American Diabetes Association 77th Scientific Sessions

June 9-13, 2017; San Diego, CA; Day #1 Highlights

Executive Highlights

And we’re off! ADA 2017 started today in sunny San Diego, CA. This report details our top 15 highlights from a jam-packed day #1. Read on for new data from SUSTAIN 6, coverage of off-site events (Diabetes Mine D-Data, Tandem Media Day), and insights from Drs. Anne Peters, Aaron Kowalski, Julio Rosenstock, and more.

The meeting only gets busier from here! If you haven’t already, be sure to check out our ADA 2017 resource hub, complete with category documents, our top picks for oral presentations, and a short list for the posters we’re most excited about. And for your downtime, see our recommendations for things to do/eat in this wonderful city of San Diego.

Diabetes Therapy Highlights

1. Very notably, Dr. Tina Vilsbøll presented brand-new analyses of the SUSTAIN 6 cardiovascular outcomes trial (CVOT) for Novo Nordisk’s once-weekly injectable GLP-1 agonist semaglutide, offering a deeper dive into the worrisome 76% increased risk for retinopathy complications observed in the trial.

2. Addressing a standing-room-only crowd, Dr. Anne Peters (USC, Los Angeles, CA) issued a compelling call for what she terms "lowercase-G guidelines" – that is, straightforward diabetes treatment guidelines designed to simply make it easier for providers to reach the right conclusions when treating an individual patient.

3. Dr. Lawrence Leiter offered his take on future directions for the design of cardiovascular outcomes trials (CVOTs) in order to enhance their utility in informing modern diabetes clinical decision-making.

4. In a very candid presentation, Dr. Julio Rosenstock provided an overview of the many indications he envisions in the future of the SGLT-2 inhibitor class.

5. Speaking to a packed room, Dr. Kamlesh Khunti offered a disappointing defense for the continued role of sulfonylureas, highlighting heterogeneity within the class, potential therapeutic benefits at low doses, and affordability. While we remain unconvinced that sulfonylureas are worth giving to most patients,  given the associated weight gain, substantially hypoglycemia risk, and potential for beta cell burnout and increased CV risk, Dr. Khunti emphasized that these agents are still featured in the ADA’s 2017 Standards of Care as an option for second-line therapy after metformin, are still used by 31% of diabetes patients in the US, and – according to Dr. Khunti – will likely maintain their role in diabetes practice until the GRADE study and CAROLINA report.

6. With the safety of SGLT-2 inhibitors currently under a microscope, FDA’s Dr. Hyon Kwon provided insight on the fracture risk associated with J&J’s Invokana (canagliflozin) and AZ’s Farxiga (dapagliflozin). He positioned these label warnings not as deterrents, but as a means to encourage thoughtful patient selection to mitigate fracture risk in the real world – we were happy to hear this perspective from FDA, since we’d hate for safety concerns to define the SGLT-2 inhibitor story when there are also tremendous glycemic, weight loss, and CV benefits to consider.

7. Dr. Jeffrey Millman, an alumnus of Harvard’s Dr. Doug Melton’s lab (and now of Washington University in St. Louis), offered a compelling overview of the current state of the stem cell-derived beta cell field, outlining the remaining challenges toward a viable beta cell replacement therapy.

Diabetes Technology Highlights

1. Dr. Bruce Buckingham and our very own Ms. Kelly Close chaired a star-studded (and packed!) session on CGM outcomes standardization with Drs. Rich Bergenstal, Thomas Danne, George Grunberger, Anne Peters, Simon Heller, and Aaron Kowalski. We’ve never felt that a consensus on CGM standardization has been so within reach, and we were happy to hear feedback from so many leaders on issues outstanding.

2. JDRF Chief Mission Officer Dr. Aaron Kowalski immediately reframed the cell replacement therapy vs. closed loop debate by changing the title of his talk to “The NEAR-TERM future of diabetes management is closed-loop pump technology.”

3. At DiabetesMine’s D-Data Exchange, Insulet’s Dr. Trang Ly showed screenshots of the OmniPod Horizon system (major design investment); FDA’s Dr. Stayce Beck called for device interoperability; Dr. Nate Heintzman updated attendees on developer.dexcom.com (launch later this year); and an AP panel shared views on DIY and beyond from Medtronic’s Dr. Fran Kaufman, Bigfoot’s Bryan Mazlish, Insulet’s Dr. Ly, Tandem’s John Sheridan, and our own Adam Brown. Kudos to Amy Tenderich and her team for pulling together so many valuable views.

4. Tandem held a compelling and confidence-inspiring media day at its headquarters today, giving us up close looks at the t:lock connector and the very impressive Tandem Device Updater. In R&D, the t:slim X2/G5 integration is still expected this summer, and in new news, a first-gen app will hopefully launch by the end of this year. PLGS is still expected to launch in early 2018. Kudos to these entrepreneurs.

5. At the Abbott-sponsored DX2 events, Mr. Joel Goldsmith boiled down the digital transformation of diabetes care to three main trends: The shifts from strips to sensors, from proprietary handheld devices to connected consumer electronics as the preferred user interface, and from desktop application analytics to cloud-based services. He also stated that diabetes may be the “perfect candidate” for machine learning and AI.

6. One Drop announced a slew of updates Friday morning, most notably integration with Amazon’s Alexa voice technology. This new offering will allow patients to track blood glucose, food, and activity, as well as to access their data, all with voice. The company also added Dr. Nicole Johnson to its already strong advisory board.

7. This morning, Ascensia announced a global partnership to connect Voluntis’ Insulia basal insulin titration app for type 2s with Bluetooth-enabled Contour Next One and Plus One BGM systems. The integration is expected to launch in 4Q17.

Other Highlights

1. ADA 2017 kicked off with a morning symposium on a critical but under-recognized and under-researched topic: the stigma of diabetes.

Table of Contents 

Diabetes Therapy Highlights

1. New SUSTAIN 6 Analyses of Retinopathy Risk, Weight Loss

Very notably, Dr. Tina Vilsbøll presented brand-new analyses of the SUSTAIN 6 cardiovascular outcomes trial (CVOT) for Novo Nordisk’s once-weekly injectable GLP-1 agonist semaglutide, offering a deeper dive into the worrisome 76% increased risk for retinopathy complications observed in the trial. In SUSTAIN 6 (n=3,297), diabetic retinopathy complications were a pre-defined and adjudicated composite endpoint consisting of four events, two related to diagnosis (vitreous hemorrhage and onset of diabetes-related blindness defined as visual acuity of 20/200) and two related to treatment (retinal photocoagulation and intravitreal agents). Overall, 50 participants in the semaglutide arm experience retinopathy complications (an event rate of 3%), compared to 29 in the placebo arm (1.8% event rate). By event type, 22 participants taking semaglutide required retinal photocoagulation (1.3%, vs. 14 on placebo [0.9%]), 10 taking semaglutide required intravitreal agents (0.6%, vs. 7 on placebo [0.4%]), 13 taking semaglutide experienced vitreous hemorrhage (0.7%, vs. 7 on placebo [0.4%]), and 5 taking semaglutide experienced new-onset diabetes-related blindness (0.3%, vs. 1 on placebo [0.1%]). Importantly, there were significant differences in the patient population that experienced retinopathy complications – in both the semaglutide and placebo arms (n=79 total) and the overall SUSTAIN 6 population. Average diabetes duration in this population was 17.5 years (vs. 13.9 years overall), mean baseline A1c was 9.4% (vs. 8.7% overall), and 76% were treated with insulin at baseline (vs. 58% in the general population). Further, and perhaps most importantly, the majority of patients who experienced complications had a history of retinopathy at baseline – 84% has a history of diabetic retinopathy (vs. 29% in the general population), 29% had a history of medical retinopathy (vs. 6% in general population), and 18% had a history of both proliferative retinopathy and treatment with laser therapy or intravitreal agents (vs. 3% in the general population). Looking only at the subset of patients in SUSTAIN 6 with a history of retinopathy, the Kaplan-Meier curves for new retinopathy events diverge sharply between the semaglutide-treated patients and placebo throughout the trial. On the other hand, the Kaplan-Meier curves are virtually superimposable for patients without a history of retinopathy (and the risk was much, much lower overall), suggesting that the signal is driven almost entirely by those with a history of retinopathy. In addition, as those who experienced new events had a higher mean baseline A1c, the early A1c reduction was generally larger and more dramatic than in the overall population – several commentators have suggested that a precipitous drop in A1c may be driving the retinopathy risk (something similar was seen in DCCT). Indeed, Dr. Vilsbøll showed that larger A1c reductions at week 16 were associated with higher incidence of retinopathy complications in those with baseline retinopathy, regardless of treatment with semaglutide or placebo.

