce the need for clinical data to determine safety. The FDA device division, since the 2012 guidance, has been open to clinical endpoints for these systems beyond A1c, including time in range and improved quality of life.
- “At the moment, Medtronic will be doing a huge post-market study, but I really don’t want years and years of postmarket studies to be the forever goal of all of the companies. The 1,000-patient, four-arm Medtronic study just began enrolling, is the biggest and most complicated run by the company to date (at least in diabetes), and won’t read out until 2021 according to ClinicalTrials.gov. While this study will be hugely informative (following just a three-month, single-arm pivotal trial powered for safety), particularly for payers, we’re glad to hear that not every company will be expected to pour millions of dollars into similar studies.
- In Q&A, Dr. Lias shared that her team, which regulates and evaluates the postmarket performance of BGM, CGM, sensor-enabled pumps, and automated insulin delivery devices is comprised of just 10 people! We knew FDA was under-resourced, but holy moly! Dr. Lias is very proud of her team, and rightfully so – they are doing a heroic job in a field that continues to move and innovate faster from a higher base.
- According to Dr. Lias, her team receives 20,000-30,000 adverse event reports per year for diabetes devices. They don’t go through each by hand, but have developed internal tools to help look for spikes in signals, after which they can look for patterns of underlying cause and reach out to manufacturers as they see fit.
- Dr. Lias opened her talk with measured enthusiasm: “670G is here, and we’ve seen great outcomes, but a patient is not a patient is not a patient. What works for one won’t always meet the needs of others.” To illustrate her point, she displayed a photo of two young boys, her sons, sitting side-by-side in a shopping cart at Sam’s Club. While the younger looks content and delighted to be doing as his big brother does, the older has an expression that screams “Mom, get me out of here.” The message of the adorable example is clear: People with diabetes need choices!
Questions and Answers
Q: Recently, most artificial pancreas teams have published a combined statement about guidelines and reporting methods (Maahs et al., Diabetes Care 2016)– would this be helpful and have an impact in your analysis?
A: Standardized ways of analyzing device results do help – we’ve been able to work with manufacturers ahead of time to find out how we would want to see data analyzed, so it does help to have communication, and standardization will help. Do I think it will speed up the process as much as some of these things I’ve talked about? No. It’s more a matter of saving a couple of weeks of work, vs. months to years.
Dr. Jay Skyler (University of Miami, FL): You mentioned a number of different components, but not insulin. They’re getting faster – do you think automated insulin delivery development teams will need to compare their pumps with newer, faster insulins separately?
A: If you understand how your algorithm reacts to certain things, sometimes you might be able to reduce the types of necessary evaluations. For example, a fewer number of subjects in a study looking at PK/PD profile of insulin in a pump, if you understand some of the underlying properties. More intentional design, it’s hard to do up front, but the more we understand about algorithms and devices, the more we’ll be able to respond to different developments.
Q: How many people actually review all of these systems? And do you have a post-market mechanism to monitor repeated problems? And third, a lot of the studies involve almost what I would call “professional people” who are in the trials, professional trial applicants who are so used to the products – is there an effort to limit that?
A: We do talk to companies about expanding the type of patients in trials, and we do try to get people who are naïve to CGM and pumps, so we do try to get at that. At the moment, Medtronic will be doing a huge post-market study, but I really don’t want years and years of post-market studies to be the forever goal of all of the companies. In my group, we regulate BGM, CGM, sensor enabled pumps, and automated insulin delivery devices, and we’re about 10 people who work very hard – I’m very proud of them. We also do post-market evaluation of devices. We get a very high volume, and sadly, diabetes is a dangerous disease, and there are a number of event reports. We get 20,000-30,000 adverse event reports per year for those devices. We’ve developed internal tools to help us look for spikes in signals, and look for the pattern or underlying cause. So, we do see information about things that go wrong – sometimes the reports are useful.
Q: Is there a way that patients on automated insulin delivery can give you direct feedback?
A: We do have the ability for people to call us, and for patients to send us reports of information. It’s called Med Watch.
Q: There are other medical devices – pacemakers, defibrillators – that I imagine to be as or more complex, but insulin pumps are patient-managed – is there a different level, stricter criteria of risk-benefit?
A: I don’t see that difference. Differences in devices are supposed to reflect the differences in the scenario. A surgeon puts in a pacemaker and the patient goes on his/her way, but people with diabetes, if they don’t have pumps, are at risk of severe hypoglycemia or long-term complications, so we try to titrate the level of scrutiny that’s appropriate for the risk. For type 1 and type 2 diabetes, you can tolerate a lot of risk in the device, because the baseline risk is so high. With a pacemaker or defibrillator, you don’t have all those companies working together. The problem here is the complexity of the system.
Q: What was the influence, positive or negative, of the so-called “hackers” of these devices?
A: One thing we learned from groups like that is the passion behind people who want to have better tools. We learn from them. When people really understand what they’re doing, really know what the algorithm is doing, there’s a little less risk. We do have some concern about people who have to have others set it up for them. We’re looking for a win-win solution – can patients get what they need safely? We’re trying to balance that, and it’s a difficult balance. We try to keep their perspective in mind.
Mr. Brandon Arbiter (Tidepool, San Francisco, CA): It’s so wonderful to see you at this conference and see the progress at FDA. One of my takeaways is that it sounds like FDA is not the thing slowing down development, but the cooperation between two to four companies that need to come together to produce one system. Any visibility into how much time in this system is spent behind closed doors arguing over contracts vs. how much time is actually the regulatory process?
A: You definitely would have to talk to the companies…I only have an impression, which is that there’s a vastly larger sum of time and money spent developing and maintaining contracts than spent dealing with us. The regulatory process right now is the way it is because of the way our framework of one company handling everything is working. If we had specifications, then we wouldn’t need this – each company could be held accountable individually, no need for contracts. Right now, regulatory is in the way because of the way the systems are being developed.
Dr. Satish Garg: What if down the road, oral drugs for type 2 got approved for type 1 diabetes, would that require additional studies for automated insulin delivery?
A: It’s hard to tell what studies would be necessary, a lot of it has to do with understanding. If the manufacturer knows that someone on this drug needs different precautions, that can be managed. The goal is to find most efficient path possible through good discussion and communication, and that’s the key to everything.
Plenary One: Is Artificial Pancreas the Future?
Hybrid Closed Loop Status & Practical Challenges in Implementation
Bruce Buckingham, MD (Stanford University, CA)
Dr. Bruce Buckingham kicked off the first Keystone plenary with a whirlwind overview of hybrid closed loop systems, reiterating that nighttime is the low hanging fruit and suggesting that integration into consumer devices “may be a giant that we just haven’t even seen yet.” On the former, he reminded attendees that in the DCCT, 55% of severe hypoglycemia occurred during sleep; in 65,000 days and nights of 670G wear (178 patient-years), there have been exactly zero severe hypoglycemic events in Auto Mode, when T1D Exchange data dictates that there would otherwise be at least 12. From a health economics standpoint, the CDC estimates that there are ~300,000 ER visits in adults each year for hypoglycemia – with an average cost of $1,161 per visit, hybrid closed loop systems could save the system quite a bit of money. With every system that’s been tested to date, Dr. Buckingham said, glucose values stay very close to target overnight, as there are few to no perturbations from food, exercise, stress, etc. Most payers have seen the value of the 670G (including Aetna, Cigna, Humana, UHC, Sutter Health), but Anthem Blue Cross Blue Shield has yet to offer coverage (Medtronic is reportedly confident they will give in). After bemoaning the all-too-common pain points of infusion sets/sites and proper CGM calibration technique – and pointing to Bigfoot, who just partnered with Abbott, as he proclaimed that it would be a huge plus to have a sensor in a system not requiring calibration – Dr. Buckingham turned to integration of closed loop systems into consumer devices (Apple, Android products). He was operating in purely speculative territory, but noted that Apple hired DIY automated insulin delivery app Loop developer Mr. Nate Racklyeft and one of Dr. Buckingham’s former fellows. Similarly, Google recently hired another two nurses who used to work with Dr. Buckingham. Of course, none of these individuals are allowed to speak about their work, but Dr. Buckingham suspects they may be working more diligently in diabetes. Of course, Apple announced on stage in June that the next version of Apple Watch will receive CGM data straight from Dexcom’s transmitter, and HealthKit will be updated this fall with basal/bolus doses. Meanwhile, Google (Verily) is developing next-gen bandage-like CGM with Dexcom, in addition to its Novartis and Sanofi (Onduo) partnerships (but no recent updates on the latter two). We wonder if either company has more in store in diabetes technology!
- Dr. Buckingham departed Keystone on Sunday at 5 am to be back in California to initiate a five-day AirBnb study of Insulet’s Omnipod Horizon closed loop system at 9 am. The study will enroll 6-12 year-olds and investigate use of Insulet’s system in an outpatient setting for the first time. In an inpatient feasibility study in this population (presented in an ADA poster), overall mean glucose was 157 mg/dl, with 70% time in range (70-180 mg/dl), 2% time <70 mg/dl, and 28% time >180 mg/dl – we wonder if these encouraging outcomes will translate to the AirBnb setting. Under the leadership of Dr. Buckingham’s disciple, Dr. Trang Ly, Insulet is cranking through clinical studies at a far faster clip than Tandem, Insulet, Beta Bionics, and others. We love seeing this commitment and Dr. Buckingham emphasized that the rubber really hits the road when systems move out of simulation modeling and into people.
Future Direction of Artificial Pancreas
Roy Beck, MD (Jaeb Center, Tampa, FL)
Jaeb Center’s Dr. Roy Beck gave a balanced overview of the commercial automated insulin delivery systems in development, noting that he uses Close Concerns’ AID competitive landscape to stay up to date on products/studies coming from Medtronic, Tandem, Bigfoot, Insulet, Diabeloop, Beta Bionics, Cellnovo, Animas, Cambridge, Roche, and Inreda – we’ll be updating this piece soon given this week’s Abbott/Bigfoot partnership (pivotal in 2018) and Beta Bionics’ delayed timing shared at FFL (pivotal studies to start in 2H18).
- Dr. Beck was impressed with a recent Insulet Omnipod Horizon exercise study (n=12 adults), noting strong 85% time in range and mean glucose of 136 mg/dl. For this particular study, time below 70 mg/dl was just 1.5% and time in range overnight was a whopping 94%. Of course, these results look better than prior studies since they occurred in the exercise setting, but nonetheless is shows Insulet is challenging its algorithm in important settings. (We also saw this topline data at the company’s product theater at ADA.)
- On a more somber note, Dr. Beck noted that the Animas’ artificial pancreas program is temporarily on hold “until strategic options for the company have been determined.” He considers the Hypoglycemia-Hyperglycemia Minimizer product with Dexcom quite “promising” (it’s been in development for over five years) and hopes it will eventually push through. We’ll listen for updates on J&J’s diabetes technology business on next week’s 2Q17 earnings call.
- Dr. Beck claimed that the greatest barrier to closed loop systems is insulin delivery, citing the need for improved rapidity of prandial insulin onset. Current insulin kinetics make meal announcement and manual insulin bolusing necessary for optimal time-in-range. Dr. Beck noted that, to date, companies developing faster injected insulins have achieved only modest outcomes that are still far from what is needed. Indeed, he highlighted Novo Nordisk’s upcoming FIasp (under FDA review, with a decision expected in 3Q17), comparing the PK/PD to ultra-fast Afrezza and current rapid-acting analogs – on that scale, FIasp basically overlapped with current analogs and looked far slower than Afrezza. He believes that the “solution” may not be possible with subcutaneous insulin delivery; rather, intraperitoneal delivery has more potential. With IP delivery, the onset and delivery of insulin are far more rapid, as is the offset, reducing the likelihood of hypoglycemia. While IP delivery is certainly not without its risks and extreme expense at this point (detailed at length at April’s JDRF-Helmsley Charitable Trust Closed Loop Intra-Peritoneal Infusion Workshop), Dr. Beck discussed the demonstrated benefits ranging from tighter glycemic control, to restoration of glucagon response, to higher portal plasma insulin levels. Quoting Montpellier’s Dr. Eric Renard, Dr. Beck observed that patients who try IP delivery never want to go back to subcutaneous. Still, he cautioned that there is a ton of work to be done in the field, demanding some serious research commitment in both time and dollars.
- To wrap up the discussion, Dr. Beck highlighted what he considers to be the future directions of closed loop systems: He finds sensors to be “pretty good already” but predicts stronger accuracy during times of rapid change (key for systems responding to both post-meal and exercise changes), longer wear duration, less calibration, reduced lag time, miniaturization, and implantable models on the horizon. Other future improvements include utilization of machine learning to personalize algorithms (we see very high potential here), multi-hormone systems with pramlintide, and multiple sensor inputs (such as exercise).
Plenary Two: Recognition and/or Management of Prediabetes
Can Lifestyle Alone Do It?
Richard Kahn, PhD (UNC, Chapel Hill, NC)
Dr. Richard Kahn pointed to the difficulty in preventing diabetes by lifestyle intervention: No clinical trial has shown the magnitude and long-term maintenance of weight loss needed to achieve clinically-meaningful health benefits, and results from RCTs rarely translate to the real world. Community programs have not replicated the results of RCTs, and there’s limited evidence on how delaying diabetes onset prevents adverse outcomes. To-date, the most successful program aimed at diabetes prevention according to Dr. Kahn has been the Diabetes Prevention Program (DPP), in which participants achieved a 58% reduction in incidence after 2.8 years, due almost entirely to weight loss. However, he pointed out that this doesn’t mean we can truly “prevent” diabetes, since if the DPP were ended years later, the proportion of cases prevented would be far less. Indeed, longer-term follow-up out to 15 years found incidence reduced by a smaller 27%, and the DPP investigators reported that lifestyle intervention only delayed the onset of diabetes by a mean four years. Moreover, Dr. Kahn explained that in the first year of the DPP, the lifestyle arm achieved a mean weight loss of ~7.4%, and from that low point, weight regain occurred throughout the trial even while the intervention was still in full-force. Dr. Kahn displayed similar data from other lifestyle trials, ultimately emphasizing that weight loss is incredibly difficult to maintain, due to the seeming imperative of the human body to return to its highest-ever weight. Dr. Kahn also mentioned that the lifestyle intervention in the DPP consisted of many strategies to help participants lose weight, such as frequent coaching, free meal replacements and health club memberships, frequent contact with a variety of support staff, personal trainers and even other material incentives, all of which are unrealistic for real world programs due to cost and limited resources. He presented a host of evidence to show that community programs have not come close to obtaining the weight loss reported in the DPP. He further argued that since no trial has shown any profound clinical benefit, we should not expect such benefits from real-world interventions that achieve lower levels of weight loss. Finally, he showed data to suggest that one has to lose ~4%-5% of starting body weight and keep it off for many years in order to see a delay in diabetes onset, for whatever that delay is worth (in his view, there is no clinical benefit). Dr. Kahn maintained that we should still encourage weight loss, because there are a small minority of individuals (~5%) who can lose a substantial amount of weight and keep it off. Unfortunately, the field currently lacks ways to identify these ideal candidates for lifestyle intervention. There’s no arguing that the massive prediabetes epidemic is intimidating (86 million people in the US alone), and that large-scale diabetes prevention is a tall task, but we maintain a more optimistic view on lifestyle intervention. Medicare is slated to begin DPP reimbursement in 2018, and the AMA has called upon private payers to cover the lifestyle program as well. The CDC is beginning to recognize virtual DPP platforms, which will make the program more scalable and bring down cost. We do think it’s important to note the value in delaying new-onset diabetes for any number of years – this lowers cost on the healthcare system (and research has projected cost-savings with a DPP-like lifestyle intervention).
William Cefalu, MD (ADA, Arlington, VA)
ADA’s Chief Scientific, Medical, and Mission Officer Dr. William Cefalu spoke to the potential of metformin in diabetes prevention. He listed a number of unresolved issues in our understanding of prediabetes that should be considered as we move to implement largescale prevention efforts. To anchor his argument in favor of metformin, he pointed to 15-year results from the DPPOS (Diabetes Prevention Program Outcomes Study), showing that when A1c is used to define prediabetes rather than glucose metrics, metformin and lifestyle intervention appear to be equally effective, lowering type 2 diabetes incidence by 36% and 26%, respectively. In contrast, the fasting plasma glucose-based diagnosis showed lifestyle intervention to be more effective, reducing incidence by 27% after 15 years vs. 18% with metformin, but accumulating evidence suggests that A1c may be a better catch-all for people at high risk for new-onset type 2 diabetes. Dr. Cefalu described metformin as a cost-effective solution as well, echoing Dr. John Buse’s remarks from WCPD 2016 – it would cost a little over $4 billion to treat the entire US prediabetes population with metformin vs. >$1.2 trillion to treat this group with high-dose liraglutide (Novo Nordisk’s Saxenda) and ~$1.4 trillion to treat this group with intensive lifestyle intervention as provided by the DPP (although lower-cost iterations of the program are also proving effective). He concluded that we should invest in both lifestyle modification strategies and metformin as diabetes prevention tactics. He also reviewed SCALE data on Saxenda and ACT NOW data on TZD pioglitazone for diabetes prevention, explaining that while both agents effectively delayed type 2 diabetes onset, each therapy came with side-effects that should be carefully considered in making treatment decisions for the individual patient. Pioglitazone, for example, was associated with weight gain and edema, which could be counterproductive to the goal of improving overall health outcomes. In concluding his presentation, Dr. Cefalu suggested that there is little disagreement in the diabetes field that metformin should be used in some stage of prediabetes, alongside strategies to control other risk factors like lipids, blood pressure, and smoking. This was music to our ears, and we can’t wait to see this take root in real-world clinical practice, with HCPs screening for prediabetes and prescribing metformin where indicated. That said, unresolved issues remain in disseminating pharmacotherapy far-and-wide for diabetes prevention. Dr. Cefalu elaborated on a few:
- How should we define prediabetes? Recent evidence favors A1c over fasting plasma glucose or an oral glucose tolerance test, but until there is standardization of diagnosis, it may be difficult to get prediabetes recognized as a disease so that FDA and other regulatory bodies can approve therapies for this indication. Dr. Cefalu also raised the question of how to efficiently screen for prediabetes in under-resourced areas.
- Can pharmacological agents maintain effectiveness over the long term? In general, the timescale of RCTs is an issue in prevention research – these studies require very long-term follow-up to determine if any given intervention is truly preventing disease onset. On the other hand, there is certainly value even in delaying diabetes onset, given the lower rates of micro and macrovascular complications that result.
- Is our goal in prevention to treat hyperglycemia, or to alter the natural history of disease? The latter calls for pharmacotherapies that intercept the process of beta cell dysfunction (which is a commonly-cited argument in favor of TZDs).
- How do we implement lifestyle interventions over long-term periods? Dr. Cefalu referred to Dr. Richard Kahn’s presentation (coverage below), highlighting that we need to help patients lose weight and keep it off in order for lifestyle strategies like those in the DPP to be truly effective.
Is Prediabetes a Cardiovascular Equivalent?
John Buse, MD (UNC, Chapel Hill, NC)
Dr. John Buse presented a key argument for the use of A1c criteria to define prediabetes (5.7%-6.4%) rather than fasting plasma glucose (95-125 mg/dl) or an oral 2-hour glucose tolerance test (140-199 mg/dl): Of these three metrics, A1c is the strongest predictor of CV disease. According to one meta-analysis, there was no association between fasting plasma glucose in the 95-125 mg/dl range and clinical complications, or between 2-hour glucose in the 140-199 mg/dl range and clinical complications, but there was a significant correlation between A1c in the 5.7%-6.4% range and CV events. More specifically, this A1c-based prediabetes diagnosis led to a 2x risk of CV disease. All-cause mortality was also significantly increased for people with an A1c in the prediabetes range vs. those with an A1c <5.7%. Dr. Buse underscored that choosing the right screening tool will be essential in population-level diabetes prevention – and he added that A1c seems best. The purpose of identifying prediabetes is to delay or prevent long-term diabetes complications, especially CV complications, given that CV disease is the leading cause of death for a diabetes patient population. We agree wholeheartedly with this sentiment, since the growing emphasis on prediabetes is not merely to predict type 2 onset, but to allow for earlier intervention and improved health outcomes. CV risk reduction is becoming a more central, critical component of diabetes management, and this extends to prediabetes management. That fasting plasma glucose and 2-hour glucose don’t show a significant correlation with future CV events makes them less useful diagnostic tools in a clinical context. Dr. Buse highlighted that A1c is most appropriate in real-world clinical settings because it can be done in a non-fasting state. It also catches people at risk for diabetes in their 20s and 30s, earlier in the history of disease progression: Individuals in this age group aren’t necessarily thinking about chronic disease prevention, but if they schedule a doctor’s visit for a broken ankle, they’ll likely be more amenable to an A1c screen vs. a fasting glucose test. Moreover, Dr. Buse mentioned that 2-hour glucose tolerance tests are rather cumbersome for most medical settings. His talk (in conjunction with Dr. William Cefalu’s and Dr. Richard Kahn’s, also covered in this report) revealed lingering questions that may be standing in the way of maximally effective diabetes prevention efforts. At the top of this list: the field needs consensus on a prediabetes definition, and we hope to see agreement on a diagnosis that correlates with outcomes. We also imagine this consensus would further initiatives to get FDA to recognize prediabetes as a disease, so that therapies like metformin can be indicated for prediabetes and prescribed with an aim toward prevention.
Why Do We Not Have an Immune Intervention for Type 1 Diabetes?
Jay Skyler, MD (University of Miami, FL)
Dr. Jay Skyler issued a compelling call for an aggressive combination therapy approach for the prevention of type 1 diabetes. Specifically, he proposed that a successful approach might combine preservation of beta cell health with simultaneous action on multiple components of the immune system: anti-inflammatory therapy targeting innate immunity, immunomodulatory therapy targeting adaptive immunity, therapy to drive regulatory immunity, and antigen-based therapy directly regulating beta cell immunity. To set the stage, Dr. Skyler gave an overview of the rather pessimistic history of type 1 diabetes prevention trials: the literature on primary prevention (preventing disease onset), secondary prevention (halting disease progression after the onset of autoimmunity), and tertiary prevention (arresting the progression of disease symptoms) all shows a very limited impact for the majority of type 1 prevention interventions. Why have such a wide variety of prevention approaches – from nicotinamide to oral insulin to GAD vaccine – all failed to show a meaningful impact? Dr. Skyler suggested that the answer to this question lies in the complexity of type 1 diabetes pathogenesis. He argued that so many biochemical pathways contribute to this process that salvaging the beta cell will require intervention in multiple targets simultaneously, hence his combination therapy proposal. Since Dr. Skyler’s first espousal of this view in a 2015 Diabetes Care article, two trials have been initiated to investigate the efficacy of this aggressive combination therapy approach. The first is Dr. Skyler’s own DIPIT (Diabetes Islet Preservation Immune Treatment) trial, which utilizes anti-TNF as an anti-inflammatory agent, ATG (anti-thymocyte globulin) as an immunomodulator, interleukin-2 and GCSF (granulocyte colony stimulating factor) to drive regulatory T-cell action, and the GLP-1 agonist exenatide to preserve beta cell health. Similarly, a study led by the University of Alberta’s Dr. James Shapiro – posted on ClinicalTrials.gov only last month – utilizes etanercept and anakinra as anti-inflammatory agents, alemtuzumab as an immunomodulator, plerixafor as a regulatory immune agent (which mobilizes stem cells for beta cell repair), and the GLP-1 agonist liraglutide to preserve beta cell health. While both these investigations pique our interest, as always with type 1 cures, we’re careful to manage our expectations. Prevention studies need to be quite long to show convincing efficacy, so this combination therapy cocktail is still far from being readily available. Moreover, “cure” is loosely-defined in the type 1 context and means different things to different people. For some, independence from daily insulin or prevention of diabetes complications (including hypoglycemia) would represent a functional cure, while others view a cure more rigorously as the prevention of beta cell destruction.
