EASD 2017 (European Association for the Study of Diabetes)

September 10-15, 2017; Lisbon, Portugal; Days #1-2 Highlights – Draft

Greetings from Lisbon! We’re reeling from all the insights that have already been shared at EASD 2017, taking place this week at the beautiful Feira Internacional de Lisboa. As usual, Monday at EASD was packed with all-day corporate symposia, and we’ve narrowed the learning down to just 24 highlights for your reading pleasure : >.

On the therapy side, anticipation is building for full EXSCEL results (on AZ’s GLP-1 agonist Bydureon) to be presented Thursday – Drs. Bernard Zinman and Naveed Sattar highlighted differences in trial design that might explain this neutral CVOT vs. other positive ones for GLP-1 agonists, while Dr. Daniel Drucker discussed molecular differences that might distinguish products in this class. Several talks focused on the potential renal benefits to SGLT-2 inhibitors, and we detail insights from Drs. Per-Henrik Groop and Hiddo Heerspink below. We heard multiple mentions of cardio-renal-metabolic syndrome, with a call for new diabetes drugs to go beyond A1c and address CV and renal complications (along with other common diabetes comorbidities like NASH) – this was fascinating, and such valuable commentary. Although this meeting is considerably lighter on the tech side overall, today we were treated to two industry symposia – Dexcom and Roche – that provided key looks into their respective pipelines. We attended a number of talks on connected diabetes care, and were captivated by a panel of providers sharing their very candid feelings about digital health – some extremely surprising.

Read on for our top 24 highlights of the first two days of this m-a-r-a-t-h-o-n meeting, and see our preview for a glance into EASD’s pipeline : >. Please note there is an excellent online planner to download and there are lots of sessions that are on live webcast! We’ve shown which ones for tomorrow in our preview …

Diabetes Therapy Highlights

1. Could EXSCEL’s design as a more “pragmatic” outcomes trial have played a role in its neutral result? Drs. Bernard Zinman and Naveed Sattar speculated “yes” during an AZ-sponsored symposium, calling attention to inclusion criteria that perhaps made EXSCEL’s study population more reflective of a real-world patient population compared to Novo Nordisk’s LEADER. Little did we know way back in the day that effectively, lack of standardization and consistency in trials would become such a big topic. We so wish there could be truly large outcomes trials now testing every GLP-1 and every SGLT-2 – we would not look for this to be industry-funded but possibly NIH or foundation funded (where is the Helmsley Charitable Trust for type 2?)

2. During Novo Nordisk’s symposium, Drs. Daniel Drucker and Ildiko Lingvay emphasized within-class differences to GLP-1 agonists, Dr. Lingvay characterizing them as “the most heterogeneous class of diabetes drug therapy.” Although that may be true, it does not seem that payers or formularies in the US yet recognize this. After a deep dive into the basic science of GLP-1 agents, Dr. Drucker shared his view that differences between them are most likely explained by differences in molecule, though much more research is needed to provide definitive answers. He further alluded to an opportunity for personalized medicine that we now have in the GLP-1 class, where patients/providers have a choice between therapies with different dosing regimens, different injection devices, and different effects on glycemia on outcomes beyond A1c. In the US as well as many other regions, however, patients and providers do not have a choice since the payers dictate what is used. This may be an area for patient advocacy in classes where heterogeneity can be proven.

3. Dr. Juris Meier offered new insights on the near-doubling of risk for lower limb amputations associated with SGLT-2 inhibitor canagliflozin (J&J’s Invokana) in CANVAS, describing potential impacts of SGLT-1 inhibition and of AMP-activated protein kinase. He qualified that his basic science explanations for why amputations were seen with one SGLT-2 agent but not with two others are highly speculative, though they did provide a mechanism that would hinder tissue healing and could conceivably lead to heightened amputation frequency with canagliflozin. We await further word on this.

4. Dr. Per-Henrik Groop established links between renal impairment and CV risk, as well as renal impairment and hypoglycemia, advocating for an approach to diabetes management that focuses on the cardio-renal-glycemia triad. He spoke to the potential renal benefits of Lilly/BI’s DPP-4 inhibitor Tradjenta (linagliptin – this is not too surprising given that those with kidney disease can take it) and SGLT-2 inhibitor Jardiance (empagliflozin).

5. Dr. Hiddo Heerspink reviewed the current thinking on mechanism of action underlying SGLT-2 inhibitor therapy and renal protection. At present, there are three main (not mutually exclusive) hypotheses: (i) restoring tubuloglomerular feedback; (ii) restoring tubular hypoxia; and (iii) lowering glucotoxicity.

6. In Sanofi’s late-morning session on fixed-ratio basal insulin/GLP-1 combinations, Dr. James Gavin established Soliqua (insulin glargine/lixisenatide) as a way to fill an unmet need for better postprandial glucose control in type 2 diabetes, while Dr. Julio Rosenstock discussed the complementary effects of GLP-1 agonists and basal insulin that lead to superior glucose-lowering and fewer side-effects. These back-to-back talks made a compelling case for increased uptake of basal insulin/GLP-1 combos in the real world, which we’re extremely eager to see – it’s been very frustrating, after years of hearing about the benefits of these combination therapies, to see so much clinical inertia.

7. During Takeda’s symposium, renowned cardiologist Dr. Robert Chilton offered a very optimistic review of TZDs, claiming that he can’t think of a better drug, that it should perhaps replace metformin as first-line therapy in type 2 diabetes in some cases, and that heart failure risk can be attenuated through a healthy lifestyle and diuretics. This was quite a surprising speech overall given the side effect profile of TZDs that includes weight gain, edema, etc – that said, we’d love to see a big trial of TZDs taken in low doses because this class does fight insulin resistance directly. While we’ve never quite heard it characterized as optimal to replace metformin, we do think it could be prescribed more for people that don’t worry as much about weight and are not as at risk of other negative side effects. In the next talk, UCSD’s Dr. Steve Edelman agreed, and criticized Dr. Steven Nissen for giving the TZD class a bad name. Panelists asserted that as a field, we have to do a better job of not inducing a hysteria at every signal, because that could have a long-term detrimental effect on uptake of effective medicines (touching on canagliflozin/amputations and Lantus/breast cancer). That said, while of course this is true at a population level, when there is still uncertainty about side effects, it is hard not to be concerned, particularly for the sub-group in question, if there is one.

8. Dr. Anne Peters positioned Sanofi/Lexicon’s SGLT-1/2 dual inhibitor sotagliflozin as a future adjunct treatment for type 1 diabetes to address the needs unmet by insulin therapy alone, namely time-in-range. We hear lots of excitement about this class from people with type 1 and we believe thousands of patients are taking it off-label globally. In a similar vein, Dr. Thomas Danne discussed the potential of sotagliflozin in type 2 diabetes, and provided reassuring commentary on DKA risk: “No one wanted to discontinue insulin because of the risk of hypoglycemia, so I certainly hope SGLT-2 and SGLT-1/2 development isn’t hindered by the issue of DKA.” We don’t have the impression that it is hindered from the rave reviews we hear from patients.

9. Dr. Christina Rondinone of MedImmune, AZ’s biologics R&D arm, positioned GLP-1/glucagon dual agonists as the future of type 2 diabetes treatment – or rather, the future of therapy for cardio-renal-metabolic syndrome. We are very much looking forward to this class.

10. In an update on the JDRF-sponsored REMOVAL trial (metformin in type 1), Glasgow’s Professor John Petrie, Edinburgh’s Professor Helen Colhoun, and other investigators presented new microvascular and safety data, as well as new subgroup analyses based on sex and BMI. All in all, the new post-hocs largely supported the message of the main REMOVAL paper, in that metformin was found to be safe on the whole without exhibiting cardioprotection in type 1 diabetes. The panel emphasized how REMOVAL captures the need for more research into adjunct therapies for type 1, and posited that these results “will change practice, but exactly how has yet to be determined” – we suspect this may prompt a lot of searching but it may not be fruitful. That said, we were glad to see a CVOT in type 1 patients and would absolutely like to see another in type 1s, this time using all brands of GLP-1 and SGLT-1s/2s.

11. In Merck’s symposium on “60 years of clinical experience with metformin,” Dr. Marinella Temprosa argued that the generic drug could be a cost-effective solution to the growing global prediabetes epidemic. She also left us with food for thought on risk stratification, where metformin could perhaps be first introduced as a preventative therapy in patients with gestational diabetes. The diaTribe Foundation has been advocating for metformin use in pre-diabetes for years; we have heard extensive support for metformin use in gestational diabetes as well. That said, BMS is the company with the patents, and it is now generic – although submission would not be expensive (several million?), it has seemed hard to gain traction. The ADA and AACE and other professional organizations have worked on this in the past behind closed doors, as we understand it, and we hope they are gaining traction!

12. We have already heard a lot of positive thoughts from cardiologists this meeting – even just at the end of the first day! For example, cardiologist Dr. Neil Poulter emphasized that his colleagues were very impressed with the positive CVOT results for Novo Nordisk’s GLP-1 agonist Victoza (liraglutide) and Lilly/BI”s SGLT-2 inhibitor Jardiance (empagliflozin). During a separate symposium, another UK cardiologist Dr. John McMurray noted that he has seen SGLT-2 inhibitors prescribed as much by cardiologists as diabetologists. With the emergence of cardioprotective diabetes drugs comes a shifting diabetes treatment paradigm, toward one that emphasizes CV risk mitigation and that invites cardiologists to be more actively involved in medication prescribing (they’ve always avoided insulin because it’s hard to dose, as we understand it). To this end, we were thrilled to hear from representatives of the cardiology community that diabetes CVOT results are having an impact on clinical practice.

13. Wondering how recent CVOT results are impacting clinical practice? Check out these results of a poll taken at Novartis’ symposium on the “new epoch of type 2 diabetes management,” in which EMPA-REG OUTCOME was voted the most influential diabetes CVOT. While this may be surprising, when one considers that empagliflozin is perceived as easier to prescribe, that may be a clue to what was driving votes.

14. In a fast-paced presentation on next-generation basal insulins, Dr. Jeremy Pettus discussed improvements in the PK/PD profiles of Sanofi’s Toujeo (insulin glargine U300) and Novo Nordisk’s Tresiba (insulin degludec U100). He also advocated for the use of CGM data to help providers better understand the patient experience on basal insulin, and emphasized the importance of glycemic outcomes beyond A1c.

15. Three speakers representing the interdisciplinary diabetes management team provided valuable perspective on how best to optimize diabetes treatment, emphasizing metrics beyond cost, mutual respect between patients/providers, and pharmacists as integral community healthcare members.

Diabetes Technology highlights

1. Dexcom SVP Mr. Jake Leach shared two new updates on the pipeline: (i) the next-gen follow-on to G5 in Europe will not be called “G6” (it goes beyond the US version of G6 to include “additional features”- this is exciting); and (ii) there is ongoing work to integrate smart pens with Dexcom’s G5 app, Clarity, and Share (two pictures included for the first time). We also heard enthusiasm for smartwatches, and new adhesive study results.

2. Roche’s Tim Juergens showed attendees the company’s open diabetes management ecosystem (“available soon”), heavily featuring Senseonics’ Eversense implantable CGM (we saw some of these live today!), recently-acquired mySugr, and even a reusable smart pen available in cooperation with Pendiq in Germany in 2H17 (per an under-the-radar German press release). The company’s own Accu-Chek Insight CGM was absent from the forward-looking slides, and a rep told us Roche will not launch further versions of Insight. Presumably it will stay on the market in its current limited launch form, but it sounds like the focus moving forward will be Eversense.

3. In a Roche-sponsored symposium, Senseonics CMO Dr. Lynne Kelley shared that the implantable Eversense CGM has now been tested in over 500 patients to date. Subtracting the 161 EU and US pivotal trial participants, that means that over 340 patients have been implanted in the EU since the limited launch began last June. She hopes that the Roche/TypeZero/Senseonics long-term artificial pancreas clinical trial will begin before the end of the year (moved up slightly). We saw the form factor today and talked to multiple patients wearing it, who were all very positive. While we think it has a long way to go before competing head to head, it seems to be a real option.

4. Dr. Bruce Bode gave an optimistic talk on use of Novo Nordisk’s faster-acting aspart (Fiasp) in insulin pumps, noting that results from the large Onset 5 study are expected in 2018. We continue to hear very positive “real world” sentiments about the insulin, including from Kelly Close who loves it. (She does not have a current source, but got multiple pens on her last trip to Europe.)

5. A diverse panel of physicians shared their views on digital health, exposing a surprising lack of knowledge and significant fear regarding regulation, additional provider burden, and potential adverse effects. This was an eye-opener for us – there is a lot of awareness building that needs to happen.