  • Overall, Dr. Vilsbøll characterized the retinopathy risk as manageable with appropriate patient selection. In Q&A, she was directly asked if she anticipated a black box warning or other strong language for the retinopathy risk on the semaglutide label, with the questioner drawing a comparison to the warning for pancreatitis for GLP-1 agonists. While Dr. Vilsbøll emphasized that the labeling decisions are up to the FDA, she was reassuring and expressed confidence in using semaglutide herself as a clinician. She recalled that, at the height of the pancreatitis controversy, there was not a clear understanding of the mechanism driving the potential increased risk. On the other hand, Dr. Vilsbøll feels comfortable with the current understanding and explanation of the increased retinopathy risk with semaglutide and expressed confidence that she will be able to identify which patients she should be more cautious prescribing semaglutide to. We’re reassured by Dr. Vilsbøll’s perspective, though it’s clear that significant provider and patient education on retinopathy will be required to optimize use of semaglutide in the diabetes patient population once it’s available. We hope Novo Nordisk will continue to demonstrate leadership in this area – and perhaps a positive consequence of this worrisome signal could be increased attention to retinopathy, a sometimes underappreciated complication of diabetes.
  • Dr. Vilsbøll also shared further analysis of the impressive weight loss benefit associated with semaglutide, demonstrating that the weight loss cannot be attributed to GI side effects alone. Overall, patients taking semaglutide 0.5 mg experienced a placebo-adjusted weight loss of 2.87 kg (6.3 lbs) and those taking semaglutide 1.0 mg experienced a placebo-adjusted weight loss of 4.35 kg (9.6 lbs). Among participants in the semaglutide 0.5 mg arm, those who experienced nausea and vomiting experienced a placebo-adjusted mean weight loss of 2.7 kg (6.0 lbs), compared to 2.8 kg (6.2 lbs) for those who did not experience any nausea or vomiting. Similarly, among participants in the semaglutide 1.0 mg arm, those who experienced nausea and vomiting lost 4.6 kg (10.1 lbs, placebo-adjusted), compared to 4.2 kg (9.3 lbs, placebo-adjusted) among those who did not experience nausea or vomiting.

2. Dr. Anne Peters Calls for Simpler, “Lowercase-G” Diabetes Guidelines

Addressing a standing-room-only crowd, the great Dr. Anne Peters (USC, Los Angeles, CA) issued a compelling call for what she terms "lowercase-G guidelines" – that is, straightforward diabetes treatment guidelines designed to simply make it easier for providers to reach the right conclusions when treating an individual patient. While there is of course a need for “capital-G guidelines” written by a multidisciplinary panel of experts and backed by a systematic review of clinical trial evidence, Dr. Peters pointed out that these often create more confusion than clarity. “There are a zillion guidelines, so who should I trust?” she noted, pointing out key differences between guidelines from organizations such as the IDF (which takes a very general global perspective), the VA (whose guidelines are tailored very specifically to the organization’s own formularies and clinical setting), and the American College of Physicians (which oddly address only oral agents). To be maximally useful for people who care for patients with diabetes, Dr. Peters argued that guidelines should ideally be (i) more or less consistent across leading societies; (ii) modifiable for variable practice settings; (iii) able to be integrated into EMRs to help with clinical decision making; (iv) updated at least annually; and (v) responsive to new developments and FDA label changes (particularly with regard to CVOT findings in today’s day and age). That said, Dr. Peters also urged the audience to realize that despite guideline makers’ most earnest intentions, they are simply “regular people pondering about how to best take care of people with diabetes” and guidelines of any sort should be interpreted as just that – recommendations and not incontestable “edicts from God.” We found this talk particularly helpful and hope that the the details of Dr. Peters’ talk go to everyone everywhere.

  • In the last few minutes of her talk, Dr. Peters pointed out that we must realize that providers are judged on their ability to bring patients to glycemic targets, so guidelines must be sensitive to the need for clear guidance with regard to A1c reduction. When pressed on this during Q&A she remarked with a hint of cynicism that “I don’t know if I can get away with saying that we are following the wrong marker in clinical practice, but we need to consider other outcomes beyond A1c.” We couldn’t agree more and believe it is such a great sign of continued progress in technology (CGM) that one of the world’s biggest thought leaders in diabetes would say this – A1c is one of a multitude of factors (including time-in-range, quality of life, emotional well-being, etc.) that treatment guidelines should ideally seek to optimize for people living with diabetes. We hope that widespread consideration of outcomes beyond A1c in a clinical setting can also help the FDA recognize the importance to evaluating these outcomes from a regulatory perspective – and help payers see the value of drugs that offer benefit on these additional endpoints. Indeed, Dr. Peters raised another concern that despite our best attempts at creating practical and well-reasoned clinical guidelines, access to appropriate therapies remains a challenge for too many people. This is, perhaps, because we are so A1c-centric, however – when there is more of an ability to compare therapeutic choices, even just on time in zone, and time in hypoglycemia, we will feel much better about patients’ abilities to make good choices, assuming reimbursement.  

3. Dr. Lawrence Leiter on the Future of CVOTs

Dr. Lawrence Leiter (University of Toronto)offered his take on future directions for the design of cardiovascular outcomes trials (CVOTs) in order to enhance their utility in informing modern diabetes clinical decision-making. Overall, he highlighted several positives resulting from the 2008 FDA CVOT guidance, but acknowledged there are many limitations to the FDA guidance in its current form as well. On the plus side, the CVOTs mandated by the FDA guidance have established the cardiovascular safety of a number of diabetes agents, even demonstrating CV benefit in some cases. As Dr. Leiter put it, diabetes drugs were essentially “crash tested” in the highest risk patients in these trials, providing confidence that these drugs are likely very safe in the lower-risk general population as well. These trials have also provided insight into important, under-characterized secondary endpoints (heart failure and chronic kidney disease, for instance), and afforded recognition of unexpected potential side effects (such as heart failure with some DPP-4 inhibitors and possibly retinopathy with semaglutide). On the other hand, Dr. Leiter acknowledged that these insights come at an extremely high cost, and although he noted that there’s no evidence yet that this has been a major deterrent to diabetes drug development (though, from our perspective, we’ve observed an increasingly high bar for new diabetes drugs, a significant attrition rate in the phase 2 pipeline, and the exit of major players in the diabetes field), the cost of these trials eventually get passed on in the price of new agents..