John Buse, MD (UNC, Chapel Hill, NC); Jay Skyler, MD (University of Miami, FL); William Cefalu, MD (ADA, Arlington, VA); Richard Kahn, MD (UNC, Chapel Hill, NC); Pamela Thornton, PhD (NIDDK, Bethesda, MD)
Q: Suppose we found a magic cocktail that works for a year or two – is it possible to protect that result 20 or 25 years down the road? Doesn’t this impair our ability to make a decision on the efficacy of any combination until a long time passes by?
Dr. Skyler: Certainly. We can’t wait 20 or 25 years, but if I could preserve beta cell function and prevent loss of function for two-five years, I’d be thrilled. The DCCT demonstrated less retinopathy, less kidney disease, less hypoglycemia, and improved quality of life. I would take a short-term effect … and I probably won’t live long enough to see a 25-year effect [editor’s note – we certainly do think Dr. Skyler would be likely to live longer than this].
Comment: Is there potential for other issues like neoplasia, or other issues of a degenerative nature that we’ll never be able to predict in a young population?
Dr. Skyler: We do have extensive experience with transplants. When you’re giving multiple different immunosuppressant drugs, the immunosuppressant drug ATG is used for two days, and the other short-term drug is GCSF and that’s only used for a couple of months. Anti-TNF drugs are the only immunosuppressant used chronically – we now have 10 years of experience with that in rheumatoid arthritis with low incidence of lymphomas. GLP-1 agonists have now been on the market for 12 years with no problem. If you choose carefully, you won’t run into increased risk and you will have potential increased benefit.
Dr. Satish Garg: Would giving statins in clinical practice make diabetes worse?
Dr. Buse: The risk is on the glycemic end, and there is an increase in the literature hypothesizing how this happens. However, that risk is so small compared to the CV benefit that I wouldn’t think twice about it. I do think that the important reason to think about this statin-associated risk of developing diabetes is that there are some people who are using statins in 20-year olds as a panacea for long life, and I do think that’s a setting where potential harm may exceed benefit.
Q: I’m a facilitator for the NDPP, so I was a little bit disheartened by the presentation from Dr. Kahn today. What I try to tell my patients is that, if I remember correctly, the stats from the original study that launched the NDPP were that only 50% of the participants met weight loss goals but 75% met activity goals. I tell people that if they are able to do the physical activity five days/week they can change insulin resistance one day at a time. I’m wondering what your thoughts are on focusing on activity rather than weight loss?
Dr. Kahn: We don’t have any trials that looked at exercise by itself, and the DPP said that 60%-75% of effect was due to weight loss and not exercise. There are small studies showing that exercise by itself helps reduce CV events, but what is the right exercise prescription – walking, running?
Comment: It says moderate intensity exercise, 150 minutes a week.
Dr. Kahn: If that was the prescription and people carried that out, would we see change in outcomes? I don’t know. It probably wouldn’t cause harm. But we don’t know what the benefits are.
Dr. Buse: David Marrero presented at ADA one year about the exercise question – there wasn’t evidence for an independent effect of exercise on diabetes development beyond its effect on weight loss. The weight loss drove the association with the incidence of diabetes.
Comment: My understanding was the opposite, because the original study showed that 75% of participants met the activity goal, but only 50% met the weight goal, so I was assuming that physical activity was the driving factor. And we know that physical activity can reduce insulin resistance.
Dr. Buse: My recollection is the opposite. As I said, the data is strongest for exercise not to have an effect on weight loss promotion, but to reduce the possibility of weight regain.
Dr. Kahn: You had 100 people, and some of them had a delay in onset, but most of them did not. Meeting goal does not necessarily mean they’re in the positive group. As John pointed out, people who lost weight were in the positive group. If you had met the exercise goal but now you have weight loss, they weren’t in positive group for diabetes prevention. There are small studies that suggest that exercise is helpful for CV disease independently of weight loss. Diabetes or no diabetes, CV disease is the outcome and exercise may well have a benefit.
Q: Staying on this question, the 4.5% loss of baseline body weight could benefit prevention efforts. Is that what you suggest?
Dr. Kahn: If you want to have a material effect on outcomes, you’ve got to maintain the population at 4% weight loss for 20 years – that means that out of 100 people who do that, there might be 10 people who benefit.
Comment: What if losing 4% body weight still keeps them in the obesity condition?
Dr. Kahn: That’s right. It was independent of obesity. Participants had an average BMI of 32-33 kg/m2, so you’re not going to bring those people down to 26 kg/m2. You’re just going to reduce it.
Dr. Skyler: What if they could get 20% weight loss and it’s sustained?
Dr. Kahn: What if I win the lottery? It happens.
Dr. Buse: That’s bariatric surgery level of weight loss – for which there is some suggestion of benefit, but it’s not the perfect solution.
Q: We’ve been getting a lot more referrals for patients who come in with hyperinsulinemia. They aren’t feeling well, PCPs are seeing elevated insulin levels, and they have A1c’s around 5.6%. I want to confirm that we’re doing the right thing. I was always told that metformin was okay for diagnosed PCOS and for A1c >6%, but now I’m seeing, with new ADA guidelines, that 5.7% is okay? The one person in particular that I’m thinking of is one whose mother I had just taken care of after open heart surgery. Her daughter comes in saying she has hyperinsulinemia and I almost feel after hearing this presentation that I should be much more aggressive with her, and instead of saying diet & exercise, I should give her metformin. What do you think?
Dr. Buse: This situation is emblematic of the problem with our healthcare system: some people are getting way too much healthcare, and others not getting enough. There is no evidence-based interpretation of her status. Insulin level is not a nationally standardized measure, so it’s hard to interpret. The normal range for insulin is so big and so dependent on what you ate, your activity, and the time of day that I would not feel inclined to do anything special for that person. But I would support them in pursuit of healthful lifestyle – if they believe it, they should go for it.
Dr. Cefalu: I agree. What if that patient came in and was obese and you didn’t have a insulin level? You’re probably going to do the same thing. I would get aggressive with diet and exercise and make your determination based on blood glucose and BMI.
Dr. Buse: But also pay attention to CV risk factors – for example, if they do have hypertension their 10-year risk is much higher.
Dr. Garg: We are talking about type 2 diabetes in this session, but let’s change the focus for a minute to type 1. We know young children are developing overweight and obesity. Does that predict or prevent type 1 diabetes? I know there was some data in past literature. T1D exchange data shows 67% of patients with type 1 diabetes have overweight or obesity.
Dr. Kahn: My knowledge of the literature suggests no relationship between obesity and type 1 onset at any age.
Dr. Skyler: There’s nothing about obesity that prevents an autoimmune reaction, so you’re still going to get that. We see this in teenagers a lot – they have type 1 plus type 2 because they really are getting enough of the features of type 2 as well, and people need to be concerned about that. I call it “type 1+2” when I see that circumstance.
Dr. Buse: I do remember a paper that suggested that if you have antibodies and are at risk of developing diabetes, and are also obese or overweight, then perhaps you develop diabetes earlier. If you had bariatric surgery when you’re an 18 year-old with obesity, could you delay onset of type 1 diabetes? I suspect you could.
Dr. Skyler: You could delay the type 2 component but you won’t stop the type 1 component.
Dr. Kahn: The critical issue is what does delay get you? In type 2, it doesn’t get you much at all. In type 1, there is some evidence that in the normal lifespan of humans, if you have type 1 diabetes, the longer you postpone getting the disease, the better you do – just by postponing it.
Dr. Skyler: Yes, that’s true. In reference to too many journals, stick to journals with impact factors of 11 or more. Will got Diabetes Care up to 11.9 – that’s really damn good.
Dr. Cefalu: If a person has type 1 diabetes and obesity, they have insulin resistance. What about adjunctive therapies? The only study is REMOVAL and that failed to show any glycemic effect of metformin on top of insulin, only effects on LDL cholesterol and weight, so maybe it supports CV risk factors but doesn’t help resistance.
Dr. Skyler: Metformin has basically no effect.
Dr. Buse: You could argue that pioglitazone CVOTs show some benefit, and rosiglitazone has an equivalent effect on improving insulin resistance. I don’t think your insulin level is a great predictor of CV risk and attacking it specifically may not be pertinent.
Dr. Skyler: I don’t even measure it. There have been a few attempts with metformin and a meta-analysis a few years ago.
Dr. Buse: Sometimes I measure c-peptide.
Dr. Garg: We’ve seen this story going back 20 years with the type 1 diabetes prevention trial DPT-1 and oral insulin – are they getting trapped again into another large clinical trial?
Dr. Skyler: If you go by what the editors want us to say, then oral insulin has not worked to prevent type 1 diabetes, period. I would agree, and we’re fighting with both the editors and the publications committee because there are others who want to say that’s only with this dose and this population, and we ought to do more. I’m sick of it.
Dr. Buse: There are other oral insulin studies ongoing, right? Look at all of them cumulatively.
Dr. Skyler: The only other one is the FRIDA study in Germany, which is using a much higher dose of 67 mg of oral insulin in infants who have high genetic risk, so it’s a totally different population and you might actually have to be doing it earlier on to have high effect.
Dr. Buse: And you might need 67 mg. But with all studies together, you can analyze them in a systematic way.
Dr. Skyler: To enroll 372 people in the DPT-1 study we screened 250,000 people and got two negative answers… I’ve had enough of it.
Dr. Garg: Well, thank you for doing an excellent job.
Dr. Thornton: There is no one magic bullet, but I have a follow-up question on the DPP about sustaining weight loss and preventing weight regain. What are your thoughts on changing the model of intervention dose or the intensity at a later period when we know we’re going to see that regain?
Dr. Kahn: My thoughts are that the weight loss studies, with the possible exception of bariatric surgery and long-term liraglutide, have been unsuccessful. What we do have are two very small studies to see if, perhaps, it’s better to prevent obesity from the get-go. The body tries to defend the highest weight it’s ever been and wants to get back there, but what if you start low and push an intervention with no weight gain after age two when the vast majority are not overweight or obese? Would that be easier, cheaper, and more effective? We don’t have any good long intervention studies and I think that’s where the money is.
Dr. Cefalu: But I think the question is a good one, in that intensive lifestyle intervention has an initial impact and maybe doing it again after a three-four year delay would have an impact.
Dr. Kahn: But that intervention was impressively expensive, and nearly impossible to carry out in the real world.
Dr. Buse: By its nature, this is crazy expensive. We need to work on the built environment, or the total environment. I remember a study on a Native American reservation with very high incidence of diabetes among children, and they just moved where the school bus dropped off children to a farther parking lot. Over a year they saw some amazing 50% reduction of new-onset cases of diabetes. If we created an environment that was less obesogenic and diabetogenic, that would have the potential to provide benefit. Dieticians have a shot at making things better, but doctors? Forget it. We’ll never solve this problem.
Dr. Skyler: You’re sitting in the state with the lowest frequency of diabetes and obesity. People here are active and exercising, and they’re maintaining those metrics.
Plenary Three: Diabetes Care Standards
ADA and EASD Guidelines for Diabetes Care
Simon Heller, MD (University of Sheffield, UK)
Through a review of ADA/EASD guidelines, Dr. Simon Heller concluded that written guidance is failing at its ultimate goal of helping people with diabetes reach their glycemic targets, although it’s a useful summary of the state of the field. Dr. Heller set the stage by describing the evolution of the ADA/EASD guidelines. The 2006 ADA/EASD Diabetes Treatment Algorithm recommended metformin as first-line therapy with later intensification using insulin or sulfonylureas – in 2009, second-line therapy options were updated to also include then “less well-validated therapies” like TZDs and GLP-1 agonists. In 2012, ADA/EASD pivoted from treatment algorithms to position statements, given the increasing array of available diabetes treatments. The 2012 ADA/EASD Position Statement outlined the risks/benefits of the major diabetes drug classes available at the time (metformin, insulin, sulfonylureas, TZDs, GLP-1 agonists, and DPP-4 inhibitors), emphasizing a “patient-centered approach” to decide which therapy would be most beneficial to an individual person, as diabetes is too complex and heterogeneous to be simplified into a universal algorithm. The Position Statement was updated in 2015, most notably to include SGLT-2 inhibitors and to recommend basal insulin/GLP-1 agonist combination therapy as an alternative to MDI. Dr. Heller surmised that the ADA/EASD’s guidance provides a comprehensive, up-to-date, and patient-centered summary of the landscape of type 2 diabetes treatment but does a poor job at actually producing improved outcomes for people with diabetes. Indeed, despite these many iterations of ADA/EASD guidance, people with diabetes are not doing much better today than they were previously, with 44% of type 2 diabetes patients at A1c goal <7% in 1999 and only 52% in 2010 – disheartening statistics, particularly considering the multitude of new diabetes therapies that have been developed alongside these more refined diabetes treatment algorithms. Dr. Heller speculated that this unfortunate trend may be due to the fact that most people with type 2 diabetes around the world are managed by busy primary care teams who may not have read the ADA/EASD guidance (or any of the multitude of other similar guidelines from other professional societies). He closed with a call for greater education of healthcare providers, particularly those in primary care. Many KOLs appear to agree – distilling the complexity and heterogeneity of diabetes management into an easily digestible form for busy PCPs is a daunting challenge, but a sorely needed task for educating the next generation of providers (who will encounter diabetes at an ever-increasing pace).
Are AACE Guidelines Too Strict?
George Grunberger, MD (Grunberger Diabetes Institute, Bloomfield Hills, MI)
The highly-esteemed Dr. George Grunberger discussed the evolution of AACE guidelines leading up to their present emphasis on individualization of glycemic goals. He advocated strongly for earlier diagnosis and intervention to avoid later complications of diabetes. In 2007, 567 evidence-based references were compiled into AACE guidelines that recommended an A1c goal as close to 6.5% (“normal”) as possible. The treatment algorithm divided patients into three groups according to starting A1c – 6.5%-7.5%, 7.6%-9.0%, or >9.0% –recommending more aggressive approaches for those with weaker glycemic control at time of diagnosis. In 2009, AACE added a caveat that the 6.5% A1c goal “may not apply to all patients,” and the 2013 algorithm added recommendations for weight management, lifestyle modifications, and consideration of CV risk factors. The most recent AACE guidelines feature further additions: the individualization of glucose targets taking life expectancy, disease duration, complications, and comorbidities into account; a goal of near-normal or normal A1c in recent-onset cases with no clinically-significant CV disease (if it can be safely achieved); and a less stringent 7%-8% A1c goal in patients with a history of severe hypoglycemia, limited life expectancy, renal or macrovascular disease, or longstanding diabetes in which they haven’t achieved glycemic goals. Moreover, the new 2017 treatment algorithm lists 14 principles, including personalization of both A1c targets and choice of therapies. Dr. Grunberger called attention to the growing importance of individualization – another new AACE guideline recommends target A1c ≤6.5% for patients without concurrent serious illness and at low hypoglycemic risk, but >6.5% for those with serious illness and hypoglycemia risk. Dr. Grunberger acknowledged that the ADA’s 2017 Standards of Care recommend <7% as a reasonable base A1c goal for non-pregnant adults, but defended the more stringent <6.5% as not too strict, especially for new-onset cases. Even patients with prediabetes, he explained, face increased risk for CV events, and diabetes complications progressively worsen in parallel to glycemic control, even if an individual hasn’t yet reached the A1c requirement for an official diabetes diagnosis. The DECODE study (n>22,000) found that 2-hour post-load glucose levels were associated with a linear increase in hazard ratio for all-cause mortality, while the Diabetes Prevention Program (DPP) investigation found diabetic retinopathy in ~8% of people with impaired glucose tolerance. Dr. Grunberger used this evidence to make an extremely compelling case for earlier diagnosis/intervention, and for more aggressive glucose-lowering early in the course of disease.
What is Wrong with Guidelines?
Jay Skyler, MD (University of Miami, FL)
What’s wrong with current diabetes treatment guidelines? According to Dr. Jay Skyler, an under-emphasis on lifestyle intervention, an over-emphasis on metformin, and insufficient differentiation between second-line therapies. In 1999, 44% of type 2 diabetes patients were at an A1c target <7%. By 2010, that number had grown only modestly, to 52%, despite advanced therapeutic options (40 new diabetes drugs since 1995) and evolving treatment guidelines. Moreover, Dr. Skyler shared that only 19% of patients between 2007-2010 achieved targets for A1c, blood pressure, and LDL cholesterol simultaneously. Clearly, there is much room for improvement in diabetes care, and that needs to start with better guidelines – we know all too well that busy healthcare providers (PCPs and endos alike) turn to professional treatment algorithms like the ADA’s Standards of Care to guide their practice, and it’s thus important for these algorithms to keep up with the latest clinical research. Dr. Skyler praised the ADA’s 2017 Standards of Care and the Canadian Diabetes Association guidelines for swiftly recommending GLP-1 agonist liraglutide (Novo Nordisk’s Victoza) and SGLT-2 inhibitor empagliflozin (Lilly/BI’s Jardiance) to diabetes patients facing high CV risk after the publication of LEADER and EMPA-REG OUTCOME. He argued that this is exactly the approach that guidelines should take, focusing on timely evidence and important clinical outcomes to rank the available treatment options, rather than listing six drug classes on one horizontal line for consideration after metformin (sulfonylureas, TZDs, DPP-4 inhibitors, SGLT-2 inhibitors, GLP-1 agonists, and basal insulin – as was the case in the ADA’s 2015 Standards of Care). Ideally, EMPA-REG OUTCOME data would have influenced algorithms even sooner, and CV effects would have been an even bigger factor in guidelines even earlier, but we’re glad to see these changes to match the growing emphasis on cardioprotection in the diabetes field. Dr. Skyler also spoke very favorably about the ADA’s and CDA’s recent emphasis on lifestyle intervention at all stages of diabetes management, simultaneous to any pharmacotherapy regimen. “The most crucial message I will tell you today,” he claimed, “is that lifestyle modification has to be the basis of all therapy. We do not put enough attention on lifestyle.” He discussed anecdotal cases in which patients prescribed lifestyle/metformin attribute all their glycemic and weight loss success to metformin, when in reality, healthy diet and exercise play a significant role. He went on to describe metformin as possibly “overrated,” and encouraged providers to support their patients in lifestyle modification at all stages of the disease. To drive this point home on the health benefits to lifestyle change, Dr. Skyler reminded everyone that UKPDS participants underwent intensive lifestyle intervention prior to randomization, and achieved a mean ~5 kg (~11 lbs) weight loss as well as ~2% A1c decline from a baseline 9% after three-six months.
- Dr. Skyler criticized the American College of Physician (ACP) guidelines for the oral pharmacological treatment of type 2 diabetes, arguing that the 2017 iteration omits crucial CVOT evidence. This was a most-welcome critique, in our view. A number of thought leaders appeared to be uncomfortable with the 2017 revision when it was released in January, and we’re happy to hear from a well-respected thought leader that putting sulfonylureas and SGLT-2 inhibitors on equal footing is no longer acceptable, when there is compelling clinical information showing that SGLT-2 inhibitors can reduce a patient’s risk for CV death, effectively saving lives. Notably, sulfonylureas can cause CV harm, plus hypoglycemia, weight gain, and beta cell burnout, and we think it is quite negative for the field that the level of acceptability is still so high for this class, which could not come close to being approved today, in our view.
- Dr. Skyler warned against relaxing A1c targets for older patients with diabetes – we were so happy to hear this since we worry about a “slippery slope” associated with such a recommendation. The ADA 2017 Standards of Care suggest a less stringent A1c goal for patients with limited life expectancy, but Dr. Skyler took issue with this recommendation: As we have questioned a number of times, what exactly does “limited life expectancy” mean? He alluded to 80-year-olds going skiing and mountain climbing, explaining how it doesn’t make sense – nor is it good diabetes practice – to determine glycemic control based solely on a patient’s age. “Let’s be careful where we decide to relax the goals,” he remarked, and we couldn’t agree more with this sentiment. While some have argued that elderly patients should aim for A1c >7% due to heightened hypoglycemia risk and frailty, we believe that for many patients, hypoglycemia risk can be managed with CGM, strong patient education, and other diabetes management support tools. No one, regardless of age, should be asked to compromise glucose control when there are strategies available to balance hypoglycemia risk (we particularly see a lot of untapped potential for CGM in the older patient population), and we’d love to see this language altered in the Standards of Care and other professional guidelines. We would also very much like to see more research on this front.
John Buse, MD (UNC, Chapel Hill, NC); William Cefalu, MD (ADA, Arlington, VA); Simon Heller, MD (University of Sheffield, UK); George Grunberger, MD (Grunberger Diabetes Institute, Bloomfield Hills, MI); Guillermo Umpierrez, MD (Emory University, Atlanta, GA); Jay Skyler, MD (University of Miami, FL)
Dr. Richard Kahn (UNC, Chapel Hill, NC): Clinical trials need to be replicated before we believe them. So, going back to the UKPDS and the ~2% A1c drop with lifestyle intervention prior to randomization, has that ever been replicated? What did that lifestyle intervention actually entail?
Dr. Skyler: I can only tell you what I’ve heard. Drs. Robert Turner and David Matthews have talked about this, and have mentioned that participants were seeing a nutritionist and nurse on a regular basis. They also mentioned that participants were working hard. I asked how they got participants to stick to a diet. Their response: well, these were newly-diagnosed individuals, so they knew they had to pay attention.
Dr. Buse: I remember finding the drop pretty extraordinary and looking it up. I don’t think this has ever been replicated.
Dr. Skyler: But the ~5 kg weight loss (~11 lbs) has been replicated.
Dr. Kahn: Is there evidence that delaying intensive therapy for one year or two years makes a difference?
Dr. Grunberger: When you intensify treatment immediately after diagnosis, you can actually see diabetes remission in a subset of patients, but it only works initially. If you wait a longer time to intervene aggressively, it doesn’t work.
Dr. Kahn: But does that result in a long-term delay of complications?
Dr. Grunberger: I’m not aware of that data, because this study was focused specifically on the role of intensive insulin therapy at the time of diagnosis for remission.
Q: Cost has got to be a guideline for what we do. Compared to DPP-4 inhibitors, SGLT-2 inhibitors, insulin products, medical nutrition therapy is cheap – it’s walking and eating one less slice of bread per day. Can you comment on medical nutrition therapy guided by CGM for people with type 2 diabetes?
Dr. Skyler: That experiment is underway.
Dr. Satish Garg: The reason I set up this session was exactly what Jay pointed out – we have all of these enormous guidelines, but most of us who see patients don’t really get anything from those guidelines. What do you all think are the rational steps to improve outcomes for our patients with diabetes?
Dr. Heller: I don’t have an answer to that, but I will also agree with Jay, in that here we are 10 years later with new guidelines and the same average A1c. Somebody has said, “madness is doing the same thing and expecting to get a different result,” and we continue to do the same thing whilst expecting to see a different result. We have to change our paradigm. Our paradigm has failed. We have to experiment with different models, and I know this isn’t as sexy as developing new drugs (which we have plenty of). In our city, diabetes specialists are working in the community to support PCPs and teams. I don’t know if it’s going to work, honestly, but it has to be better than the current state of affairs. I’m sure there are other models, too. There are lots of approaches that might be working in the US – these need funding.
