September 10-15, 2017; Lisbon, Portugal; Full Report – Diabetes Technology – Draft

Executive Highlights

In this chapter of our EASD 2017 full report, we’re bringing you everything pertinent to diabetes technology. While this year’s gathering was light on tech, there were some notable sessions, including results from CONCEPTT strongly suggesting CGM use in pregnant women, Dexcom next-gen updates, and a diverse panel of physicians who gave their candid (and somewhat surprising) opinions on mHealth. We were also impressed by a poster demonstrating substantial reductions in hospital admissions and work absenteeism in Belgium thanks to national CGM reimbursement. As you scroll down you’ll see our coverage of relevant symposia, oral presentations, corporate symposia, and posters (in that order). At the top of the page, you’ll see we’ve included themes outlining what we consider to be the main takeaways from EASD 2017’s tech coverage.

Talk titles highlighted in yellow were some of the most notable from this meeting (in our view), happy reading!

Themes

A Strong Case for CGM in Pregnancy (CONCEPTT) and Big Cost Benefits in Belgium (RESCUE)

• Results from the JDRF-funded CONCEPTT RCT (n=215) made a strong case for CGM use in pregnant women, even with Medtronic’s older (!) Guardian CGM driving significant reductions in the incidence of large for gestational age or LGA (OR =0.51, p=0.01), fewer NICU admissions lasting 24+ hours (OR=0.48, p=0.02), fewer incidences of neonatal hypoglycemia (OR=0.45, p=0.03), and one-day shorter length of hospital stay (p=0.01). Wow! While not the primary endpoint, we find these neonatal outcomes extremely compelling, as did the study authors, who concluded that “CGM should be offered to all pregnant women with type 1 diabetes using intensive insulin therapy.” We’d go so far as to say that although this study didn’t test a much broader population, these results are strong enough to encourage CGM use for any women with diabetes who are pregnant, period (there’s a lot of controversy on when women with gestational diabetes should go on insulin if at all – we would not want to see these women not set up for success with CGM, particularly now that CGM use is expanding overall. As for the primary maternal glycemic outcomes, there was a small 0.2% A1c advantage for CGM at 34 weeks (p=0.02). More importantly, mothers on CGM spent a significant 100 more minutes/day in range (68% vs. 61%, p=0.003), 72 fewer minutes/day in hyperglycemia (27% vs. 32%, p=0.03), and a non-significant ~14 fewer minutes/day in hypoglycemia (3% vs. 4%, p=0.1). As expected with the older Guardian sensor, wear time was lower than in more recent CGM studies – just 70% of pregnant participants used CGM for 75%+ of the time, and ~80% reported frustrations with the device. Due to the length and scope of the trial, updating to a more recent sensor would have proved challenging, but we can’t help but speculate what the results may have looked like if a newer device had been used.
  