Larger limitations of the current guidance, in Dr. Leiter’s view, are the de-emphasis of CV benefit, potential use of inappropriate CV endpoints (since the FDA mandates three-point MACE or MACE-plus as the primary endpoint, the components of which have not necessarily all moved in the same direction),), or use of inappropriate comparators (placebo, rather than an active drug). Further, the current trials rarely focus on a “primary prevention” population that makes up the majority of patients with diabetes – and by focusing on patients with established cardiovascular disease, we may be missing a window of opportunity for intervention with some agents. Overall, Dr. Leiter recommended also enrolling lower-risk and more diverse populations, including longer follow-up, modifying endpoints and analyses as appropriate, standardizing definitions of non-CV endpoints, and incorporating active comparators (for which CV data is available). In addition, Dr. Leiter envisions a role for innovation, real-world trial designs that harness EMRs to conduct randomized, controlled trials. He also emphasized the importance of creating biorepositories to better understand biomarkers and genetic predictors of both response and safety, as currently done with some oncology drugs. Finally, Dr. Leiter highlighted the importance of patient-reported outcomes, highlighting data from The diaTribe Foundation and dQ&A on patient priorities for diabetes treatment and noting that many of these priorities are not well-assessed in current trials. We’re pleased that Dr. Leiter provided such a balanced and comprehensive look at the benefits and limitations of current CVOTs and we hope that pharmaceutical companies will take his suggestions into consideration, even if they are not mandated by FDA guidance.

4. Many Future Indications for SGLT-2 Inhibitors, According to Dr. Julio Rosenstock

In a very candid presentation, Dr. Julio Rosenstock provided an overview of the many indications he envisions in the future of the SGLT-2 inhibitor class. While acknowledging that there has been a steady stream of safety warnings for the class, he emphasized that most of the concerns are manageable and the overall risk-benefit profile for these agents favor their use in a number of indications. Within type 2 diabetes, based on the EMPA-REG OUTCOME data and the CVD-REAL data, Dr. Rosenstock asserted that, it would be highly questionable for a patient with type 2 diabetes and a prior history of cardiovascular disease to not be on an SGLT-2 inhibitor, unless there was a contraindication, intolerance issues, or other clinical concern – he also appeared optimistic that the impressive cardiovascular benefit observed in EMPA-REG OUTCOME is a class effect, based on CVD-REAL. We certainly look forward to the CANVAS results presentation this Monday to potentially substantiate this! Further, Dr. Rosenstock suggested that SGLT-2 inhibitor and metformin combination therapy will increasingly become the preferred first line treatment for all patients with newly-diagnosed type 2 diabetes, not just those with established CV disease. He also suggested that SGLT-2 inhibitor/DPP-4 inhibitor fixed-dose combinations (FDC) will become the preferred second-line treatment for patients who are not well managed on metformin monotherapy – he argued that it makes little sense to intensify with only an SGLT-2 inhibitor or only a DPP-4 inhibitor when the combination of the two has been demonstrated to be more efficacious than either component. Beyond type 2 diabetes, Dr. Rosenstock forecasted a role for SGLT-2 inhibition in type 1 diabetes adjunct therapy. He acknowledged that there are clear safety issues – characterizing the highly publicized DKA risk as “real” – but emphasized that the risk is predictable, detectable and preventable. That said, Dr. Rosenstock shared rumors that Janssen is unlikely to pursue a type 1 diabetes indication for Invokana (canagliflozin) further, following phase 2 results. On the other hand, he was more optimistic about Janssen pursuing an obesity indication for a combination of canagliflozin/phentermine, which reported promising phase 2 data at ADA 2016. Dr. Rosenstock was also excited about the potential of SGLT-2 inhibitors in chronic kidney disease and in heart failure – several trials are ongoing for both of these indications and we’re similarly excited to see these results. Finally, Dr. Rosenstock also highlighted a potential role of SGLT-2 inhibitors in prediabetes and primary CV prevention. Indeed, J&J has previously shared plans to conduct a CVOT for Invokana in people with prediabetes and we’re very intrigued by this prospect as well.

5. Awaiting GRADE Study and CAROLINA CVOT for Final Verdict on Sulfonylureas

Speaking to a packed room, Dr. Kamlesh Khunti offered a disappointing defense for the continued role of sulfonylureas, highlighting heterogeneity within the class, potential therapeutic benefits at low doses, and affordability. While we remain unconvinced that sulfonylureas are worth it given the associated weight gain, substantially hypoglycemia risk, and potential for beta cell burnout and increased CV risk, Dr. Khunti emphasized that these agents are still featured in the ADA’s 2017 Standards of Care as an option for second-line therapy after metformin, are still used by 31% of diabetes patients in the US, and – according to Dr. Khunti – will likely maintain their role in diabetes practice until the GRADE study and CAROLINA report. Dr. Khunti presented mixed evidence on the weight gain, hypoglycemia, and CV events stemming from sulfonylureas. In the ADVANCE study, sulfonylureas appeared to be weight-neutral and demonstrated a durable A1c-lowering effect. A collection of real-world data shows that 5% of patients taking a sulfonylurea experience severe hypoglycemia vs. 21% of patients taking insulin and 5% of patients taking other non-sulfonylurea drugs, though Dr. Khunti acknowledged that definitions of hypoglycemia were not standard across these different trials. The CV outcomes data surrounding sulfonylureas is perhaps the most contentious – a recent randomized controlled trial (RCT) found a 32% greater risk for heart failure with sulfonylurea treatment vs. metformin therapy (p<0.05), and a metaanalysis of RCTs found that sulfonylureas confer a 46% greater risk for CV mortality and a 26% greater risk for all-cause mortality vs. placebo. The big caveat here, Dr. Khunti underscored, is that all sulfonylureas were grouped and analyzed together, whereas other research shows glimepiride to be CV safe at low doses and the sulfonylurea of choice for diabetes patients with underlying coronary artery disease. Ultimately, the field lacks reliable evidence on the CV effects of sulfonylureas, as studies so far have used a variety of comparators and have been subject to selection bias. This is why GRADE and CAROLINA will be so valuable for the community, and why we’re eager for these trial results: GRADE will analyze diabetes therapies head-to-head to determine the optimal combination treatment for long-term care, while CAROLINA is Lilly/BI’s CVOT comparing DPP-4 inhibitor Tradjenta (linagliptin) vs. glimepiride, expected to complete in March 2019 (which, suddenly, doesn’t seem that far away). At CMHC 2016, Dr. Robert Ratner suggested that GRADE and CAROLINA data could be just what ADA needs to extract sulfonylureas from treatment algorithms once and for all. For now, cost considerations keep sulfonylureas in rotation for diabetes care – though we have never found this argument particularly convincing, given the substantial downstream costs of severe hypoglycemia and the availability of other, generic, low-cost options now (including TZD pioglitazone). Dr. Khunti described how the controversy over sulfonylurea use is perpetuating clinical inertia, to some extent, a topic he’s well-versed in – instead, providers should swiftly prescribe whatever glucose-lowering therapy a patient can afford in order to reduce risk for long-term complications of hyperglycemia. The importance of affordability/access is not lost on us, and we certainly appreciate that sulfonylureas are a viable therapeutic option for some – though we vastly prefer metformin and pioglitazone as the “low-cost option.” That said, we hope that as newer agents approach generic status – including DPP-4 inhibitors, SGLT-2 inhibitors, and GLP-1 agonists like liraglutide, which has already demonstrated a significant CV benefit – sulfonylureas will slowly but surely fall out of practice, yielding to superior therapies that offer A1c-lowering, weight loss, and other advantages to outcomes beyond A1c without any associated CV or hypoglycemia risks. We note that other thought leaders, including Dr. Jay Skyler, are fierce supporters of eradicating sulfonylureas from treatment algorithms, and this is the direction we wish for the diabetes field in the not-too-distant future.