Dr. Cefalu: Guidelines are getting more complicated with new drugs. But let me underscore – no algorithm is going to tell you how to treat your patient. There’s still something called the art of medicine. What the guidelines tell you is to consider patient factors – consider weight gain, consider hypoglycemia – and your regimen will change. CV benefits and weight effects have to be configured into glycemic management. Above all, we still need education of the provider, because with more and more new drugs, it’s only going to get more difficult.
Dr. Grunberger: I agree with my esteemed colleagues. There’s no question that lifestyle modification is key for the management of diabetes. We live in an obesogenic society, and while physicians can’t fix society-wide issues, we can make sure politicians understand the value of sidewalks in neighborhoods. Telling a patient to lose weight unfortunately doesn’t carry as much weight as writing a prescription – it almost feels as if you haven’t done your job as a physician until you write a prescription. So, a long time ago, I used to actually write out prescriptions for exercise. I think we have to be creative. And, we should recognize that many patients come to our attention way too late, by the time their A1c is already at 8% or 9%. I agree 100% with Jay that metformin is probably overrated. The AACE guidelines clearly specify strength of recommendation. We rank medications to help providers according to the order we feel they should be prescribed. We decided to put GLP-1 agonists and SGLT-2 inhibitors as the top two choices (either as initial combination therapy with metformin or as the first choice after a maximum of three months on metformin) back in 2013, even before CVOTs came out.
Dr. Buse: I recommend we stop the conversation on differences between guidelines, because they’re actually 99% the same.
Dr. Larry Hirsch (BD, Franklin Lakes, NJ): Yesterday, I walked out of a session here convinced that lifestyle has not really shown to be effective (following Dr. Kahn’s talk). Jay, you were up on stage this morning championing lifestyle intervention. I respect both of you. So where does that leave the rest of us? I’m also having a hard time understanding why the ADA standards only give a B rating to CVOT data on liraglutide and empagliflozin. These were large, prospective, well-done RCTs – why are they not given an A rating?
Dr. Skyler: Well, they haven’t been replicated. There’s only one study on each agent.
Dr. Buse: I do think these deserve an A rating, and I’m sure the ADA committee will take this up. I’d like to defer the debate on lifestyle, because the truth of the matter is that diet/exercise work differently for different people. If lifestyle modification works in three months, great! If it doesn’t, move on. The issue comes in waiting 10 years, repeating “bubba, you’re too fat,” and classifying that as diabetes treatment.
Comment: I’d like to see a head-to-head study comparing the AACE vs. ADA guidelines in the real world. I’d like to see a cost-effectiveness guideline that helps me choose my medication based on cost criteria.
Dr. Grunberger: We’d all like to see this. One issue is in defining cost. Guidelines are sometimes criticized for favoring branded medications, not going for the cheapest stuff, but in response to that I ask: what is the cost of a patient’s life over a long lifespan of living with a chronic, incurable condition? Furthermore, cost is an artificial milepost since it depends on a specific insurance plan that month and also pales in terms of total cost of diabetes care over the patient’s lifespan.
Q: Is there a reason we so strongly recommend continuing metformin once we start patients on MDI?
Dr. Buse: There was a trial that randomized people to continue metformin or not, and while there was no difference in A1c, you did see less weight gain in the persistent metformin group.
Dr. Heller: There is some evidence from a very few hundred people (who were all overweight/obese) showing slightly less CV disease with metformin therapy.
Q: I don’t see TZDs prescribed as much anymore. Have these been replaced with SGLT-2 inhibitors?
Dr. Skyler: Low-dose pioglitazone (≤30 mg) does not have the side-effect profile it was once proposed to have. So, we continue to use that. I’ve sensed a renewal of interest in pioglitazone since the IRIS study in people without diabetes but borderline A1cs showed that the agent prevents stroke. I think we’ll see some degree of resurgence, particularly since it’s generic. People love to see generics. DPP-4 inhibitor sitagliptin is going to be generic soon.
Q: It seems like guidelines are designed toward physicians only. You don’t see a whole lot in algorithms that helps dieticians or psychiatrists, and that’s a bit frustrating. There are ways these major organizations could touch on that, and give some instruction to other allied health professionals. [Applause.]
Dr. Cefalu: I absolutely agree with you. One thing we’re doing in our PCP initiative is including nurse practitioners, educators, physician’s assistants. This information has to get to people at the primary care level. But as far as what to use for different patients, it’s going to be the same regardless of whether you’re a nurse practitioner, a PA, or a provider.
Dr. Buse: The groups that write these guidelines also include diabetes nurse educators, pharmacists, etc. A lot of language in the ADA Standards of Care incorporates behavioral approaches, medical nutrition therapy, exercise, etc.
Dr. Grunberger: AACE actually has a lot of these documents available – look it up! There’s a whole section on lifestyle modifications that discusses options and strategies. There’s also the ABCD initiative – adiposity-based chronic disease – taking the stigma out of the name “obesity.”
Q: My question is about ELEMENT 5 and biosimilars. That study was done in patients with type 2 diabetes, 18 years or older. What about patients with type 1 diabetes who are very insulin-sensitive? Are there studies that support that piece?
Dr. Buse: I think not, actually.
Comment: I think there’s something missing in guidelines. There are social issues here. I had one patient who was unemployed, uninsured, and unable to get medicine. Another woman was a hoarder, and wouldn’t go into her kitchen to eat so she wouldn’t take her insulin. As a care coordinator, what am I supposed to do with that? Another patient told me that if she died, people wouldn’t blame her – they’d blame her diabetes. My goal there was to connect her to her counselor. But a lot of patients don’t call back.
Dr. Buse: I really appreciate that comment. I think it’s spot on, and there are many hours of discussion we could have surrounding it. But, Satish is anxious for us to go outside right now and have a break.
Plenary Four: Role of Nonprofits in Diabetes Care and Research
NIH Perspective: Health Disparities
Pamela Thornton, PhD (NIDDK, Washington, DC)
NIDDK Division of Diabetes, Endocrinology, and Metabolic Diseases Program Director Dr. Pamela Thornton detailed current and future NIH efforts to combat health disparities in the diabetes landscape. In particular, she discussed the NIH’s emphasis on pragmatic and natural experiments aimed at fast-tracking translation and implementing effective intervention in diverse healthcare settings. Projects will be evaluated with an eye towards cost-efficacy, scalability, and sustainability – great metrics for sure! Dr. Thornton was especially proud of the time-sensitive obesity policy and program evaluation, a trans-NIH initiative comprised of six participating institutions NIH Institutes/Offices (NIDDK, NCI, NICHD, NIA, OBSSR, and ODP) dedicated to accelerating the time between grant submission and funding to only three months. She also highlighted several NIH studies and findings pertinent to diabetes, including SEARCH for Diabetes in Youth, FL3X, and the DPP. She characterized the SEARCH data as “extremely concerning and disturbing,” due to the demonstrated massive disparities by race and ethnicity (see our coverage from this year’s ADA examining pediatric patients with type 2 diabetes in a post-hoc analysis and the original report here). The ongoing FL3X study – run by PIs Drs. David Maahs, Elizabeth Mayer-Davis, and Michael Seid – aims to address poor glycemic control in the pediatric population with a coaching intervention, and, according to Dr. Thornton, the results will be available soon. In other news, Dr. Thornton mentioned that eight Centers for Diabetes Translation Research grants were awarded in 2016, with the next competition expected in 2021 (see information about CDTRs at http://www.diabetes-translation.org). She concluded with a brief discussion of future directions and next steps for NIDDK, expressing an interest in work investigating social determinants, public health frameworks for obesity, and the outer rings of influence such as social context. These issues, as noted by Dr. Thornton, are multifactorial and extremely complicated, and we applaud NIDDK’s focus on understanding the reasons behind the slow uptake of interventions in real-world circumstances, which are often a far cry from the ideal environments simulated in research.
- Dr. Thornton mentioned that an upcoming NIDDK workshop will focus on strategies to address obesity and type 2 diabetes disparities. Dr. Thornton indicated meeting logistics will be available on the NIDDK website soon and anyone interested in attending should contact her at email@example.com. Seating is limited. Dr. Thornton called for recommendations on research priorities focused on enhancing lifestyle and integrating social context into diabetes management. The meeting is intended to help clarify important contextual level factors and the role social determinants play in informing practice and adherence.
American Diabetes Association (ADA)
William Cefalu, MD (ADA, Arlington, VA)
ADA Chief Scientific, Medical, and Mission Officer Dr. William Cefalu opened his presentation with a battery of impressive ADA statistics, referencing 4,600+ research projects and $770 million invested in diabetes research since the program’s inception in 1952. In 2016, ADA provided $34.5 million to more than 378 projects. Dr. Cefalu maintained that the operative word to keep in mind is “collaboration,” noting that diabetes is way too large a disease for any one organization to tackle and that ADA must be recognized as just part of the diabetes ecosystem. Dr. Cefalu envisions all organizations working together under one umbrella and mission, emphasizing the need to move away from silos. We agree, though the devil is always in the details when it comes to great partnership and collaboration. The ADA has had a strategic re-organization over the past six months to achieve these goals. Of note are the changes implemented to the ADA standards of care – Dr. Cefalu remarked that updating these guidelines once a year is far too infrequent and aims to convert the standards of care to a “living, breathing document” with new information clearly marked and incorporated in real time – how very exciting! We especially hope to see CGM more firmly recommended for all insulin users and those taking medicine that is associated with hypoglycemia. Eventually, Dr. Cefalu hopes the standards will be available on an app, enabling providers (especially PCPs) to easily stay up to date. The Professional Membership initiative to further support PCPs is also noteworthy – as Dr. Cefalu commented: “I have three brothers in primary care and I can’t imagine them trying to keep up with all the available information.” We couldn’t agree more and applaud the ADA’s efforts to get actionable guidelines into the hands of primary care providers, where most of diabetes is handled. Dr. Cefalu ended his discussion on a bittersweet note, remarking, “the strategic realignment can only help us in this time of diminishing resources; we do have some very exciting initiatives moving forward.”
- Dr. Cefalu seemed most excited about ADA Pathways to Stop Diabetes, a relatively new program initiated in 2013 geared towards accelerating diabetes research and supporting young investigators. We have been encouraged by the goals of this initiative – see our ADA coverage on Dr. Zhen Gu’s work on insulin patch delivery for just one example. Dr. Cefalu noted that he hopes to expand this initiative over the next couple of years, perceiving massive potential in programs of this kind, which provide early-career investigators typically overwhelmed with pressure to bring in grants a rare dose of freedom. We would love to a see a similar program to encourage medical students to go into endocrinology! (See our FFL 2017 coverage for Drs. Irl Hirsch and Bruce Buckingham on the concerning state of the field.)
Helmsley Charitable Trust
David Panzirer (Helmsley Charitable Trust, New York, NY)
In his first Keystone appearance, Helmsley Charitable Trust’s Mr. David Panzirer made an impassioned plea for greater CGM adoption, suggesting that he would love to see 50% of type 1s wearing one by the time Keystone 2018 rolls around. No doubt ambitious, but Mr. Panzirer is of the mind that we have to shoot for the stars if we want to see change - bravo! This portion of his talk is included in more details in the first bullet immediately below. Within a span of just over two minutes, he masterfully packaged T1D Exchange data showing that diabetes in the US is “neither safe nor managed”; called for CGM to be put on every single newly-diagnosed person; shared his hopes for the CGM landscape; compared diabetes in the US to Rwanda; and a whole lot more – definitely worth a read (or two!). We absolutely love the mindset shift he prescribed clinicians, suggesting that they ask themselves “why wouldn’t I put this patient on CGM,” instead of the traditional “opt-in” approach. Many KOLs appear to agree – CGM needs to become the default option in insulin users rather than the exception – and we believe that will happen as CGM becomes even easier to use, more accurate, etc. New technologies and drugs will only see adoption, of course, if they are prescribed. As an example of where CGM is going, Mr. Panzirer showed the slide of both generations of the Dexcom/Verily sensors, first shown at in Dexcom’s JPM 2017 presentation in January. Separately, Mr. Panzirer shared that Helmsley will be funding a prevention study in Europe beginning in late 2017/early 2018: 400,000 newborns will be screened at birth and, if found to be at-risk, put on a regimen of oral insulin beginning at three months of age for three years. As a reminder, the TrialNet oral insulin study presented at ADA 2017 demonstrated mixed results, with an overall negative signal, but a significant delay in diagnosis in a pre-specified secondary strata. This study will presumably have more statistical power, screening 400,000 babies, while the TrialNet study screened “just” 140,000, and will also (i) use much larger doses of oral insulin and (ii) intervene before autoimmunity. Mr. Panzirer added that the screening platform will eventually be used for many other diseases, not just type 1 diabetes – “This is massive and very expensive to do, it’d be insane to not think more broadly.” Read on for a history/description of the Trust since Mr. Panzirer became a Trustee, plus his view of his organization’s role in the diabetes ecosystem.
- “Data from the T1D Exchange shows that we’re failing our patient population pretty miserably, yet we have access to a technology that can improve outcomes – CGM. But adoption remains at 24% in the T1D Exchange (and presumably far lower overall in the US and globally). T1D is the only disease I know of where patients and caregivers are making dosing decisions with a drug that could kill them. They make these decisions 24/7 without the benefit of a clinician and if they get it right 60% of the time they are doing amazing! I don’t know of another disease that places so much burden on patients and clinicians. Think about how much things have changed in the past 10 years: When I first started, type 1 diabetes was completely misunderstood – people thought it was a safe and managed disease. But even today, 8.5% is the average A1c in the T1D Exchange population, and almost 10% of people have had severe hypoglycemia in the past year. That’s neither safe nor managed. And that’s in best clinics in US, with the best providers we have to offer. The common denominator to improve outcomes is CGM. CGMs should be put on every single newly-diagnosed person, full stop. Why? It’ll show them exactly what they need to learn. CGM’s not for everyone – we know about the issues related to form factor, cost – but seeing a naïve clinician should not be a barrier to adoption. We have proof that it works and just 24% of people wear it – that’s just not good enough. I get excited when I look at the future of CGM because a lot of the barriers, they’re coming down. Even FDA has realized these things are ready for primetime – Medtronic’s 670G automatically doses basal insulin off of it, and a fingerstick confirmation is no longer needed with Dexcom’s G5. We all need to be aligned and help get people on best tools. And the more people that get on devices, the more industry players will be brought in, and we will see innovation speed further. I recently traveled to Rwanda. In Rwanda, they couldn’t dream of a technology like this – patients there have one strip per day, if they’re lucky, and they’re on premixed or human insulin. I could never go there and give a talk like this. But compare what we have here and we still don’t adopt it. At the end of the day, patients trust the person in the white coat – don’t let them down. Get them on the latest and greatest technologies. Next time you’re sitting next to a patient, ask yourself: ‘Why wouldn’t I put this person on CGM?’ Next year, I would love to see adoption at 50%. Everyone needs to join us and be advocates for these devices. Today we’re failing our patient population, but together we all hold the keys to change their lives.”
- Helmsley is a $5.5 billion Charitable Trust employing 100 people that has given $1.8 billion to date and ~$400 million to type 1 diabetes. Mr. Panzirer shared the story of his daughter’s diagnosis and journey founding the Trust and T1D Exchange – see our 2014 interview for more on this incredible journey. Mr. Panzirer stated that one of the Trust’s goals is to improve the lives of all people living with diabetes. He continued: “Notice that the word ‘cure’ is not in the goal. We want a cure a much as anyone else, but cure is a fundraising word. We haven’t cured too many diseases, and if we do find a solution tomorrow, it’d still be 10-15 years until we could get it to patients. And it’s not for a lack of money, anyone who tells you that is full of it.” So, our mission is to take better care of people now, so that when we do find a cure, they can participate.” (We love the alignment here with JDRF, who has also moved in this direction in the last decade, most notably with automated insulin delivery.) Mr. Panzirer emphasized that since Helmsley doesn’t have to fundraise, it is obligated to think differently, filling gaps in funding and taking on higher degrees of risk. Recent grants have included machine-learning predictive analytics for type 1 diabetes and a mental health provider diabetes education program.
- Mr. Panzirer hit the road for 18 months of diligence before writing his first check at the Helmsley Charitable Trust. He spent time with members of the largely-successful Michael J. Fox and Cystic Fibrosis Foundations. He is particularly inspired by former CFF CEO Dr. Bob Beall whose work had a very tangible impact in his 30+ year stint at the foundation. In this time, the average lifespan for a person with Cystic Fibrosis swelled from ~7 to ~48! And in Mr. Panzirer’s view, almost every improvement in Cystic Fibrosis can be attributed to the Foundation, and this was accomplished by taking a business approach, aligning incentives for all stakeholders (payers, regulatory, and industry). See our 2014 interview with Mr. Panzirer for more perspective on this journey and the Helmsley Charitable Trust’s T1D program’s founding – for even more from the renowned Dr. Beall, see this interview with him and Ms. Margaret Anderson at Faster Cures last year.
Juvenile Diabetes Research Foundation (JDRF)
Aaron Kowalski, PhD (JDRF, New York, NY)
JDRF’s Dr. Aaron Kowalski picked up where Mr. David Panzirer left off, with a strong push for greater CGM adoption, followed by a review of JDRF’s scientific priorities. Mr. Kowalski noted that CGM adoption comes down to the age-old question: “If you build it, will they come?” In this case, it depends on the delicate balance between glycemic control and “diabetes happiness” (quality of life) – the Biostator, a bulky closed loop system from the 1980s may have driven perfect glycemic control, “but you can’t hike a mountain with it.” Of course, glucose monitoring has come a long way in the past four decades in terms of accuracy and form factor, stabilizing the teeter-totter of glycemia and quality of life more than ever before. Still, as Mr. Panzirer pointed out in the prior talk, only an estimated 24% of T1D Exchange patients in the US use CGM (far lower outside of the Exchange) – Dr. Kowalski asked that clinicians push for the newest and best advances for their patients so adoption of clinically proven technologies can increase. He also shared a unique perspective on the recent Medicare therapeutic CGM victory, acknowledging its monumental nature, but pointing out that for the population most vulnerable to severe hypoglycemia (seniors), CGM was not covered for more than a decade! Indeed, we are ecstatic that the Medicare population can now have access to potentially life-saving CGM, and we hope the access lag time shortens moving forward. On the topic of JDRF’s scientific portfolio, Dr. Kowalski focused on the automated insulin delivery program he spearheaded with former CEO Jeffrey Brewer. He enthusiastically exclaimed “we are here!” in reference to the MiniMed 670G launch, and told of amazing emails he frequently receives from patients detailing not only improved glycemic outcomes, but improved emotional wellbeing. Miniaturization/form factor and post-prandial control are JDRF’s top automated insulin delivery priorities at the moment, but multi-hormone is also notably high on the list – in Dr. Kowalski’s view, because hypoglycemia is so reduced in closed loop and postprandial excursions are “the biggest nut to crack,” amylin has tremendous potential. (Dr. Kowalski always emphasizes this dual-hormone combination more than glucagon.) As a reminder, Adocia hopes to enter clinical trials this year with a co-formulation of insulin lispro with pramlintide (see 1Q17). Lastly, he called the DIY community an incredible untapped resource of ingenuity in the type 1 diabetes community, and hinted that JDRF will be “weighing in more here” in the future – this caused some ears to perk up! We too believe that tremendous learning is happening in this community, and we hope the lessons and novel user experiences make it into commercial products! On the plus side, we’re starting to see this: Dexcom hired Ben West and Chris Hannemann from the OpenAPS community last year; Loop developer Nate Racklyeft now works on Apple’s Health team; Insulet shared at ADA that it has spent hours learning from the OpenAPS community; and Nighscout’s John Costik now works at Beta Bionics.
- “We at JDRF often get criticized for working with industry. We can’t develop new products – we need companies to do this. We have to work with industry and see them take research developments and bring them to patients.” (This short-sighted JDRF-industry criticism was most recently brought up in Elizabeth Rosenthal’s book, American Sickness; see Jim Hirsch’s take in diaTribe here.) Dr. Kowalski pointed out in Q&A that many companies in diabetes take a long time – or don’t ever – turn a profit, and if they are driven out of business, patients lose. For automated insulin delivery specifically, Dr. Kowalski noted that many players are not on firm financial ground (e.g., Animas, Cellnovo, and Tandem come to mind, though he didn’t mention them), and part of the problem is that there are not enough people on devices – he firmly believes that outcomes on available systems (670G at the moment) will justify that more people should use diabetes devices. Many KOLs agree - we also hope that automation changes the conversation around diabetes technology from burdens to benefits.
- Dr. Kowalski also touched on the glucose control (diabetes drugs), complications, prevention, beta cell replacement, beta cell restoration, and exercise (PEAK) programs in JDRF’s portfolio. Within these categories, he called glucose-responsive insulin the holy grail, spoke to funding into diabetic retinopathy and nephropathy, urged everyone to encourage participation in TrialNet, called the packaging of beta cells (for replacement) a big area of focus, noted that gene editing for beta cell restoration is “super hot right now,” and shared that the PEAK program (to help patients exercise successfully) has now rolled out 14 chapters across the US. There is certainly no shortage of opportunities to fund, and we’d have to guess JDRF’s job is getting more challenging every year!
Plenary Five: Diabetes and Cardiovascular Outcome Trials
Cardiovascular Disease: An Issue in Type 2 Diabetes
Dr. John Buse provided a comprehensive overview of the burden of CV disease in type 2 diabetes, discussing best practices for CV risk reduction and suggesting that hyperglycemia may not be as important as other risk factors (blood pressure, lipid levels, smoking). One study he presented showed that longstanding type 2 diabetes confers risk for MI equivalent to that of patients without diabetes who have already experienced an MI event. Noting that CV disease is the leading cause of morbidity/mortality for people with diabetes, accounting for 31% of diabetes-related deaths in 2013, Dr. Buse outlined the risk factors for atherosclerotic CV disease that are commonly comorbid with type 2 diabetes. CV disease can manifest as MI, transient ischemic attack, peripheral vascular disease, or even amputations, and risk reduction strategies should include lifestyle modification, platelet inhibition, management of dyslipidemia and hypertension, and individualized glycemic control. Smoking more than doubles CV risk in people with type 2 diabetes, and unfortunately, Dr. Buse shared that smoking rates in this patient population have not declined significantly in recent decades. He suggested that a risk calculator be used in prescribing antiplatelet agents to those facing high atherosclerotic risk, and also reminded providers to pay attention to aspirin (it isn’t prescribed and is often forgotten). Multiple trials have shown statins to reduce CV events in people with diabetes, and Dr. Buse explained that this benefit is seen with 30%-40% LDL-lowering regardless of baseline level. He articulated that lifestyle intervention should be a cornerstone of diabetes management, especially in the context of CV risk reduction, and that statins should be prescribed to anyone with high CV risk or overt CV disease. Turning to blood pressure, Dr. Buse described how UKPDS results showed significant reductions in mortality (32%), microvascular complications (37%), and stroke (44%) with tighter blood pressure control (≤150/85 mmHg). ACCORD indicated that a systolic blood pressure <140 mmHg confers near-maximum CV benefit, but Dr. Buse underscored that we don’t yet have the right clinical trials to know just how low blood pressure should be for optimal outcomes. Notably, a review of first CV-related hospitalizations for patients with type 2 diabetes found that only 6% had blood pressure under control. Considering all these results together, Dr. Buse urged HCPs to implement strategies to lower blood pressure and lipid levels in all patients with diabetes facing high CV risk, expanding the scope of treatment beyond A1c reduction.