6. Dr. David Kerr’s message was clear: integration of diabetes care cannot be achieved without accurate patient segmentation via technology. He believes smart pens will “revolutionize” care. He urged the field to move towards Value = (Quality + Experience)/Cost. We love the priority on this piece – we have heard lots of chatter about the importance of patients’ opinions, but it is less clear what the impact of some of this more “vague” chatter is. We believe finding alignment between value, as defined above, and patient enthusiasm and engagement, makes great sense.

7. Mills-Peninsula Medical Center's Dr. David Klonoff discussed the factors that will augment digital health adoption and suggested how to lower patient and HCP barriers. He also touched on the quality of digital health clinical data, a lack of research into the benefits of social media on adherence, and pharma’s growing involvement in digital therapeutics. This was a good talk and reminded us of his expert talk on digital health at DTM 2012.

8. mySugr’s Mr. Kyle Jacque Rose shared insights from IDF Europe’s 16-page position paper on mobile apps in diabetes, stressing the fallibility of the “one-size-fits-all” model.

9. Dr. Boris Kovatchev believes the future of diabetes technology will revolve around the concept of a “digital twin,” a virtual image of an individual patient incorporating the person’s condition, genetic information, and data from various sensors.

Table of Contents 

Diabetes Therapy Highlights

1. Drs. Zinman, Sattar on EXSCEL Trial Design Compared to Other GLP-1 Agonist CVOTs

Could EXSCEL’s design as a more “pragmatic” outcomes trial have played a role in its neutral result? While veteran clinical trialist Dr. Bernard Zinman didn’t explicitly pose this question, he did highlight that AZ’s outcomes trial for once-weekly GLP-1 agonist Bydureon (exenatide) was designed to be more reflective of real-world clinical practice than other more “traditional” CVOTs.

  • Dr. Zinman underscored that the enrollment criteria for EXSCEL were quite inclusive. Notable features included (i) enrolling patients with and without CV risk factors at baseline, (ii) allowing a wide range of concomitant medications, (iii) not enriching the study population with elderly patients, and (iv) not including a run-in period to rule out patients with low medication adherence. Perhaps an implied comparison is that the LEADER CVOT for Novo Nordisk’s Victoza (liraglutide) specifically targeted patients facing high CV risk, had a higher minimum age, excluded patients on DPP-4 inhibitors at baseline, and had a run-in period to establish adherence – though it did have a few “pragmatic” features as well. Notably, the FDA recently approved a new CV indication for Victoza reflecting reduced risk for adverse CV events, but this applies specifically to type 2 diabetes patients with established CV disease, in line with the high-risk participant pool in LEADER.
  • Dr. Naveed Sattar echoed Dr. Zinman’s sentiments, adding that EXSCEL was a much larger trial with more than 14,000 patients (compared to LEADER’s n=9,340), with treatment according to “locally-accepted clinical practice,” and with no selection of patients with better adherence. Dr. Sattar estimated that <50% of patients in real-world practice would meet the strict CV disease inclusion criteria commonly used in “explanatory” CVOTs, praising AZ for attempting to create a more realistic and translatable trial by including a primary prevention cohort. In his opinion, we need more trials like EXSCEL to figure out what these new agents can do in a larger population. Nonetheless, Dr. Sattar praised the work done in previous CVOTs as well, for shifting the paradigm of diabetes management in patients with CV disease. We add that CVOTs are a massive investment of time and resources, which is one (understandable) reason for enrollment of higher-risk patients to meet a minimum number of CV events.
  • EXSCEL’s neutral primary result – compared to the positive results seen in LEADER and SUSTAIN-6 (for Novo Nordisk’s semaglutide) – is one of the biggest discussion topics coming into this year’s EASD. Full EXSCEL data will be reported Thursday evening (5:15 PM in Roma Hall). We’re eager for insight and opinions on whether the neutral result in EXSCEL is more likely to be a product of the study design or the molecule itself. Dr. Zinman and Dr. Sattar’s observations in this AZ-supported session provide a plausible argument that study design may have played a role. If that is the case, it raises tough questions about the role of “pragmatic CVOTs” that are designed to reflect the real world (which is laudable) but may have a harder time demonstrating CV superiority. It also makes us wonder what role FDA could play in standardizing CVOT design, and what responsibility manufacturers have to conduct trials in a way that they could be compared for key clinical learnings. In contrast to these talks, Dr. Daniel Drucker spoke in a Novo Nordisk-sponsored symposium about molecular differences between various GLP-1 agonists that may explain differential effects (on CV outcomes, on A1c-lowering efficacy, and on body weight). See our coverage of Dr. Drucker’s talk below. There is so much to unpack here, and we’ll continue to keep our ear to the ground …

2. Dr. Drucker’s Basic Science Perspective on Within-Class Differences to GLP-1 Agonists

During Novo Nordisk’s symposium, Drs. Daniel Drucker and Ildiko Lingvay emphasized within-class differences to GLP-1 agonists, Dr. Lingvay calling them “the most heterogeneous class of diabetes drug therapy.” Perhaps the most patent example of this is the mix of neutral and positive CVOTs, with LEADER (for Novo Nordisk’s liraglutide) and SUSTAIN 6 (for Novo Nordisk’s once-weekly candidate semaglutide) showing significant CV risk reduction vs. placebo and EXSCEL (for AZ’s once-weekly exenatide, full results to be presented Thursday at this meeting), ELIXA (for Sanofi’s lixisenatide), and FREEDOM-CVO (for Intarcia’s ITCA 650, an implantable exenatide mini pump) demonstrating CV safety but not efficacy. Body weight effects also differ between various GLP-1 agents, as do glycemic effects. In fact, recent topline results from SUSTAIN 7, a head-to-head comparison of semaglutide vs. Lilly’s dulaglutide (Trulicity), showed a significant ~0.4% A1c treatment difference in favor of semaglutide plus an approximate doubling of weight loss benefit with semaglutide, despite both products being once-weekly, human GLP-1-based agents. Some have speculated that the divide between neutral and positive GLP-1 agonist CVOTs may be explained by molecular differences in exendin-4-based agents (exenatide and lixisenatide) vs. human GLP-1-based agents (liraglutide and semaglutide), while others have put more weight on variations in trial design – Thursday’s EXSCEL symposium will hopefully shed some light. While we don’t yet know with certainty what distinguishes one GLP-1 agonist from another, Dr. Drucker explored possibilities through a deep dive into the basic science of these compounds. He described semaglutide has having very similar features to native GLP-1, with a few slight but key differences from liraglutide: One amino acid substitution makes the once-weekly candidate more resistant to DPP-4 degradation, while another results in higher affinity binding to albumin. These small molecular changes underlie an improved GLP-1 agonist therapy: Semaglutide has demonstrated impressive potency across its phase 3 clinical program, and phase 2 studies in obesity imply superior weight loss efficacy vs. any obesity drug currently available (including Novo Nordisk’s market-leading Saxenda, a high-dose formulation of liraglutide). That said, Dr. Drucker acknowledged Trulicity’s weight loss efficacy as well. He pointed out that dulaglutide is a larger molecule that wouldn’t be able to enter the brain as rapidly as a smaller molecule like liraglutide, and still, dulaglutide is communicating effectively with the brain to suppress appetite and promote weight loss. He highlighted this as an interesting question for future studies. Dr. Drucker shared his view that differences between GLP-1 agonists are most likely explained by differences in molecule, though much more research is needed to provide definitive answers. On the bright side, he alluded to a tremendous opportunity for personalized medicine that we now have in the GLP-1 class, where patients/providers have a choice between therapies with different dosing regimens, different injection devices, and different effects on glycemia on outcomes beyond A1c. We appreciated this sentiment, and we hope it takes root in real-world clinical practice but are skeptical given how important formularies have become in determining what drugs patients take (outside the US, although they are not called formularies, it’s also often down to negotiation).

3. Dr. Meier Introduces SGLT-1 Inhibition and AMPK Activation as Potential Mediators of Amputation Risk in CANVAS

Dr. Juris Meier offered new insights on the near-doubling of risk for lower limb amputations associated with SGLT-2 inhibitor canagliflozin (J&J’s Invokana) in CANVAS, describing potential impacts of SGLT-1 inhibition and of AMP-activated protein kinase. Dr. Meier noted that regulatory authorities have not viewed canagliflozin’s amputation signal as a class effect: While the EMA took a more conservative approach and recommended warnings be added to all SGLT-2 product labels, the labels for AZ’s Farxiga (dapagliflozin) and Lilly/BI’s Jardiance (empagliflozin) read, “It is unknown whether this constitutes a class effect.” The FDA issued a black box warning on all canagliflozin-containing medicines with the caveat that this “does not apply to dapagliflozin or other SGLT-2 inhibitors.” Dr. Meier summarized evidence to show the lack of an amputation signal in dapagliflozin or empagliflozin trials, contrasting this with a nonsignificant numerical imbalance in low-trauma bone fractures (HR=1.23 in favor of placebo, 95% CI: 0.99-1.52) and a near-doubling of lower-extremity amputations (HR=1.97, 95% CI: 1.41-2.75, p<0.001) in CANVAS. Naturally, this begs the question of what distinguishes the canagliflozin molecule from its in-class competitors, and Dr. Meier speculated. Canagliflozin has a longer half-life than the others, which keeps it circulating in the blood for an extended duration. J&J’s agent also has lower selectivity for the SGLT-2 receptor, since it also inhibits the SGLT-1 transporter abundantly expressed in endothelial cells, where it contributes to both glucose uptake and nitric oxide production. Thus, partial SGLT-1 inhibition may reduce endothelial nitric oxide synthase 3 (eNOS) activity and nitric oxide production in some blood vessels, hindering vasodilation and oxygen delivery to tissues. Moreover, in vitro studies have shown that canagliflozin, but not dapagliflozin or empagliflozin, induces AMP-activated protein kinase activity in human cells at concentrations measured in human plasma in clinical trials. While AMPK has positive effects, including the induction of lipid oxidation, it is also a negative regulator of osteoblastic and chondrogenic differentiation activation and has been shown to reduce cell proliferation and wound healing in vitro. While these explanations are, by Dr. Meier’s own admission, highly speculative, they do provide a mechanism that would hinder tissue healing and could conceivably lead to heightened amputation frequency with canagliflozin. While we continue to develop our understanding of SGLT-2 inhibitors as a class and as individual agents – adding to the immense learning we’ve done so far –  we appreciated Dr. Meier’s explanation on amputation signal grounded in basic science. We eagerly await results from DECLARE, AZ’s CVOT for Farxiga, expected to read out in 2H18, and from VERTIS CV, Merck/Pfizer’s CVOT for ertugliflozin, expected to complete in October 2019. These outcomes studies will shed more light on the SGLT-2 inhibitor class, hopefully building even more compelling evidence for a cardioprotective class effect while elucidating differential effects on lower limb amputations.

  • On this hypothesis, we have received some thought-provoking response. In particular, some KOLs pointed out that the SGLT-1 inhibiting effect of canagliflozin is about 1/2,000th of its SGLT-2 inhibiting effect, so this action may not be significant except perhaps in the gut where drug concentration is high before absorption – otherwise, canagliflozin would give a significant bump to urinary glucose excretion compared to other SGLT-2 inhibitors. There remains a lack of good data for empagliflozin and dapagliflozin on amputations, as EMPA-REG OUTCOME collected this data using a different process than CANVAS, and DECLARE is not expected to complete until the second half of 2018 (we’re not sure how amputations are being recorded in this latter, ongoing CVOT). Moreover, other thought leaders have mentioned that certain people have complete SGLT-1 deficiency (i.e. 100% inhibition), and are not known to have problems with amputations – though it is possible that risk factors associated with diabetes, including peripheral neuropathy, could play a crucial mediating role. 