6. FDA Perspective on SGLT-2 Inhibitors and Bone Fracture Risk

With the safety of SGLT-2 inhibitors currently under a microscope, FDA’s Dr. Hyon Kwon provided insight on the fracture risk associated with J&J’s Invokana (canagliflozin) and AZ’s Farxiga (dapagliflozin) but not Lilly/BI’s Jardiance (empagliflozin). He positioned the label warnings for Invokana and Farxiga not as deterrents, but as a means to encourage thoughtful patient selection to mitigate fracture risk in the real world – we were happy to hear this perspective from FDA, since we’d hate for safety concerns to define the SGLT-2 inhibitor story when there are also tremendous glycemic, weight loss, and CV benefits to consider. Dr. Kwon noted that canagliflozin was only associated with a significantly increased risk for fractures in the CANVAS trial, but not in other studies within the Invokana clinical program, so heightened fracture risk may only apply to patients at high CV risk. An interim analysis of CANVAS found a hazard ratio of 1.51 in favor of placebo (95% CI=1.04-2.19), which doesn’t cross the line of unity and thus meets the threshold for statistical significance. Non-CANVAS studies reported a hazard ratio of 1.09 in favor of placebo (95% CI=0.71-1.66), but this fracture risk did not meet statistical significance. Dr. Kwon displayed graphs for time to first fracture in CANVAS, in which the curves diverge early on. He explained that a separation of curves <12 weeks after randomization suggests that fractures are due to falls rather than an impact on bone metabolism, an effect that would only accrue with longer duration of treatment. Moreover, interim CANVAS results showed a 60% increased risk of falls for participants on 300 mg canagliflozin vs. placebo (HR=1.60; 95% CI=1.11-2.32), which contributes to this hypothesis. It’s unclear if this increase in falls is a chance finding or if something about the canagliflozin causes increased risk of falls (through balance issues or confusion, perhaps?). As such, based on current data, the FDA cannot rule out that this particular SGLT-2 inhibitor may confer excess fracture risk for all patients, regardless of their CV risk factors. A pooled analysis of CANVAS and other Invokana clinical trials resulted in a hazard ratio of 1.32 in favor of placebo (95% CI=1.00-1.74). That said, we’re reserving judgement until we see the full, integrated results from CANVAs and CANVAS-R, which will be presented on Monday. In addition to long-awaited CV data, our ears will be perked for any safety details on the bone fracture risk (and the newly characterized amputation risk). Turning to Farxiga, Dr. Kwon showed that there was no imbalance in fractures between dapagliflozin-treated patients and placebo-treated patients overall, but that one study enrolling individuals with moderate renal impairment did find excess fracture risk associated with AZ’s SGLT-2 inhibitor. Fractures were most common in participants with eGFR between 11-45 ml/min/1.73m2. This was added to the drug label under the “warnings & precautions” section, but again, this risk could be well-managed through diligent patient education, allowing many people with diabetes to still benefit from a highly-effective, advanced therapy.

  • We think we speak for many at this meeting when we say we’re anxious for CANVAS to report full results on Monday afternoon. No matter what, this data will be telling – we have our fingers crossed for a statistically significant CV benefit that builds evidence for a cardioprotective class effect (following EMPA-REG OUTCOME) and highlights the therapeutic advantages of SGLT-2 inhibitors, but we’ll also need to scrutinize fracture data from the completed trial as well as data on amputations considering the FDA’s decision to add safety warnings for lower limb amputations to the Invokana label. All in all, our sense is that SGLT-2 inhibitors have a complicated risk-benefit profile and we’re always eager for more data to aid patients and providers in clinical decision-making regarding this class.

7. Remaining Challenges in Stem Cell-Derived Beta Cells According to Dr. Jeffrey Millman

Dr. Jeffrey Millman, an alumnus of Harvard’s Dr. Doug Melton’s lab (and now of Washington University in St. Louis), offered a compelling overview of the current state of the stem cell-derived beta cell field, outlining the remaining challenges toward a viable beta cell replacement therapy. Dr. Millman highlighted two main ongoing challenges: (i) cell potency; and (ii) cell delivery. Of the two, he characterized cell potency as a largely solvable problem. He noted that, while current stem cell-derived beta cells are very similar to native, primary beta cells, there are still substantial differences in the expression levels of several important genes – this suggests that the stem cell-produced cells are not completely identical to human beta cells, which may have important functional implications. Notably, for instance, stem cell-derived beta cells have poorer insulin secretion than endogenous human beta cells. Dr. Millman showed data demonstrating the per-cell level of insulin secretion of the very best of stem cell-derived beta cells is comparable to the very worst of isolated human islets. That said, Dr. Millman emphasized that much progress has been made on this front and that the latest cells produced from his lab’s new, revised protocol appears to match the insulin secretion levels of human islets more consistently. On the other hand, Dr. Millman views cell delivery as the much larger limitation currently facing beta cell replacement therapy. As he put it, transplanted cells must be able to survive, which requires that they receive a steady stream of oxygen and nutrients while being protected from autoimmune attack. At the same time, the protection system must still allow for rapid diffusion of glucose to and away from the cells, or else there would be an unacceptable lag in the system, which could produce an unacceptable risk of hypoglycemia. Finally, concerns about the tumorigenic potential of these stem cell-derived products persist as well. Overall, given the novel nature of these cells, Dr. Millman emphasized the importance of being able to retrieve the cells for safety reasons – which rules out the gold standard Edmonton protocol that is currently used to transplant human islets. He highlighted a few of the ongoing efforts in beta cell encapsulation, including his work in collaboration with Dr. Dan Anderson’s lab at MIT to encapsulate cells in an immune-protective alginate device. We heard similar commentary on the limitations of beta cell replacement therapy from Dr. Doug Melton at Levine-Riggs 2017. While these challenges are to be reckoned with for sure, we’re encouraged that these greats don’t view them as insurmountable and we’re eager to see where this field goes in the next couple of years.

Diabetes Technology Highlights

1. Reaching an International Consensus on Standardizing CGM Outcomes – Aligning Clinicians, Researchers, Patients, and Regulators

Dr. Bruce Buckingham and our very own Ms. Kelly Close chaired a star-studded (and packed!) session on CGM outcomes standardization with Drs. Rich Bergenstal, Thomas Danne, George Grunberger, Anne Peters, Simon Heller, and Aaron Kowalski “Reaching an International Consensus on Standardizing CGM Outcomes – Aligning Clinicians, Researchers, Patients, and Regulators”. We’ve never felt that a consensus on CGM standardization has been so within reach; it was terrific to hear from such a range of experts total acceptance that A1c was no longer enough - necessary but not sufficient. It reminded us of so many other leaders in the field like Dr. Irl Hirsch who have been saying this for years, even before the technology evolved (the technology has, as of G4 and the 670G, caught up!) Dr. Rich Bergenstal led off with a number of statistics: There have been nine CGM outcomes consensus statements (six published, three pending) since 2013, comprised of 100 total CGM experts – he concluded that “we probably don’t need more consensus meetings, it’s time to align on a consensus.” And after representatives from a number of those committees presented their group’s work (Dr. Danne on the ATTD International Consensus Statement, Dr. Grunberger on the AACE/ACE Consensus Conference on CGM, Dr. Peters on the EASD and ADA Technology Working Group, Prof. Heller on the International Hypoglycaemia Study Group, and Dr. Kowalski on the T1D Outcomes Program), Dr. Buckingham concluded that “we’re pretty close to consensus, if we’re not there.” His final slide stole a line from the smash musical Hamilton, claiming “You were all in the room where it happened.” The excitement in the room was palpable, even though it was the last session of day one. We as an organization are over the moon at Close Concerns though we realize there is still so much still must happen to make sure that outcomes beyond A1c are reported and considered. There has been so much discussion and so many stakeholders involved – it is amazing that we’ve come to a near-consensus on the time-in-range and variability thresholds to use for clinical trial reporting and beyond (see below). The terminology will be absolutely critical and we’re very excited that this will be a major topic at the July 21 gathering in Bethesda, Maryland on this topic.  