- Although it wasn’t quite the focus of his talk, Dr. Buse mentioned the importance of cardioprotective therapies in type 2 diabetes management. Speaking to the promise of newer agents with demonstrated CV benefit, he showed that only 39 people need to be treated with empagliflozin (Lilly/BI’s SGLT-2 inhibitor Jardiance) and 98 with liraglutide (Novo Nordisk’s GLP-1 agonist Victoza) for three years to prevent one death, compared to 100 people for five years with statins, 125 people for five years with anti-hypertensive agents, and 333 people for five years with aspirin. Dr. Buse also advocated for personalized A1c goals based on patient characteristics, preferences, and engagement. For individuals struggling with medication adherence, Dr. Buse suggested metabolic surgery for people with obesity not at glycemic goal and mentioned that Intarcia’s ITCA 650 (implantable exenatide mini-pump) as a good future GLP-1 option to guarantee adherence.
Update on CVOTs
Jay Skyler, MD (University of Miami, FL)
In his second talk of the day, Dr. Jay Skyler offered his view on how all the diabetes CVOT data published to-date should affect clinical practice: Stop using DPP-4 inhibitors and pay attention to surprise findings. Summarizing results from completed outcomes trials, he showed that no DPP-4 inhibitor agent has demonstrated cardioprotection, while some have shown a worrisome signal for heart failure hospitalization: In SAVOR-TIMI, saxagliptin (AZ’s Onglyza) was associated with a 27% increased risk of hospitalization for heart failure (p=0.007 vs. placebo). In EXAMINE, alogliptin (Takeda’s Nesina) reported a hazard ratio of 1.07 for heart failure hospitalization, which trended in the wrong direction even though it didn’t reach statistical significance (95% CI: 0.79-1.45). In TECOS, sitagliptin (Merck’s Januvia) reported a neutral hazard ratio of 1.00 for heart failure hospitalization (95% CI=0.8-1.20), but the FDA issued a Complete Response Letter (CRL) for inclusion of this data on the Januvia product label. A meta-analysis of these three CVOTs found an elevated heart failure hospitalization risk associated with DPP-4 inhibitors as a class (HR=1.13, 95% CI: 1.01-1.27), though this effect was clearly driven by the saxagliptin data. More importantly, in reviewing CVOT results on GLP-1 agonists (Novo Nordisk’s liraglutide and semaglutide) and SGLT-2 inhibitors (Lilly/BI’s empagliflozin and J&J’s canagliflozin), Dr. Skyler posed the question of why diabetes care providers would still consider DPP-4 inhibitors when our therapeutic arsenal now includes cardioprotective drugs. “Why use DPP-4 inhibitors at all when they show no CV benefit and have this issue of heart failure hanging over them? They’re not particularly cheap, either.” We’ve heard this position from Dr. Skyler before, at CMHC 2016, when Dr. Robert Ratner notably responded by defending DPP-4 inhibitors for their long history of safety/tolerability (which makes them especially useful for elderly patients and individuals with renal impairment). We see validity in Dr. Skyler’s argument, in that newer therapy classes like GLP-1 agonists and SGLT-2 inhibitors offer superior glucose-lowering efficacy vs. DPP-4 inhibitors as well as improvements to outcomes beyond A1c (CV morbidity/mortality, body weight, etc.). Some KOLs have pointed out that (i) DPP-4 inhibitors are oral agents and some patients may thus prefer them over injectable GLP-1 agonists, and; that (ii) generic DPP-4 inhibitors will likely become available prior to generic SGLT-2 inhibitors, making them a more affordable/accessible option for type 2 diabetes management. Still, Dr. Skyler’s emphasis on incorporating CVOT findings into real-world practice was invaluable commentary – after all, why conduct long, large outcomes trials if we’re not going to take that reliable evidence and use it to advance best practice diabetes care for patients? He added that providers, regulators, and guideline-writers should look to the (sometimes unexpected) non-CV results from these trials as well:
- CANVAS, which just reported at ADA 2017, found a nearly two-fold risk of lower limb amputations associated with Invokana (canagliflozin). One of Dr. Skyler’s slides listed a hazard ratio of 1.94 for minor amputations of the toe or metatarsal (95% CI: 1.31-2.88) and a hazard ratio of 2.03 for major amputations at the ankle, below the knee, or above the knee (95% CI: 1.08-3.82). While he didn’t explicitly express an opinion on how Invokana should be prescribed from here on, he suggested that HCPs now have tough decisions to make surrounding SGLT-2 inhibitor starts and perhaps switching patients from Invokana onto Jardiance, which showed a significant CV benefit in EMPA-REG OUTCOME and which is indicated for the reduction of CV death. From our end, we’re terribly curious to see how CANVAS results will impact the Invokana business as well as prescription volume for the SGLT-2 class overall. Some experts, including Janssen’s Dr. Robert Cuddihy, have argued that the amputation risk will be manageable with proper foot care, more vigilance, and better education, and we hold out hope that future analyses of the holistic canagliflozin dataset may shed light on factors that mediate this risk so that patients broadly can still reap the cardioprotective benefits of canagliflozin medicines. In a way, we wish Dr. Skyler had shared his expert perspective on how HCPs should approach Invokana in the context of CANVAS results – the 14% risk reduction (p=0.0158 for superiority) for three-point MACE (non-fatal MI, non-fatal stroke, and CV death) vs. the hazard ratio of 1.97 in favor of placebo for lower-extremity amputations (95% CI: 1.41-2.75, p<0.001) – but perhaps this speaks to the incredible complexity of canagliflozin’s risk/benefit profile. For much more insight on CANVAS, read our coverage from ADA 2017.
- A happier “surprise” finding appeared in the DEVOTE CVOT comparing Novo Nordisk’s Tresiba (insulin degludec) vs. Sanofi’s Lantus (insulin glargine). While Tresiba demonstrated CV neutrality, it showed a distinct hypoglycemia benefit vs. Lantus, reducing severe hypoglycemia by 40% (p<0.001) and severe nocturnal hypoglycemia by 53% (p<0.001). We thought these were very notable findings when presented at ADA 2017, and we were glad to hear Dr. Skyler endorse the importance of this clinical benefit. Hypoglycemia wasn’t the primary endpoint of this trial, but he advocated that the results are unambiguous and should be duly considered in treatment decisions. We agree wholeheartedly, and hope to see this take root in real-world clinical practice, just as it’s crucial for patients/providers to be aware when a diabetes therapy demonstrates significant CV benefit.
Justification for CVOTs
Steven Nissen, MD (Cleveland Clinic, OH)
Cleveland’s Dr. Steven Nissen gave a passionate defense of diabetes CVOTs, arguing that the 2008 FDA requirements led to “one of the greatest explosions of medical knowledge in the history of diabetes treatment.” This extends not only to knowledge surrounding the CV effects of different drugs, but also to unanticipated benefits and safety signals – we were very moved by this characterization, and some have floated the idea that these studies shouldn’t really be called “CVOTs,” but rather “outcomes trials” more broadly. The renal outcomes data from both EMPA-REG OUTCOME (for Lilly/BI’s SGLT-2 inhibitor empagliflozin, branded Jardiance) and LEADER (for Novo Nordisk’s GLP-1 agonist liraglutide, branded Victoza) turned out to be real positives, providing important insight on the renal protective properties of these therapies. The nearly two-fold risk for lower limb amputations found in CANVAS (for J&J’s SGLT-2 inhibitor canagliflozin, branded Invokana) was a “particularly disturbing” unanticipated finding, according to Dr. Nissen. He reviewed the risk/benefit profile of canagliflozin as we currently understand it: In five years, we’d expect to see one fewer CV event per 43 patients treated vs. one excess lower-extremity amputation per 69 patients treated. Since these number-needed-to-treat values are in the “same ballpark,” Dr. Nissen explained that amputation risk is a serious consequence that should be very carefully considered by HCPs prescribing Invokana. He added that CANVAS and other CVOTs have refuted the idea of class effects. Invokana and Jardiance, for example, demonstrated exactly the same 14% risk reduction for three-point MACE (non-fatal MI, non-fatal stroke, and CV death), but only the former has a boxed warningfor amputations on the US product label. Victoza has shown a distinct CV benefit, but two other GLP-1 agonists – AZ’s Bydureon (exenatide once-weekly) and Sanofi’s Lyxumia (lixisenatide) – have not. AZ’s DPP-4 inhibitor Onglyza (saxagliptin) showed a significant increase in heart failure hospitalizations, but this wasn’t seen for Merck’s Januvia (sitagliptin) and wasn’t significant for Takeda’s Nesina (alogliptin), even though it trended in the wrong direction (Dr. Nissen supported Dr. Skyler’s commentary on DPP-4 inhibitors from earlier in the day, emphasizing that they offer no CV benefit and are still rather expensive). Dr. Nissen established that all this accumulating knowledge from CVOTs since 2008 brings us to the “dawn of a new era in pharmacological management of diabetes,” in that we can now treat to reduce outcomes and prevent death. Evaluating therapies based on their ability to lower glucose is inadequate and unacceptable, Dr. Nissen argued, since A1c is only a surrogate biochemical marker for what we really care about (outcomes, mortality). We completely agree, and we echo Dr. Nissen’s call to the ADA, FDA, payers, and other players to recognize the critical clinical significance of cardioprotection and other benefits to outcomes beyond A1c. “Let’s integrate this knowledge into medical practice and overcome the residual inertia from decades of complacency.” Overall, this was a very important talk by Dr. Nissen and pointed out to many, including us, a number of the major advantages of this once-controversial group of trials (notably, for much time, we were particularly negative on the required timing).
John Buse, MD (UNC, Chapel Hill, NC); Richard Kahn, MD (UNC, Chapel Hill, NC); Jay Skyler, MD (University of Miami, FL); Steven Nissen, MD (Cleveland Clinic, OH)
Dr. Kahn: We know underlying insulin resistance affects virtually every organ system in the body. Here we have a disorder that affects everything, and large outcomes trials tell us things we don’t expect to see. You can’t find out if you don’t measure it. In future trials related to diabetes drugs, should we expand measurements that we do to encompass a wide variety of things?
Dr. Buse: The answer is no. The hardest thing about doing these trials is keeping patients in the study and measuring the endpoint you want to measure. The more things you measure, the less likely you are to find an answer. The more complicated the trial, the less likely you’ll get to an answer.
Dr. Nissen: I agree to some extent, but let me make another point – you have to pick a primary endpoint, and anything beyond that, you can have complex hierarchical testing. But as you get more obscure, you have to consider this as hypothesis-generating. And I do think the burden of these trials on patients is quite substantial. But we also need to have our eyes open to thing like amputations or fractures. We can get a lot of information, but it’s going to be hypothesis-generating and we can’t burden patients more.
Dr. Skyler: It’s important to keep the patient on the therapy during the trial, and Steven pointed out that in the trial of the GLP-1 agonist exenatide they were using the dose tray, and you had to mix up your exenatide with a microsphere, get it right, and make sure it’s not getting stuck to the bottle – and patients in that trial were only seen very infrequently. Before seeing the data, because we only have the press release, it’s possible people weren’t actually exposed to the drug, and you need to bear that in mind when evaluating the trial.
Dr. Buse: It’s a waste of time to talk about EXSCEL until we see full results (at EASD 2017 in Lisbon, Portugal).
Q: There were differences between CANVAS and EMPA-REG OUTCOME, particularly that HR was exactly the same but secondary endpoints were dramatically different. What do you make of that? To the primary care community, who may not know this data in detail, how do we translate it to patients? What other trials are we going to need to figure out what this means? I find it very confusing that differences were as big as they were. At a higher level, what are you guys doing to help insurance companies pay for these drugs in light of these studies.
Dr. Buse: I think it is immoral that as a society we mandate a certain set of trials be done from a regulatory perspective, and then not require that insurance companies cover these drugs if they’re shown to reduce mortality. We’re not talking about reducing toenail fungus. We’re talking about reducing mortality.
Dr. Skyler: I would add that we should also look at the negative ones, and ADA should stop putting DPP-4 inhibitors in guidelines. Let the market drop to zero where it belongs.
Dr. Nissen: Cardiologists and endocrinologists should come together and do something about the rationing of care that’s hurting patients.
Dr. Buse: CANVAS was unblinded at the beginning, then combined with two other studies, and from a clinical trials perspective perfectionist point of view, it’s a couple notches below EMPA-REG OUTCOME in study design – but the results were remarkably similar.
Dr. Skyler: The amputations will come up when there are TV ads from local lawyers, “Call 1-800-GET-REVENGE.”
Q: Is there a lower limit for normal LDL? I believe the AJCC guidelines suggest a lower limit of 40 mg/dl. In your clinical practice, do you implement a lower limit of normal, and is there any research being done on that?
Dr. Nissen: Forget the AJCC guidelines. We just did a trial and there has been another trial recently, and half the people were below 30 mg/dl and we saw no problems.
Dr. Guillermo Umpierrez (Emory University, Atlanta, GA): CVOTs are performed in very high-risk CV patients, not representative of the majority of patients with type 2 diabetes. I would take away insulin because it’s never shown benefit, and also sulfonylureas, and DPP-4 inhibitors. What would you do with patients who don’t have high CV risk factors?
Dr. Buse: I think that’s a great question. We’re talking to funding agencies about doing a study in a lower-risk population. The only studies right now are CANVAS and LEADER where there doesn’t seem to be much benefit in lower-risk patients. We just don’t have trials right now to show much benefit. There is a statement in the treatment algorithm saying that inadequately controlled and high CV risk patients should use empagliflozin or liraglutide – I think that’s totally appropriate.
Dr. Skyler: Use both.
Dr. Buse: No, we don’t have any evidence on that combination. In fact, one makes glucagon go up, the other makes glucagon go down.
Dr. Skyler: If you want to do a CVOT with a drug that’s just coming along, and you want to compare it to standard of care, you can’t really exclude the use of other GLP-1 agonists like liraglutide in the control group. So, we really have to think more carefully about design – do exactly what Guillermo is suggesting and go earlier in the course of disease. It may require bigger numbers and longer time, but look at a group outside the high-risk category where you need to be using drugs with demonstrated benefit.
Dr. Nissen: We’ve actually done this in a lot of CV medicine, starting with high-risk patients and then moving down strata. It’s too early in diabetes. We’re not there yet.
Q: We’ve looked at CV outcomes and death, but I’m wondering if microvascular outcomes have been looked at, because those have a lot to do with quality of life. Also, I have a question about the durability of A1c benefits.
Dr. Buse: The GRADE study is looking at durability for the four agents participants are randomized to in that study. As for your other question, we don’t have a lot of good data on complications – you saw the retinopathy data.
Q: The glycemic component of CV prevention and protection has been consistently not as strong as the other risk factors. In the last 10 years, we’ve seen a decrease in the percentage of patients who had better A1c. A1c of <7% dropped from 56% to 54% of our patients. Do you think it’s related to starting guidelines by medical society, or introduction of newer/better medications, or lack of use of artificial intelligence in a disease that is data-driven?
Dr. Buse: I think the difference between 54% and 52% is probably statistical noise. There are all kinds of things going on in our healthcare system now, so who knows what it is, but I don’t think it’s guidelines.
Dr. Nissen: We are getting fatter. So as patients are getting bigger and bigger, it’s harder to get there. We haven’t won the obesity battle.
Dr. Skyler: We’ve had 40 new drugs since 1995 and we haven’t moved the needle on A1c.
Dr. Buse: Particularly in setting of type 2 diabetes, what is the benefit of taking an individual’s A1c from 7.5% to 6.9%. But for society, that would make a huge difference.
Q: I wanted to offer a real-world scenario, in particular, the post-op stent, MI patients. Primary care doctors have them on liraglutide, pioglitazone, and metformin and you have to stop all of those in the hospital. Then cardiologists get involved and have them on diuretics, and post-op people have some heart failure. When we choose medications for people whose A1cs are around 8%, and if I put them on empagliflozin after they are discharged, the cardiologist will be mad at me. How do endos, cardiologists, and PCPs learn to communicate with each other?
Dr. Nissen: We have to work together. More than half of my patients in coronary care have diabetes, and we need approaches to take and integrate the best knowledge from the cardio and diabetes worlds to take better care of our patients.
Dr. Buse: If they have heart failure, the evidence is overwhelming for empagliflozin. Atherosclerosis but not heart failure, I would prescribe liraglutide. You can do both but I’m a little afraid they might neutralize each other’s benefit. At a minimum, they’re sub-additive and you get only about 1.5x the effect.
Plenary Six: CGM Advances
AACE and ATTD Guidelines for CGM
George Grunberger, MD (Grunberger Diabetes Institute, Bloomfield Hills, MD)
The great Dr. George Grunberger closed his second Keystone talk with a stirring call to action: “CGM is here to stay. It’s the standard of care for patients on intensive insulin therapy, and it’s high time we reach out and teach patients, providers, and payers how to use it.” He emphasized the need for actionable CGM data and a standardized outcomes reporting system, citing his commonly-stated goal to make CGM reports as universally understandable as an EKG. Given the variety of glucose targets and hypoglycemia thresholds found on different devices, Dr. Grunberger praised Dexcom’s recent addition of the standardized, one-page Ambulatory Glucose Profile to its Clarity platform as an important step towards standardization (Dexcom joined Abbott, Roche, and Glooko/Diasend as key adopters). He also noted that A1c misses the mark when it comes to actionable data, calling for clinicians to move past the A1c-centric culture and instead focus on expanding time in range. We loved his shout out to this Friday’s Glycemic Outcomes Beyond A1C workshop – he will not be in attendance due to a prior conflict, but plenty of thought leaders, including AACE representative Dr. Zachary Bloomgarden, will be. Dr. Grunberger emphasized that, while clinicians should be responsible for analyzing CGM data alongside their patients, CDEs are critical in ensuring that patients can interpret CGM data in real time before device initiation – that includes education on arrows/trends, best practices for wear and calibration, and dosing off a CGM (he reviewed the DirecNet, Edelman/Pettus, and Scheiner methods). According to Dexcom’s Dr. Claudia Graham, people pick up on CGM use pretty quickly, usually within 45 minutes. The recently published AACE/ACE guidelines derived from a consensus conference echoed Dr. Grunberger’s recommendations, focusing on patient and provider education and comprehensive, standardized analysis. On the importance of provider education, Dr. Grunberger gravely noted: “This is not for the fainthearted, providers make life and death decisions and it’s really important that they understand glucometrics. If you’re not interested, send your patient to someone who is.” Dr. Grunberger also discussed ATTD CGM guidelines slated for publication soon. The ATTD group recommends a minimum of 14 consecutive days of CGM data for an actionable report and suggests five threshold buckets to interpret time in range (<54 mg/dl, <70 mg/dl, 70-180 mg/dl, >180 mg/dl, >250 mg/dl). We very much appreciate all of the efforts that have been put into consensus meetings; Now, we turn our attention to implementation, getting CGM routinely used in drug trials, incorporated into regulatory decisions, and used widely in clinical practice to make therapeutic changes.
CGM in MDI Patients and Future Sensors
Bruce Buckingham, MD (Stanford University, CA)
In this session on CGM advances, Dr. Bruce Buckingham discussed the DiaMonD and GOLD study results and highlighted several future sensors in development for the US. On the landmark studies of CGM in MDI, Dr. Buckingham was particularly impressed with sensor wear in the DIaMonD study, calling attention to the incredible 93% wear time amongst type 2 adults after six months. Type 1 subjects demonstrated equally impressive usage, with an average wear of 6.7 days/week at six months. (We’d note that patients who didn’t wear the CGM were screened out of the study – a smart design move on Dexcom’s part.) According to Dr. Buckingham, one of the major benefits indicated by the DIaMonD results is the ability to record glucose levels overnight – this is obviously a huge gap in SMBG! Importantly, the study demonstrated no significant differences due to age, education, or numeracy, and Dr. Buckingham hopes this will drive high levels of Medicare adoption (now that Dexcom G5 is reimbursed and shipping, see above!). The GOLD data reinforced findings from the DIaMonD study, proving that patients on MDI can and will wear CGM on a daily basis to the effect of reductions in both A1c and hypoglycemia. As Dr. Buckingham rather bluntly commented, “you need to use the system for it to work…you sort of expect that.” Following Dr. Buckingham’s presentation, Dr. Aaron Kowalski vocalized what the majority of the room was likely thinking: “I’m bubbling with frustration that we’re still talking about getting people on CGM. The evidence is irrefutable.” As for up-and-coming sensors, Dr. Buckingham shared optimism for implantables (Senseonics, Glysens), as well as smaller/less expensive sensors like the Dexcom/Verily and FreeStyle Libre (for which he sees a “real-time future” given last week’s major Bigfoot agreement).
- Dr. Buckingham expressed excitement regarding the Senseonics Eversense implantable CGM (under FDA review) and the in-development Glysens CGM. So far, the fluorescence-based Eversense has been tested in 500 patients for over 100,000 days. While the quick in-office insertion procedure is relatively simple, it will be fascinating to see how clinical adoption of this goes – endocrinologists are not used to procedure. Dr. Buckingham also mentioned the Glysens implantable, which is calibrated monthly, and cautioned that it’s been hard to find published results – the one study he did discuss published in IEEE Biomedical Engineering showed a MARD varying monthly from 8.1%-28% (see picture below). Still, he sees a future for Glysens, commenting that “if people are looking for an implanted sensor that lasts for a year, this seems to be one of the ones coming down the road.” This company has not moved as quickly as some others, though the long implant time does lengthen testing and development; we’re not sure at what point we’ll see a Glysens pivotal trial or commercialization.
When Will CGM Replace SMBG?
Roy Beck, MD (Jaeb Center, Tampa, FL)
Jaeb Center’s Dr. Roy Beck reviewed the plentiful evidence for CGM’s benefits in both type 1 and type 2 diabetes. He concluded that CGM yields better glycemic outcomes than SMBG, and with the latest technology, is accurate enough to replace fingersticks. In his widely cast literature review, Dr. Beck briefly touched on Dexcom’s DIaMonD study, the GOLD study, Abbott’s REPLACE and IMPACT studies (FreeStyle Libre in type 2 and type 1, respectively), and REPLACE-BG (a T1D Exchange study testing non-adjunctive use with Dexcom’s G4). While he did glance over the overwhelmingly positive glycemic outcomes from these trials, on every data slide, wear time and treatment satisfaction/quality of life were highlighted, sending a clear message that CGM drives glycemic benefits, but only when it is worn – in our view, now it’s about bringing this technology to a wider population, dropping the cost, and simplifying users’ wear experience. The field has come far from the poorly-tolerated GlucoWatch! All of these studies, which came out in just the past three years, indicate to Dr. Beck that CGM could be near-total replacement for all patients with type 1 diabetes and patients with type 2 diabetes on MDI or pump therapy. “Near-total” refers to the need for calibrations (except for FreeStyle Libre), and even with factory-calibrated sensors, he would like to see the ability to re-calibrate in scenarios when CGM values look off. (We expect this will be an increasing point of debate, and it will be fascinating to see how FreeStyle Libre and next-gen Libre comes to market in the US, especially with Bigfoot’s automated insulin delivery system.) How about replacement in type 2s on just basal insulin? There is no substantive clinical data to turn to, so the Jaeb Center and Dexcom will embark on a clinical study (the MOBILE study) soon to fill this knowledge gap. Nice! Dr. Beck believes that CGM, in its current form, is unlikely to be widely adopted by type 2 patients not taking insulin, though future simple, unobtrusive, low-cost sensors (e.g., Dexcom-Verily’s second-gen sensor) could change this. We like the potential of CGM providing behavioral feedback – even in people with prediabetes – perhaps at diagnosis and a few times per year. Before wrapping up, Dr. Beck announced a series of upcoming studies to evaluate CGM in understudied age groups (conducted by the T1D Exchange clinic network): The SENCE trial of CGM in children under eight years old (funded by Helmsley Charitable Trust), the CITY trial of CGM in adolescents (starting soon, expected to be funded by the Helmsley Charitable Trust), and the WISDM trial of CGM in the elderly (starting soon, looking at the interaction between cognitive issues and CGM efficacy, funded by JDRF and the Helmsley Charitable Trust).