  • The numbers needed to treat (NNT) were compelling: Six women with CGM to prevent one event of LGA (large gestational age); eight women with CGM to prevent one event of neonatal hypoglycemia; and six women with CGM to prevent one NICU admission over 24 hours. This last one was particularly compelling short-term and of course the first one is profoundly important when thinking about prevention over the long term. Economic analysis wasn’t presented, but we’d guess that 72-96 months of CGM use (nine months per pregnancy * NNT) would be cost-effective relative to those expensive negative events. 
  • A sub-group analysis suggested that MDI+CGM had a bit of an advantage over pump+CGM for a few outcomes. Pumpers had higher rates of gestational hypertension, preterm delivery, and NICU admissions for 24+ hours. Pump users also had lower A1c reductions, though they spent slightly less time in hypoglycemia. This is clearly very positive news for CGM+MDI, and we wonder how it would compare to automated insulin delivery during pregnancy and delivery. We also doubt that one can just say flatly that MDI is “better” however – it may be that those using pumps had more complications overall, etc. We can imagine however that perhaps those on pumps had less disciplined dietary habits because it is “easier” to take insulin using a pump – hard to know!
  • Interestingly, there were fairly significant differences in large for gestational age across countries, leading commentator Dr. Elisabeth Mathieson to exclaim “learn from Spain!” This discrepancy, to her, is “probably more important” than the influence of CGM on pregnancies. It was a good point – as we focus on technology, we cannot forgot the obvious opportunities for quality improvement in comparing different healthcare systems.
• We also saw convincing evidence of CGM’s health- and cost-efficacy in an incredibly valuable poster sharing 12-month outcomes from national Belgian CGM reimbursement in 515 insulin pump users (RESCUE). This most-valauble academic study tracked outcomes in the 12 months prior to CGM initiation and then in the 12 months following CGM. Notably, the percentage of patients experiencing a hypoglycemia/DKA hospitalization declined by a striking 75% following CGM initiation (16% of patients without CGM to 4% with CGM; p<0005). Meanwhile, CGM drove a 64% decline in the percentage of patients experiencing a work absence (25% to 9%; p<0005). From these data, the poster estimates a nationwide cost reduction of €345,509 – assuming this was calculated from the sub-set of 379 users with 12-month CGM data, it implies €911 saved per person! CGM use also drove improved quality of life, improved fear of hypoglycemia, and improved emotional burden due to diabetes. This is exactly the kind of data we hope to see more of, providing a strong case for CGM reimbursement that will hopefully convince other healthcare systems to perform similar analyses. We’d also love to better understand how healthcare costs look on CGM+MDI vs. CGM+pump….

Industry News: Dexcom Pipeline, Roche Reinvented, & No Medtronic in Exhibit Hall

• In a corporate symposium, Dexcom SVP Mr. Jake Leach shared two updates on the pipeline: (i) The next-gen CGM in Europe will not be called “G6,” as it has “additional features”; and (ii) there is ongoing work to incorporate smart pens with the G5 app, Clarity, and Share. Though Mr. Leach didn’t specify, we imagine that factory calibration will be a logical add-on feature for the G5 follow-on, as well as possible 14-day wear. Both of these amenities will keep pace with Abbott’s FreeStyle Libre, which now has more than 400,000 users worldwide (just approved in the US for 10-day wear). With respect to smart pens, Mr. Leach confirmed that Dexcom has smart pen “partners” – none were disclosed, but slides included images of Lilly and Novo Nordisk pens. Which of the three insulin companies will get there first with a compelling, easy-to-use, widely accessible smart pen? Or perhaps smaller players will drive this field like Bigfoot, Companion Medical, and Common Sensing? Dexcom’s booth featured a slide touting collaborations with Tandem, TypeZero, Insulet, Beta Bionics, and the University of Virginia, with first-time-appearances (that we’ve seen) for Diabeloop and Oregon Health and Science University. 
• After a notable absence from the ADA exhibit hall, Roche came to EASD with new-look diabetes business prospects and pieces at EASD. At the corporate symposium and exhibit hall, the company touted a new “integrated diabetes ecosystem,” which will include Accu-Chek connected BGMs and Connect app, the recently acquired mySugr app, GoCarb (an AI-powered carb counting app), Senseonics’ Eversense CGM (in lieu of Roche’s in-house Insight CGM), the connected Pendiq pen, and other pieces will “hopefully” be available before next year’s EASD. A rep told us that the “open ecosystem” means that the platform will be device-agnostic in 1.5-2 years – and Roche will push forward with prevention programs, early diagnosis, and decision support, in addition to value-based payment models. It’s a refreshing and bold change from the pump- and BGM-centric business we were talking about even a year ago!
  