  • Dr. Buckingham slide below fleshes out the near-agreed upon core CGM metrics: (i) Level two hyperglycemia is >250 mg/dl; (ii) Level one hyperglycemia is >180 mg/dl; (iii) Time in target range is 70-180 mg/dl; (iv) level one (alert) hypoglycemia is <70 mg/dl; (v) level two hypoglycemia is <54 mg/dl; (vi) glycemic variability should be measured in coefficient of variation and possibly standard deviation; (vii) Mean glucose and eA1c should be presented; (viii) AGP is the CGM visualization medium of choice; (ix) An episode of hypoglycemia or hyperglycemia is comprised of 15 minutes; (x) Sleep/wake time blocks are from 12pm-6pm and 6pm-12pm; (xi) data should be collected for a minimum of two weeks with 70-80% CGM wear to ensure sufficiency. Not all working groups settled on exactly these numbers or even addressed every question, but those who did tackle a problem settled on numbers and metrics that look very similar.

  • The next step, of course, is to discuss these levels with regulators and payers – this will be easier to do framing it as coming from recommendations of 100 experts. The diaTribe Foundation, along with partners in the diabetes community ADA, AACE, JDRF, and Anna McCollister-Slipp, took a big step by organizing an FDA Workshop on Outcomes Beyond A1c last August, and will hold another Consensus Conference entitled “Glycemic Outcomes Beyond A1c: Standardization & Implementation” in Bethesda, MD in the presence of CDER Director Dr. Janet Woodcock on July 21. For other imminent events on CGM metrics consensus, see this slide (credit to Prof. Heller). This means so much to the whole diabetes community – standardization of data visualization and agreement on which outcomes matter, how to measure them, and what threshold should be used (in general), will benefit the entire field
  • Dr. Aaron Kowalski pointed out that the device side of FDA (CDRH) has largely adopted Outcomes Beyond A1c, but the drug side (CDER) hasn’t to the same degree. From our view, this reflects a range of factors, most notably that CGM use in drug trials has still be the exception rather than the rule – and we understand that, since the evolving tools (CGM) has only in the last couple of years made that much easier. (Dexcom’s G4 was the first CGM that had the accuracy levels in hypoglcyemia). Drs. Courtney Lias and Stayce Beck have done an incredible job engaging patients and compromising to enable them to get beneficial technology quickly and with endpoints of relevance like time-in-range and hypoglycemia. This comes also from the presence of a very active and vocal type 1 patient community in technology, which hasn’t been the case yet on the drug side – on the type 1 side, this has been propelled by JDRF, who has been a very impressive model. Dr. Kowalski’s talk reviewed the T1D Outcomes Program led by Dr. Kowalski and the Helmsley Charitable Trust that includes a range of stakeholders and a steering committee of clinician leaders who are all extremely involved in type 1. Their program includes a very smart multi-step process to achieve consensus for each outcome – reviewing existing evidence, developing draft definitions, seeking community input, and developing a consensus definition. We are strong proponents for outcomes beyond A1c to be considered on the drug side as well, particularly given that the tools have improved so much (CGM) and particularly given that there are and will be drugs that type 1 patients seek that are approved only for type 2. Ultimately, we have high hopes that such outcomes will begin to be reported, largely thanks to JDRF and other groups that have come to agreement! We look forward to hearing more from Dr. Kowalski as the JDRF work continues.
  • Dr. Peters’ EASD/ADA Technology Working Group discussed five main themes in a manuscript, which is pending approval: (i) More systematic and structured pre-marketing evaluation of the performance of CGM systems; (ii) Greater investment in trials to provide evidence of CGM value and reliability for all patient groups; (iii) Standardization of CGM-measured glucose data reporting from clinical trials (see above); (iv) Improved consistency and accessibility of safety reports to regulatory authorities after market approval; and (v) Improved consistency and accessibility of safety reports to regulatory authorities after market approval. We’ll be keeping an eye out for this paper for sure!

Selected Questions and Answers

Q: Everyone agrees that 70-180 mg/dl is the target range – should I tell my patients that as well?

Dr. Grunberger: The key is that every patient is an individual. For an individual, these are your targets, but it’s different for someone who’s pregnant or say nine years old. That range is quote-on-quote “normal” that you’ll see in healthy individuals. Advice for individual patients can differ.

Dr. Bergenstal: With hybrid closed loop, control is getting tighter and tighter overnight, and some people are considering going for 70-140 mg/dl overnight. This is a starting point.

Ms. Close: A lot of patients will have exactly this question. 140 mg/dl is also being measured (even level is measured in CGM), so we can individualize what patients see. Many people also have this concern, so thank you so much for bringing it up.

Q: Can you give specific guidance for individual products that have inherently different properties?

Dr. Danne: You’re really putting your finger in the wound. Obviously we try to be independent of manufacturing, industry, etc. And this is very much changing. A device calibrated twice per day today might be factory calibrated tomorrow, so it’s difficult to make recommendations on specific technology, but we try to give a grand scheme so that we can use CGM safely.

2. Dr. Kowalski Reframes Future of Diabetes Care Debate: “The near term future of diabetes management is closed-loop pump technology”

Upon taking to the podium, JDRF Chief Mission Officer Dr. Aaron Kowalski immediately reframed the cell replacement therapy vs. closed loop debate by changing the title of his talk to “The NEAR TERM future of diabetes management is closed-loop pump technology.” We agree that an ultimate win might be cell and immune therapies, but with the state of diabetes care today and the time horizon for advanced biological therapies, we need better near-term solutions for patients. “Mechanical solutions are much easier than biological solutions,” he explained, “It’s hard to replicate evolution – hummingbirds flap their wings very fast. Try to have a man fly – it’s a really, really hard problem to solve. With technology, we can do not exactly the same thing (i.e., a helicopter), but amazing things. The goal to create a machine that functions like an islet is a lofty goal. To fly like a hummingbird is hard, but we’re taking incremental steps – low threshold suspend, and now the first hybrid closed loop.” He expressed great enthusiasm for the closed loop landscape, first overviewing the “really exciting” Medtronic MiniMed 670G pivotal data (shared at ADA last year), and then alluding to other companies looking to commercialize similar products: Animas, Bigfoot, Tandem, Insulet, Roche, and Beta Bionics (and also DIYers). Still, he acknowledged that there are many challenges relating to hardware that keep it from behaving like an islet: (i) Insulin kinetics – subcutaneous insulin is not physiologic. To Dr. Kowalski, IP insulin delivery is a slam dunk and a “better way to do it,” but the challenge lies in creating a device that people will want to adopt en masse (this topic was debated extensively at the recent JDRF/Helmsley Charitable Trust IP AP Workshop); (ii) Burden of having to wear a device – “ nobody in the history of man that I’m aware of wears an insulin pump just for kicks”; (iii) Biologic variability on a patient-to-patient basis; and (iv) Exercise. While a cell therapy would presumably address all of these issues, JDRF is still investing resources in next-generation closed-loop technologies (smaller form factor, implantable, longer wear, more automation, additional inputs, adjunct therapies) – see this slide for a list of new JDRF projects in 2016 and projects in the pipeline for 2017.