4. Dr. Groop Speaks to Importance of Renal Protection in Diabetes Care, Possibilities for Lilly/BI’s Tradjenta and Jardiance

Dr. Per-Henrik Groop established links between renal impairment and CV risk, as well as renal impairment and hypoglycemia, advocating for an approach to diabetes management that focuses on the cardio-renal-glycemia triad. He spoke to the potential renal benefits of Lilly/BI’s DPP-4 inhibitor Tradjenta (linagliptin) and SGLT-2 inhibitor Jardiance (empagliflozin). Where diabetes alone increases premature death by 4.1% over 10 years vs. a background population, albuminuria increases premature death by 17.8%, impaired eGFR by 23.9%, and albuminuria plus impaired eGFR by 47%. Dr. Groop followed this slide with one on the ADVANCE trial showing a clear correlation between diabetic kidney disease (DKD) and frequency of CV events. He then shared data on how DKD on top of type 2 diabetes essentially doubles risk for all-cause death, peripheral vascular disease, acute MI, and stroke/transient ischemic attack. To sum up: “the more albumin that leaks into your urine, the more likely you are to experience a CV event.” Less well understood is the relationship between DKD and hypoglycemia, but Dr. Groop showed that this association undoubtedly exists. The incidence of severe hypoglycemia nearly doubles when chronic kidney disease (CKD) is added onto a diabetes diagnosis, and ~74% of sulfonylurea-induced severe hypoglycemia episodes occur in patients with reduced renal function. Dr. Groop suggested a couple mechanistic explanations for this renal/hypo link: (i) some insulin is excreted via the kidneys, so lower eGFR aligns with a higher amount of insulin left circulating in the blood, and (ii) there’s less compensatory glucogenesis from the kidneys (particularly overnight) with impaired renal function. On an optimistic note, Dr. Groop pointed to new diabetes drug classes – DPP-4 inhibitors, SGLT-2 inhibitors, GLP-1 agonists – that do not cause hypoglycemia and that may additionally offer cardio- and renal protection. We were so glad to hear this perspective on the importance of where glycemic control, CV risk mitigation, and kidney function intersect. How payers value improved outcomes is of course the question of the day. Diabetes management is moving, at an increasingly fast pace, toward an emphasis on outcomes rather than the biomarker of A1c, and it is beyond exciting that patients can now take medicine not just to lower blood glucose, but to prevent heart attacks, strokes, worsening kidney disease, and death. On CVOTs, Dr. Groop remarked: “We’re always asking for something extra in these outcomes trials. What else can this drug do for me?” In our view, this is exactly the right question to be asking as the bar continues to rise for diabetes therapies on outcomes beyond A1c.

  • While all DPP-4 inhibitors are safe in patients with renal impairment, Dr. Groop underscored that Tradjenta (linagliptin) is the only agent in this class that doesn’t have to be adjusted even with falling eGFR, as linagliptin is excreted via the gut instead of the kidneys. The 24-week MARLINA-T2D study, presented at ADA 2016 and published recently in Diabetes, Obesity and Metabolism, found a 6% decline in urine albumin to creatinine ratio (UACR) with linagliptin vs. placebo, though this did not reach statistical significance (p=0.1954). UACR decreased by a mean 10% on linagliptin vs. placebo for participants with baseline UACR <300 mg/gCr, and this finding neared statistical significance (p=0.059). While this data alone doesn’t support any renal protection associated with Tradjenta, Dr. Groop suggested that upcoming CARMELINA CVOT results will be more telling, since the kidney effects of linagliptin are believed to work via a longer-term, anti-fibrotic mechanism. According to ClinicalTrials.gov, CARMELINA is expected to complete in December 2017, and we’ll be eager to see the macrovascular and microvascular outcomes data next year.
  • Dr. Groop also touched upon the kidney benefits seen in EMPA-REG OUTCOME for SGLT-2 inhibitor Jardiance (empagliflozin), but encouraged everyone to “take two steps back” and keep in mind that this was not a dedicated investigation into renal outcomes. The good news is that Lilly/BI have a planned outcomes study for Jardiance specifically in people with CKD (with or without type 2 diabetes), which will reveal the full scale of empagliflozin’s renal effects. Interestingly, Dr. David Fitchett mentioned at ESC 2017 last month that diabetes patients with eGFR <60 ml/min/1.73m2 may actually reap the greatest benefits from SGLT-2 inhibitor treatment in terms of CV and renal risk reduction. The SGLT-2 class is poised to target all three aspects of the cardio-renal-glycemia triad, which we find extremely exciting, and we’re pleased to see continued investment from Lilly/BI to probe the full extent of these benefits (the companies have launched the EMPEROR HF program to investigate empagliflozin in heart failure as well). AZ also has ongoing studies of its SGLT-2 inhibitor Farxiga (dapagliflozin) in heart failure and CKD.

5. What Mechanism Powers the Renal Protective Effect of SGLT-2 Inhibitors?

Dr. Hiddo Heerspink reviewed the current thinking on mechanism of action underlying SGLT-2 inhibitor therapy and renal protection. To-date, all reported CVOTs of an SGLT-2 inhibitor have shown evidence of renal protective effects: This includes a 39% relative risk reduction for diabetic nephropathy seen in the EMPA-REG OUTCOME trial of Lilly/BI’s empagliflozin, as well as a 40% risk reduction for the composite renal outcome (renal death, renal replacement therapy, or 40% reduction in eGFR) in the CANVAS trial of J&J’s canagliflozin. Still, as Dr. Heerspink pointed out, the precise mechanism underlying this beneficial effect remains a mystery. At present, there are three main (not mutually exclusive) hypotheses: (i) restoring tubuloglomerular feedback, (ii) restoring tubular hypoxia, and (iii) lowering glucotoxicity. The tubuloglomerular feedback hypothesis comes from evidence that SGLT-2 inhibitor treatment prevents the increase in levels of KIM-1, LFABP, and NGAL, well-known markers of subclinical tubular injury. The hypothesis regarding restoration of tubular hypoxia originates from evidence that dapagliflozin increases serum erythropoietin, reversing the phenomenon in diabetic kidney disease (DKD) whereby excessive glucose reabsorption in the kidney renders renal fibroblasts dysfunctional, producing a decrease in erythropoietin. Finally, the glucotoxicity-lowering hypothesis is based on the SGLT-2 inhibitor class’ well-known glucose-lowering effect (via urinary excretion).

  • Dr. Heerspink unveiled, to our surprise, that the mortality rate of patients with comorbid diabetes and kidney disease is higher than the average mortality rate of all cancers (55% vs. 50% 10-year cumulative incidence, respectively), a powerful illustration of the need for not only more DKD therapies but also a much greater focus on renal-protection.  No new DKD indications have been approved in the past 17 years, the most recent being irbesartan and losartan in 2000. SGLT-2 inhibitors represent a promising and long-awaited option. To this end, all three SGLT-2 inhibitors on the market have a dedicated renal outcomes trial either planned or ongoing: the CREDENCE trial for J&J’s canagliflozin (enrolling subjects with comorbid type 2 diabetes and CKD; completion expected June 2019), the Dapa-CKD trial for AZ’s dapagliflozin (enrolling subjects with CKD both with and without type 2 diabetes; completion expected November 2020); and a soon-to-begin trial of Lilly/BI’s empagliflozin (enrolling subjects with CKD both with and without type 2 diabetes; timing not yet specified). Indeed, Dr. David Fitchett suggested at the recent ESC 2017 meeting in Barcelona that diabetes patients with eGFR <60 ml/min/1.73m2 may actually stand to benefit the most from treatment with an SGLT-2 inhibitor, in terms of CV and renal outcomes alike – the truth will lie in outcomes data, and we look very forward to that.

6. Drs. Gavin and Rosenstock Tout Benefits to Basal Insulin/GLP-1 Combos

In Sanofi’s late-morning session on fixed-ratio basal insulin/GLP-1 combinations, Dr. James Gavin established Soliqua (insulin glargine/lixisenatide) as a way to fill an unmet need for better postprandial glucose control in type 2 diabetes. He summarized findings from the DECODE and Diabetes Intervention Study (DIS) trials, both of which found an independent effect of postprandial hyperglycemia on CV and all-cause death. In the former, postprandial excursions were associated with a significantly increased risk for CV death across all subgroups of fasting plasma glucose. In the latter, mean postprandial glucose >180 mg/dl was associated with significantly heightened risk for fatal MI and for all-cause death vs. mean postprandial glucose between 80-145 mg/dl (p<0.05 for both comparisons). These were merely two examples – Dr. Gavin asserted that there’s an abundance of data on these adverse outcomes stemming from poor postprandial control – and yet a majority of diabetes drugs only address the fasting component of hyperglycemia. Products in the highly-anticipated new drug class of basal insulin/GLP-1 fixed-ratio combos simultaneously tackle fasting blood glucose (with the basal insulin piece) and post-meal glucose (with the GLP-1 agonist piece). Indeed, GLP-1 agonists have introduced competitive pressure for rapid-acting insulins on the market because of their positive postprandial effects, and it is our sense that Sanofi has long been emphasizing the benefits to short-acting GLP-1 agonists (like lixisenatide) on post-meal glycemia. We first heard Sanofi’s categorization of “prandial” GLP-1 agonists vs. “non-prandial,” longer-acting GLP-1 agonists years ago, and this characterization has been confirmed by further clinical evidence and KOL commentary. At EASD 2016, Dr. Boris Kovatchev presented a post-hoc analysis of LixiLan-O to emphasize how lixisenatide contributes to Soliqua’s overall A1c-lowering benefit by acting primarily on postprandial hyperglycemia. That said, Novo Nordisk’s Xultophy (insulin degludec/liraglutide) also contains a short-acting GLP-1 agonist component by this categorization, since both liraglutide (branded Victoza) and lixisenatide (branded Adlyxin) are indicated for once-daily injection. Dr. Gavin reviewed key phase 3 results on both products, revealing that Soliqua is weight neutral while Xultophy appears to promote weight loss. Moreover, we note that liraglutide’s demonstrated CV benefit in the LEADER trial and the recent FDA approval of a new CV indication for Victoza may lend further advantage to Xultophy. The SWITCH and DEVOTE studies have also shown lower hypoglycemia risk with insulin degludec vs. insulin glargine, another variable that may be meaningful for patients/providers choosing between the two advanced combinations. Of course, the most important takeaway from Dr. Gavin’s talk was how both Soliqua and Xultophy represent a leap forward in diabetes care: Both agents have shown superiority vs. component monotherapies, alongside a milder side-effect profile, and we so hope to see a boost in real-world uptake (whole class sales in 2Q17 were underwhelming at $34 million compared to billions for GLP-1 as a single-agent class). Dr. Gavin described the “urgency” that HCPs should feel in getting more of their type 2 patients on this class of combination therapy (especially those with baseline A1c >9% and/or those uncontrolled on two oral agents), and we couldn’t agree more.

  • Dr. Julio Rosenstock followed Dr. Gavin, launching off the discussion of postprandial control with an emphasis on the complementary effects of GLP-1 agonists and basal insulin that lead to superior glucose-lowering and fewer side-effects. Where insulin causes weight gain, GLP-1 agonists promote weight loss. When insulin is used to deliver the GLP-1 agonist, as in a fixed-ratio combination, it ameliorates GI side-effects that affect patient quality of life. Dr. Rosenstock shared data to support that side-effects of both monotherapies are not trivial. GLP-1 agonists, he explained, are plagued by discontinuation. One analysis found discontinuation rates after six months as high as 48% for exenatide (AZ’s Bydureon), 36% for liraglutide (Novo Nordisk’s Victoza), and 28% for dulaglutide (Lilly’s Trulicity). Moreover, 40%-50% of real-world withdrawal is due to nausea, vomiting, and diarrhea stemming from GLP-1 agonist treatment. Basal insulin is not without its side-effects, namely hypoglycemia risk and weight gain. It also comes with issues of low adherence to titration and low persistence: According to Dr. Rosenstock, 50%-60% of people have stopped insulin after a 12-month follow-up. He outlined three intensification options for patients uncontrolled on basal insulin: (i) rapid-acting insulin before the largest meal, (ii) a standalone GLP-1 agonist, and (iii) a switch to a fixed-ratio basal insulin/GLP-1 agonist combination. Dr. Rosenstock argued that the last is the most appealing, as it minimizes injection burden and co-pays, offering simplicity and the greatest chance at maximizing adherence. We found this to be another fascinating talk in favor of basal insulin/GLP-1 agonist fixed-ratios, and we hope real-world HCPs are similarly compelled by the ability to help their patients with medication adherence, improve glycemic control, and enhance patient quality of life with a milder side-effect profile.