  • Notably, Roche does not plan to launch further versions of the Accu-Chek Insight CGM. The sensor will stay in existing limited launch markets (“specialized diabetes centers” in the Netherlands, Norway, Denmark, and Sweden), but it sounds like Roche will not expand the device to other countries. We ultimately think the decision to prioritize Senseonics’ Eversense is a prudent one, otherwise the company would be competing against itself to some degree – plus we’ve long wondered how the Insight sensor would have stacked up against Dexcom and Abbott sensors that have strong user experiences and deep pipelines.
  • While we were at EASD, mySugr launched a direct-to-consumer Pro bundle in the US, including unlimited test strips delivery, an Accu-Chek Guide BGM, the mySugr app, and 24/7 CDE access for $39.99 per month. The mySugr bolus calculator, offered in Europe, is not included in the bundle, but we’ve since learned – at Health 2.0 last week - that it is currently under FDA review.
• Medtronic didn’t make an appearance in the exhibit hall, giving conference-goers plenty of fodder for gossip. The pump+CGM giant was absent, and only two posters on the 670G were shared in the hall (both cuts of the pivotal data, but nothing highly notable). Medtronic’s international business is really carrying the company’s sales (see 2Q17), so it was even more surprising to see the absence – particularly in Europe where the 640G has been doing well. There is still no word on the MiniMed 670G in the US, which we had previously expected to launch this year. Many in the hall were gossiping about the sensor supply shortage that has slowed MiniMed 670G shipments in the US, as well as the infusion set recall reported earlier in the conference.

Real World Issues in Digital Health

• Can digital health improve medication and regimen adherence? In a panel discussing real-world challenges in type 2 diabetes, Dr. William Polonsky identified worrisome patient beliefs surrounding medication, like the tendency for patients to equate more drugs with a more severe prognosis, as critical drivers in non-adherence. Commenting on Healthimation’s virtual weight management program, Dr. Polonsky said he believes it can be successful if it provides the right mix of cheerleading, connectivity, and support to make sense of data, frankly adding that “most apps we see in type 2 diabetes are pretty darn boring.” We wonder if VR, simulation, and higher tech education might help to close the adherence gap – lots still to prove there. During The diaTribe Foundation’s Fourth Annual Solvable Problems gathering, Professor David Matthews discussed how type 2 patients don’t typically appreciate the full severity of their disease. Clear messaging is going to be crucial to help patients comprehend the seriousness of a diabetes diagnosis. Technology can help, he added – beyond serving as an education tool, technology that brings patients closer to their providers may also help drive adherence. According to Professor Eduard Montanya, telemedicine may be useful, although the literature is mixed at this point. We were excited to hear that Ascensia is launching a global innovation competition for digital solutions that improve the lives of people with type 2 diabetes – a promising sign that this BGM company is trying to broaden, in addition to its growing partnerships. We see the greatest potential for digital health in capturing data seamlessly, driving more continuous HCP care and education, providing more in-the-moment feedback, more intelligently titrating insulin, and helping users see the interaction between glucose and other factors.  
• It was also clear that not everyone is ready to jump on board the digital health bandwagon. A diverse panel of EU physicians moderated by Dr. Partha Kar, Clinical Director of Diabetes at Portsmouth Hospitals NHS Trust, expressed a surprising lack of knowledge and substantial fear regarding regulation, additional provider burden, and adverse effects surrounding digital health. Insulin titration apps and bolus calculators were of particular concern, with Dr. Lawrence Leiter worrying that many insulin adjustment apps have not been validated, Dr. Steven Kahn believing that free options will lack sufficient regulation and maintenance, and Dr. Michael Nauck nervous that the process will become “too autonomous” (not involving providers enough). None of the physicians on the panel had heard of WellDoc’s BlueStar type 2 diabetes management app and were shocked to learn from an audience member that it is an FDA-cleared, prescribed, reimbursed digital therapeutic. Wow! Several questioned whether there were even regulatory bodies to evaluate digital health apps. This was, of course,  an international panel, and it would be interesting to see how attitudes and knowledge might differ if some US participants had been included. FDA guidelines continue to be updated, but the regulatory pathway for digital health apps feels more straightforward. However, there’s a lot more needed to spread awareness and validate apps in the eyes of providers. As positive outcomes mount and providers realize that digital health can reduce their burden, we hope adoption will take off. As one example, a Glytec poster showed how use of the outpatient Glucommander decision support system resulted in an astounding 2.5% A1c drop from a high baseline of 10.3%. The improvement was sustained with adjustments every ~57 days after goal was reached. With risk stratification and automatic alerts when insulin should be titrated along with recommended adjustments, Glucommander – and other products like it – should save providers time and allow them to focus on the whole person.