3. Diabetes Mine D-Data Exchange: Insulet Shows Cool Horizon Screens; FDA’s Strong Call for Interoperability Between Companies, Possible Workshop; Dexcom API Coming This Year

At DiabetesMine’s D-Data Exchange, we enjoyed seeing the DIY community and industry in what we felt was the most productive discussion yet. Highlights included Insulet’s Dr. Trang Ly on the OmniPod Horizon system (first screenshots from near-final design – major investment here), FDA’s Dr. Stayce Beck on why device interoperability really matters for automated insulin delivery progress (FDA may even have a workshop), Dr. Nate Heintzman gave an update on Dexcom’s APIs for retrospective data at developer.dexcom.com (launching later this year), and an artificial pancreas progress panel included views from Medtronic’s Dr. Fran Kaufman, Bigfoot’s Bryan Mazlish, Insulet’s Dr. Ly, Tandem’s John Sheridan, and our own Adam Brown. MIT innovation professor Dr. Eric Von Hippel gave an outstanding keynote, emphasizing that the lead-user (DIY) community is a critical driver of innovation in all fields – diabetes is no exception. The HOW of this for industry is still an interesting question – how should/can/will industry create open sandboxes to enable innovation for the DIY community and build it into commercial products? We felt the conversation dynamic shifted this year and was more patient-friendly, “how-to,” and pro-DIY than ever before.

  • Insulet’s Dr. Trang Ly (VP & Medical Director) gave a first glimpse of the Horizon hybrid closed loop user interface on the Dash PDM – wow is Insulet investing heavily in user experience! The screenshots below are “close to the finish line” of the design process, with a prominent display of the CGM value and trend, IOB, and bold use of colors. Other information has been kept to a minimum, a good move in our view. In addition to the clinical trials testing the algorithm, Insulet has already performed six usability studies (31 unique participants to date, including some 670G users) to get feedback on the Horizon’s user interface and data display. Dr. Ly also highlighted Insulet’s cool use of Lightning Labs – condensed user experience design processes that occur in a short period of time with cross functional teams. The group designs and iterates quickly based on user feedback. Insulet even invited six members of the OpenAPS community and spent hours hearing about their experiences – yes! She noted that user interface’s use of colors is “controversial” (some like it, some don’t), and the company is also debating how to display the system’s insulin dosing graphically (microboluses vs. basal rate can be confusing). Dr. Ly shared sincere commitment to getting lots of patients’ feedback (including from MDIs), and Insulet is clearly investing deeply in this area. She reiterated the expectation for a pivotal trial of the Horizon product next year. As previously described, the algorithm will be embedded on the pod and talk directly to the Dexcom G6 CGM, meaning users will remain in closed loop even when the PDM is out of range.
    • To date, Insulet has completed studies of the algorithm in 82 patients, collecting ~3,500 hours of closed-loop data: “The algorithm is doing what it should be doing – reducing mean glucose and increasing time-in-range without causing more hypoglycemia. We’re well on our way to creating a commercial artificial pancreas product.”

  • FDA’s Dr. Stayce Beck hoped for an interoperable future where AID systems have multiple interchangeable components made by different manufacturers (“plug-and-play”). The Agency “hopes” to have a workshop on this topic and seems highly committed to continuing this discussion. Nice! Noted Dr. Beck, “The anticipated pace of AID innovation challenges the current regulatory framework for medical devices. Every time one of the components is modified, a company has to come in to FDA with a new submission. Users can’t mix and match systems that meet their needs. We’re at a point where technical solutions can be implemented.” We’ve heard this in theory before from FDA’s Dr. Courtney Lias, but it sounded like things have progressed internally at FDA, and Dr. Beck said the solution is “under construction” –  the entire community now must come together to help the FDA figure out how to do this. For instance, the field must nail down the interoperability, connectivity, and data approaches (the HOW), enabling devices from different companies to seamlessly and safely talk to one another. We see enormous innovation potential and patient choice enabled by plug-and-play systems – using one company’s pump, another company’s sensor, a third company’s algorithm, and being able to swap components in and out as desired. We hope a workshop does indeed happen and it drives progress and standardization in the field. Dr. Beck also commented on dosing insulin from a smartphone, sharing that the agency is open to it and very platform/device agnostic – companies must simply demonstrate the device works as intended and is robust to different failure scenarios (e.g., the mobile medical app will be prioritized when battery is low, a game is being played, etc.). We loved her opening comment, “We don’t see mHealth as a ‘challenge,’ but as an ‘opportunity.’”
  • Dexcom’s Director of Data Partnerships Dr. Nate Heintzman shared that the company’s open API for retrospective data will launch “later this year” at developer.dexcom.com. As a reminder, this will allow third parties to access Dexcom’s APIs (retrospective data, three-hour-delay), create and manage pre-commercial (prototype) apps, play with simulated (sandbox) data, learn how to become a Dexcom data partner, and even submit an app for commercial approval. This important effort was first announced at the D-Data Exchange last fall, but clearly there are a lot to details to work out – the “early 2017” planned launch has slipped a bit, but things sounded very close to launch at this point. Dr. Heintzman shared a “top 10 things to know list,” noting that 500+ people have already signed up for email updates on developer.dexcom.com. He reminded attendees that developers will have access to quite a bit of information to develop novel retrospective data apps, including glucose data, statistics, device info, and calibrations. Like Dexcom Clarity, this platform is a class I medical device (retrospective CGM data), and Dexcom will support data partners and share best practices through the developer portal. This is clearly a huge internal investment from Dexcom and we hope it drives an ecosystem of innovation and novel ways to use retrospective CGM data.
  • A lively panel discussion featuring closed loop industry members (Insulet’s Dr. Trang Ly, Medtronic’s Dr. Fran Kaufman, Bigfoot’s Mr. Bryan Mazlish, and Tandem’s Mr. John Sheridan) and moderated by our own Mr. Adam Brown showed encouraging industry openness to engaging with the DIY and broader patient communities. From the audience, Dr. Eric von Hippel called for data to be readily available to patients, providing what Adam called “a sandbox” for innovators to play in and access devices. “It’s crazy when 90% of the effort of the user community has to go to hacking into devices, just to get access to the data. Life is slightly unsafe. If you ensure safety, you also ensure slow progress. There must be a way – in every other field, users can take risk on themselves. If I want to build a rocket-powered car, I can do it, even though it’s unsafe. There must be a way to sign rights that I want access to this damn thing and it’s no longer your [industry’s] problem.” Another audience member emphasized that remote monitoring on a pump is absolutely not an optional feature – kids with diabetes are sent to school, where there are no or few trained professionals, and parents have the right and need to see how their child is doing. Still others asked for companies to re-think and improve infusion sets, the traditional four-year pump warranty cycle, and algorithm transparency. To our delight, none of the panelists once responded “No, we can’t do that.” Of course there is work to be done on the best vehicle for the DIY community to interact with industry productively, but panelists were very open to hearing the audience – Dr. Kaufman even asked attendees to “go on a date” with Medtronic so they can get as much input as possible. We find this level of progress quite remarkable, since this dialogue didn’t exist even two years ago – we owe a hearty thanks to these industry leaders and the patient innovators who have pushed the field ahead.
  • MIT Sloan School of Management’s very smart Dr. Eric von Hippel, speaking to a room full of DIYers and lead users, encouraged some collaboration with industry…but not too much! In collaborating with companies too closely, non-industry innovators may end up with “indicia of commerciality,” which could result in a product that FDA can regulate (under the Commerce Clause, FDA can not regulate non-commercial medical innovations). According to Dr. von Hippel, there’s more to lose than, for example, the OpenAPS community’s right to use their DIY closed-loop systems. He explained that truly patient-led, grassroots innovation systems interact quite robustly with the producer innovation paradigm to the profit of both parties: During a producer’s R&D phase, it will offer innovation support to free innovators, who in turn churn out innovation designs upon which manufacturers can base products. It’s a difficult line to toe, however, as too close an interaction – a blended system – could lead to FDA involvement, and the scaffold could crumble.
    • According a study from Dr. von Hippels’ group, the number of medical patient innovators outnumber producers by over 100:1. Holy moly! Innovation has traditionally been seen as something that just producers do, and this is perpetuated by the fact that innovation is only accounted for in government statistics until a product is formally introduced onto the market – the user innovator is typically invisible. In the US alone, there are an estimated ~384,000 individuals working on medical consumer innovations.
  • According to Companion Medical CEO Sean Saint, Apple added insulin doses into Health Kit as of the Worldwide Developer Conference earlier this week. It will be available starting in iOS 11 this fall, and the beta is out now – see the iOS 11 developer page here. This has been long awaited and could be a nice data ecosystem enabler – especially as connected pens and connected pumps come out. 