7. Cardiologists on TZDs: “Can’t Think of a Better Drug”

During Takeda’s symposium, renowned cardiologist Dr. Robert Chilton offered a very optimistic review of TZDs, claiming that he can’t think of a better drug, that it should perhaps replace metformin as first-line therapy in type 2 diabetes in some cases, and that heart failure risk can be attenuated through a healthy lifestyle and diuretics. In the next talk, UCSD’s Dr. Steve Edelman agreed, positing that no class leads to longer or more durable glycemic changes. He directed blame for giving TZDs a bad name toward Cleveland Clinic’s Dr. Steven Nissen: “He was very wrong. It was a major disservice to the field. I give him no credit for making us do CVOTs. Yes, good things came out of it, otherwise we’d never see cardiologists at our meetings. Bottom line, it’s an important class of agents…it has a lot of baggage, but when used early in the natural history of type 2 diabetes, you don’t see the side-effects [Editor’s note: especially with a low dose].” In the aftermath of rosiglitazone’s link to increased risk of MI and CV death, Dr. Nissen played a major role in drafting the FDA’s 2008 guidance on diabetes CVOTs. While we, too, were negative on the required timing at first, we must acknowledge the wealth of learning that has come from these large outcomes studies, including four agents with demonstrated cardioprotection (GLP-1 agonists liraglutide and semaglutide, SGLT-2 inhibitors empagliflozin and canagliflozin). The bad reputation assigned to TZDs since the rosiglitazone scare does seem very real, and is perhaps unfounded given certain benefits seen with pioglitazone – last year’s IRIS trial, for example, showed CV benefits to low-dose pioglitazone. There were higher rates of heart failure in the RECORD and PROactive trials, but Dr. Chilton pointed out that PPARg works by increasing sodium and water retention – a fluid overload – not by damaging cardiocytes, so a diuretic would likely be an effective risk mitigation strategy. Even in the PROactive study, he underscored that fatal heart failure was not an issue. In-patient admissions for heart failure were higher, but many who were admitted went home on pioglitazone and a diuretic. Moreover, Dr. Chilton dismissed concerns of TZD-induced bladder cancer (“a consideration that’s pretty much dead”) and bone fracture (though TZDs are not the drug of choice for women with existing osteoporosis). Weight gain and edema are also potential side-effects, but relatively minor. This was a clear endorsement, to us, of a drug that had been held in contentious regard for many years. Takeda markets a branded formulation of pioglitazone called Actos, though the company has ceased breaking out sales in recent quarters, we imagine because most prescriptions go to generic versions. Indeed, the low cost of TZDs is an advantage that can’t be overlooked in modern diabetes management.

  • In the subsequent Q&A, a number of prominent clinician-researchers cautioned against panicking when a study picks up on an adverse signal. The initial question pertained to SUSTAIN 6, in which Novo Nordisk’s GLP-1 agonist semaglutide showed a profound CV benefit but also a 76% relative risk increase for retinopathy. Dr. Edelman replied brilliantly and succinctly: “Lantus caused breast cancer. Rosiglitazone, thanks to [Dr.] Steve Nissen, caused heart failure. The toe amputation in CANVAS needs to be looked at in not such a hysterical way. Same thing here. Society tends to focus on abnormalities, ignoring the benefits.” On the other hand, Dr. Chilton pointed out that there is some evidence that GLP-1 agonism stimulates VEGF – “it’s possible there could be a problem, but we won’t know until we look at it long-term.” Human nature forces us to be risk averse, latch on to outliers, and fall victim to negative framing. Dr. Chilton explained how he asked nurses in the coronary care unit if they would take drugs that might cause blindness or toe amputation, but might also reduce CV death. Fascinatingly, they said no.
  • The message from the panel was clear: As a field, we have to do a better job of not inducing a hysteria at every signal, because that could have a long-term detrimental effect on uptake of effective medicines. Pioglitazone, according to one audience member, is only taken by 3% of people with diabetes, despite its valuable action as an insulin sensitizer.

8. Drs. Peters, Danne on Sotagliflozin for Type 1 and Type 2 Diabetes: Addressing Unmet Need of Time-in-Range, DKA Risk Highly-Manageable

In a heartfelt talk, Dr. Anne Peters characterized the heavy demands of type 1 diabetes management as a psychological and physiological battle between hypo and hyperglycemia. She positioned Sanofi/Lexicon’s SGLT-1/2 dual inhibitor sotagliflozin as a future adjunct option to address the needs unmet by insulin therapy alone, namely time-in-range. Dr. Peters vividly described the phenomenon of diabetes distress, which involves feelings of powerlessness, management fatigue, and fear of hypoglycemia – all related to the constant variability in blood glucose that characterizes type 1 diabetes. In the Lexicon-led inTandem clinical trial program, sotagliflozin has shown a promising ability to increase time-in-range and reduce glycemic variability in people with type 1 diabetes (in addition to A1c-lowering, weight loss, and minimal risk of DKA). Dr. Peters argued that time-in-range is a key clinical feature to improve patient quality of life in type 1 diabetes. We couldn’t agree more with her emphasis on this important outcome beyond A1c, and we’re excited by the prospect of an oral adjunct type 1 treatment that address time-in-range – long overdue for people with type 1 diabetes. To this end, recent data from dQ&A highlights time-in-range as the defining factor in patients’ daily lives, and Dr. Peters underscored that this crucial outcome should be elevated to a position of much higher importance in clinical trial design and regulatory decision-making.

  • Agreement on how to standardize this and other outcomes beyond A1c is the first step toward this goal, and Dr. Peters alluded to a soon-to-be-published consensus statement from the “endocrine world” (that is, AACE, ADA, the Endocrine Society, JDRF, the Helmsley Charitable Trust, the Pediatric Endocrine Society, and the T1D Exchange – all of which took part in a recent gathering organized by The diaTribe Foundation called “Glycemic Outcomes Beyond A1c: Standardization & Implementation”) that will do precisely this. On hypoglycemia, the consensus statement proposes a classification system encompassing level 1 (70-54 mg/dl), level 2 (<54 mg/dl), and level 3 (altered mental state and/or requiring assistance). Notably, this is free of subjective adjectives like “mild” or “moderate” since no experience of hypoglycemia is mild from the patient’s point of view.  The consensus statement further defines time-in-range as the percentage of blood glucose readings between 70-180 mg/dl per unit of time, and DKA as either elevated serum ketones or evidence of acidosis (serum bicarbonate <15 mol/L or blood pH <7.3). Our eyes will be peeled for forthcoming publications in Diabetes Care.
  • In a similar vein, Dr. Thomas Danne discussed the potential of sotagliflozin in the type 2 diabetes population – particularly those with kidney dysfunction. Unlike SGLT-2 inhibitors, which are not currently indicated for type 2 diabetes patients with renal impairment since the drug is filtered through the kidneys (though Dr. David Fitchett’s comments at ESC 2017 suggest there may be some need to change this), sotagliflozin maintains its efficacy even in patients with lower eGFR levels, thanks to its additional inhibition of SGLT-1 transporters in the small intestine. To this end, following promising reductions in A1c, body weight, and blood pressure with sotagliflozin in phase 2 trials, a Sanofi-led phase 3 program for sotagliflozin in type 2 diabetes is ongoing, with new trials slated to begin in 2H17. We appreciated Dr. Danne’s framing of the potential DKA risk with this agent (albeit a smaller issue in type 2 vs. type 1 diabetes) as a solvable problem: “No one wanted to discontinue insulin because of the risk of hypoglycemia, so I certainly hope SGLT-2 and SGLT-1/2 development isn’t hindered by the issue of DKA.” We very much agree that DKA is preventable with proper patient education, and represents a manageable risk when considered in light of the strong benefits of SGLT-2 and SGLT-1/2 dual inhibition from a glycemic perspective, as well as a variety of outcomes beyond A1c, including weight loss, blood pressure reduction, and increased time-in-range. We’ll be hearing much more on sotagliflozin at this conference… stay tuned.

9. GLP-1/Glucagon Dual Agonists as the Future of Combination Therapy

Dr. Christina Rondinone of MedImmune, AZ’s biologics R&D arm, positioned GLP-1/glucagon dual agonists as the future of type 2 diabetes treatment – or rather, the future of therapy for cardio-renal-metabolic syndrome. Dr. Rondinone explained how NASH, type 2 diabetes, CV events, and insulin resistance are all interconnected. Each may be a separate disease state, but she emphasized that “we’re talking about one patient – the cardio-renal-metabolic patient.” The next generation of pharmaceutical medicines should go beyond treating the individual diseases and treat the syndrome more holistically, and according to Dr. Rondinone, a dual peptide combining GLP-1 agonism with glucagon holds the most multifaceted potential. Clinical and real-world data has established, rather convincingly, that GLP-1 agonists lower A1c very effectively and promote weight loss via suppressed appetite and greater gastric emptying. Glucagon offers additional weight loss, plus improvements in lipid levels and liver fat. Studies of bariatric surgery have found that oxyntomodulin levels rise post-procedure. This is the same gut hormone secreted after meals to decrease appetite and increase energy expenditure, and it’s thus an intriguing therapeutic target for diabetes, obesity, and related comorbidities. Several companies have oxyntomodulin analogs in the GLP-1/glucagon dual agonist competitive landscape, including OPKO Health (for obesity) and Lilly (for type 2 diabetes and NASH); AZ’s MEDI0382 is a GLP-1/glucagon dual agonist in phase 2 for type 2 diabetes and obesity. Dr. Rondinone went on to review preclinical data on GLP-1/glucagon dual agonists demonstrating decreasing insulin requirements, conversion of white fat to brown fat, and improvements in glucose tolerance. In animal models of NASH, specifically, these dual peptide agents have shown reduced steatosis, reduced fibrosis, and dramatic drops in liver triglycerides. Given Dr. Rondinone’s enthusiasm for this emerging therapy class, it’s great to see a robust competitive landscape, with many candidates in preclinical development, phase 1, or phase 2. We’d certainly like to see faster forward progress. We also love this concept of cardio-renal-metabolic syndrome, an idea also touched upon by Dr. Per-Henrik Groop during a Lilly/BI sponsored symposium, and one receiving increasing attention of late. The outcomes beyond A1c movement goes hand-in-hand with a focus on diabetes comorbidities and complications – it’s no longer acceptable to treat glycemia in isolation, without attending to CV disease, renal disease, NASH, etc.

10. Update on REMOVAL, Metformin in Type 1

In an update on the JDRF-sponsored REMOVAL trial, Glasgow’s Professor John Petrie, Edinburgh’s Professor Helen Colhoun, and other investigators presented new microvascular and safety data, as well as new subgroup analyses based on sex and BMI. The original results were presented in a dedicated symposium at ADA 2017: Three years of metformin therapy in adults with type 1 diabetes (n=428) had no significant effect vs. placebo on the primary endpoint of mean carotid intima-media thickness (cIMT), although there was a significant protective effect on the tertiary endpoint of averaged maximal cIMT (p=0.0093). Both are common CV biomarkers, surrogate measures for CV disease risk. Dr. Colhoun shared new findings on sex and BMI, neither of which showed a significant interaction with metformin treatment on the primary endpoint. She did report a significant three-way interaction (p<0.05) for treatment, time, and sex on maximal cIMT, with a greater slowing of slope for maximal thickness occurring in females vs. males, but qualified that this is “by no means conclusive evidence.” Metformin’s impact on reducing insulin requirements was driven by people with BMI <30 kg/m2, with daily dose actually increasing slightly among participants with BMI >30 kg/m2 (p=0.0443 for treatment interaction). That said, the overall decrease in daily insulin dose in REMOVAL was only ~2 units/kg for metformin vs. placebo (p=0.0018), which is not necessarily clinically-meaningful. As Dr. Julio Rosenstock pointed out during the ADA REMOVAL symposium, “two units is absolutely nothing in terms of reduced insulin dose.” Moreover, Dr. Colhoun shared that the A1c-lowering benefit to metformin was greatest among patients with BMI >30 kg/m2 (p=0.0019 for this subgroup on its own), although once again there was no significant three-way interaction. She concluded that these subgroup analyses do not change the message of the main REMOVAL paper, published in Lancet Diabetes & Endocrinology, in that metformin was found to be safe on the whole without exhibiting dramatic cardioprotection. Dr. Colhoun suggested that the lack of a significant interaction based on BMI calls into question that current diabetes treatment guidelines recommend metformin as an adjunct type 1 therapy for patients with overweight/obesity. However, it’s important to note that these algorithms take into account metformin’s weight loss effects, which were confirmed in REMOVAL (2.6 lbs treatment difference, p<0.0001). In our view, it seems there would still be a very distinct benefit to metformin in this population with type 1 diabetes/high BMI because of the benefits to body weight alone, regardless of CV risk management. In fact, this discussion also came up at ADA, and Dr. Partha Kar suggested that REMOVAL actually underscores current practice trends, with metformin as a helpful adjunct tool in people with type 1 diabetes who would benefit from weight loss.