Detailed Discussion and Commentary

Symposium: Continuous Glucose Monitoring Before and During Pregnancy in Women with Type 1 Diabetes: Results from CONCEPTT; a Multicentre Multinational Randomized Controlled Trial

Results

Rosa Corcoy, MD, PhD (Hospital de la Santa Creu i Sant Pau, Barcelona, Spain) Denice Feig, MD (Mount Sinai Hospital, Toronto, Canada) Elisabeth Mathiesen, MD (University of Copenhagen, Denmark) Helen Murphy, MD (Cambridge University NHS Foundation, Cambridge, UK)

The JDRF-funded CONCEPTT RCT testing CGM in pregnant women (n=215) showed positive neonatal outcomes with Medtronic’s older Guardian CGM. Though not the primary endpoint, significantly improved neonatal outcomes were the headline – CGM drove a significant reduction in the incidence of large for gestational age (OR=0.51, p=0.02), fewer NICU admissions lasting 24+ hours (OR=0.48, p=0.02), fewer incidences of neonatal hypoglycemia (OR=0.45, p=0.03), and one-day shorter length of hospital stay (p=0.01). The numbers needed to treat (NNT) were compelling – NNTs of just 6-8 women with CGM to prevent one of those negative outcomes. The primary A1c endpoint showed a small -0.2% A1c advantage for CGM at 34 weeks (p=0.02). However, mothers on CGM spent a significant 100 more minutes/day in range (68% vs. 61%; p=0.003), 72 fewer minutes/day in hyperglycemia (27% vs. 32%; p=0.03), and a non-significant ~14 fewer minutes per day in hypoglycemia (3% vs. 4%; p=0.1). Results were published in The Lancet, a major visibility win!

As expected with the older Guardian sensor, wear time was lower than in more recent CGM studies – 70% of pregnant participants used CGM for 75%+ of the time. In addition, ~80% of women reported frustrations with the CGM device. We brought this limitation up in Q&A (it was not mentioned), and would guess the trial probably underestimated current CGM’s potential benefit in pregnancy. What would outcomes have looked like with G4/G5, FreeStyle Libre, or Guardian Sensor 3? Since the trial took three years to run, a year to plan, and spanned six countries (Canada, UK, Spain, Italy, Ireland, and the US), getting the latest devices in was obviously a challenge. The study concludes that “CGM should be offered to all pregnant women with type 1 diabetes using intensive insulin therapy” – hear, hear! According to The Lancet publication, it’s also the first study to indicate potential for improvements in non-glycemic health outcomes from CGM use. Nice!

There were a few big surprises from this trial: (i) pump+CGM outcomes looked worse on a few notable endpoints vs. MDI+CGM outcomes (see below); (ii) CGM had no significant benefit on severe hypoglycemia; and (iii) the difference in outcomes was quite large between some countries (a fascinating source of commentary from Dr. Elisabeth Mathiesen). See more details below. We look forward to cost-effectiveness data when it is published. The trial also included a second arm testing CGM in women planning pregnancy, but showed no A1c benefit at 24 weeks or conception.