4. Tandem’s Compelling Media Day: Up Close Looks at t:lock, Impressive Device Updater; G5 by Summer; First-gen App to Hopefully Launch this Year; PLGS in Early 2018

Tandem held a compelling, confidence-inspiring media day at its headquarters today, sharing updates on the pipeline and a tour of its manufacturing. From a patient perspective, we left the day feeling very positive about Tandem’s innovation path and priorities ahead. Highlights included:

  • Tandem’s new t:lock infusion set connector continues to be expected to launch in 3Q17. We learned that some of Tandem’s distributors actually buy Luer Lock sets in bulk from Animas (!) at a lower price, resulting in “tens of millions of dollars” in lost revenue over the past four years. With the new t:lock connector, distributors will now have to buy infusion sets directly from Tandem, allowing it re-capture a meaningful amount of lost revenue. Unomedical will still manufacture the sets and all current models will still be available – just with a different cartridge-set connector. Tandem’s customers also win too, as moving away from the Luer Lock connector (invented in 1896 (!) and not designed for insulin delivery) and to the t:lock will save wasted insulin and reduce priming time by 30 seconds, correcting major desired customer improvements. (Both have been on customers’ top 5 wish lists for the past two years straight.) We saw the connector in person and the difference is hardly noticeable:

  • We were blown away by the Tandem Device Updater demo, which took just a few minutes to update a t:slim X2 to add Dexcom G5 CGM integration. Wow! This is a very compelling feature and one we imagine all pumps will move to. Once the t:slim X5 G5 is approved (under FDA review and still expected this summer), customers will be able to update their t:slim X2 to add G5 integration before the new pumps even start shipping – talk about rolling out new innovation quickly via software!  The update process has clearly had a ton of human factors work put into it, with a series of checklists and a simple step-by-step process spelled out via an email and a user-specific update code. (Cool subject line: “Dexcom G5 Update Now Available for your t:slim X2.”) The software works on Windows and Mac and longer-term, over-the-air updates delivered to the pump via a phone and Bluetooth might be possible. We remain enormously excited about this update feature for pumpers, as it removes the hardware and cost hassles of upgrading. It will only become more compelling as Tandem moves to automation.
  • We saw the first screenshots of Tandem’s first-gen secondary display mobile app. For the first time, management shared it hopes to launch by the end of the year. The app will talk to the t:slim X2 via Bluetooth, wirelessly upload pump data to t:connect, and mirror key metrics from the pump display. Bluetooth BGM integration is also a goal (retrospective data only), and phone users will also receive notifications of pump alerts. Future generations (no timing given) hope to add more ambitious features, like remote bolusing, decision support, training and education, share notifications, and automated pump setup.
  • Tandem is “preparing” for pivotal study enrollment for its predictive low glucose suspend device with Dexcom’s G5. A launch is still planned for early 2018. This is right in line with the 1Q17 update, which expected the pivotal to wrap up in 3Q17.
  • The second-gen TypeZero hybrid closed loop is still expected to launch by the end of 2018. We confirmed that the main study phase of the pivotal trial (IDCL) still hasn’t started yet. Management implied the hardware changes to go from the research platform on a smartphone to an integrated t:slim X2 with Dexcom’s G6 may be part of the reason for the delay. This isn’t surprising, given the magnitude of this trial and learning from the initial site training phase. Dexcom’s G6 sensor wasn’t finished with its pivotal study as of a month ago, so perhaps it isn’t ready quite yet.
  • Tandem’s t:sport patch pump is still in development (no timing shared), and we got a first hands-on look at the small on-body component (roughly the size of Insulet’s OmniPod). Similar to Cellnovo, the plan is to have a 4-inch tubing that connects the pump to the infusion site. It’s still unclear whether smartphone app control will be possible, or whether a handheld will be the only way of interacting with the system. Tandem has obviously de-prioritized this project relative to the nearer-term automation pipeline.

  • Tandem is doing everything with international in mind.” No further details were presented, but obviously this represents another potential growth opportunity beyond the US – although one with potentially high costs. No timing has ever been given on this front.
  • Management was honest that Tandem’s stock price is quite low right now ($0.82; a “financing overhang” from a recent fundraise), and the company will need to raise additional capital. We believe the financial community continues to undervalue Tandem’s pipeline and overvalue the competitive impact of the MiniMed 670G. Management again characterized it as a pausing of the market and looked forward to the G5 integration launching. The power of Bluetooth connectivity and Tandem’s Device Updater should enable a steady stream of innovation, and Tandem’s marketing and attention to patient needs remains outstanding. Certainly, sales will need to improve as the year goes on, but this should happen assuming G5 integration launches as expected.

5. Digital Transformation in Diabetes Consists of Shifts from Strips to Sensors, Proprietary Devices to Connected Consumer Electronics, and Desktop to Cloud

Abbott’s Mr. Joel Goldsmith boiled down the digital transformation of diabetes care to three main trends: The shifts from strips to sensors, from proprietary handheld devices to connected consumer electronics as the preferred user interface, and from desktop application analytics to cloud-based services. CGM is becoming the standard of care, making the capture of dense glucose data almost effortless and much more cost effective – this dense data makes it easier to visualize trends and patterns. [He took the opportunity to remind attendees that FreeStyle Libre consumer is currently available in 35 countries and used by 300,000+ patients, though is still under review by FDA.] Similarly, smartphones are becoming intertwined with standards of medical care – they are pervasive, and are more and more an integral part of traditionally highly-regulated medical devices. Not only do they offer a familiar user interface and a constant source of connectivity, but they reduce the burden associated with carrying additional devices on one’s person. Finally, moving to the cloud is enabling instantaneous, widespread sharing and new forms of advanced data analytics, “helping to deliver on the promise of precision medicine.” Taken together, these three shifts are lowering the barrier to both insight generation and access, and are beginning to deliver outcomes. Mr. Goldsmith concluded by explaining why diabetes may be the “perfect candidate” for machine learning and AI: It is data-intensive, largely self-managed (increasingly through connected consumer electronics), and a growing global epidemic. We are seeing signs of life in this turf – automated retinopathy screening, Medtronic/IBM Watson’s Sugar.IQ (more on this in an oral session tomorrow), and One Drop just laid the foundation for future AI intervention this morning with it’s Amazon Alexa integration.