- Two recent studies confirm that CGM is non-inferior, if not superior, to SMBG in terms of accuracy. Ekhlaspour et al. (JDST 2017) found that the MARD of a number of FDA-cleared BGMs ranges from 5.6% (Ascensia Contour Next) to 20.8% (Trividia Sidekick) - nine of them have a MARD >10%! Meanwhile, Dexcom’s G5, Medtronic’s Guardian, and Abbott’s FreeStyle Libre range from 9.0%-12.3% MARD. In a Diabetes Technology Society study, 18 BGMs were each tested in three sub-studies among 1,035 participants. In order to pass the assessment, >90% of tested meters had to read standard blood glucose within 15% of reference for blood glucose >100 mg/dl and within 15 mg/dl for blood glucose <100 mg/dl. The results were rather disturbing: Only 6/18 tested had passing grades in all three sub-studies (Ascensia Contour Next, Roche Accu-Chek Aviva Plus, Walmart ReliOn, Agamatrix CVS Advanced, Abbott FreeStyle Lite, and Roche Accu-Chek Smart View); 5/18 passed in two of the three sub-studies; 3/18 passed in one of the three sub-studies; and 4/18 failed in all three sub-studies! These studies will be crucial for the education of providers in the near future – there was audible shock in the room when the Ekhlaspour data was on the screen, and we’re sure that at least some are now convinced that CGM is not less accurate than BGM (see the full results here). We’re glad to see some of the accuracy baggage dissipating from early-gen CGMs that did not deliver.
- Even if CGM isn’t more accurate than BGM, Dr. Phillip reminded that trend arrows are just as valuable, if not more, than point accuracy. He referenced an old study from Europe where a sensor with MARD 19.7% caused an A1c drop of 1%, the same as seen in the recent DIaMonD study with the much more accurate Dexcom G4. This was a point that Adam and others made at last year’s Dexcom-FDA meeting on non-adjunctive use of CGM – trend arrows provide far more valuable information than point-in-time fingersticks, even if the point accuracy is not as good as the most accurate meters (slides here).
- Drs. Jeremy Pettus and Bill Polonsky tackled the question of which type 2s should be on CGM in an entertaining debate at ADA. They reached the same conclusion as Dr. Beck, though the debate of CGM in type 2s on basal swung convincingly to the “pro” side – we wonder if this will be supported by data from the MOBILE study.
Plenary Seven: Hypoglycemia and Diabetes
Role of Decision Support Systems Used by Professionals
Moshe Phillip, MD (Schneider Children’s Hospital, Israel)
Schneider Children’s Dr. Moshe Phillip provided a glance into the type of recommendations the Glooko-embedded Advisor Pro will provide, and highlighted the NextDREAM Consortium study, which is now set to begin in September (delayed slightly). Within the Glooko platform, providers can see the patient’s current therapy alongside the suggested adjustments – for pumpers, there are currently pages for basal rates, carb ratio, correction factor, and active insulin time. In addition to very specific suggested adjustments (e.g., change basal rate from 12pm-3pm to 0.85 u/hr), the Advisor will rationalize with 400+ unique notes describing detected patterns relating to behavior and insulin dosing. Examples include: “Due to a pattern of postprandial hyperglycemia, the carb ratio was updated to deliver more insulin”; “Your patient tends to skip boluses at lunch”; or “Your patient skips boluses every second weekend of the month.” This sort of pattern detection is very exciting, hard for busy clinicians to do, and refreshingly specific. Indeed, Dr. Phillip estimates that optimizing pump settings – including poring over 25+-page CareLink reports (which he doesn’t read in full) – requires 10-20 minutes of valuable provider time for each patient. This clinic time can be liberated for discussion of things that really matter to people with diabetes – food, exercise, behavior changes, foot exams, etc. Dr. Phillip then turned to the clinical validation of the Advisor Pro, a job for the NextDREAM consortium, which will conduct a multi-center study beginning in September (back from the late July/early August timing provided at AACE 2017). Ljubljana, Schneider Childrens, Auf Der Bult, Yale, Barbara Davis, University of Florida, and Joslin comprise the impressive Consortium – Dexcom will provide the G5 for the study. As a reminder, Advisor Pro was non-inferior to esteemed physicians in a pilot study (MED-Logic Advise4U; presented at ATTD). In the words of Dr. Phillip: “We are happy. It’s just another team member.” Yes, another team member, but one that can sift through tomes of data, scale time-pressed providers, and drive better outcomes.
Best Way to Decrease Hypoglycemia in Type 1 Diabetes
Bruce Buckingham, MD (Stanford University, CA)
Dr. Bruce Buckingham gave a hard-hitting presentation on the sobering reality of hypoglycemia in type 1 diabetes and how to prevent it, beginning with unpublished results on hypoglycemia during exercise from Dr. Michael Riddell. Dr. Riddell (whom we last heard speak at this year’s ADA on exercise and the artificial pancreas) found starting glucose levels can be predictive but not always protective of blood glucose following aerobic activity (see data below; red bars represent individuals who dropped below 70 mg/dl). In the Dskate Camp study (also below), some individuals saw blood glucose drop immediately after while others saw it rise. These data show striking variation in individual responses to exercise, indicating a need for personalized plans and the use of a sensors with decision support or sensor-augmented pump/hybrid closed-loop systems. Dr. Buckingham also warned against the dangers of hypoglycemia unawareness, which he’s seen in the majority of “dead-in-bed” cases. To those with this condition, Dr. Buckingham recommended “never to sleep alone” and joked that he offers this advice to all of his patients going off to college. Humor aside, hypoglycemia unawareness is reported in an estimated ~20%-30% of type 1 adults, and unfortunately was not found to reverse after five weeks on closed loop in a study referenced by Dr. Buckingham. However, a separate study (Ly et al., Diabetes Care, 2011) found that CGM use improved the autonomic response to hypoglycemia in adolescents with type 1 diabetes. Dr. Buckingham praised remote monitoring and real-time CGM as critical in mitigating the risks associated with hypoglycemia unawareness, referencing one of his own camp studies of 7-16 year-olds (n=60), which demonstrated benefits of remote monitoring using the G4 sensor (he mentioned that the experience of monitoring alongside Dr. Buckingham convinced Dexcom’s Mr. Andy Balo to rapidly push Share through the pipeline!). However, there is a lack of research investigating remote monitoring and more work in this field is needed.
- Dr. Buckingham ended his discussion with these final words of wisdom about how to avoid hypoglycemia: “Get a sensor, or sensor-augmented pump, or hybrid closed loop system – probably what you expected from me.” This is exactly what we expected – see our preview if you don’t believe us : > Day-to-day variability in insulin sensitivity makes it nearly impossible to prevent glucose excursions (both up and down) without real-time feedback, ideally supplemented with automation.
- To highlight the value of real-time CGM, Dr. Buckingham discussed a tragic example of a driver who got behind the wheel with a 108 mg/dl reading. 30 minutes later, the driver crossed the divider and killed a mother in another vehicle – his glucose reading was 20 mg/dl. Had the driver had been wearing a real-time CGM with trend arrows, this preventable death could likely have been avoided.
- According to a recent 2017 study published in Pediatric Diabetes, parents of children with diabetes three years old or younger express significant fear of hypoglycemia at night. Not surprisingly, the data also suggest highly significant (p<0.001) fear at night amongst parents of pump users. Concerningly, Dr. Buckingham found that 71% of parents fail to recognize when their child is low – imagine how impossible this would be for a teacher in a crowded school setting! CGM and remote monitoring need to become the standard of care in all insulin users, and especially in the pediatric population.
Plenary Eight: New Therapeutic Choices for Diabetes Treatment
Are New Basal Insulins Any Better?
Simon Heller, MD (University of Sheffield, UK)
Dr. Simon Heller outlined the major advantages of next-generation basal insulins – Novo Nordisk’s Tresiba (insulin degludec) and Sanofi’s Toujeo (insulin glargine U300) – focusing especially on reduced hypoglycemia, an outcome beyond A1c that we cannot emphasize enough. Dr. Heller shared current statistics indicating that people with type 1 diabetes experience one severe episode of hypoglycemia per patient-year, while people with type 2 experience one severe episode per three patient-years, on average. Studies using CGM show that unrecognized hypoglycemia is common, occurring in 63% of patients with type 1 and 47% of patients with type 2 diabetes. Moreover, 74% of these unrecognized cases happen at night. Another study Dr. Heller presented found that 54% of hypoglycemia is nocturnal, and 83% is unrecognized. He emphasized that nocturnal hypoglycemia is associated with a nearly 10x increase in bradycardia, which is one of many reasons that the complication is so dangerous. While Sanofi’s Lantus (insulin glargine U100), a current standard of care, is associated with a 14% decrease in nocturnal hypoglycemia vs. NPH insulin (Dr. Heller pointed out that this finding led to a most-welcome change, promoting widespread use of Lantus), Tresiba does one better. Novo Nordisk’s SWITCH 1 study in type 1 diabetes reported an 11% risk reduction for the primary endpoint of severe or blood glucose-confirmed symptomatic hypoglycemia with Tresiba vs. Lantus (p<0.0001) as well as a 36% risk reduction for severe or blood glucose-confirmed symptomatic hypoglycemia overnight (p<0.0001). SWITCH 2 used the same trial design but enrolled participants with type 2 diabetes, and found a 30% risk reduction for the primary endpoint with Tresiba vs. Lantus (p<0.0001), plus a 42% risk reduction overnight (p<0.0001). Full results from the DEVOTE CVOT comparing Tresiba vs. Lantus were presented at ADA 2017, and insulin degludec showed a remarkable 40% risk reduction for severe hypoglycemia vs. insulin glargine in a much larger sample size (p<0.001). Even more impressive was the data on nocturnal hypoglycemia: Risk for a severe low overnight was reduced by 53% with insulin degludec vs. insulin glargine (p<0.001). The EMA approveda label update for Tresiba to include the SWITCH 1 and 2 hypoglycemia data in 1Q17, and we’re eagerly awaiting an FDA decision on this same label revision by September 2017. Dr. Heller described how regulatory authorities were reluctant to include hypoglycemia as a known benefit of the degludec formulation due to lack of double-blind studies, so SWITCH 1 and SWITCH 2 were designed to address this. Given the persistence of severe and nocturnal hypoglycemia as diabetes complications, this benefit is a major advantage of insulin degludec therapy, as it could address one of the great looming health and health economic consequences of diabetes (hypoglycemia has a distinct adverse impact on patient quality of life, and is also very costly for the healthcare system). Indeed, our fingers are very crossed that this important benefit is reflected on the Tresiba product label in the US, soon.
- Dr. Heller concluded that while insulin degludec currently seems to provide the most robust and clinically-significant reductions in severe hypoglycemia in type 1 and type 2 diabetes vs. insulin glargine U100, similar trials with Sanofi’s Toujeo (insulin glargine U300) are underway. We’ve heard from thought leaders that Tresiba offers a flatter PK/PD profile for less daily glycemic variability, and that the flexible dosing of Tresiba makes it an even more convenient therapy vs. Toujeo. That said, we know the value of having multiple products with high efficacy on the market. Moreover, we underscore that many people with diabetes aren’t yet accessing either next-gen basal insulin product, so we see more than enough room for both Tresiba and Toujeo to do well commercially and enhance diabetes care broadly in type 1 and type 2.
Can Residual Beta Cells in Type 1 Diabetes Be Rescued?
Lori Sussel, PhD (Barbara Davis Center, Aurora, CO)
Representing the basic science wing of the Barbara Davis Center, Dr. Lori Sussel provided a fascinating overview of recent research on beta cell physiology and its implications for the future of type 1 treatment and cures. The most exciting breakthroughs in her view are the discovery of multiple beta cell subtypes and an alternate theory for type 1 pathophysiology whereby rather than beta cell death, islets are losing their cellular identity (a process that may be reversible):
- Recent findings demonstrate that “not all beta cells are created equal.” Beta cells come in four subtypes, distinguished by different gene expression profiles and patterns of basal and glucose-stimulated insulin secretion – this finding was published in Nature Communications in July 2016, and beta cell heterogeneity was a key theme at Levine-Riggs 2017. Subsequent studies have revealed that people with type 1 diabetes have a different ratio of these beta cell subtypes vs. the general population. This raises important questions regarding whether an individual’s distribution of beta cell subtypes plays a causal role in determining type 1 diabetes risk, whether these different beta cell subpopulations serve unique functional roles, and whether certain beta cell subpopulations are more susceptible to the autoimmune response than others, Dr. Sussel explained. This research is still very early-stage, but it underscores that beta cells are more complex than was originally appreciated, and this must be factored into any beta cell replacement strategy.
- Dr. Sussel’s own research is focused on beta cell plasticity, the idea that different mutations can cause beta cells to differentiate into other cell types, or to produce other hormones besides insulin. Her team demonstrated that deletion of the Nkx2.2 gene decreases the glucose responsivity of beta cells by causing them to lose glucose transporters. Instead of dying, these mutated beta cells begin to change identity, producing somatostatin instead of insulin. Dr. Sussel pointed to evidence showing that a similar loss of beta cell characteristics is happening in people with diabetes. Investigation of pancreatic islets in both type 1 and type 2 diabetes shows increased somatostatin levels, an indication that beta cells are losing their normal insulin-secreting characteristics. The discovery of beta cell plasticity challenges the traditional model of type 1 diabetes in which the primary defect is beta cell death, suggesting instead that the loss of beta cell function may be due to the cells changing identity. The natural extension of this finding, according to Dr. Sussel, is a new approach to type 1 therapy involving the repair – rather than replacement – of these cells via gene therapy. We’d be very excited for a therapy in this vein to next join the competitive landscape for type 1 diabetes therapies and cures.
Role of SGLT-1 and 2 Inhibitors in Type 1 Diabetes
John Buse, MD (UNC, Chapel Hill, NC)
In the final plenary of the meeting, Dr. John Buse discussed SGLT-1/2 dual inhibitors, namely Lexicon’s phase 3 sotagliflozin, which mitigates the DKA risk associated with current SGLT-2 inhibitors in type 1 diabetes. Safety concerns surrounding DKA and euglycemic DKA in particular (when the absence of hyperglycemia makes it more difficult for patient/provider to identify and treat the complication) have been a major roadblock in the clinical development of SGLT-2 inhibitors for a type 1 indication. According to Dr. Buse, patients with type 1 diabetes taking an SGLT-2 inhibitor off-label face a 5%-10% risk for DKA over one year of treatment, and that’s “scarily high.” That said, he pointed to a recent study which found that 67% of DKA episodes attributed to SGLT-2 inhibitor therapy had an obvious precipitating event, something like alcohol intake, reduced insulin dose, or dehydration. He maintained that SGLT-2 agents can have profound benefits in type 1 diabetes care, as long as the patient is trained to check ketones, stay hydrated, consume carbs with full doses of insulin if feeling unwell, and proactively hold the SGLT-2 therapy ahead of potential precipitants (i.e. a hike that will cause major energy expenditure and calorie burn). We appreciated this commentary and Dr. Buse’s practical recommendations for off-label SGLT-2 inhibitor use – we continue to believe that DKA risk can be effectively managed in type 1 patients who want to include an SGLT-2 inhibitor in their medication regimen, and we see massive need for better adjunct therapies in type 1 diabetes. Lexicon’s sotagliflozin is closest-to-market for this indication (the company scheduled a meeting with the FDA in 2Q17 to discuss a New Drug Application). Dr. Buse announced with distinct excitement that presentations of inTandem1 and inTandem2 at ADA 2017 were the first phase 3 studies to report for any oral type 1 therapy. He reviewed phase 2 and phase 3 results from the inTandem clinical program, showing sotagliflozin to be effective in lowering A1c without increasing hypoglycemia, reducing bolus insulin dose, promoting weight loss, and decreasing both fasting and postprandial glucose. Importantly, DKA event rates were very small across all inTandem trials, and were mostly in the setting of insulin pump therapy. Dr. Buse interpreted this as a strong safety profile for the drug candidate, one that supports continued development and eventual commercialization. We certainly hope that SGLT-2 inhibitors may one day be an adjunct therapeutic option for people with type 1 diabetes, but near-term, we echo Dr. Buse’s enthusiasm for sotagliflozin and the promise it holds to sidestep DKA-related concerns from providers and regulators.
- Lilly/BI and AZ have ongoing phase 3 programs for their SGLT-2 inhibitor products in type 1 diabetes. Lilly/BI’s EASE-2 and EASE-3 trials for Jardiance (empagliflozin) are expected to complete in October 2017 and September 2017, respectively. AZ’s DEPICT 1 and DEPICT 2 for Farxiga (dapagliflozin) are scheduled to complete in August 2017 and April 2018, respectively. These completion dates are coming up soon, and we’re incredibly eager to see the data. Our fingers remain oh-so crossed that empagliflozin and dapagliflozin demonstrate clinically-meaningful efficacy alongside a highly-manageable safety/tolerability profile among study participants with type 1 diabetes. That said, these companies face multiple investment opportunities for their SGLT-2 inhibitor products – type 2 diabetes, type 1 diabetes, chronic heart failure, chronic kidney disease, etc. We understand that pursuing a type 1 indication may take the backburner for a heart failure indication, given that both Lilly/BIand AZ have initiated studies of their SGLT-2 agents in people with chronic heart failure with or without diabetes. J&J reported phase 2 data for Invokana (canagliflozin) in type 1 diabetes at ADA 2016, but the future of this clinical development project is uncertain. The company is also conducting a dedicated study of Invokana in diabetic kidney disease (CREDENCE, expected to complete in June 2019), and will have to evaluate options in the aftermath of CANVAS full results, which showed significant CV risk reduction but also a nearly two-fold increase in lower limb amputations with canagliflozin vs. placebo.
Achieving Targets Beyond Lifestyle and Prescriptions
Richard Kahn, PhD (UNC, Chapel Hill, NC)
In the highly-anticipated last session of the conference (an event alluded to in Q&A since the very beginning of the meeting) UNC’s Dr. Richard Kahn posed a hard-hitting question: Why are so many people with diabetes “left behind” and not achieving their desired outcomes despite the abundance of available therapies and technologies? He argued that the problem has less to do with whether we are using the “right” drugs or the most advanced devices, and is rather a consequence of our incomplete understanding of behavior and how to change it. Commonly-cited reasons for a high percentage of diabetes patients not reaching target A1c include the cost of diabetes therapy and provider disincentives – lack of awareness of diabetes treatment guidelines, insufficient time to spent with patients, and sheer lack of bandwidth in primary care clinics, where most people receive their diabetes care. But Dr. Kahn pointed out that the issue runs much deeper. Even in the setting of clinical trials where participants receive world-class care, frequent visits and calls, free drugs and supplies, and more of everything if needed, there are non-responders who are “left behind” and don’t reap the benefits of the therapy under investigation. In the DCCT and ACCORD trials, for instance, a sizeable proportion of participants could not get their A1c down to the starting goal of 6% despite strong motivation and the best possible care. He further remarked that A1c didn’t budge after implementing CGM for 15% of participants in the DIaMonD study, and the LEADER trial’s North American participants fared 20% worse than their European counterparts on CV outcomes with liraglutide despite controlling for baseline demographics, disease characteristics, A1c, and body weight (a significant talking point at the recent FDA Advisory Committee meeting for Victoza). In short, “there are people for whom these therapies and technologies don’t work.” Instead, he focused on the fact that there is much left to learn about behavior: How can we best increase motivation, improve rational thinking, and streamline decision-making? These challenges loom even larger against the backdrop of persistent patient disincentives like the cost of therapy, appointment hassles, stress, comorbidities, aversion to a complicated treatment regimen, and the list goes on. Dr. Kahn closed with an impassioned call-to-action, highlighting our “urgent need of robust and comprehensive systems of care” and value-based healthcare that better aligns the incentives of patients and providers as a starting point. We were left feeling the magnitude of this persistent challenge in diabetes care, a fitting note on which to end this conference, and one that reminds us why we come to work every day.
John Buse, MD (UNC, Chapel Hill, NC); Richard Kahn, MD (UNC, Chapel Hill, NC); Steven Nissen, MD (Cleveland Clinic, OH); Simon Heller, MD (University of Sheffield, UK); Lori Sussel, PhD (Barbara Davis Center, Aurora, CO)
Q: Lori, you mentioned keeping beta cells active and reminding them that they are beta cells. Do you have any ideas as to what that might entail?
Dr. Sussel: That’s a great question, and something we’re trying to figure out. We’re looking at signals outside the cell that are telling regulators that they need to be turned on and keep working. But what are the signals from outside the cell talking to the inside of cell – that’s our knowledge gap right now and that’s what we’re trying to figure out.
Dr. Nissen: How far are we from largescale diabetes trials with stem cells that don’t require immunosuppression?
Dr. Sussel: These sorts of trials are going on with ViaCyte’s encapsulation trials right now. We haven’t heard the final outcome, but anecdotally, we’ve heard that maybe cells aren’t surviving, but we’re really close. They were using old-gen cells, and new-gen cells are better. The key is to get the right encapsulation. We’re closer than ever to being able to do that, in studies in both type 1 and type 2 diabetes.
Q: Dr. Buse, what’s the cost-effectiveness of this newer medication (sotagliflozin)? For beta cell preservation, have you tried any of the present medications we use for type 2 diabetes to see what they would do for the hypothesis you suggested?
Dr. Buse: Sotagliflozin isn’t marketed yet, so we don’t know about cost-effectiveness. As far as beta cell preservation goes, I’m not aware of any studies with SGLT-2 inhibitors and beta cell preservation, but I don’t know for sure. Pioglitazone and rosiglitazone have the best data on beta cells in type 2 diabetes. There is probably a negative effect with sulfonylureas and applying these drugs from type 2 diabetes to type 1 diabetes has been, overall, really disappointing.
Q: Are there animal models being used to look at maternal hypoglycemia and fatal outcomes? Perhaps in NOD or obese mice?
Dr. Sussel: There are, and they’re mostly being done at Arizona and University of Colorado with sheep models. They’re doing inter-uterine growth restriction, on different diabetic models of sheep, and looking at babies born and their islets. There is compromised function and often compromised beta cell mass in those babies while they were in the womb. Those studies are ongoing in sheep models.
Q: Can you talk a little bit more about the stress of over-nutrition on beta cell function?
Dr. Sussel: What we know from rodent models is that cells are trying harder and harder to pump out more and more insulin, and over time, they just can’t keep up with the demand. In the past, it looked like mostly you were getting beta cell death, but now at the structural level you’re seeing that these cells are really sick but not dead. So, we hope in that sense, they can start to recover. Those cells aren’t gone – this could be a reversible process. But I must clarify that this is in rodent models. We don’t know in humans if this same process is going on.
Q: Who would you envision using these SGLT-2 agents? Will this medicine affect other nutrient absorption?
Dr. Buse: There is a net effect on calorie balance. It won’t affect nutrient absorption that I know of, but maybe I haven’t thought about it enough. It all boils down to greater precision on the DKA potential adverse event. I do think that requires a substantial amount of vigilance on the patient’s part – they would have to be a reliable patient. In patients with inadequately controlled type 1 diabetes, if they are vigilant and will check ketones and accept the education, I think pretty much everyone with type 1 diabetes would be a good candidate.