• An editorial from Dr. Satish Garg in The Lancet was very positive, with a nice beyond-A1c mention: “We believe that the CONCEPTT results support CGM use during pregnancy for all women with type 1 diabetes and ; thus endocrine and obstetric medical societies could consider advocating or recommending revising their guidelines accordingly.” We wonder if this study could help validate time-in-range as a meaningful surrogate endpoint, independent of A1c. The study follows a very positive hybrid closed loop study during labor/pregnancy from Dr. Helen Murphy and colleagues at Cambridge, which was published in NEJM in 2016 – automation is a definitely an exciting frontier for pregnancy, along with use of next-gen devices! Dr. Murphy did mention in Q&A that a FreeStyle Libre in pregnancy study is ongoing.
  • Neonatal outcomes – paramount in a diabetes pregnancy study – were very positive in favor of the CGM group. Babies from mothers who wore CGM were less likely to be large for gestational age (LGA; >90th percentile – 53% in CGM group vs. 69% in control group; p=0.02), lower incidence of neonatal hypoglycemia requiring IV glucose (15% vs. 28%; p=0.03), were less likely to require NICU admissions >24 hours (27% vs. 43%; p-0.02), and had significantly lower median customized centile (a measure of birthweight standardized for maternal ethnicity, height, weight, and neonatal sex and gestational age at delivery – 92% vs. 96%; p=0.05). Further, infants from mothers in the CGM group had hospital stays reduced by nearly a full day (3.1 days vs. 4.0 days; p=0.02). Co-PI Dr. Denice Feig pointed out that not only were the median customized centiles lower in the CGM group (across each of the four study sites), but the lower portion of the box plot was much wider, indicating that many more babies were closer to the normal weight range than in the control group. The numbers needed to treat (NNT) were quite compelling: Six women with CGM prevented one event of LGA; eight women with CGM to prevent one event of neonatal hypoglycemia; and six women with CGM to prevent one NICU admission over 24 hours. Economic analysis wasn’t presented, but we’d guess that 72-96 months of CGM use (nine months per pregnancy * NNT) would be cost-effective relative to those expensive negative events. There were no differences in serious adverse pregnancy outcomes (miscarriage, stillbirth, termination, or congenital anomaly), obstetric outcomes (hypertensive disorders in pregnancy, C-section, maternal weight gain, maternal length of hospital stay), or gestational age at delivery between groups.
  • We would’ve loved to see primary outcomes beyond A1c, but a JDRF representative told us that a primary neonatal outcome would’ve required much more statistical power – he estimated 10,000 participants, compared to the 215 pregnant women in this study! We’re not all that familiar with pregnancy outcomes and their frequency, but in this case, it seems to have made sense to not power for neonatal events. The same rep also mentioned that there will be some follow-up of both baby cohorts to look for long-term impacts of maternal CGM use on offspring development.
• A subgroup analysis of pump vs. MDI CGM users revealed that pump users achieved lower reductions in A1c (-0.32% vs. -0.55%; p=0.001) and slightly less time spent in hypoglycemia (according to the speaker, though we didn’t notice a large difference in the publication’s appendix) However, pumpers had concerning higher rates of gestational hypertension (14.4% vs 5.2%; p=0.02), preterm delivery (43.2% vs 36.2%; p=0.04), and NICU admissions for greater than 24 hours (44.5% vs. 29.6%; p=0.01) than MDI users. This result was surprising, especially since pumpers at baseline seemed to be more engaged with their health (lower rates of smoking, take preconception vitamins, booked appointments earlier, …). Infants of pump users also experienced higher rates of hypoglycemia requiring IV dextrose (31.8% vs. 19.1%; p=0.03), although once adjusted (not specified, but presumably for baseline maternal characteristics), the difference was no longer significant. There were no other observed significant differences in diabetes status or neonatal outcomes. These results are disappointing for pump users, as it is more expensive therapy that did not deliver better outcomes in this study. Why? We wonder if pumps psychologically loosen eating restrictions, while the hassle of injections might make expectant mothers more likely to hesitate before eating or choose different foods (pure speculation on our part). We look forward to seeing the cost-effectiveness data, and certainly, this is very positive news for MDI+CGM.
  • Could higher proportions of MDI users in clinics that tend to have better outcomes (see Dr. Mathiesen’s call to “Learn from Spain” below) underlie MDI vs. pump discrepancies? In other words, Spain had a significantly lower rate of LGA than a number of other countries (even in the control group vs. other countries’ CGM groups) – were Spanish patients simply more likely to be on MDI?  
• The 0.2% A1c advantage for CGM at 34 weeks was characterized as “small,” and in our view, outweighed by the time-in-range and time-in-hyperglycemia data. We must go Beyond A1c in studies like this! CGM users saw a 0.54% decline in A1c by 34 weeks (baseline: 6.8%) vs. a 0.35% decline in the control group (baseline: 6.95%) – the 0.2% difference was statistically significant (p=0.034), though it missed the goal for a 0.5% difference and comes in smaller than recent studies like DiaMonD and GOLD. Strangely, ~20% of A1c samples were missing, though the investigators do not believe it impacted results. The time in range (63-140 mg/dl) data were very strong: pregnant women on CGM spent 100 more minutes per day in the tight target range and 72 fewer minutes per day in hyperglycemia relative to the control group at 34 weeks. Time in hypoglycemia did not statistically favor CGM (~14 minutes better with CGM), given low rates in both groups (3% vs. 4%; p=0.1). Coefficient of variation favored the CGM group at 34 weeks (32% vs. 34%), but just barely missed statistical significance (p=0.058).