  • Dr. Peter Rossing discussed new post-hoc analyses that employed different calculations of kidney function, confirming the hint from original REMOVAL results that metformin may confer renal benefit. In the original presentation, the eGFR secondary endpoint showed a treatment difference of 4 ml/min/1.73m2 in favor of metformin after 36 months (p<0.0001), mostly driven by a sharp initial rise in eGFR during the first three months that was maintained until the end of the study period. Initially, eGFR was calculated using the MDRD equation, but this latest analysis describes eGFR in terms of the CKD-EPI equation, which is tailored specifically to diabetes. Based on serum creatinine levels, eGFR (via the CKD-EPI equation) was an average of 2.5 ml/min/1.73m2 higher in the metformin group vs. placebo (95% CI: 1.21-3.78, p=0.0002). This trend persisted when eGFR was calculated using CKD-EPI based on cystatin C rather than creatinine: Here eGFR was an average of 2.9 ml/min/1.73m2 higher in participants treated with metformin vs. placebo (95% CI: 0.65-5.10, p=0.011). Unlike creatinine, cystatin C is not influenced by body weight, suggesting that metformin’s apparent ability to improve eGFR is a consequence of the drug’s direct action on the kidney, and not a mere byproduct of weight loss or a direct effect on tubular creatinine excretion. Moreover, progression to albuminuria tended to be slower in people treated with metformin: The drug showed a 37% reduction in time to onset of microalbuminuria (HR=0.63, 95% CI: 0.34-1.14), but this did not reach statistical significance (p=0.1275). With the assays and statistical analysis finalized just days ago, Dr. Rossing underscored that this is very preliminary data and that the findings cannot be “overstressed” until a more detailed analysis occurs based on rate of change in albuminuria excretion. That said, we are hopeful about the potential of a renal protective drug for the many people with type 1 diabetes at risk of kidney disease – no less one that is inexpensive, widely known, and widely available. Given the high cost of end-stage renal disease care and dialysis, even a moderately protective renal effect from metformin could have a substantial ROI. We keenly await the full analysis, which Dr. Rossing alluded will also include information on regression from albuminuria and rate of change in albuminuria excretion to provide a fuller picture of metformin’s effect on the kidney.
  • On safety, Dr. Coen Stehouwer reported a number needed to harm (NNH) of 13 for vitamin B12 deficiency (<150 pmol/L) from metformin use. This data from REMOVAL closely matches findings from the HOME study of metformin, further supporting that vitamin B12 monitoring is essential with long-term use of this agent. Indeed, the ADA’s 2017 Standards of Care calls attention to this need for B12 monitoring in the context of metformin therapy. Dr. Stehouwer underscored that the diabetes field has known for >50 years that metformin can induce vitamin B12 malabsorption, and Dr. Colhoun later chimed in that this safety issue should not be of enormous concern. There was a very slight decrease in hemoglobin levels seen in the REMOVAL trial (the key question here is “are the effects on B12 clinically-meaningful? Do they correlate with increased anemia risk?”), but according to Dr. Stehouwer, any risk of anemia is unlikely to be caused by B12 deficiency given a lack of effect on mean corpuscular volume (p=0.38). Further in-depth analysis into this topic is needed, and he assured that these more granular post-hocs will be done.
  • The panel emphasized how REMOVAL captures the need for more research into adjunct therapies for type 1 diabetes, and agreed that these results “will change practice, but exactly how has yet to be determined.” As Dr. Colhoun put it, conducting a large CVOT for metformin in type 1 diabetes was (and is) impractical, given the lack of industry investment behind a generic drug. That said, she urged pharmaceutical companies to focus more R&D on adjunct treatments in type 1 diabetes. The speakers also agreed that there’s a chance metformin may show greater benefits with longer-term use, or initiation earlier in the course of disease, perhaps in patients <18 years-old as opposed to adults with a mean 33 years diabetes duration as in REMOVAL. This is another practical challenge for pharmaceutical clinical research. Dr. Colhoun outlined other forthcoming pre-specified analyses that will be done on the REMOVAL primary cIMT endpoint: age, baseline cIMT, background CV disease, duration of diabetes, baseline A1c, smoking status, LDL levels, systolic blood pressure, insulin pump users (yes/no) – a list that looked like the rolling end credits after a movie. We so appreciate the commitment to gleaning as much insight as possible from this dataset, since it’s so true that the type 1 patient population is understudied and that there’s a lot we don’t understand about metformin. Having more definitive answers about metformin’s health effects, even if this study wasn’t entirely positive, is most valuable for the diabetes community.

Questions and Answers

Dr. Sanjoy Dutta (JDRF, New York, NY): Doing a study of this magnitude in type 1 diabetes is not easy, and the REMOVAL team (along with the CONCEPTT study team – that trial is being presented later at this meeting) is showing to the world that it is possible to do a large trial in type 1. Hopefully, pharma companies will take an opportunity to learn from this. After some time and additional analyses, will the panel (plus other investigators) put together some kind of guidance or learnings for how to successfully conduct a trial like this in such a non-abundant population? Can we write some kind of summary on this, offering tidbits that others can use to conduct large trials?

Dr. Petrie: It’s all about having a great team. There are always challenges, but if you have the right people, you can make it happen.

Dr. Colhoun: I agree with you – the pharma industry uses the excuse that it is difficult to run trials in type 1 as a reason for not examining drugs in this population. We need much greater ambition from them, and much greater support from that sector to realize insights.

Dr. Petrie: Trials with SGLT-2 inhibitors in type 1 diabetes, so far, have been run for six months or a year. These agents have potential, but we do need to see the effects on safety and complications in the long term. In my view, the regulators should need to see this also.

Dr. Dutta: Yes, that’s the point I was getting at – that it is, after all, quite possible to do a complications study. Another sidebar: How can we investigate in populations below 18 years of age? How do we design studies in adults that provide the necessary amount of safety information to go in populations <18, which in the context of type 1, is a critical population?

Dr. Hramiak: Keep in mind – this was a study of people who were survivors of type 1 diabetes. That point isn’t always emphasized enough in these presentations. If we are going to take your leadership from JDRF and translate that into studies that are practice-changing in the care of patients with type 1 diabetes, we have to start perhaps earlier than in our survivors, who in this case had a mean duration of diabetes of 33 years at study start. You’re right – maybe it has to start in teenagers. Those of us who look after patients with type 1, we see people struggle daily to achieve the level of control they need to prevent diabetes complications, and the tool we have in our hands are limited. Despite SGLT-2 and GLP-1 studies, we haven’t yet seen better than a 0.2% or 0.3% A1c-lowering effect. So, JDRF deserves some kudos, that they had the courage to do this trial with metformin. It will be practice-changing – we just don’t know how quickly, or in what direction.

Q: How does this change practice in type 1 diabetes care?

Dr. Petrie: I think in a sense, as chief investigator of a trial, you have a conflict of interest. You see the results through rose-tinted glasses, since you’ve worked on it for so long. In these people who have had type 1 for so many years, it’s quite tantalizing to see effects on the vascular wall, and it’s powerful that you see a reduction in weight and LDL (a potent biomarker for CV disease). This is only three years of their lives, even though they’ve had diabetes for so long and will have it for many more years after. What if they had been on metformin for longer? If we used statin therapy (the standard of care) more aggressively in this population, would this have more of an effect? Our participant pool used statins aggressively and we saw an effect.

Dr. Colhoun: An important question is whether or not we saw any dis-benefits to metformin. And, I think we can safely say no. We saw small effects on vitamin B12, but they are not of enormous magnitude. So that’s one thing, it’s useful to know. There’s no a priori reason, if you’re considering metformin as an adjunctive therapy in type 1, that you should limit it to people who have obesity. And we’ve learned that metformin is not a dramatic magic bullet for CV disease prevention. It may have accrued benefit over the long term, and some of the data collectively points that way, but would it compete as a cardioprotective agent against other diabetes drugs out there? The answer there is fairly clear: it wouldn’t. Where does that leave you therapeutically? Metformin is a safe drug. If you have a patient in front of you who is struggling to manage their glucose on insulin, it’s still worth giving metformin a try. Some patients will see weight loss and A1c reductions, and if your patient isn’t one of that group, you can always stop the drug. The results aren’t dramatic – rather, they’re more of a reassuring context for what you might consider for the individual patient with type 1 diabetes.

Q: How large does the evidence base have to be before we change our practice? Do we need a less detailed, larger RCT assessing outcomes? Is there observational data we can look back on?

Dr. Colhoun: I don’t think we have sufficiently unbiased observations to definitively answer this question. As for a CV prevention trial, it would certainly be worth trialing metformin in a factorial design. But as John and I know, to get a CV outcomes trial for a drug like metformin, which is off-patent, is nearly impossible.

Dr. Petrie: Right. We already wrote the protocol for a pragmatic trial – we just need the resources.

11. A Health Economic Argument for Metformin in Diabetes Prevention

In Merck’s symposium on “60 years of clinical experience with metformin,” Dr. Marinella Temprosa argued that the generic drug could be a cost-effective solution to the growing global prediabetes epidemic. She reviewed DPPOS results, noting the 31% reduction in diabetes development after ~three years on metformin and the 18% reduction in new-onset type 2 diabetes over 15 years. She also detailed data from the 2002 study published in Diabetes Care demonstrating 10-year cost-effectiveness of lifestyle intervention and metformin, concluding that both are good investments. We were reminded of Dr. John Buse’s talk at WCPD 2016, when he made a very compelling case for metformin as a population-level prediabetes intervention: 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 GLP-1 agonist liraglutide. Meanwhile, intensive lifestyle intervention as provided by the DPP costs ~$100/person/session – treating 86 million Americans with prediabetes would run a bill of ~$1.4 trillion. All in all, we’re convinced that metformin should be prescribed more readily for type 2 prevention, and were thus disappointed (though not entirely surprised) to hear from Dr. Temprosa that metformin uptake for this purpose in the US is quite low. She attributed this to an absence of a prediabetes indication (indeed, a key first step may be getting prediabetes recognized as a disease in and of itself) and failings in education. After surveying 15 treatment guidelines for people at high-risk for new-onset type 2 diabetes, Dr. Temprosa found that lifestyle is the preferred treatment option over metformin. Still, she is optimistic that diabetes prevention messages are being disseminated around the US, and she expressed hope that prevention practices (both lifestyle and metformin) will spread globally. Promisingly, DPP will be reimbursed by Medicare starting in 2018, although digital DPP will not be included (a major hit, given the potential gains in access). As of 2015, 84 million Americans were living with prediabetes, per CDC estimates (shockingly, only 12% were aware of their prediabetes status). In the words of Dr. Temprosa, “Do nothing? Is that really what we want to do? Diabetes can be prevented. It is not inevitable.”

  • Dr. Temprosa also alluded to Dr. David Nathan’s data from ADA 2017, showing that people with gestational diabetes continue to see greater benefits to metformin over 15 years follow-up. This supports greater use of metformin in gestational diabetes, which is a key population to consider in type 2 prevention. Indeed, several thought leaders have suggested risk stratification as a way to facilitate the introduction of metformin as a prediabetes therapy (in other words, start by prescribing the drug to those at highest-risk for type 2 diabetes). The gestational diabetes patient population could be a practical place to start, as this group is high-risk and more easily identified in clinical practice settings although there is always much worry about how therapies will impact pregnant women for obvious reasons.

12. SGLT-2 Inhibitors as Cardiology Drugs

Cardiologist Dr. Neil Poulter noted that his colleagues were very impressed with the positive CVOT results for Novo Nordisk’s GLP-1 agonist Victoza (liraglutide) and Lilly/BI’s SGLT-2 inhibitor Jardiance (empagliflozin). Speaking during Novo Nordisk’s symposium, he added that many cardiologists see it as their job to prescribe glucose-lowering medications if they play a part in secondary CV prevention. However, he noted that the average cardiologist still finds it intimidating to prescribe an injectable glucose-lowering agent, so for the moment, the cardiologists he knows are mostly sticking with SGLT-2 inhibitors. During AZ’s morning symposium, another UK cardiologist Dr. John McMurray noted that he has seen SGLT-2 inhibitors prescribed as much by cardiologists as diabetologists. We’re curious whether this trend is limited to the UK, or if it’s comparable in other geographies, although this commentary falls closely in line with what we heard at ESC 2017 in Barcelona last month: Cardiologists are stepping up to prescribe diabetes drugs with known CV efficacy, and they’re more comfortable with oral agents, although GLP-1 agonists seem to offer superior weight loss (and the patient with diabetes/CV disease is likely to also have overweight/obesity). The implications of cardiologists getting more involved in diabetes drug prescribing are profound, both in terms of benefits – such as earlier treatment intensification and a greater focus on outcomes beyond A1c – and potential risks – such as the need for more coordination between providers. We certainly lean more toward the benefits here. Moreover, on the topic of SGLT-2 inhibitors vs. GLP-1 agonists for cardioprotection, we note that it’s pretty incredible that HCPs now have a choice between two diabetes therapy classes with demonstrated CV benefit. At ESC, Dr. Poulter mentioned “the art of medicine” and the opportunity for more personalized medication regimens. SGLT-2 inhibitors have more potential for heart failure indications (both Lilly/BI and AZ have ongoing studies of Jardiance and Farxiga, respectively, in heart failure patients with or without diabetes), while GLP-1 agonists seem to exert their CV benefit via atherosclerotic mechanisms. Different patients will stand to benefit more from one or the other.