6. One Drop Integrates with Amazon Alexa Voice Technology; Brings Dr. Nicole Johnson on to the Advisory Board

One Drop announced a slew of updates this morning, most notably integration with Amazon’s Alexa voice technology. This new will allow patients to track blood glucose, food, and activity, as well as to access their data, all with voice. This represents a sizable leap forward in improving on manual entry, particularly for those who may be physically or visually impaired. The integration is set to launch on June 15th through the Amazon Alexa Skills Store (presumably for free in the One Drop app) and even allows caregivers in separate locations to access patient data summaries (i.e., “Alexa, did mom take her medication today?”). We love the commitment to simplifying data logging in all modalities and can’t wait to try the voice component out. Could voice become the new user interface in diabetes? It is relatively uncharted territory in diabetes, though one with serious potential (see Merck/Amazon’s competition) – In the same accessibility vein, One Drop introduced “Light Mode,” which is designed to improve readability for the visually impaired. The announcement also includes news of two new One Drop Experts in-app education programs – “Overcoming Diabetes Burnout” and “Advanced Carb Counting” – and the addition of Dr. Nicole Johnson to the One Drop Experts Advisory Board (joining Dr. David Marrero, Ms. Martha Funnell, Dr. Carla Miller, Ms. Heather Gabel, and Doug Warren). We look forward to digging into One Drop’s three new sources of outcomes data (two posters, one late-breaking poster) on Sunday and Monday – Jeff Dachis, Dr. Chandra Osborn, and co. already have two published retrospective posters demonstrating improved outcomes from use of One Drop Mobile and the Experts program.

7. Ascensia + Voluntis Partner to Connect Contour Next and Plus One BGMs with Insulia Basal Titration App; Launch in 4Q17

This morning, Ascensia announced a global partnership to connect Voluntis’ Insulia basal insulin titration app for type 2s with Contour Next One and Plus One BGM systems. The integration is expected to go live for people with type 2 diabetes in 4Q17. We’re not sure exactly how the combo will be deployed – Insulia is a prescribed app, but we’re not sure how that will come to market in combination with Ascensia’s BGMs. Will the products be bundled and sold together directly to patients? Will providers prescribe the two together? Or will the commercialization be separate, with Ascensia simply feeding data into Insulia as an integrated device? Voluntis has moved quickly, establishing partnerships with Livongo, Sanofi, and now Ascensia after announcing FDA clearance for Insulia in December. Ascensia is fresh off announcing development agreements with Insulet and Glooko and is clearly doubling down on digital diabetes care and connectivity. Notes CEO Mr. Michael Kloss in the press release, “[This] is our first partnership in the area of medication management, which is a critical component of integrated diabetes management…” We’re glad to see both companies partnering widely and look forward to seeing the business model and how Insulia comes to market at scale.

Other Highlights

1. Combatting Diabetes Stigma

ADA 2017 kicked off with a morning symposium on a critical but under-recognized and under-researched topic: the stigma of diabetes. Dr. Susan Guzman, a clinical psychologist, Director of Clinical Education Services, and co-founder (alongside the great Dr. William Polonsky) of the Behavioral Diabetes Institute (the only nonprofit dedicated to psychological issues of diabetes) led with a discussion of the feelings of guilt, shame, blame, embarrassment, isolation that too often accompany living with diabetes. Drawing largely on data from diabetes market research firm dQ&A (outlined in detail at AADE 2016 by our very own Mr. Adam Brown), Dr. Guzman described how these negative emotions are exacerbated in people with more intense therapeutic regimens, higher BMI, higher A1c, and poorer self-reported “control” – in other words, those most in need of help are also the most negatively impacted by diabetes stigma. She powerfully illustrated the judgment and misunderstanding surrounding diabetes with a timely allusion to a statement made a month ago by Budget Director Mr. Mick Mulvaney, who, when asked about how healthcare policy should handle pre-existing conditions, remarked that the US government shouldn’t have to “take care of the person who sits at home, eats poorly and gets diabetes” in future iterations of healthcare reform. Against this troubling backdrop, Dr. Guzman reminded the audience that diabetes is not a choice, and managing this disease is very hard work, underscoring the crucial role healthcare professionals can play in replacing society’s negative messaging surrounding diabetes with facts and empathy. We’re so glad that Dr. Guzman is drawing attention to this very important topic. Further, we’re impressed by the primetime positioning for psychosocial issues related to diabetes care at ADA 2017 – we’re also very excited for a symposium highlighting the ADA’s brand-new psychosocial position statement Saturday afternoon.

  • Harvard University’s Dr. Lindsay Jaacks continued the discussion, delving into the arguably even more severe diabetes stigma that exists in low- and middle-income countries (where the majority of people with diabetes live). Her research on the experiences of living with diabetes in China and India reveals a widespread phenomenon of people hiding their diabetes from friends, family, and co-workers and uncovered several key structural issues that people with diabetes face in emerging countries, such as difficulty finding a spouse due to extreme stigma, and a lack of institutional policies to prevent the discrimination of people with diabetes.
  • Though diabetes stigma is experienced differently across cultures, Dr. Jaacks argued for a universal underlying framework: stigma leads to mutually reinforcing cycle of distress/depression and suboptimal self-management practices, ultimately giving way to poor glycemic control and elevated risk of diabetes complications. Thus, anywhere in the world, educating the general public about diabetes could not only reduce the stigma that people with diabetes experience, but also potentially improve self-management and health outcomes.

Detailed Discussion and Commentary

Genetic Predictors of Cardiovascular Outcomes during Intensive Blood Pressure Control in ACCORD

Hetal Shah, MD (Joslin Diabetes Center, Boston, MA)

The 2008 ACCORD trial demonstrated that intensive blood pressure control did not improve cardiovascular outcomes in people with type 2 diabetes overall, but using a genome-wide association screen, Dr. Hetal Shah and her team identified genetic variants that could be used to pinpoint the subset of people with diabetes for whom intensive blood pressure is effective for the prevention of cardiovascular outcomes. The researchers conducted a GWAS test for 6.8 million common genetic variants for association with the primary outcome of 3-point MACE (cardiovascular death, non-fatal MI, and stroke) among consenting study participants (n=1,151) in the intensive blood pressure control arm of the ACCORD study. One loci on 2p22 exceeded the threshold (p=5x10-8) for genome-wide significance: an intron on 2p22 near the non-coding RNA gene LOC101929596 (p=3x10-8). Four other loci achieved near-threshold significance (p<10-7) – SNPs in close proximity to the non-coding RNAs on 22q21 and 18q2, the HDAC9 gene on 7p21, and the Syntaxin-8 gene on 17p13 responsible for protein trafficking. Sixteen other loci achieved notable significance (p<10-6). In a joint analysis of both the intensive and standard blood pressure control arms of the ACCORD study (n=2,295), individuals with the dominant allele for the top SNP experienced a significant benefit in the primary outcome when undergoing intensive blood pressure control (HR 0.66; 95% CI 0.49-0.88; p=0.006), whereas those with the recessive allele actually experienced a near doubling in cardiovascular events in response to intensive therapy (HR 2.22; 95% CI: 1.21-4.06; p=0.01). Dr. Shah was careful to note that these findings must be confirmed in additional studies, but this preliminary evidence provides an important basis for a future precision medicine approach to preventing cardiovascular events in people with type 2 diabetes. While we look forward to a future where an individual’s genetic makeup can be used to inform what strategy for blood pressure management has the best chance of preventing cardiovascular events, there is a long road ahead on this front – nonetheless, we’re glad to see the continued immense interest and progress in this area!

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