• Despite raising a number of concerns about the study, and especially, diabetes pregnancy care overall, Dr. Elisabeth Mathiesen (Head of Diabetes Treatment at the Copenhagen Centre for Pregnant Women with Diabetes) concluded that CGM “is the future” and that the CONCEPTT study “will change the future for pregnant women with diabetes.” She began by acknowledging that CGM proved effective in the study, reducing A1c greater than in the control group and preventing many adverse neonatal events. However, she found the lack of an effect on maternal severe hypoglycemia “a little disturbing” and pointed to the downsides of using CGM (80% of users reported problems and 30% used the sensors less than 75% of the time) – again, we believe the use of a better sensor would’ve made a difference on both of these points. Other points of weakness for Dr. Mathiesen were generalizability (the study took three years to enroll at 31 centers) and moderate endpoint data collection (86% of A1c values; 77% of sensor data). In light of this data, will Dr. Mathiesen implement CGM in all pregnant women as suggested by the study authors? In favor of “yes,” she said, many will ask for it, the study recommends it, and her “stomach feeling” is that CGM is the future. On the other hand, she questioned the quality of treatment in the study overall (more in first bullet below), and worried that the cost of CGM will prompt reduction in other aspects of care –  “the cost of CGM use in 20 pregnant women is the cost of the salary of one working nurse.” Conversely, if CGM prevents expensive neonatal outcomes, it should drop healthcare resource – it is an upfront investment with upside, especially in pregnancy, when there are two bodies who can benefit. In our opinion, pregnant women with diabetes, who clearly have a lot at stake and are asked to keep their blood glucose levels to very tight ranges (63-140 mg/dl in this study), need access to their glucose values at all times to stay in range most of the day . The glycemic findings from this trial were not as strong as some would have hoped, but they still suggest definite benefit (+100 minutes/day), in tandem with improved neonatal outcomes. We hope that economic analysis and/or follow-up studies with more accurate and user-friendly sensors will tip consensus more toward an unequivocal “yes.”
  • Dr. Mathiesen pointed out the care that pregnant women were getting in the trial, even in the CGM group, presenting a slide with the simple question: “Treatment of Excellence?” She questioned whether a lack of A1c guidelines for pregnancy in the two main countries of this study (Canada and UK) impacted quality of care. In the CGM group of CONCEPTT, A1c late in pregnancy was 6.4%, there was a 38% rate of preterm delivery, and 53% rate of LGA. While these figures compared favorably to the control group, “routine results” from her center in Copenhagen are significantly better: In pre-publication data from this clinic (n>400), A1c late in pregnancy is 6.1%, preterm delivery rate is 17%, and LGA rate is 38%. Dr. Mathiesen then showed a figure from earlier in the presentation depicting LGA rates from the control and CGM groups in Canada, the UK, Italy, and Spain (below), and the clear message “Learn from Spain.” Indeed, the rate of LGA in the Spanish control group was less than half that in the other countries’ control groups, and even lower than that of the CGM groups in two of the three other countries! This discrepancy, to her, is “probably more important” than the influence of CGM on pregnancies. She implored attendees to “please listen to how [Dr.] Rosa [Corcoy] (an endocrinologist in Barcelona) is treating her patients. It probably has to do with diet – carb counting, weight gain, and attitude.”
• Dr. Murphy gave the perfect response to Dr. Mathiesen’s criticism: “No doubt, if we could clone Dr. Mathiesen and put her in every center, we could get much better glucose control. This took place in 31 centers. What we have is generalizable. A1c, with all standardizations, is still different. It’s not correct to compare a single center to labs across 31 sites.
  • During Q&A, Dr. Feig noted that we don’t know the relative contributions of glucose control throughout the whole pregnancy vs. in the 24-48 hours pre-delivery on neonatal outcomes. Existing literature, she said, is “quite variable” about the contribution during labor, but she believes it may contribute a little. It’s an interesting scientific question, especially as we think about automated insulin delivery and the previous finding from Dr. Murphy’s NEJM study. Theoretically, better glucose control with less hypoglycemia would be good for the mother, so even if 100% of the contribution on neonatal glycemia were from the labor period and just prior, we still hope that the mother could be given access to CGM.
• Dr. Mathiesen began her commentary by applauding the PIs – Drs. Feig and Murphy – for their bravery in forging ahead and conducting an RCT in pregnancy. “Until these two women dared to take it on, no one would dare. These women are truly brave.” Hear, hear!