13. EMPA-REG OUTCOME Voted the Most Influential Diabetes CVOT by Symposium Attendees

If you’re looking for evidence that recent CVOT results are already impacting clinical practice, check out these results of a poll taken at Novartis’ symposium on the “new epoch of type 2 diabetes management.” An audience response question asked “which CVOT has most influenced your prescribing habits?” The ranked results were as follows:

  • EMPA-REG OUTCOME: 33%
  • UKPDS: 29%
  • LEADER: 13%
  • ACCORD: 12%
  • DEVOTE: 5%
  • TECOS: 4%
  • CANVAS: 2%
  • SAVOR: 2%
  • PROACTIVE: 0%

With the caveat that we don’t know how many people actually voted (it was a relatively small symposium at around 100 to 200 attendees), the results are quite interesting. We wonder why EMPA-REG OUTCOME scored so much higher than LEADER and CANVAS. We would expect Lilly/BI’s CVOT to get a bit of a bump because it was first, but the magnitude of the difference was striking. In any case, we’re sure it was a tough choice.

14. Dr. Pettus Summarizes Benefits to Next-Gen Basal Insulins

In a fast-paced presentation on next-generation basal insulins, Dr. Jeremy Pettus discussed improvements in the PK/PD profiles of Sanofi’s Toujeo (insulin glargine U300) and Novo Nordisk’s Tresiba (insulin degludec U100). According to Dr. Pettus, a perfect basal insulin would have a duration of action ≥24 hours to allow for flexible, once-daily dosing (several thought leaders have cited flexible dosing as an advantage to Tresiba). The perfect basal would come with a flat PK profile, providing evenly-distributed exposure over the course of a day, as well as a flat PD profile, with a peak-to-trough ratio near one to minimize hypoglycemia risk. Last but not least, Dr. Pettus’ perfect basal insulin would exhibit low between-day variability. He showed how both Toujeo and Tresiba, when compared to Lantus, have a more even distribution of glucose-lowering effect, with flatter PK/PD profiles. Moreover, both products last ~24 hours or more, allowing for more flexible dosing. In a head-to-head euglycemic clamp study of Toujeo vs. Tresiba, Sanofi’s product demonstrated a more even glucose infusion rate and lower fluctuation throughout the day.

  • Dr. Pettus also advocated for the use of CGM data to help providers better understand the patient experience on basal insulin. Four patients’ 24-hour CGM data was displayed: All had an A1c of 8.0%, but average blood glucose readings were 195 mg/dl, 195 mg/dl, 163 mg/dl, and 156 mg/dl, which would predict A1cs between 7.0% and 8.4%. Moreover, A1c can hide hypoglycemia – a patient with an A1c of 6.5% may be happily sent on their way by their doctor, because fingersticks don’t show daily lows that pull down A1c measurements. We absolutely agree about the value of time-in-range data, which can be provided by CGM, as opposed to A1c (for more, read our report on diaTribe’s Glycemic Outcomes Beyond A1c consensus conference). Certainly, more work needs to be done to make CGM data actionable and better utilized by regulatory authorities.

15. IDF Symposium: Perspectives on the Diabetes Care Team, Cost, & Trust

Three speakers representing the interdisciplinary diabetes management team provided their perspective on how best to optimize diabetes treatment, emphasizing metrics beyond cost, mutual respect between patients and providers, and pharmacists as integral community healthcare members. For Dr. Dario Rahelic, an IDF board member and President of the Croatian Society for Diabetes and Metabolic Disorders, diabetes therapy is not just about direct cost. When evaluating a new therapy, he considers the broader impact, making sure to assess indirect effects like loss of productivity, quality of life, life years gained, and hospital visits. From the patient perspective, Ms. Sophie Hindkjaer, an IDF Young Leader living with type 1 diabetes, found that her doctor visits markedly improved once she viewed herself as an expert in her own diabetes. While her initial clinic visits felt like exams and were comprised solely of reviewing blood glucose numbers, after participating in the IDF youth leadership camp, she realized that her physician should not be scolding her, but rather working with her to improve her life. She began having productive conversations with her healthcare team by supplying and asking for context surrounding her glucose numbers. In her own words, “if you only focus on the numbers, you might miss the whole picture.” We love the idea of the empowered patient, but not everyone will have the opportunity to learn in the IDF context, so we hope to see more efforts go toward teaching providers how to be more effective.  Just as the patient should be considered an essential member of the healthcare team, so, as argued by IDF board member Dr. Iryna Vlasenko, should pharmacists. Pharmacists are often overlooked by physicians, yet they can educate patients about proper therapy use, recommend ancillary products and services, help maintain glycemic control, and prevent complications, all within a community setting. Dr. Vlasenko finds that pharmacists are underutilized, largely due to poor social and professional acceptance. Stigma doesn’t only apply to the people living with diabetes…

  • Dr. Rahelic urged the audience to avoid thinking exclusively in terms of direct cost. For a patient population whose numbers exceed those of HIV/AIDS, tuberculosis, and malaria combined, solutions can only be reached by thinking creatively. Dr. Rahelic provided the example of when he negotiated with the Croatian Ministry of Health and national insurance to make modern insulin available to type 2 patients in his country. While both entities were quick to dismiss the proposal at first due to expenses, Dr. Rahelic pointed out that the costs of hypoglycemia and weight gain associated with premixed insulin outweigh savings. Ultimately, he was able to reach a compromise, in which type 2 patients could receive modern basal insulin analogues for a more reasonable co-payment of 10-20 EUR. Up-front investment in tools that enable better glycemic control is a no-brainer, since the alternative is costly hypoglycemia and/or complications down the road.
  • We were pleased to hear Dr. Rahelic mention that diabetes management encompasses more than just medication. He stressed the effects of stigma, empathy, and the amount of time patients spend with physicians, which he finds to be insufficient. In his home country of Croatia, there are only 140 diabetologists and 2,500 general practitioners, each of whom are tasked with seeing 40-60 patients per day (aka 8-12 minutes/patient). To this end, Dr. Rahelic noted the importance of nurse educators, and we add that remote and AI coaching will likely fill huge gaps in care. 
  • Dr. Vlasenko detailed several studies showing the benefits of pharmaceutical intervention by pharmacists. A study published in the International Journal of Clinical Pharmacy suggested that pharmacists can reduce medical expenses and contribute to safety and efficacy, estimating the total cost savings associated with 500 interventions to be over $200,000 – more than half of the interventions helped prevent adverse drug reactions. A randomized control trial of elderly patients with diabetes and hypertension found that pharmaceutical care significantly improved health outcomes and did not increase total direct healthcare costs significantly, designating pharmaceutical intervention as a cost-effective option.
  • Ms. Hindkjaer emphasized the need for patient trust. Patients are expected to talk to their healthcare team about topics they might not even be ready to discuss with their families. As an example, women with diabetes are asked to make decisions regarding pregnancy very early on. This kind of trust can only be achieved through confidentiality and shared respect. Ms. Hindkjaer also noted that providers should be open to including the patient’s support network during visits, although acknowledged that not every patient will be ready for this step immediately, if at all. IDF Europe President-elect Dr. Niti Pall later added that the patient-provider relationship comes down to four factors: trust, empathy, expertise, and information. “If you don’t get trust and empathy right, they’ll never take your expertise and information.”
  • Dr. Rahelic proposed several solutions to ease the global burden of diabetes, including increasing awareness, involving politicians, facilitating cooperation between healthcare providers and national diabetes programs, and thinking globally yet acting locally. The last concept is particularly relevant given disparities across healthcare systems regarding access, technology, and reimbursement. Even in Europe, which is generally associated with high-quality care, people in Albania pay for all diabetes therapies out of pocket. There is no one-size-fits-all solution, though Dr. Pall strives for the “holy grail” that is elimination of all user fees and co-payments in medicine across the globe.

Diabetes Technology Highlights

1. Dexcom Pipeline Updates: Next-Gen System in EU Won’t Be “G6,” as It Has “Additional Features” (Factory Cal?); Smart Pen Integration Work Ongoing

Dexcom SVP Mr. Jake Leach shared two new updates on the pipeline: (i) the next-gen follow-on to G5 in Europe will not be called “G6” (it goes beyond the US version of G6 to include “additional features”); and (ii) there is ongoing work to integrate smart pens with Dexcom’s G5 app, Clarity, and Share (two pictures included for the first time). We also heard enthusiasm for smartwatches, and new adhesive study results. Mr. Leach’s closing comment summarized the pipeline vision nicely: “Imagine a world where fingersticks are completely eliminated, CGM is the first tool for all newly diagnosed patients, and insulin delivery is optimized using CGM-integrated smart pens and automated insulin delivery systems.” See the details below!

  • In discussing the next-gen pipeline for the EU audience, Mr. Leach did not once use the term “G6.” He revealed in Q&A (we asked!) that the EU follow-on to G5 will actually not be called “G6” – it will have “additional features” beyond the US version of G6. (The latter will be submitted to the FDA by the end of this month and include 10-day wear, one calibration per day, a one-button inserter, a 30% smaller profile wearable, and acetaminophen blocking.) Mr. Leach confirmed that the next-gen Dexcom product for Europe “depends on regulatory and clinical studies,” suggesting it is indeed still in progress. We’d infer factory calibration is a clear additional EU feature for the G5 follow-on, given all the mentions of it in the pipeline (e.g., showing the G6 pre-pivotal data from DTM 2016). We’d guess 14-day wear is also in the cards, as there was a separate mention of this today (“we are now examining sensor performance out to 14 days”) and previous expectations for G6/Verily. Both features are strategically smart for Dexcom to incorporate in the immediate next-gen in Europe, as it must stay competitive with Abbott’s 14-day, factory calibrated FreeStyle Libre – waiting a bit of time to get these features in makes sense. We’re not sure what other “additional features” will be included, though Mr. Leach did discuss a new sensor adhesive we’ve never heard about before (more below). In the US, 14-day wear and factory calibration are expected in the first-gen Dexcom/Verily product (timing update to come in the 3Q17 call).
  • On the smart pen front, Mr. Leach confirmed that Dexcom has smart pen “partners” (none disclosed) and is currently working on integrating insulin injection data straight into the G5 app, Dexcom Clarity, and Dexcom Share. The blue pen shown on the slide was not branded (see below), though it looks fully disposable and without any add-ons. A separate slide with smart pens showed Lilly’s Luxura and Novo Pen Echo (see second picture below). This was the deepest confirmation yet of Dexcom’s commitment to this critical area, and the first suggestion that it could potentially partner with Novo Nordisk and Lilly (our speculation). Which of the three insulin companies will get there first with a compelling, easy-to-use smart pen?

  • Mr. Leach spent more time than ever on Dexcom’s commitment to additional wearable displays, including Apple Watch, Android Wear, Fitbit Ionic (announced last week), and direct CGM transmitter-to-watch communication (“untethered,” meaning no nearby phone needed). We were glad to hear the latter following Apple’s plans for WatchOS4 and Dexcom CGM shared in June. To be clear, Dexcom has never given timing on launching direct CGM-to-Apple Watch transmission, presumably because the regulatory path is under discussion. (This “Native Core Bluetooth” feature in WatchOS4 will launch this fall.) We see this direct CGM-to-watch communication as highly compelling for CGM users, especially once Watches have Wifi and cellular built in (e.g., pediatrics could wear a watch alone and still use Dexcom Share). Mr. Leach shared definite excitement for the brand-new Fitbit Ionic integration partnership, but did not offer further details beyond our coverage last week. As we’ve come to expect, a big R&D goal remains “building an ecosystem of devices compatible with Dexcom CGM.”
  • We also heard some compelling marketing claims for the next-gen, one-button sensor applicator that will now launched with G6: 76% of pediatric subjects rated the applicator as “didn’t feel anything” vs. 30% for G5. In addition, 98% of pediatric subjects rated the new applicator system as “very easy” or “Somewhat easy” compared to 59% for G5.
  • Mr. Leach shared a never-before-seen 14-day adhesive patch survival study (n=21 adults). With the new patch, Dexcom found a 20% improvement in survival at 14 days vs. its current G5 patch (~90% vs. ~75%). The curves started to separate at day 10, and this also suggests 14-day wear is very much on the radar. Mr. Leach said this new adhesive will be included in “next-gen devices,” though it wasn’t clear if this will also apply to the soon-to-be-submitted G6 in the US. We wonder if this new adhesive will also reduce site reactions that prevent some from using CGM.
  • We’ve long known acetaminophen blocking is planned for G6, though Mr. Leach showed a 24-patient study that confirmed the benefit relative to G5. Dexcom gave participants a 1000mg dose of extra strength acetaminophen (paracetamol), showing a +60 mg/dl peak bias for G5 and little-to-no change for the next-gen sensor. Said Mr. Leach, “We have high confidence in the superior interference.” This will also help with FreeStyle Libre competition, as Abbott’s sensor doesn’t have acetaminophen interference.
  • Dexcom is “excited” with the Verily partnership progress, and more information is expected at “upcoming meetings” as Dexcom “starts to move into clinical trials and feasibility studies.” Mr. Leach showed the same slide we’ve seen throughout the year, with two generations of Verily systems both expected to be 14-day wear, real-time CGM, and factory calibrated (low-cost expected in gen two). The 2Q17 call did not give a firm timing update on Verily gen one (previously planned for end of 2018); an update should come in the 3Q17 call.