Q: The theme of this meeting is practical ways to achieve targets, and it’s clearly a difficult thing. If we can encourage our patients to go to sleep with glucose in the range we prescribed, we have an idea and can test what’s supporting them for one-fourth to one-third of their lives. What technologies do we have to show us this?
Dr. Buse: I think what Dr. Kahn didn’t say, which is worth saying, is that probably the most certain route to improving glycemic control in your patient is to keep doing what you’re doing and just do it more vigorously. With any patient that doesn’t respond well to therapy that you know how to deliver with competence, I think there’s a role for re-setting the entire relationship, referring the patient to a different clinician even within same specialty, to really explore what the issues are. In general, I find that most patients do get better over time, but it often requires a lot of creativity rather than just hitting the same nail with the same hammer and hoping that finally the nail drives through. It needs creativity. One of the things I do that’s a little uncomfortable is tell patients this isn’t working out, and though we’ve both tried our best, we should think about what other kind of helper might be able to help you get to the next step. Sometimes that’s another endocrinologist, sometimes it’s a psychiatrist, or sometimes it’s bariatric surgery.
Diabetes in Special Populations – Pediatric
More Than One Year of HCL in Pediatrics
Gregory Forlenza, MD (Barbara Davis Center, Aurora, CO)
BDC’s Dr. Gregory Forlenza presented un-published data from MiniMed 670G use in 10 of his pediatric patients in the continuation phase and at an ADA diabetes camp, as well as a look at how the system was optimized over time in the pivotal trial. 10/12 BDC pediatric patients (baseline A1c: 8.0%) enrolled in the pivotal trial opted to continue on the system – at three months, A1c had fallen to 7.0%, but this rose to 7.3% at six months, 7.5% at nine months, and 8.1% at 12 months (essentially back to baseline). This drift upwards is a bit surprising to us, since we’d assume these are a pretty engaged group. (We also wonder what happened with hypoglycemia, time in range, and patient-reported outcomes – Dr. Forlenza told us that groups at BDC, Stanford, and Yale have started a 670G Pediatric Collaborative and will be investigating this over the next few months). Dr. Forlenza made the outstanding point that some of these patients are going from age 14 to 16: “they’re supposed to get worse. I consider it a mild victory that their A1cs didn’t go up to 9%.” Prior to the ADA camp, Drs. Forlenza and team were concerned about the transition from Cheeto- and video game-filled days (not at camp) to active days (at camp), considering that the 670G operates based on the insulin requirements of the past six days. They made some preemptive tweaks to the pumps when the kids arrived at camp, and were happy to see that it worked – everyone had the blue shield displayed prominently on their pump home screens, indicating they were in Auto Mode. Relative to the six days of home 670G use, six days of 670G use at camp was very successful: Mean blood glucose was roughly the same (158 mg/dl at home vs. 156 at camp), percent of time in closed loop improved by about an hour per day (82% to 88%), as did time in range (68% to 71%) and time >180 mg/dl (30% to 27%). Time in hypoglycemia stayed flat at a very low 2%. As expected, total daily dose at camp plummeted by a remarkable 26% (from 51 to 37 units per day), indicating how much more active the kids were.
- A paper on optimizing hybrid closed loop in pediatrics, authored primarily by Ms. Laurel Messer and the 670G Pediatric Collaborative, will be published soon. Previewed data indicated that mean TDD, mean basal/autobasal insulin, mean bolus insulin, % basal/bolus split, and mean 24-hour basal program did not significantly vary over the course of the pediatric pivotal trial, indicating that glycemic improvements were likely unrelated to these parameters. Rather, the analysis found that significantly more aggressive carb:insulin ratios over time correlated with improved time in range. We’d note that this is a sneaky way to compensate for the 670G’s more conservative daytime dosing – give more manual bolus upfront and let the system shut off insulin if necessary. This is a viable strategy if patients are bolusing, though probably not a solution if patients are missing boluses.
- Another plot showed, as expected, that time in Auto Mode correlated well with time in range – another reason that clinicians (and Medtronic) will need to focus on keeping patients in Auto Mode for as much time as possible.
- Dr. Forlenza emphasized the importance of updating basal rates for situations when patients get exited from auto mode: “One of my patients grew like two feet in two years since he started the study – he started as a pre-pubertal 14 year old, and now he’s a 16 year old man.” Insulin requirements change drastically in this time. To keep basal rates updated, Dr. Forlenza takes the total daily dose, divides it by 24, and multiplies by 0.8 to be cautious, then goes up or down depending on the time of day (more insulin resistant in the morning, exercise in the afternoon, etc.). As a reminder, the MiniMed 670G does not continuously update the background manual mode pre-programmed basal rates, meaning clinicians/patients will still need to do this.
- Dr. Forlenza had a number of quotable quotes putting the 670G in the broader closed loop context and reflecting on patient experiences:
- “The 670G is analogous to Zack Morris 1980s cell phone – it doesn’t have games or widgets – but in the 1980s, it was just amazing that you could be talking on the phone while not touching a wall. My kid would say “you were excited about this?” The system has constraints on it, but does amazing things relative to where we are right now.”
- “The coolest thing we see with artificial pancreas systems is the shattering of the paradigm of trading between lower A1c and less hypoglycemia – minimizing variability does both.”
- “Glycemic spread, standard deviation is the real measure of frustration. Patients always come in and say, ‘I just feel like it’s out of control, I’m always 300 or 50.’ If you reduce that, you improve quality of life.”
- “Telling people ‘2.5 more hours in range’ is much more impactful than saying ‘7% more.’ And 45 minutes per day less time less than 70 mg/dl is huge, anyone with diabetes knows 45 minutes feels like two hours at less than 70 mg/dl.”
- “Adolescents are more difficult than adults – everyone in this room knows that. We have a much harder job then the group next door.”
Early Diagnosis of Type 1 Diabetes Through Antibody Screening
Andrea Steck, MD (Barbara Davis Center, Aurora, CO)
Dr. Andrea Steck delivered an engaging talk on the etiology of type 1 diabetes, offering a comprehensive review of what we know so far about the natural history and causes of type 1, and discussing current trials. People with type 1 diabetes generally progress from genetic risk to immune activation, immune response (single autoantibody development), and then through four stages of the disease: (i) ≥two autoantibodies with normal glucose tolerance, (ii) abnormal glucose tolerance, (iii) clinical diagnosis, and (iv) long-standing type 1 diabetes. ADA diagnostic criteria require fasting plasma glucose >126 mg/dl, 2-hour glucose >200 mg/dl, or A1c >6.5%. The natural history of diabetes can be monitored via biomarkers of immune response to beta cells (autoantibodies, t-cell response) and via biomarkers of metabolic changes (oral glucose tolerance test, A1c, CGM). In the Barbara Davis Center’s DAISY study, children age 0-11 who were either a first-degree relative of someone with type 1 diabetes or who screened positive for high-risk HLA antibodies were followed for development of islet autoantibodies. Participants were provided with education, glucose meters, and test strips. Among children who progressed to type 1 diabetes, those in the DAISY trial were diagnosed at a lower-onset A1c vs. other children in the community not enrolled in the study – 7.2% vs. 10.9%, respectively. Dr. Steck described this as an encouraging result, given that earlier intervention affords more opportunity to treat hyperglycemia and prevent long-term complications of diabetes. Another positive finding from DAISY was that many children were diagnosed outside the context of DKA or a hospitalization. Dr. Steck stated that in Colorado, 40%-50% of new-onset type 1 diabetes is diagnosed during a DKA episode – being able to avoid this is an important step in advancing screening and treatment for pediatric type 1 diabetes. Of particular note, DAISY used CGM to mark early glycemic changes. Dr. Steck shared one particularly striking anecdote of a DAISY participant who wore a CGM leading up to diabetes onset. Six months before onset, 14% of blood glucose readings were >140 mg/dl and A1c was 5.8%. Two months before onset, 44% of readings were >140 mg/dl and A1c was 6.8%. At onset, 53% of readings were >140 mg/dl and A1c was 6.1%. CGM data allowed this patient to begin insulin therapy with only Humalog (Lilly’s insulin lispro) at dinnertime, as his providers could see this is where he was having the highest blood glucose readings. Not that we needed more convincing, but this illustrates the critical value of CGM during all stages of diabetes to help people achieve their optimal glycemic control, to help personalize treatment strategies, and to give patients the best possible diabetes management for long-term prevention of complications.
- The TEDDY study, an international, multi-site trial that screened participants at birth for high-risk HLA genes and followed-up with antibody screening, also showed lower rates of DKA at time of diabetes diagnosis. Comparatively, rates of DKA at diagnosis for children <two years-old were significantly lower in TEDDY vs. SEARCH and the Swedish, Finnish, and German registries. This trend remained statistically significant for children <five years-old vs. SEARCH and the German registry. In an analysis of 43 TEDDY cases matched to community controls, TEDDY children had significantly lower A1c, age, rates of DKA, and hospitalization at diagnosis, and only 50% showed symptoms at diagnosis compared to almost 100% of community controls. C-peptide levels among TEDDY participants were also higher on average throughout the first year post-diagnosis. Ultimately, Dr. Steck suggested that earlier diagnosis is key to better long-term outcomes (starting with less DKA and fewer hospitalizations).
Diabetes Care Challenges in Minority Populations
Andrea Gonzalez, MD (Barbara Davis Center, Aurora, CO)
Dr. Andrea Gerard Gonzalez highlighted the Barbara Davis Center’s newly-established Latino Program for type 1 diabetes, which has improved diabetes outcomes in this harder-to-reach population. She set the stage with a description on the elevated risk for poor metabolic control and diabetes complications in minority populations – a phenomenon she noted is not well understood, but likely has a great deal to do with differences in health literacy and suboptimal communication between HCPs and people from different backgrounds. The Barbara Davis Center’s Latino Program was established to address this issue. More than 700 Latino-Hispanic families affected by type 1 diabetes receive care from this program, which features culturally-sensitive educational materials, Spanish-speaking HCPs, and regular group clinic appointments designed to build a strong sense of community and foster open discussion of diabetes care challenges. This approach works: Dr. Gonzalez shared that after two years, participants in the program experienced significant reductions in A1c: -1.2% in the first year (p=0.01) and -0.6% in the second year (p=0.007) from a baseline of 9%. The population also saw a significant increase in insulin pump use. These are impressive findings, and we would love to see more examples of this kind of culturally-sensitive and community-driven approach to diabetes care. Beyond reaching minority populations in this way, we agree with Dr. Gonzalez that it is crucial to further elucidate the causative mechanisms that place minority populations and groups from low socioeconomic status at higher risk of poor diabetes outcomes in the first place. This is certainly one of the more challenging systems-wide issues in diabetes care.
Diabetes in Special Populations – Adult
Cardiologist View on Glucose Control
Steven Nissen, MD (Cleveland Clinic, OH)
Dr. Steven Nissen offered the cardiologist’s perspective on diabetes care, arguing that it has taken the field far too long to emphasize CV outcomes. Merely lowering glucose is far too simplistic as a treatment goal, because ultimately, we want to improve outcomes. Dr. Nissen described the era of diabetes management pre-CVOTs as the “Dark Ages,” when endocrinologists and regulatory authorities were satisfied with a therapy based solely on its A1c-lowering efficacy (he provided a memorable visual of two ostriches burying their heads in the sand, one representing FDA, the other representing diabetologists). A meta-analysis of the ACCORD, ADVANCE, and VADT trials found no significant association between a modest ~1% A1c decline and CV outcomes: The hazard ratio was 0.97 for stroke (in favor of glucose-lowering) and 1.03 for coronary heart failure (trending against glucose-lowering). Dr. Nissen reminded the audience that large diabetes CVOTs employ a glycemic equipoise design, meaning patients are treated toward the same target A1c in the treatment and placebo arms. In EMPA-REG OUTCOME (for Lilly/BI’s SGLT-2 inhibitor empagliflozin), LEADER (for Novo Nordisk’s GLP-1 agonist liraglutide), and CANVAS (for J&J’s SGLT-2 inhibitor canagliflozin) alike, A1c was ruled out as an explanation for cardioprotection. Instead, there must be something inherent to each therapeutic molecule conferring CV benefit, and Dr. Nissen issued a wake-up call to regulators and guideline-writing committees to recognize the value of cardioprotection in diabetes management. We were pleased to see Jardiance (empagliflozin) and Victoza (liraglutide) recommended to type 2 diabetes patients at high CV risk in the ADA’s 2017 Standards of Care, and the FDA approval of a new CV indication for Jardiance was a big step in this post-Dark Ages era of CVOTs. We’re hopeful that the FDA will follow-through with a new CV indication for Victoza as well, following last month’s Advisory Committee meeting.
- Pushing for even more forward progress, Dr. Nissen suggested that one next step for CVOTs might compare a GLP-1 agonist vs. an SGLT-2 inhibitor, or might investigate the additive CV effects with co-administration of both agents. AZ’s DURATION-8 is the first major clinical trial to evaluate this particular combination: Participants in the treatment arm received GLP-1 agonist Bydureon (exenatide once-weekly) alongside SGLT-2 inhibitor Farxiga (dapagliflozin), and quite notably, achieved statistically significant A1c decline and weight loss vs. either monotherapy. That said, Dr. John Buse has suggested that there isn’t enough evidence right now to assume an SGLT-2 inhibitor and a GLP-1 agonist would have additive CV benefit, especially since they have differential effects on glucagon.
- Dr. Nissen further argued that TZD pioglitazone is under-utilized in diabetes care, based on CV outcomes data. A secondary outcome in the PROactive study showed a statistically significant 16% risk reduction for three-point MACE (non-fatal MI, non-fatal stroke, and CV death) with pioglitazone vs. placebo (HR=0.84, p=0.027), which Dr. Nissen characterized as “very similar to what was reported with empagliflozin and liraglutide.” More recently, the IRIS trial showed a statistically significant 24% risk reduction for stroke or MI associated with low-dose pioglitazone in patients without diabetes but exhibiting insulin resistance (p=0.007). We also can’t ignore the fact that pioglitazone is generic, and thus lower-cost vs. empagliflozin or liraglutide currently. In Dr. Nissen’s words, “pioglitazone ought to be considered.”
Diabetes Complications Update
George Grunberger, MD (Grunberger Diabetes Institute, Bloomfield Hills, MI)
Past AACE president Dr. George Grunberger followed Dr. Nissen and shifted focus from macro to microvascular disease, where meticulous glucose control is the crux of preventing complications. In contrast to CV outcomes, which seem to depend on much more than A1c, Dr. Grunberger explained that “microvascular complications are a direct consequence of hyperglycemia.” In reviewing the latest guidelines on retinopathy, nephropathy, and neuropathy, he showed how time and time again optimizing blood glucose (as early as possible) is at the core. Only ~3% of people with newly-diagnosed diabetes present with nephropathy, for example, and ~50% of cases of diabetic nephropathy occur in people with diabetes duration ≥20 years, when longer exposure to high blood sugar has done its damage. Dr. Grunberger positioned the Steno-2 study as a paradigm of what diabetes care providers should be doing to minimize microvascular disease – treat glucose, lipids, blood pressure, and smoking all at once. We recently learned the 21-year results from Steno-2 at ENDO 2017, and indeed, multifactorial intervention was associated with a median increase in survival of 7.9 years and a 45% risk reduction for all-cause death (HR=0.55, p=0.005). Four-year data from Steno-2 was enough to demonstrate clinically-meaningful reductions in microvascular disease, according to Dr. Grunberger.
Patient/Provider Question and Answer Panels
Pediatric Patient Panel
Drew; Gavin; Yanci
The patient/provider discussion panels are a beloved and highly-anticipated tradition at Keystone, and this year certainly didn’t disappoint. Several Barbara Davis Center patients took the stage to discuss their unique stories on life with diabetes. The pediatric panel, featuring 16 year-old Drew (who participated in the 670G pivotal studies), eight year-old Gavin (who was diagnosed with type 1 diabetes two years ago through the TEDDY study), and 18 year-old Yanci (who participates in the Barbara Davis Center’s Latino clinic), touched upon the impact of diabetes technology and the ways in which this chronic disease affects family dynamics and life at school. We capture the power of this session best through a collection of the most quotable quotes.
- On Having Diabetes at School
- Gavin: “It’s kind of helpful that everyone in my class knows cause then they know that if I don’t hear a beep and they do then they can tell me about it.”
- Drew: “I wouldn’t say that many people know about my diabetes – I don’t talk about it unless it’s absolutely needed. My close friends know as a safety net so that they can get help if I start acting strangely. I’m in high school and people aren’t the nicest. I’ll answer them honestly if they ask about my pump or meter, I’ll have a discussion, but I don’t like to advertise it.”
- Yanci: “I just graduated from high school this May. Mostly everybody knew about my diabetes. When I was younger people made such a big deal of it because it was so rare in this small school. What I most remember is “do the shots hurt?” “Can you eat this?” I know good people, and I don’t have to hide my diabetes. What I didn’t like was the pity – “you’re so little, you don’t deserve this.” Half the school knew I had diabetes because I would go to the nurse to take my medicine. I’m pretty open about it.
- On Family Dynamics
- Drew: “I think my parents did treat me differently for a year or two after being diagnosed. I would go to sleepovers before, and I didn’t go to one the week after I was diagnosed and I felt that pattern of worry for a year or two after being diagnosed […] After I was diagnosed it wasn’t something I really cared about and my mom handled most of it for me, but when I got on the 670G I started to pay attention and learn how to do everything myself for my treatment.”
- Gavin’s mom: “We’ve had some struggles with site changes and we don’t want him to feel like he has no control over what’s going on in his life, so we explain and discuss that he has to have insulin. He decides if he wants to do a site change or change and go back to shots for a while. We want him to be in control and try to make sure we all understand what’s going on.”
- Yanci: “The only time we’ve had conflicts are when I have to check my blood sugar. I used to try to ignore it and we would talk about it that later that day, and they had expected me to check 4-6 times and I would just say that I would but then not check. Since I was little I’ve done my own shots. Now they just have me check in front of my mom, or sister, or dad, or they follow me on their phones.”
- On New Technology
- Yanci: “The Dexcom does make me more aware of my highs because it beeps every 5 minutes and is so annoying. So this helps me bring my blood sugars down much quicker. I can just look at my phone and take action really quick.”
- Drew: “The biggest suggestion I can give from personal experience with the 670G is that it isn’t an end-all, be-all solution. It’s a treatment tool like any other. Just remember that. You need to use the tool correctly.”
- Gavin’s mom: “Worry is all relative. After he was diagnosed, Dexcom – or a CGM in general – was on our mind. If I had my way we would be finger poking every five minutes for my peace of mind, so CGM was very important. It comes into perspective when we need to recalibrate and can’t get readings for 2 hours. We just had a sensor expire when he was pretty low, which brings to mind how much we rely on it when we aren’t in those good numbers.”
Meet-the-Peers Sessions – Adult
Issues with Diabetes Therapy in the Elderly
Simon Heller, MD (University of Sheffield, UK)
Dr. Simon Heller discussed the Lilly-sponsored IMPERIUM study, a phase 4 investigation of low hypoglycemia strategies vs. standard of care for elderly patients with type 2 diabetes, which was terminated early because of what may have been the wrong choice for primary endpoint. Participants with type 2 diabetes age ≥65 (n=191) were randomized to one treatment arm with pharmacological interventions designed to avoid hypoglycemia (TZDs, metformin, GLP-1 agonists) or to another with standard of care (insulin glargine and a sulfonylurea, to start). After 24 weeks, the study found no significant difference on the primary endpoint of treatment success, or the proportion of patients in each group (n=98 in low hypo strategy, n=93 in traditional strategy) achieving A1c goal with no clinically-relevant hypoglycemia (defined as a period of low blood sugar that interrupts normal activity): 55% of the low hypo group and 65% of the traditional strategy group achieved treatment success (p=0.19). A1c decline was also similar in both IMPERIUM arms, dropping by a mean 1.1% in the low hypo group and by 1.2% in the traditional strategy group (from a baseline 8.3% across the study). That said, Dr. Heller pointed to impressive treatment differences on endpoints of asymptomatic hypoglycemia (only 8% in the low hypo arm vs. 32% in the standard of care arm, p<0.001), documented symptomatic hypoglycemia (5% vs. 39%, p<0.001), and total hypoglycemia (10% vs. 54%, p<0.001). No episodes of severe hypoglycemia occurred over the 24 weeks. Nocturnal hypoglycemia was numerically less frequent in the low hypo group (4% vs. 11%), although this association didn’t quite reach statistical significance (p=0.077). Dr. Heller remarked that IMPERIUM might have continued if the investigators had chosen a different primary endpoint, given that glucose-dependent therapies like TZDs, metformin, and GLP-1 agonists were associated with significant, meaningful reductions in asymptomatic, symptomatic, and total hypoglycemia. He advocated that these results still be used to inform diabetes care in older patients, a population that is particularly prone to hypoglycemia and to hypoglycemia unawareness. We’d love to see sulfonylureas eliminated from treatment regimens, definitely for patients at high-risk for hypoglycemia but also for patients with diabetes more broadly, given the weight gain and possible CV harm. We’re also curious how the low hypoglycemia strategies in IMPERIUM affected daily insulin requirements, and how insulin dose may have mediated the frequency of low blood sugar (although it also seems that older patients with longer duration of diabetes would be more likely to be on insulin therapy). Dr. Heller emphasized the importance of individualized glycemic targets, recommending to HCPs that they set an A1c goal <8.5% for elderly patients with frailty, but otherwise choose an A1c goal on par with what they would suggest to a younger patient (closer to A1c <7%). We were pleased to hear this clinical advice from Dr. Heller, since there have also been voices in the field advocating for less stringent A1c targets for elderly patients based on age alone. We’re opposed to the idea that any individual should have to compromise their desired glycemic control when there are glucose-dependent agents available (like those prescribed to IMPERIUM participants in the low hypo strategy), as well as CGM and educational tools that can help manage hypoglycemia risk.
- Dr. Heller pointed to the irony that the vast majority of people with type 2 diabetes in the US are ≥60 years-old, and yet clinical research in this patient population is scarce. One literature search found that 289 of 440 investigations of type 2 diabetes treatments had an upper age limit (66% of studies), which Dr. Heller argued was rarely justified. Only six trials in this search were designed specifically to evaluate therapies in older adults. We certainly understand the major resources that go into conducting clinical trials, but we also appreciate Dr. Heller’s suggestion that the diabetes epidemic – costing the US healthcare system >$421 billion annually – is currently driven by older adults, and so more dedicated research in this population is more than warranted. Perhaps payers and regulatory agencies could better align incentives for industry to sponsor clinical trials specifically in elderly patients.