2. “Roche Diabetes Care’s Open Ecosystem” Features Senseonics’ Eversense, mySugr, Pendiq Connected Pen; Accu-Chek Insight CGM Absent

Roche’s Tim Juergens showed attendees the company’s open diabetes management ecosystem (“available soon”), heavily featuring Senseonics’ Eversense implantable CGM, recently-acquired mySugr, and even a reusable smart pen available in cooperation with Pendiq in Germany in 2H17 (per an under-the-radar German press release). The company’s own Accu-Chek Insight CGM was absent from the forward-looking slides, and a rep told us Roche will not launch further versions of Insight. Presumably it will stay on the market in its current limited launch form, but the focus moving forward will be Eversense. Roche’s own Accu-Chek Insight underwent a limited launch in the EU last year (we’re not sure of the size), but a Roche scientist noted that, while it performs up to par with the competition, it doesn’t add anything novel, unlike the implantable 90-180-day Eversense. As a reminder, Roche currently distributes Eversense widely, invested ~$30 million in the company in May, and is supplying the Accu-Chek Insight pump for the development of an automated insulin delivery system with Senseonics and TypeZero. We wonder if Roche might even buy the implantable CGM manufacturer, as Senseonics’ current market cap of ~$300 million arguably puts it in M&A reach. Also included in Roche’s proposed open diabetes ecosystem are Roche solutions (Emminens eConecta, Accu-Chek Smart Pix, mySugr, BGM, pumps,), third party solutions (Senseonics Eversense, Pendiq connected pen), and the data backbone (perhaps in reference to the new, slightly vague partnership with Accenture).

  • Mr. Juergens presented a visually-appealing depiction of a “day-in-the-life” with Roche’s integrated diabetes ecosystem. You can see our photos of the slides here. We definitely recommend taking a look – you’ll see the Eversense sensor and mySugr prominently displayed, examples of feedback from a mySugr-affiliated diabetes nurse educator (“Your blood glucose went a bit low just before you woke up. Having looked at your data, I recommend your normal breakfast but cover it with a smaller insulin bolus”), automated insulin dose titration/connected pen, automated carb counting, support through a smartwatch (“Please stop running…arrhythmia detected…Your doctor will reach out to you”), payer and pharmacy integration, care delivery, and caregiver communication. This was a mock-up and seems to be in the concept stage, but we like the vision – acquiring elements and forging partnerships to create a seamless diabetes care experience. This is surely a far cry from the product-based business model , but theoretically the direction we’ll see more diabetes tech companies head. Of course, executing on this vision and getting payers to buy in is the truly hard part. Can Roche pull it off? Also in this model, Mr. Juergen indicated that Roche will push forward with prevention programs, early diagnosis, and decision support, in addition to value-based payment models.

  • The positive stated ambition of this ecosystem is to “enable people with diabetes to spend more time in range and experience true relief.” Nice outcomes beyond A1c! According to Mr. Juergen, this care delivery redirection is necessitated by more engaged and informed patients – higher health literacy, increased use of smart personalized health apps, and online education.

3. >340 Patients Implanted with Senseonics Eversense CGM Since Launch; Remains Under FDA Review

In a Roche-sponsored symposium, Senseonics CMO Dr. Lynne Kelley shared that the implantable Eversense CGM has now been tested in over 500 patients to date (>100,000 sensor wear days). Subtracting the 161 EU and US pivotal trial participants, that means that over 340 patients have been implanted in the EU since the limited launch began last June. This patient base is in line with revenue, which totaled $800,000 in 2Q17 (<$2 million cumulatively). The company expects availability in 14 countries by the end of the year and a pretty big uptick in sales: $4-$6 million expected for 2H17. As a reminder, active discussions with FDA continue – management still expects there will be an advisory committee panel in late fall with approval hopefully soon after (the last update projected a 4Q17 approval). Dr. Kelley also provided a timing update on the clinical study for the Senseonics/Roche/TypeZero automated insulin delivery system, hoping that it will begin prior to the end of this year (moved up from “early 2018” timing shared on the 2Q17 call). Elsewhere on the pipeline front, Dr. Kelley showed the Eversense Apple Watch display and indicated that the company is “looking toward compatibility on a variety of other mobile devices.”

  • According to Dr. Kelley, there have been very few reports of irritation due to the transmitter adhesive across the launch and trials. Skin irritation is still an issue with other systems that are worn for multiple days – it is encouraging to hear that Eversense may avoid this hurdle, though the tradeoff is daily-adhesive changes. Perhaps the adhesive formulation is also less irritable on the body, since it doesn’t have to stick for six days or more.
  • The average total clinic time for an insertion procedure (including patient intake, etc.) is 15-20 minutes, with the actual Eversense insertion taking 2.5-4 minutes. This is faster than we would have guessed. Further, Dr. Kelley suggested it takes ~2-3 rounds for physicians to feel comfortable with the insertion and removal procedures. As a reminder, there was only one SAE in PRECISE II (the US pivotal trial), and it was due to a sensor that was placed too deep. Otherwise, it seems like the procedure is rather easy to learn and perform. Scaling this product will require buy-in from HCPs, so we’ll be interested to see if these early sentiments carry to a broader population of prescribers. 

4. Dr. Bruce Bode’s Optimism on Fiasp in Insulin Pumps; Onset 5 to Report in 2018

Dr. Bruce Bode gave an optimistic talk on use of Novo Nordisk’s faster-acting aspart (Fiasp) in insulin pumps, noting that results from the large Onset 5 study are expected in 2018. Dr. Bode covered two published studies (Heise et al., Diabetes Obes Metab 2017 and Bode et al., DTT 2017) and the in-press Onset 4 study (Zjilstra JDST 2017) showing that Fiasp in pumps works faster than aspart (especially in the first 30-60 minutes), might lessen hypoglycemia (“we don’t know for sure yet”), and is stable in insulin pump tubing. Interestingly, a slide comparing PK profiles suggested that Fiasp has a bigger speed advantage over aspart when delivered via pump – a 26-minute faster time to peak PK in pump vs. a smaller 7-minute advantage with injections (see picture below). Dr. Bode wondered if Fiasp’s excipients give it this larger advantage when it is infused continuously rather than as single bolus injection doses. Looking ahead, the “definitive” Onset 5 trial will share results in 2018, as the last patient came out of the trial this past month. The multi-national study enrolled ~450 adults with type 1 diabetes in a randomized, blinded comparison between Fiasp and aspart in pumps. The primary endpoint is change in A1c at 16 weeks, though we’re excited to see the CGM data on time <70 mg/dl. Dr. Bode closed with his view on hybrid closed loop, which he called “a “gamechanger” – “You as a professional don’t adjust insulin.” He hopes to study use of faster aspart in hybrid closed loop in the “near future,” as many 670G users still report post-meal glucose values that rise up to ~180-200 mg/dl. As a reminder, Novo Nordisk’s 2Q17 update confirmed that an FDA decision on Fiasp (next-gen faster-acting insulin aspart) is anticipated in 3Q17 (this month!), following a Class II resubmission in March 2017. The next-gen mealtime insulin is already approved in Europe and Canada, and we continue to hear resounding positive feedback.

  • Dr. Bode said that “over 50,000” people have signed up to get on hybrid closed loop in the US (i.e., 670G), and “over 25,000” are already on it – these numbers are overestimates based on what we heard in Medtronic’s 2Q17 earnings call (~2.5 weeks ago). At the time, management shared that “close to 35,000” patients were in the Priority Access Program to eventually get on the 670G (i.e., less than “50,000”), with shipments to all of these customers expected to complete later this fall. It’s possible that more have signed up for the priority access program since that time, though we doubt an additional 15,000 have come on in the past couple weeks. Meanwhile, far fewer than 25,000 are likely on the MiniMed 670G right now, as only ~1,000 patients were on it as of late July and the ongoing sensor shortage has slowed new 670G shipments (not expected to resolve until April 2018). Read more in Medtronic 2Q17.

5. Surprising Lack of Phsycian Knowledge and Substantial Fear Surrounding Digital Health; Concerns Mainly Due to Perceived Absence of Regulation

A diverse panel of physicians moderated by Dr. Partha Kar, Clinical Director of Diabetes at Portsmouth Hospitals NHS Trust, discussed their views on digital health, exposing a surprising lack of knowledge and substantial fear regarding regulation, additional provider burden, and adverse effects. Dr. Lawrence Leiter noted that insulin adjustment apps make him particularly nervous, as he believes some have been validated but many have not. Dr. Steven Kahn echoed these sentiments, questioning the evaluation process behind insulin titration apps and worrying that patients will choose free options that likely lack sufficient regulation and maintenance. On the other hand, Dr. Michael Nauck said that basal insulin titration could eventually be supported by an app, but stipulated that the process shouldn’t be “too autonomous” and that, “you have to also involve a healthcare professional, otherwise things may have a chance to go wrong.” We’d note here that the FDA has already cleared three basal-only titration apps (Voluntis’ Insulia, Sanofi’s My Dose Coach, and Amalgam Rx’s iSafge Rx), which must meet a fairly high bar and do require prescriptions and HCP setup (though after that, they run on their own). Dr. Kahn expressed concern regarding the time commitment digital health tools require of providers, stating that, “these interactions become loops that never stop,” and Dr. Nauck feared that patients will become so attached to their apps that they will forget to see their physician and discuss their diabetes in person. We find the likelihood of the latter highly doubtful – the time patients spend with their providers is extremely limited and digital health should help provide support between visits. Dr. Kar acknowledged this opportunity, finding that digital technology is most effective when used to bolster self-management. Dr. Nauck also expressed fear that apps could produce adverse responses, which may go unreported. This panel discussion reinforced the need for companies to engage physicians and prove the value of their tools. While digital health is often consumer focused, providers are still gatekeepers, and having their buy-in could go a long way. While early digital health efforts in diabetes were mostly disappointing, we believe the bar has risen and companies are quickly moving to gather medical device data passively and offer decision support. These products will be more useful and will, by necessity, need to secure regulatory clearance. 

  • Although fearful of the potential for mHealth utilization to go awry, the panelists did express some optimism. Dr. Nauck sees value in technology that reinforces standard training courses, and Dr. Leiter said digital health brings “wonderful potential” to enhance patient-provider communication and involve the entire healthcare team. Dr. Leiter called for studies evaluating apps, but emphasized that they must consider outcomes beyond A1c, claiming that even apps that don’t improve A1c but do boost patient involvement and behavioral modifications can be positive – we agree! A1c also won’t capture value from apps that reduce both highs and lows. Plus, by the time a study is enrolled and a single A1c endpoint is gathered at 3 months, the app might have evolved in a meaningful way. Dr. Leiter also noted the potential of social support and experiential apps to be educational tools.
  • We were surprised by the lack of digital health knowledge on this panel, with participants questioning whether any regulatory body was responsible for approving mHealth apps. There is clearly more that can be done to educate providers on mHealth options. At one point, Dr. Nauck asked: “Who is guiding this process of scrutinizing [mHealth apps]? Do they get approval or do they just appear?” None of the panel members responded – not even the moderator! Obviously the answer to this question depends on whether the app qualifies as a medical device, though the pathway is pretty clear in the US. Similarly, when an audience member asked which organizations control health apps and whether apps will be treated as a medical product, Dr. Kar noted that “there will come a responsibility for all healthcare provider bodies to ensure it’s safe” and advised physicians to “put faith” in apps that companies like Roche and Dexcom have partnered with. We’d note that valid apps like BlueStar and mySugr can come from small companies, but have also received regulatory approval. FDA guidelines for digital health continue to be updated, including the recent pre-cert program and Digital Health Innovation Plan.  Indeed, to the surprise of Dr. Nauck, one audience member mentioned that BlueStar is approved and can be prescribed and reimbursed. Dr. Nauck, who had never heard of the app, asked: “Is that true, or is that going too far?” Neither the panelists nor Dr. Nauck responded. Of note, this was an international panel, and we wonder how attitudes and knowledge would differ if panelists were based in the US – FDA seems to be particularly forward-thinking on digital health regulation (and possibly education thereof). 