Transition of Care from Inpatient to Outpatient
Guillermo Umpierrez, MD (Emory University, Atlanta, GA)
Dr. Guillermo Umpierrez called attention to an important but seldom-discussed aspect of diabetes care: how to manage diabetes following hospital discharge. He reviewed new data just presented at ADA 2017 demonstrating the efficacy of DPP-4 inhibitor linagliptin (Lilly/BI’s Tradjenta) as an alternative to the typical prescription of basal insulin. Linagliptin resulted in equivalent glycemic control and lower rates of hypoglycemia – a key consideration in patients who are already at elevated risk of hypoglycemia from recent hospitalization. The study enrolled people with type 2 diabetes (n=140) on oral antidiabetic agents and low-dose basal insulin with A1c>7.5%. Participants were randomized to linagliptin or insulin glargine (Sanofi’s Lantus) for 24 weeks of long-term post-operative care. Mean daily blood glucose did not differ significantly between the linagliptin and insulin glargine groups (146 mg/dl vs. 157 mg/dl, p=0.06), but the frequency of hypoglycemia (defined as blood glucose <70 mg/dl) was significantly lower among linagliptin-treated patients (3% vs. 37%, p<0.001). This bolsters evidence for the utility of DPP-4 inhibitor therapy during the transition from inpatient to outpatient care. Similar results were presented at ADA 2016 for sitagliptin (Merck’s Januvia) in the Sitagliptin Discharge Trial. Dr. Umpierrez emphasized that the use of agents like linagliptin associated with lower hypoglycemia with no compromise in glycemic control should be preferred over basal insulin for post-operative management of diabetes, going so far as to recommend that insulin therapy should be entirely avoided in post-operative diabetes care unless the individual’s A1c is in the 8-9% range.
Management of Comorbidities
Aaron Michels, MD (Barbara Davis Center, Aurora, CO)
The Barbara Davis Center’s Dr. Aaron Michels discussed the strong association between type 1 diabetes and other autoimmune diseases, urging providers to screen for these accordingly. More than 25% of people with type 1 diabetes have at least one other autoimmune disorder, according to the T1D Exchange Clinic Registry. Thyroid autoimmunity (Hashimoto’s disease [hypothyroidism] and Grave’s disease [hyperthyroidism]) accounted for 68% of these comorbid cases, GI diseases (celiac disease and inflammatory bowel diseases such as ulcerative colitis and Crohn’s disease) accounted for 22%, muscle and joint conditions (rheumatoid arthritis, psoriasis, lupus, and scleroderma) accounted for 6%, skin diseases (vitiligo, alopecia, and dermatomyositis) accounted for 4%, and Addison’s Disease, a condition involving reduced cortisol secretion from the adrenal glands, accounted for 1%. Dr. Michels highlighted thyroid disorders and celiac disease as the “Big Two” that tend to cluster together with type 1 diabetes. He recommended increased screening for these autoimmune conditions particular (ideally, every two-three years in the absence of concerning symptoms). As for the likelihood of developing another autoimmune disease, Dr. Michels underscored that the biggest risk factor is time. Across the age spectrum, the incidence of autoimmune diseases in addition to type 1 diabetes steadily increases without an apparent plateau, rising from 20% in those age 0-13, to 35% in those age 26-50, to nearly 45% in those older than 65. Unsurprisingly, diabetes duration is also associated with more autoimmunity; 40%-50% of people develop another autoimmune condition after 50 years of diabetes, and those diagnosed before age 18 are at particularly elevated risk. Additional risk factors include female sex and white ethnicity. Notably, A1c is entirely uncorrelated with autoimmunity. Dr. Michels concluded by remarking that when it comes to autoimmunity “no disease is an island – if you look for more, you’ll find more.” We hope that Dr. Michels’ call for increased screening for other autoimmune diseases in people with type 1 diabetes takes root in real-world clinical settings, and that earlier detection will ease the burden of these conditions.
Meet-the-Peers Sessions – Pediatric
Psychologial Challenges in the Young
Shideh Majidi, MD (Barbara Davis Center, Aurora, CO)
Dr. Shideh Majidi advocated for increased screening of youth with type 1 diabetes for diabetes distress, depression, suicidal ideation, and anxiety. She also discussed a number of programs at the Barbara Davis Center aimed at addressing these all-too-often overlooked issues. Dr. Majidi acknowledged that providing high-quality psychosocial care is no easy feat – it requires a very personalized, patient-centric view and attention to social, behavioral, and environmental factors affecting an individual’s experience with chronic disease. Endocrinologists face many constraints (keeping appointments to 30 minutes, charting in the room to finish work on time, etc.), but still, Dr. Majidi argued that every provider should be putting more emphasis on psychosocial aspects to diabetes management. More specifically, she suggested that HCPs place greater value on teaching proper self-care behaviors to their patients, and on screening frequently for diabetes distress, disordered eating, cognitive capacities, anxiety, and depression using standardized, validated tools. This call-to-action is particularly compelling given that ~one-third of adolescents with type 1 diabetes show signs of diabetes distress and burnout, which inevitably impairs diabetes management. Children with diabetes face double the risk for depressive symptoms and suicidal ideations vs. children without diabetes, according to Dr. Majidi. Depression is associated with increased A1c over time. Anxiety (persistent fear or worry causing distress and affecting quality of life) is observed in ~20% of children with diabetes vs. 5%-15% of children without diabetes, and is also associated with increased A1c. This anxiety can present as both Generalized Anxiety Disorder and specific phobias of hypoglycemia or needles – the latter is present in 27% of newly-diagnosed children, and is only noticed by HCPs half of the time (we couldn’t believe this). Fear of hypoglycemia is common in adolescents with high frequency of low blood sugars, especially when these episodes occur at school, and among patients with longer duration of type 1 diabetes. Fear of hypoglycemia often leads to avoidance behaviors that most commonly include over-treating low blood glucose and only treating high blood glucose at 250-300 mg/dl (essentially allowing for more exposure to hyperglycemia over the course of life). The ADA has recently taken a strong stance emphasizing psychosocial care, and we hope to hear even more on this topic at future diabetes meetings.
- The Barbara Davis Center has implemented a number of patient-centered care models to address the psychosocial side. Clinical screening for depression and suicidal ideation has been implemented on a yearly basis, and 659 children have been screened since January 2016 – ~11% of BDC patients screen positive for depression, while ~7% screen positive for suicidal ideation. Providers also screen for fear of hypoglycemia, and have found this psychological complication in ~24% of pediatric patients. More than 70% of these patients maintain high blood glucose as a result, and more than 30% have excessive feelings of worry and helplessness. The BDC has launched the Plugged In Program to improve long-term outcomes in recently-diagnosed type 1 patients – this program offers group visits (’Betes Club) as part of a teenager’s regular three-month appointments to promote engagement and facilitate sharing among adolescents with similar social and academic experiences.
Telemedicine and Diabetes Care in Children
Paul Wadwa, MD (Barbara Davis Center, Aurora, Co)
BDC’s Dr. Paul Wadwa positioned telemedicine as the next major shift in diabetes management, but acknowledged possible barriers to implementation including reimbursement, provider skepticism, licensure across state borders, consent, and security. Dr. Wadwa provided a useful breakdown of terminology: telehealth comprises the delivery of health-related services (e.g. electronic health records, phone consultations, etc.), while telemedicine uses information technology to provide clinical health care at a distance. While remote monitoring of CGM and closed loop devices are common in research, Dr. Wadwa believes we’ll eventually see these services in the clinic (beyond a single generous doctor tracking patients on Dexcom Follow). We find substantial potential for telemedicine in hard-to-reach rural populations, serving to reduce administrative and patient burden, improve cost-efficiency, and increase provider productivity. Dr. Wadwa discussed somewhat promising results from a Barbara Davis Center study last presented at the 2014 Keystone conference implementing telemedicine for type 1 pediatric patients across five active sites. Data from two sites showed an increase in the number of visits/year (2.0/year to 2.9/year) and in the proportion of patients visiting four or more times/year as per ADA guidelines (21% to 33%). However, A1c levels, which were already a high initial mean value of 9.0%, did not significantly change after one year. More recent two-year follow-up data (n=34) presented at IPSAD also failed to demonstrate A1c improvement. Dr. Wadwa cited variable glycemic control to explain these results, as A1c ranged from 7.1-13.7% with 50% of participants experiencing decreased or stable A1c. Those using an insulin pump were more likely to see A1c reductions, as were those with higher initial A1c values (not surprising). Now, Dr. Wadwa and the BDC team will turn their attention to improving outcomes, expanding the BDC telemedicine program, exploring other uses (they’re already piloting use of telemedicine to train patients on the 670G system), ensuring sustainability, and facilitating home use. Telemedicine is one of the big question marks in digital health, though it has shown promise in niche applications, such as early detection and treatment of retinopathy (see NIH’s Dr. Judith Fradkin’s talk from ADA). In its most ambitious form, Virta Health hopes to reverse type 2 diabetes in 100 million people by 2025 through its “online specialty medical clinic.”
Corporate Symposium (Sponsored by Insulet)
The Artificial Pancreas: Expectations, Experiences, and Evolution
Trang Ly, PhD (Insulet Corporation, Billerica, MA); Bruce Buckingham, MD (Stanford University, CA); Laurel Messer (University of Colorado, Denver, CO); Adam Brown (Close Concerns, San Francisco, CA)
To kick off this year’s Keystone Conference, Insulet hosted a panel discussion featuring Stanford’s legendary Dr. Bruce Buckingham, BDC’s Ms. Laurel Messer (University of Colorado, Denver, CO), Insulet’s Dr. Trang Ly, and our very own Mr. Adam Brown. In front of ~100 attendees, the panel explored the current state of closed loop systems, expectation management, and future must-haves. Dr. Buckingham led off, calling this an “exciting, amazing, revolutionary, and historic time in terms of control and management. With devices, we’ve consistently introduced more burden, and this is the beginning of coming down the other side.” We don’t undervalue the significance of such a remark coming from a pioneer of the field who has as close to a birds-eye view as anyone we know! Even with such optimism, the panelists all acknowledged that there is no shortage of difficulties associated with the use of a new hybrid closed loop system – Ms. Messer went so far as to refer to the first month of using the 670G as “more work” and a “learning curve.” That is to say, overnight control is remarkable when patients are in Auto Mode, but they still need to calibrate and count carbs during the day, and 670G users still spend an average of ~20% of time in manual mode. It’s crucial that they retain their diabetes self-management skills for these nearly five hours a day when they won’t have the luxury of automated insulin delivery. Similarly, panelists mused on the fact that after using the system for a while, patients (and parents) are not used to adjusting basal rates anymore – all of the clinicians on stage emphasized the importance of holding onto this skill. Moreover, if patients drift out of Auto Mode, they revert to their previous pre-programmed basal rates in open loop – if these are not consistently updated (the 670G doesn’t), they may be inappropriate. To properly manage expectations, Dr. Buckingham recommended underselling hybrid closed loop and having patients be pleasantly surprised if and when they see positive outcomes. Adam highlighted the importance of managing patient behavior (e.g., to avoid manual dosing/hypoglycemia correcting on top of what the system is doing), the amazing overnight impact (even in those in tight control), and why automated insulin delivery may change the conversation around diabetes tech and even enable CGM uptake.
- The panelists culminated their discussion by detailing a few items at the top of their closed loop wish-lists: Dr. Buckingham focused on system adaptability for different patient personalities; Ms. Messer emphasized remote monitoring and clarity on how patients are to handle insulin dosing during the transition from Auto to Manual mode; and, lastly, Mr. Brown called for customizable glycemic targets, use of the most up-to-date CGM and a pathway to quick sensor/transmitter upgrades (i.e., let’s avoid what happened with the Animas/Tandem/Dexcom G4), and the ability to remotely update pump software (“we need to get out of the model of a four-year pump cycle”). Both Ms. Messer and Mr. Brown highlighted the need for Auto Mode to ideally inform the pre-programmed open-loop basal rates, but Dr. Ly confirmed this will not be a feature in Insulet’s first Horizon system (it could introduce risk).
- Our favorite quotes from the panel discussion:
- “This is an exciting, amazing, revolutionary, and historic time in terms of control and management. With devices, we’ve consistently introduced more burden and this is the beginning of coming down the other side.” – Dr. Buckingham
- “Getting patients on closed loop systems will be more work, not less work. As a provider, you need to learn and work with the patients. There will be more alarms, more hassles during the day, and more to keep the system in closed loop. I recommend having patients come in with fairly low expectations and have them be happy when things go well. Undersell this – let them know all the things they will have to do and remind patients that the payoff is great control at night and possibly during the day, but not without work.” – Dr. Buckingham
- “The first month on 670G is the hardest. I always tell patients not to make a decision on this until one month later. It’s a learning curve unlike anything else.” – Ms. Messer
- “There’s no question that CGM is a learning curve accelerator, and since I wear one, I expected little benefit from wearing a closed loop system. But I cannot manage my diabetes while I’m sleeping, so closed-loop has really benefitted me too. It’s also clear that we need more options, because people aren’t doing well enough.” – Mr. Brown responding to an audience question that wearing and learning from CGM is likely just as good as wearing hybrid closed loop
- “The reason to have closed loop is to get rid of variability, have more time in range, and to have a great night sleep. It should control your glucose overnight, which is such a relief to families, to young kids, and to all patients.” – Dr. Buckingham
- “If I’m not running closed loop, I go to bed with one pre-programmed basal program regardless of what happened that day. When you go on closed loop, you realize that is insane.” – Mr. Brown
- “The amazing thing about this, I think, is that you’re going to have a G5 or G6 sensor talking to the Pod and you can leave that PDM in your car and still be modulating your basal rate 24/7, eliminating the need to carry your handheld with you.” – Dr. Buckingham
- “One really exciting thing is that CGM is really coming of age, which is critical for closed loop – allowing for less calibration and better form factor. Investigators used to be forced to use clunky research devices, and now we’re finally seeing a commercial landscape where companies are building real products around the research that patients can actually use.” – Mr. Brown
- “The next step is to handle meals so we can get rid of carb counting – how great would it be if people with diabetes could just get up and start eating? It won’t be here in a year, but I think we’ll see it in three-to-five years.” – Dr. Buckingham
- “Remote monitoring is a must for all pediatric patients. This should be obvious.” – Ms. Messer
- “Companies are realizing they can’t keep charging more for their products. They either need to improve outcomes if they want to charge more, or charge less.” – Mr. Brown responding to a question on how expensive new diabetes technology is.
Corporate Symposium (Sponsored by Medtronic)
Hybrid Closed Loop: Advancing Your Practical Knowledge of the MiniMed 670G System
Fran Kaufman, MD (CMO, Medtronic Diabetes, Northridge, CA)
Medtronic Diabetes’ CMO Dr. Fran Kaufman hinted that there will be a next-gen 670G system with connectivity “in the future,” provided a comprehensive update on the 670G clinical trial program (7-13 year olds almost complete, 2-6 year olds started, 1,000-patient outcomes RCT has begun randomization), and broke out more granular data from the pivotal trial (prior CGM use vs. CGM naive, >50 years old). ~1,000 patients have used the MiniMed 670G at this point, implying the Priority Access Program launch to 630G users is still proceeding quite cautiously.
- A next-generation Medtronic closed loop system with connectivity will be coming “soon.” We knew connectivity was coming ever since Medtronic signed a deal with Roche to provide Bluetooth-enabled BGM for future Medtronic pumps (announced in February). Dr. Kaufman immediately followed her comment with a precautionary “but soon could mean anything, right?” On a recent Roche Accu-Chek Guide webinar, remarks implied that integration with a MiniMed pump could occur as soon as the middle of 2018, but this was not confirmed by Medtronic. We wonder if this next-gen pump will simply be a 670G with Bluetooth built in, if Dr. Kaufman was referring to the advance hybrid closed loop with DreaMed, or something in between. Whatever form it takes, this is a huge win – many view connectivity and remote monitoring as must-haves, especially in pediatric populations. It will also help Medtronic staying ahead of the curve, since several other closed loop systems in development (e.g., Tandem, Insulet, Bigfoot, Beta Bionics) plan to have Bluetooth and smartphone display apps.
- Medtronic’s expansive 670G clinical trial program includes two pediatric studies (7-13 years old and 2-6 years old) and a 1,000-patient, randomized post-approval study.
- The 7-13 year-old study is almost complete and data will be ready “soon.” This is on track with timing for a mid-summer readout shared by Dr. Robert Vigersky at ENDO – he also suggested that data would be submitted to FDA by the end of the year. The trial enrolled 110 patients, 64 of which are in a continued access phase. Dr. Kaufman didn’t share glycemic outcomes data, but she did say that in a total of 16,200 patient-days (36 patient-years), the safety profile is equivalent to that seen in previous studies.
- The 1,000-patient RCT – “the biggest and most complicated trial [Medtronic] has ever done” – has begun the process of randomization. As a reminder, this multi-national trial (US, Canada, and the EU) will randomize patients to 670G, CSII, MDI, or SAP for six months, followed by six months during which every patient uses 670G. People of all ages and durations of diabetes will be included in the trial, though the study cohort will be enriched for the Medicare population – Medtronic hopes this will help its case for reimbursement. The only people excluded from participation are those on dialysis, those who have had a severe cardiac event in the past year, and those recently diagnosed who are still in the honeymoon phase. According to CT.gov, this trial isn’t expected to read out until mid-to-late 2021. We hope interim readouts are possible, since the technology will have moved a long way four years from now!
- There are currently 10 patients enrolled in the 2-6 year-old 670G trial. The plan is to enroll 25 patients in the 5-6 year-old group and 25 in the 2-4 year old group. Great to see this moving quickly, since many parents would probably welcome a better night of sleep. The system is currently approved for ages 14+, and requires patients to have a minimum daily dose of eight units, though we assume this is because it has not been tested in these populations; that said, perhaps some modifications will need to be made for a safer device in these super tough populations.
- A Stanford study examining the clinical startup of 670G is listed on clinicaltrials.gov as “not yet recruiting.” Investigators aim to track 100 patients’ time in auto mode and time in range over a one year period to assess the clinical approach to starting the system. This could lead to improved guidelines for initiation. We love this, since it’s a major concern of several providers we’ve talked to.
- Dr. Kaufman shared that ~1,000 patients have now used 670G, implying it has only reached a couple hundred additional people beyond the Customer Training Phase (~750 people) and pivotal study (124 participants). Members of the pivotal trial continued access phase have now given Medtronic 57,000 patient-days (158 patient-years) worth of trial and real-world date to learn from. The safety profile in all patients is strong, hashing out to roughly one to two episodes of severe hypoglycemia per 100 patient years (that’s just two to four in the entire continued access phase population). Dr. Kaufman pointed out that most episodes have occurred in open loop (e.g., bolusing for a meal and forgetting to eat), but Medtronic still tracks and reports these outcomes because they are part of the system – even the most conscientious patients don’t spend 24 hours a day in auto mode.
- Medtronic remains in talks with FDA regarding a non-adjunctive (replacement) claim for the Guardian Sensor 3 CGM, which would eliminate the need to check blood glucose with a fingerstick before meals when using the 670G system. This is excellent to hear, though with a recommended 2-4 calibrations per day, we wonder if the sensor’s accuracy on fewer calibrations will need to improve before this claim is granted. As a reminder, Guardian Sensor 3 has an adjunctive claim in the 670G, since it modifies basal but is not approved for taking boluses. This claim would (i) reduce user burden (though presumably not every patient performs fingersticks before every single meal); (ii) might open the door for Medicare coverage for the whole system; and (iii) knock down a key step for automatic correction boluses in Medtronic’s planned Advanced Hybrid Closed Loop.
- The immediate next-generation, dubbed “advanced hybrid closed loop” incorporates DreaMed’s Fuzzy Logic algorithm to assist with post-prandial corrections. It will be pitted against the 670G in the NIH-funded FLAIR trial beginning in late 2017.
- In Dr. Kaufman’s view, competition from the field is “exciting,” as it keeps everyone striving to do better. She went on to add that competition helps payers realize that the field is “real.” The 670G has been received well by most payers – she characterized the one holdout (Anthem) as “problematic,” though hoping that they will eventually get on board.
- Much of the presentation was devoted to new sub-analyses from the pivotal study, demonstrating 670G’s benefits, especially overnight. The most compelling analysis was that comparing the 670G outcomes of CGM-naïve patients (n=78) with experienced users (n=78). Experts have voiced that patients with difficulty wearing CGM may not have the best 670G experiences, but this analysis found no difference in time in range between the two groups during the pivotal study. The data wasn’t shared, but Dr. Kaufman added that there is similarly no impact of prior pump use (and some believe it may be easier to initiate pump-naïve patients because there’s less need to re-teach bad habits).
- Another sub-analysis looked at the >50 year-old pivotal trial cohort (n=31): This group saw significant one-hour per day improvements in time between 70-180 (run-in: 71.6%; study: 75.7%), an ~50% reduction in time ≤70 mg/dl (run-in: 6.5%; study: 3.0%), an ~50% reduction in time ≤50 mg/dl (run-in: 1.1%; study: 0.5%), a 0.3% drop in A1c (baseline: 7.2%), and improvements in glycemic variability. We assume this data set is too small for Medtronic to go for Medicare coverage before the 1,000-patient RCT.
- A fascinating slide quantified the variability in nighttime insulin delivery in the pivotal trial that we have qualitatively heard so much about. Unsurprisingly, SD and CV of insulin delivery skyrocketed in auto mode (each increasing by a multiplier of ~eight compared to the run-in period!), and the duration of no-insulin delivery approached two hours/night in auto mode vs. just four minutes during the run-in. The pie chart on the left really helps to visualize the heterogeneity of delivery – ranging from 0-100% of max Auto Mode Delivery, and this is without a change in the total nightly dose! Concluded Dr. Kaufman, “we can’t possibly recapitulate this ourselves.” Time in range improved by an impressive nine percentage points over night (67%->75%), hypoglycemia was halved (6% to 3%), and hyperglycemia declined from 27% to 22%. A particularly strong benefit was observed between 3 am and 6 am (prime dawn phenomenon time).
- We hope future cuts of the date begin using the consensus time-in-range endpoints of <70 mg/dl and 70-180 mg/dl. Though 71-180 mg/dl and <70 mg/dl is not a big difference, having consistency would be ideal.
- The Medtronic team goes into CareLink every week for signals that 670G behaves differently in the real world from how it did in the pivotal study. Based on the most up-to-date data (below), time in auto mode, time in ranges, and mean sensor glucose values still strongly resemble that seen in the pivotal trial. If anything, as operators gain more experience, it may be that time in target is actually creeping up (72% in the pivotal, 74% in data from May, and 76% now).
- Dr. Kaufman shared that, according to CareLink, patients are only really using the 150 mg/dl temporary exercise target ~2% of the time (~50 minutes per day, assuming everyone uses it with equal frequency). This isn’t surprising to us, since getting benefit out of this temp target during exercise requires planning ahead – setting the temp target at least an hour before exercise, which is hard to remember to do in real life. We assume many are simply eating before exercise and letting Auto Mode run, or perhaps others are going back to Manual Mode.
- Dr. Kaufman shared strong views on terminology related to the automation of insulin delivery: “Artificial pancreas is what we all dreamed of, but no one has the same vision of what an artificial pancreas is. I tell people on a plane I work on artificial pancreas, and they say, ‘Oh really, does that cure cancer?’ No, it’s something that has virtually no user interaction, but that’s not where we are, and we don’t want patients to feel over promised with these current systems. We still use a lot of different terms, and I think we’ve been able to confuse a lot of different people with them.” We think Medtronic has done a good job of using hybrid closed loop and being very clear about what the 670G does and does not do; popular media and JDRF, on the other hand, continue to use “artificial pancreas.”
- Medtronic still plans to use IBM Watson’s cognitive computing in future closed loop system (two iterations down the line). According to a briefly-displayed roadmap slide (below), this system will move Medtronic “towards personalized closed loop” by incorporating PID, MPC, and DreaMed’s Fuzzy Logic algorithms, along with Watson’s capabilities. They will together be leveraged to improve interface and meal dosing and recognize patterns, and the slide also suggests that Medtronic will look at additional sensor input signals and sensor/infusion set failure detection. We can’t wait to hear more about the capabilities of the pattern recognition feature – we could see it being highly beneficial in adapting to recurring event-based discrepancies in insulin requirements (e.g., menstruation, soccer practice every weekday at 3, fatty meals Friday at lunch). The timeline for this latest system wasn’t disclosed, but it will presumably require communication from a smartphone to gather additional data and leverage IBM Watson. Medtronic partnered with IBM in April 2015 to improve diabetes care through cognitive computing, analytics, and Big Data, and closed loop algorithms have always been on the agenda for this partnership. When explaining the long-term trajectory of the artificial pancreas program, Dr. Kaufman proclaimed that once the loop is fully closed, then she’ll retire.