6. Dr. David Kerr on Using Technology for Care Integration – Patient Segmentation will be key, smart pens will revolutionize care; Value = (Quality + Experience)/ Cost

Dr. David Kerr’s message was clear: integration of diabetes care cannot be achieved without accurate patient segmentation. To this end, Dr. Kerr, believes technology will be critical. He asserted that smart insulin pens will revolutionize healthcare, and also mentioned the Apple Watch and Garmin Watch as noteworthy devices. Dr. Kerr predicted an explosion in the use of telehealth and foresees expanded use of robots/algorithms, including things like diabetes help chat bots. Dr. Kerr and his team are hoping to work on creating a ride share program using geolocation to match patients with their A1c test appointments, essentially “uberizing” the process– how amazing. (As an aside, at an Aspen Institute session earlier this year, we heard that what was most requested among an AARP session of those over 65 was “Uber by regular phone” where people could call Uber rather than summon it by app.)  This system will have a greater impact on A1c control, he said, than introduction of a new therapy. If we had to guess, we’d agree – the field is certainly not lacking for tools, but better and more intelligent use of them. Still, Dr. Kerr cautioned against creating a digital divide and stressed access and affordability. For him, the current status of diabetes care is inadequate, as evidenced by the racial divide in the US, in which minority populations are disproportionately affected. Differentiating by type 1 vs. type 2 is simply not enough, and all five determinants of health must be considered including: (i) genetics (many products are based on evidence that fails to include minority populations who suffer the greatest disease burden); (ii) biology (variations for absorption and action exist); (iii) behavior (adherence, lifestyle); (iv) psychology (diabetes distress, fear of hypoglycemia); and (v) society (affordability, stigma). The bottom line, according to Dr. Kerr, is that if we continue on the same track, we’re going to bankrupt health systems around the world. Value needs to become the main currency, which Dr. Kerr defines as the sum of quality and experience of care divided by cost.

  • With an eye towards the future, Dr. Kerr detailed several fascinating diabetes tech solutions on the horizon. He described a hypothetical system in which a patient’s glucose readings are interpreted by an algorithm stored within a device and explained to the patient by a projected virtual physician. He also predicted that Amazon and Google will become major healthcare players in the future, and proposed the potential of a “doctor in the house” using voice tools like Amazon Echo or Ok Google to provide on-demand support, advice, and education. In addition to a digital/automated physician, Dr. Kerr foresees each patient having a virtual population clinician, who can evaluate all the patient’s data recorded from various sensors and make recommendations, which are then automatically implemented via smart devices.

7. How to Diminish Barriers to Digital Health Adoption – Patient and HCP Perspectives

Mills-Pensinsula Medical Center's Dr. David Klonoff discussed the factors that will augment digital health adoption and suggested how to lower patient and HCP barriers. He broke down the primary factors that each stakeholder looks for in digital health products: Usability (for patients), clinical benefit (for healthcare providers), economic benefit (for payers), security (to satisfy product regulators), and data privacy (to satisfy legal regulators) – of course, there is plenty of overlap in this list. He went into more detail on how to make these products more appetizing for patients and providers: Providers look for interoperability with digital systems (something he believes the market will enforce in the long run), EMR compatibility, compatibility with professional standards, and safety in a mobile platform environment (Does the phone/software prioritize the medical app while you’re playing Angry Birds?.. Something FDA is certainly aware of and taking into consideration as companies seek to use phones as primary displays and control device functions from apps). Dr. Klonoff believes patients look for easy log-in (though noted simplicity must be balanced with security), simplified data and alert displays, no increase in (or less) work, time, and cost, coupled with improved outcomes and “no friction.” We think all of these can be boiled down to a slightly modified version of his third bullet: Patients will widely adopt digital health for diabetes if the quality of life and/or health benefits outweigh the burden of using them. As that balance improves, more will adopt and use the products. He went on to speak briefly about the quality of digital health clinical data, a lack of research into the benefits of social media (prominent patient advocate Mr. Bastian Hauck pushed back), and pharma’s growing involvement in digital therapeutics.

  • Dr. Klonoff listed a number of common flaws he sees in mHealth data generation and analysis: “mHealth clinical trials have produced good outcomes, but aren’t necessarily producing the best data of all time.” He advised audience members to first ask whether or not the data was generated via a randomized controlled trial. “Some digital health companies advocate for getting rid of RCTs – they say that once the trial is done, analyzed, and published, the technology is out of date and a next-gen product is on market. Make sure you’re looking at good data.” He didn’t offer many alternatives, except for doing n=1 trials at scale, wherein one patient and all his/her possible confounds are examined at a time, and then all conclusions from all patients are analyzed – sort of like a meta-analysis of individual level data. RCTs are certainly still needed, but we do see value in complementing them with real-world data (as does FDA), since the technology innovation cycle is rapid and apps are often multi-modular and therefore difficult to study in a simple RCT.
    • We agreed wholeheartedly with Dr. Klonoff’s caveat to look out for a small n, big p, and small t. Indeed, it is fallacious to draw definitive conclusions from studies with small sample sizes, statistically insignificant differences, and/or performed over a short time period. Dr. Klonoff suggested that trials in digital health have to be at least a year, but then suggested products must constantly be refreshed to maintain engagement.” We assume the only way for companies to navigate this balance is to choose one side, or do one-year studies with built-in product updates throughout.  
  • Patient advocate and active #dedoc member, Mr. Bastian Hauck – thinking that Dr. Klonoff had denigrated social media during his talk – pushed back during Q&A. Dr. Klonoff later clarified via email that he believes research into the benefits of social media on treatment adherence is lacking – he didn’t comment on overall benefit. To be clear, Dr. Klonoff doesn’t discourage social media use – he just doesn’t outright encourage it either based on the evidence he has seen. Mr. Hauck’s passionate comments were worth sharing anyhow: “The counterpoint is, we always talk about social media without defining it. We’re not doing anything new. We don’t need RCTs here, in my opinion. We have a lot of evidence showing peer-to-peer support, getting patients together to talk things through, is helpful. Social media is just a new means of communication. Same community work, just at a much faster pace. We’re always trying to scale things up and make things digital, and we’re not there yet in many cases, like AI, but with social media, we are already there. Making it faster and scaling. Yet we’re still getting so many counterpunches. We don’t need evidence to prove that communication is going to work.” The only reason we can think of for performing an “RCT” of social media use is to demonstrate benefit so that hesitant healthcare providers would more actively direct their patients to try it. On the other hand, social media is free, so there’s little barrier to access, and therefore little need to convince payers that it’s effective (though perhaps they could financially incentivize people to use social media).
  • When Dr. Klonoff first became a doctor, he noted that every innovation at big meetings was a drug. “Now, what really gets the buzz is new software and digital therapeutics,” he said. He pointed to Lilly’s FDA-cleared Go Dose, Novo Nordisk and Glooko’s recently-launched Cornerstones4Care, and Sanofi’s partnership with Evidation Health to mine behavioral trends and outcomes for insights into new product design and how to deploy current products. The list goes on – and this digital explosion is only starting to take off . Where will it be in five years?

8. Kyle Rose on Diabetes Apps: One Size Doesn’t Fit the Whole Diabetes Journey

mySugr’s Mr. Kyle Jacque Rose shared insights from IDF Europe’s 16-page position paper on mobile apps in diabetes, stressing the fallibility of the “one-size-fits-all” model. Patients require vastly different levels of specificity from their apps on their journey from prediabetes diagnosis to familiarity with one's chronic condition – a concept Mr. Rose illustrated through carb counting apps. During prediabetes, learning how to begin evaluating lifestyle habits including food choice is an important prevention step like what is offered in Accu-Chek View or Omada's programs. When first diagnosed, just tracking total carbs would be a victory for most patients, a feature offered by simple nutrition databases. From there, Mr. Rose suggested that patients might move on to an application like Calorie King, which allows users to track whole nutrition (macronutrients). As acquaintance with the disease increases further, patients can begin to identify interactions between nutrition choices and blood glucose – “interactive problem solving” – with the help of an app such as Meal Memory. (Dexcom recently hired Meal Memory founder Doug Kanter, a very big win.) And finally, deep data analysis (e.g., Medtronic’s CareLink + IBM Watson) might help patients to figure out how to handle “all foods.” We often consider that one app may not be designed optimally for every person, but we appreciated this perspective that needs across the diabetes journey change just as drastically as between individuals, and found it to be a good argument for the open digital ecosystem Mr. Rose described. On the one hand, there were 165,000 health care-related apps as of March 2016 – plenty to fill every niche imaginable – though a vast majority are not validated. Mr. Rose also surveyed the different functions of diabetes apps, touched on their functions beyond improving glycemia (adherence, motivation/inspiration, logging), and suggested that cost is a major hurdles to access in some cases, and emphasized that there are important differences between apps that are important for both patients and HCPs to recognize. We believe FDA guidance is fairly well laid out for what counts as a mobile medical app vs. not, though perhaps there is still plenty of nuance overall, especially on decision support and device connectivity.

  • A big point of excitement for Mr. Rose is the potential for smart pens to “bring the connected cloud to the mainstream.” He alluded to his experience in numerous automated insulin delivery trials, sharing that giving up control to a system is very exciting, but scary for many – when he was in a Montpellier trial with Prof. Eric Renard, it took him a few days to stop performing fingersticks and trust the system. Soon after, he felt like he was in good hands! Automated insulin delivery systems, he continued, are particularly compelling if national insurers provide access, but otherwise, this technology may only be available to a select few. Even if national insurers do get on board, connected pen-based automated insulin titration systems will likely expand access to the broader population, both for those who can’t afford pumps and for those who would prefer to not wear one. It will fascinating to see how payers compare these two options, and whether automated insulin pump-based systems show superior outcomes to automated insulin pen-based systems. And if so, what incremental outcomes will encourage payers to reimburse for a pump over MDI?

9. Dr. Boris Kovatchev on “Digital Twins” as the Future of Diabetes Technology

For Dr. Boris Kovatchev, the future of diabetes technology will revolve around the concept of a “digital twin,” a virtual image of an individual patient incorporating the person’s condition, genetic information, and data from various sensors – a sort of n=1 model that describes someone’s physiology. Dr. Kovatchev said suggested that all digital twins would be stored in a database, periodically updated with lab records and physician opinions so as to constantly improve the representation. In this way, a global precision treatment ecosystem would be stablished, which physicians could use to glean information. In just one example of this database’s far-reaching applications, a new treatment or algorithm could be optimized by testing it across the ecosystem. Dr. Kovatchev also foresees a local ecosystem surrounding each individual comprised of data updated every five minutes from sensors, which could be used to facilitate decision support, predictive algorithms, and closed-loop management.

  • Dr. Kovatchev detailed the pathway to closed loop systems, crediting the UVA/Padova simulator as a key step in reducing time and cost. According to Dr. Kovatchev, “diabetes is the best quantified disease – no one else is even close.” Oh the irony that patients are not doing better, especially insulin users! Dr. Kovatchev and his team developed a computer simulator for type 1 diabetes, which he presented to the FDA in 2007. This project helped significantly accelerate the closed-loop field and served as an alternative to animal studies during early trials of automated insulin delivery algorithms. Testing in humans moved much faster from that point. We wonder how a “digital twin” database in the future could similarly accelerate development of new therapies and technologies.
  • Dr. Kovatchev briefly reviewed three recent artificial pancreas studies (Medtronic 670G, JDRF Pilot trial, home use of bihormonal bionic pancreas) and was impressed with the low rates of hypoglycemia and substantial time in range. He noted that time spent in hyperglycemia still needs to be improved. Dr. Kovatchev found the skiing studies conducted in Virginia and Colorado heartening (ADA 2016), and expressed optimism that closed loop systems will continue to work in real-life settings. 

 

-- by Adam Brown, Ann Carracher, Abigail Dove, Brian Levine, Payal Marathe, Maeve Serino, Manu Venkat, and Kelly Close