- To date, Medtronic and IBM Watson have been busy developing and slowly rolling out the Sugar.IQ pattern recognition app (first demoed at Health 2.0 last September). At ADA, Medtronic Head of Innovation Dr. Huzefa Neemuchwala shared the first data from the “limited learning launch” phase of the Sugar.IQ app with Watson – now tag-lined, “Intelligent Diabetes Assistant App.” Relative to baseline metrics (one month prior), a small group of Sugar.IQ users experienced a solid 37-minute/day improvement in time-in-range, an 11% reduction in sustained hypoglycemia, and an 8% drop in sustained hyperglycemia. We assume the gating factor for this launch is Guardian Connect, the company’s standalone mobile CGM that will compete with Dexcom’s G5.
Therapy Initiation and Management in the Real World
Nancy Lea (Medtronic, Northridge, CA)
Medtronic’s Ms. Nancy Lea discussed updates to the CareLink data management platform, which includes three new reports: assessment and progress, weekly review, and the meal bolus wizard, all of which can be generated regardless of the amount of data collected. The assessment and progress report includes percentile comparisons using current and historical data, time in range, exit information, and a slew of statistics such as time in auto mode, sensor wear, daily dose information, and average blood glucose. The weekly review report provides much of this information but over the course of a week, diving in a bit more with an active insulin curve and dated pump suspension information. Lastly, the meal bolus wizard facilitates observation of trends by collecting data at three time points: one hour pre-bolus, time of bolus, and three hours post-bolus. We find these views to be very user-friendly and a welcome addition to the platform, and we appreciate Medtronic’s commitment to listening to providers to incorporate the most helpful features. We were also reminded that the MiniMed 670G comes with a “suspend before low” (PLGS) feature, which was highlighted by Medtronic’s Ms. Kelsey Winger – this is recommended by Medtronic when not in auto mode. The setting induces pump suspension when sensor glucose is at or within 70 mg/dl of the set low limit and is predicted to fall an additional 50 mg/dl within 30 minutes. We especially like how the feature occurs without alerts (for a max of 2 hours), freeing up some much-needed headspace and correcting a huge criticism of the MiniMed 530G. We assume most patients will use Auto Mode and then have this feature turned on for Manual Mode – the predictive suspend in the MiniMed 640G has been very well received in Europe, though Medtronic leapfrogged this in the US to get straight to the MiniMed 670G. Ms. Winger emphasized that the 670G is designed to gradually adjust blood glucose and to avoid rollercoasters, but is not capable of correcting missed meals or boluses.
Corporate Symposium (Sponsored by Dexcom)
Practical Applications of Therapeutic CGM with Dexcom G5
Bruce Buckingham, MD (Stanford University, CA)
Dr. Bruce Buckingham prefaced his Dexcom symposium presentation on remote monitoring, non-adjunctive use/calibration, and extended G4 wear with trademark humor and energy, cautioning: “Almost everything I say will be off-label. Pediatricians by definitions are outlaws.” Dr. Buckingham highlighted the ability of remote monitoring to significantly cut down parental stress and deemed it essential for children under six, although setting up boundaries for a sharing relationship can be problematic when expectations don’t align – see more on this topic from diaTribe’s panel discussion at FFL. He was particularly excited about non-adjunctive use of CGM, citing the REPLACE-BG study as the first major trial to strongly support non-adjunctive use without sacrificing glycemic control. He recommended continuing fingersticks during the first 12 hours of a new sensor and waiting four hours before using the sensor again after taking acetaminophen, stipulating that it’s important to remain realistic about non-adjunctive use. Dr. Buckingham sees non-adjunctive use as helpful in mitigating risk of mis-calibration, as it requires only two calibrations per day (typically done when waking up and before bed, times where hands are more likely to be clean). Still, he emphasized the importance of washing hands before calibration, referencing one study that demonstrated 50% higher blood glucose values after peeling fruit (even with use of an alcohol wipe!). Echoing Dr. George Grunberger’s talk from earlier in the day, Dr. Buckingham called for consistent CGM reporting and was pleased by Dexcom’s addition of the standard AGP to Clarity, appreciating the ability to delve into each day’s data and clearly view patterns and variability. Still, he’s well aware that most patients almost never look at their download but do view their real-time data 10-15 times per day in hopes of achieving a “no-hitter” (100% time-in-range). He finds trend arrows absolutely critical in attaining this goal, but warns that algorithms pairing trend arrows with insulin dosing adjustments have not been validated and are only meant as rough guidelines – this is a very new field and we expect this will improve markedly over the coming years as decision support comes online for both pumpers (automated insulin delivery) and injectors.
- Dr. Buckingham presented new data investigating extended sensor wear for the Dexcom G4 CGM. Welsh et al. (2017) demonstrated what Dr. Buckingham considered to be nice accuracy over the course of normal seven-day + seven-day consecutive wear times (n=79 pediatric; n=51 adult). Another study examined Dexcom G4 wear for three weeks (n=20): Interestingly, adhesive failures leveled off by day 15, but sensor failure continued to occur increasingly (see picture below). For those sensors that survived, accuracy remained flat over the 21-day period. These data explain why so many people are comfortable using sensors for longer than their intended duration (and why Dexcom CEO Mr. Kevin Sayer loves Germany – “they’re all analytical, they take it off in seven days”). As a reminder, G6 will be 10-day wear and is technically capable of 14-day wear; we don’t believe a mandatory shutoff will be required, but presumably Dexcom will discuss this with the FDA.
CGM Use in Seniors: Clinical Outcomes and Reimbursement
Claudia Graham, PhD (Dexcom, San Diego, CA)
Dexcom Senior Vice President of Global Access Dr. Claudia Graham gave the update we’ve all been waiting for: It has taken a while to implement, but Medicare shipments are up and running…slowly! According to Dr. Graham, Dexcom now has “thousands and thousands and thousands of patients in the queue, and we haven’t even started advertising…bear with us, it’ll take several months to work through all of the patients in the pipeline.” This progress report means that, following the FDA’s non-adjunctive label approval for G5 in December, Medicare’s subsequent benefit category determination (DME, Part B) in January, and the announcement that coverage will be provided in March, “final” local coverage decisions and administrative logistics have been worked out (Dexcom projected in May that this would happen before the end of 2Q17). The company is now in the process of shipping G5 receivers that last for three years (~$236-$277 each), along with G5 sensors, 90-day G5 transmitters, 60 test strips/month, Ascensia glucose meters (partnered earlier this month), lancets, and control solution in a monthly bundled subscription model – the only such model in Medicare besides oxygen! – for ~$240/month (patients pay ~$50/month out of pocket). Dr. Graham noted that 60 test strips will frequently not be enough for a 30-day month (~65-75 would be ideal), nor will four seven-day sensors – as the distributor, it is incumbent upon Dexcom to call the patient every 30 days to ensure that he/she has exactly what is needed for the month. (A reminder that Medicare opens up a new market, but also adds a lot of administrative hassle for Dexcom.) We love how hard Dexcom has pushed to get this done – management could easily say “our work is done” and leave the rest to suppliers/distributors, but they want to be absolutely certain that this goes well, given the arduous battle they fought to have this opportunity. Dr. Bruce Buckingham took to the microphone following Dr. Graham’s talk to assert that “Dr. Graham should be sainted.” Hear, hear! We look forward to hearing how many bundles have already been shipped and how many are in the queue.
- Dr. Graham got heated when describing “one of the dumbest thing [she’s] ever seen”: Even when Medicare patients use their receiver, they are not allowed to use their smart phone to share or view CGM data – if they use their cell phone, even as they use their receiver, they are ineligible for reimbursement. Accordingly, for the time being, the only way for Dexcom to ensure compliance is to turn off the functionality of the app for Medicare transmitters. This is something that Dexcom will be implementing in short order. This is extremely unfortunate to hear and something we had feared. She was visibly irritated by the policy.
- Both Mr. Sayer and Dr. Graham understand the value of remote monitoring, and are working aggressively to remedy the current situation. Said Mr. Sayer in Q&A, “We have literally plans A, B, C, and D in development if they won’t let us use the phone, because we believe remote monitoring is so important. In a year, we won’t be talking about this issue.”
- Submitted but yet-to-be published data shows the benefits of remote monitoring in seniors. The study found that over 43% of older adults using the Dexcom Share Cloud had at least one follower. Compared to those with no followers, these patients had slightly higher glucose values, but they used their sensors more regularly and had 14% fewer sensor glucose readings <70 mg/dl. Data like this underscores the insanity of depriving this population of remote monitoring.
- To Dexcom’s utter surprise and joy, former CMS Acting Administrator Mr. Andy Slavitt signed an administrative ruling (like a presidential executive order), one of only 18 in history, mandating that therapeutic CGM be covered. “It caught us off guard, we didn’t think it would happen that fast,” commented Dr. Graham. Once the administrative ruling, including a clause that everything needs to be included in a bundle, came through, Dexcom spent “about $8 billion” (jokingly) in consultants trying to figure out implementation.
- Dr. Graham joked that Christmas 2016 was the worst in her life. Word of FDA approval of a non-adjunctive (insulin dosing) claim – the primary hurdle with Medicare – came in on December 20. Dr. Graham immediately tried to get in touch with CMS, but many of the key players were on vacation. All her team did for the next few days was try to reach CMS. They knew they had a deadline, because on January 20, a new administration would take over.
- According to CEO Mr. Kevin Sayer, obtaining Medicare reimbursement and getting it up and running was “a bigger mess than [Dr. Graham] can possibly describe.” Part of the reason for the headache was the timing of Medicare approval – Mr. Sayer told investors on January 11th at JP Morgan that it wouldn’t come until Spring 2018, and it came the very next day [commencing a months-long scramble at Dexcom]. Mr. Sayer also noted that Dexcom loses money when it ships the first bundle to patients, taking on a level of risk – the company is exploring how to manage that risk. See our 1Q17 coverage for more on how the business model changes under Medicare – less upfront and more ongoing revenue.
- Dexcom will make training as simple as possible for patients, with instruction on how to use the receiver, a special training video, and a phone call. If the patient can’t be reached by a phone call, then trainers will be sent to train the patient one-on-one. Wow! The training protocol is also expected to evolve – the kit that Dexcom ships in a month is expected to look very different from the current version.
Dexcom CGM Technology Now and in the Future
Peter Simpson (Dexcom, San Diego, CA); Kevin Sayer (Dexcom, San Diego, CA)
VP of Advanced Technology Peter Simpson wrapped up Dexcom’s information-packed dinner with a look at Dexcom’s pipeline, with some help from CEO Mr. Kevin Sayer. The speakers touched on G6 (pivotal trial wrapping up, FDA submission by the end of this September), first- and second-gen verily products, G5 Mobile, a hint at strategic partnerships, and more.
- Mr. Sayer confirmed that Dexcom plans to submit the impressively accurate G6 sensor by the end of September, keeping the planed 2018 launch timing on track. This sensor has one calibration/day after startup, 10-day wear, a 30% thinner wearable than G5, and no acetaminophen interference – a very meaningful improvement and excellent to see Dexcom keeping up with the timeline laid out in 1Q17! We assume this FDA review wouldn’t last more than a year, meaning a launch is actually possible in the first half of 2018. Mr. Sayer also shared that the pivotal trial (n=300+; 30,000+ matched pairs) will wrap up next week – we can’t wait to see how the data lines up with the pre-pivotal data shared at DTM (n=49) – an MARD of 8.1% on one calibration per day after startup (10% on day one!), with excellent potential for a no-calibration algorithm. Mr. Sayer stated that the leap from G5 to G6 will be almost as big as Seven+ to G4 – considering that many consider G4 to be the first viable consumer CGM, these are strong words! Wow!
- Mr. Simpson hinted that the first-gen CGM with Verily is very well into development, and we can expect to hear more about it soon, and the second-gen CGM with Verily is still in the feasibility stage (animal and human studies) with a lot of work to do. The timeline hasn’t changed for either version: Gen-1 is slated for a 2018 launch, and gen-2 for a 2020-2021 launch. As a reminder, the first-gen CGM leverages G6 sensing technology, but is smaller by 30%, single use disposable, zero-calibration, 14-day wear, and is inserted with an auto-applicator. The second-gen CGM is the diameter of a penny and the thickness of two, also has a single use disposable, zero-calibration, 14-day wear, has a new auto-deployment system, and features new electronics/sensing technology. In our view, the potential for these small, simple, and cost-effective sensors in type 1 and type 2 can’t be overstated. IN an update from the January JPM presentation, the investor deck now notes that the cost reduction is targeted for the second-gen Verily sensor.
- Dexcom is leasing a new facility in Flagstaff, Arizona, capable of manufacturing 50 million sensors per year – this is the first quantification we can recall hearing of this facility’s capacity. For context, Dexcom has only made 10-12 million sensors cumulatively to this point. This is a serious investment, as the company will pour $70 million into just the duct and air flow work – wow! This is another step on the quest to make CGM ubiquitous – Mr. Sayer stressed that he has every intention of making sensors simple and cost-effective enough to be used everywhere. This includes prediabetes, a ways down the road: “That’s a strategic issue we battle with internally with resources. This is a great tool, but the system we have today won’t fix it. We need the new products…Once we get through type 2 diabetes, I think you’ll see prediabetes after.”
- Dexcom’s post-market study of G5 Mobile for non-adjunctive use is “just ramping up now.” The comprehensive post-market study to ensure the safety of non-adjunctive use was condition of FDA approval – debated heavily at the July Advisory Committee meeting. We’re not sure what form this study will take, but have little doubt it will show safety and effectiveness (especially given the T1D Exchange REPLACE BG study).
- Mr. Simpson also spoke about G5 Mobile for Android and the Android Wear app (approved last month and already launched to somewhat mixed reviews), Apple opening up Bluetooth communication allowing direct flow of Dexcom CGM data to the upcoming WatchOS4 without a phone nearby (announced last month ahead of the Watch OS4 update this fall – we’re not sure when Dexcom will launch this, but it’s a highly compelling user experience win in our view), and the new high-reliability G5 touchscreen receiver (seen at ADA; it’s a form factor step back from the current receiver, but it has to be designed to last three years for the Medicare DME bundle). This company does not rest!
Corporate Symposium (Sponsored by Medtronic)
Hybrid Closed Loop Three Months Later: A Panel Discussion Between Providers, Educators, and Patients
Fran Kaufman, MD (CMO, Medtronic Diabetes, Northridge, CA)
In an emotional, much-anticipated evening hosted by Medtronic, we had the great privilege to hear from several patients regarding their experiences with the 670G. Diabetes CMO Dr. Francine Kaufman chaired the session, drawing invaluable insights from the panelists who differed by age, duration of diabetes, and use of different devices. One aspect they all shared in common, however, was their utter infatuation with and appreciation for the 670G. The impact of this device on both quality of life and glycemic control is undeniable, and we are SO happy to see this actionable technology making a difference in the hands real-life patients. With all the caveats we hear about managing patient expectations, we were particularly blown away by the recurring commentary that 670G allows them to not think about their diabetes for long periods of time, and then look down at their pump and be in range. Amazing! See below for some of our favorite quotes of the night.
- Quotable Quotes
- “The best part isn’t something you can quantify medically. The trust that I have since wearing the system has been life changing. I don’t think I realized how much of my life has been controlled by trying to be a well-controlled diabetic. My life has been drastically changed because anytime I want to do anything I know I can do it. I live alone and the only time I’ve ever had to call a paramedic for my diabetes was in the middle of the night, and it was the most terrifying experience. I haven’t had a low at night since I’ve put the 670G on. This pump is so well-tuned, I can eat dinner and 25 minutes later take my dog on a walk and not worry about it.” – Amanda (diabetes duration: 17 years; 670G use: ~3 months)
- “We worry most about hypo. The first day I had the pump I was driving home and I was amazed at what was happening to my blood glucose. On my way home, I had to pull over because I was in tears because I didn’t believe I didn’t need to have this fear. My spouse has had therapy over my fear of hypo – to be able to have that reassurance, now my husband doesn’t even think about my diabetes.”– Dr. Gerard (diabetes duration: 30 years; 670G use: ~3 months)
- “There’s something empowering about instead of going to the doctor to manage my diabetes, I’m finding out how to master it.” – Amanda
- “I have no problem going to the doctor now. It’s hard when your A1c is not where it’s supposed to be and I think the doctor is going to yell at me. But even my mom can tell you my mood has changed about going to the doctor now.” – Ronny (diabetes duration: 16 years; 670G use: ~2 months)
- “When I kept getting kicked out of auto mode in the beginning it was frustrating. After I figured everything out, it’s kind of second nature to get back into auto mode, it’s pretty easy.” – Kendrick (diagnosed 9 years-old; 670G use: 22 months)
- “This pump has allowed us both to have some freedom and independence, you gain so much freedom and trust. She lives alone and my fears are my fears, but with this pump I can go to bed at night and know that she’ll get woken up with this low and I don’t have to worry about it, so thank you. [through tears]” – Ronny’s mother
- “Kendrick doesn’t just survive with diabetes, he thrives and I’m so thankful.” – Kendrick’s mother
- “The single most important thing is that nocturnal hypo is no longer an issue. The control of hypo has greatly improved my quality of life. During the night, you’re flat.” – Dr. Gerard
- “My kids no longer hear my pump beeping and say ‘mom are you ok?’ The 670G has changed not just my thinking but also my family’s. I don’t look at my pump most of the day because I’m not worried about my blood sugar.” – Shannon
- “My overnights were perfect right away in the clinical trial. I have a perfect straight line at 120.” – Shannon (diabetes duration: 34 years; 670G use: ~2 years)
- “It really eases the burden so much. At the end of the day we still have diabetes, it doesn’t go away without a cure. But this is definitely the easiest diabetes management I’ve had and I’ve been on four different kinds of sensors and two different pumps, I love it.” – Kendrick
- “I do a lot of my workouts at night so I have a lot of lows at night. Since I started the 670G, I’ve only had two to three lows, and it’s been huge.” – Ronny
- “OMG you have to have this. #omg. I’m active on a lot of type 1 platforms and I’ve heard a lot that one device or another is the biggest innovation, that it will change your life. This is the only time I’ve felt like it really did. My brother hasn’t been on a pump, and this is the first he’s been really interested in.” – Amanda
- “I come from using pumps and sensors and I didn’t like how they were constantly not in alignment, but with the 670 I’ve gone hours without thinking about diabetes and then I look and its 110. Last week I was at diabetes camp, and I was in auto mode 95% of the time and in range 83% of the time.” – Kendrick
- “My third day with 670G in auto mode I was in range 100% of the time, I took a picture of it and put it on every social media post and thought: this was the day I’m never giving it up.” – Amanda
- “The first night in the hotel study [the pivotal trial] I ate an entire pizza and then I went, ‘oh wait this thing works.’” – Kendrick
- “I don’t have to pay any more attention during the day with the 670G than I used to, but because I sit all day at work I was having a lot more highs. After adjusting my insulin ratio it was fine. It took a little more tweaking, but almost every night is pretty perfect even if I’m high after dinner. I will wake up fine, which is remarkable.” – Amanda
- “My patients need a refresher course on carb counting before using the 670G because the better you are at carb counting the better the 670G will work. It’s not a bigger burden than expected. There’s a little more room for error and we want to be more aggressive because of the reduced fear of hypo.” – Dr. Gerard
- “The visits to the doctor have become more manageable. I used to think it was such a hassle, but I think it goes more smoothly.” – Kendrick
- “I like to talk to patients more about time in range than A1c.” – Dr. Gerard
- “The biggest hurdle for me is to figure out how much insulin I need when I have a hard workout. Leaving my pump on during soccer didn’t work out, so I’d resume it and immediately put it on right after the game. I have had a little trouble with exercise.” – Ronny
- “I set the glucose target to 150 mg/dl before exercise and I’ve actually done extremely well with that. In the morning, I don’t need to do the temp, but you need to individualize this to your patients.” – Dr. Gerard
- “There have been times where I’ve told myself I don’t know if I can do this anymore, but I just kept going. I told my family I would do this for six months and I stuck through it and it’s been a lot better.” – Ronny
- “I used to exit a lot, if I calibrate my blood glucose before bed I can’t remember the last time I exited overnight.” – Shannon
Corporate Symposium (Sponsored by Novo Nordisk)
The Choice is Yours: An Exploration into Patients with Type 2 Diabetes
Anita Swamy, MD (La Rabida Children’s Hospital, Chicago, IL)
In an engaging Novo Nordisk-sponsored breakfast symposium, Dr. Anita Swamy lamented the treat-to-fail paradigm of diabetes management, instead endorsing a DeFronzo-style initial combination therapy regimen of three to four agents that address as many members of the “ominous octet” as possible. She began her remarks on a personal note: Half of her father’s 12 siblings have type 2 diabetes, as do all 10 of her mother’s siblings, and Dr. Swamy herself has prediabetes. This background explains why she has dedicated her endocrinology practice exclusively to diabetes. Dr. Swamy described how the treat-to-fail paradigm led to inadequate glycemic control for so many of her relatives, being prescribed a mild treatment regimen only to have it repeatedly intensified as their glucose control and diabetes complications inevitably worsened. Instead, from the time of diagnosis, Dr. Swamy advises her patients that “this isn’t your grandma’s diabetes.” She prescribes multiple therapies right off the bat to give patients their best chance at optimal health outcomes. Dr. Swamy noted that in her experience, this more aggressive approach leads to a more positive mindset in her patients, who avoid the disheartening cycle of repeatedly added therapies after repeatedly worsening glycemia. She highlighted two therapies in particular that have helped improve patient quality of life in her practice: Novo Nordisk’s GLP-1 agonist Victoza (liraglutide) and next-generation basal insulin Tresiba (insulin degludec). She characterized Victoza as offering “more bang for your buck” compared to other diabetes drugs –appetite suppression, weight loss, decreased blood pressure and fasting plasma triglycerides, decreased insulin resistance, and preservation of beta cell function – a reason she generally prefers GLP-1 agonists over SGLT-2 inhibitors. On Tresiba, Dr. Swamy emphasized the product’s flexible dosing, noting how this makes adherence easier for people who find it challenging to take their insulin at the same time every day (college students, shift workers, busy parents, etc.). She closed by urging the audience, “rather than throwing your patients the most common drug, think about what drugs would benefit them the most” – both in terms of ease of use and addressing the underlying pathophysiology of diabetes.
- Although not mentioned in Dr. Swamy’s prepared remarks, we also add that recent CVOT data provides additional evidence for the benefits of these agents on the diabetes complications front. The LEADER trial, first presented at ADA 2016, demonstrated that Victoza can reduce the risk of CV events in high-risk patients (the basis of a proposed label update for the drug), and the DEVOTE trial, hot-off-the-press from ADA 2017, demonstrated significant reductions in severe hypoglycemia with Tresiba vs. Sanofi’s Lantus (insulin glargine). The importance of these outcomes beyond A1c for patient quality of life and long-term prevention of diabetes complications can’t be overemphasized.
-- by Ann Carracher, Abigail Dove, Brian Levine, Payal Marathe, Maeve Serino, Adam Brown, and Kelly Close