Symposium: Achieving Improved Compliance to Diabetes Care: The Common Task for Care Providers, Health Systems and People with Diabetes

Healthcare Provider Perspective: How Mobile Applications Contribute to Improving Compliance

David Klonoff, MD (Mills-Peninsula Health Services, San Mateo, CA)

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?

Patient Perspective: How Mobile Applications Contribute to Improving Compliance

Kyle Jacques Rose (mySugr, Vienna, Austria)

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?

Symposium: Advances in Infusion Sets and Insulin Pumps

Glucose Monitoring and Insulin Delivery: a Single Device?

William Tamborlane, MD (Yale School of Medicine, New Haven, CT, USA)

Dr. William Tamborlane reviewed much of the back half of his lecture from AACE back in May, spelling out the “Inconvenient Truth” of today’s diabetes management (poor), illuminated the light at the end of the tunnel (new tools, including adjunct therapies), and shared a 670G wish list from two colleagues who were in the pivotal study. Dr. Tamborlane, a diabetes technology pioneer, was enthusiastic about adjunctive therapies in type 1 diabetes – “they’re obviously not a cure, but there’s lots of excitement at this meeting, particularly about SGLT-2 inhibitors in type 1.” He was of course referencing DEPICT 1 (AZ’s trial of Farxiga (dapagliflozin) in type 1 diabetes) and inTandem 3(Lexicon’s SGLT-1/2 inhibitor, sotagliflozin.) We hope to see Dr. Tamborlane’s Yale group study SGLT-2s on top of closed loop, something his colleague Dr. Eda Cengiz has mentioned in the past. Dr. Tamborlane later shared some MiniMed 670G feedback provided by two of his colleagues who were in the pivotal trial: They’d like to: (i) be exited from closed loop (Auto Mode) less often; (ii) adjust target glucose levels (it’s fixed at 120 mg/dl); (iii) manually set temporary basal rates for periods of stress; (iv) manually give correction doses that correct to glucose levels <150 mg/dl; and (v) track glucose and insulin delivery remotely on smartphone apps. We note that this list has grown by one since we last heard him speak at AACE, with the latest addition of “fewer exits.”

Oral Presentation: Improvements in Insulin Therapy

The Effect of an Automated Bolus Calculator on Glucose Control, Glucose Variability and Quality of Life in Patients with Type 1 or 2 Diabetes Treated with Insulin Pumps

Lian van Meijel, PhD (Radboud University Medical Centre, Nijmegen, Netherlands

A randomized controlled trial (n=32) found that use of an automated bolus calculator improves glycemic variability, but does not change A1c, instances of hypoglycemia, quality of life, or glucose levels in type 1 adults with good A1c control and pump experience. While previous studies have shown that automated bolus calculators can reduce A1c and improve quality of life, the majority have consisted of patients new to pumps and with high A1c values. In this four-month study, 32 type 1 adults who had used pumps for at least six months and with A1c <10% (a bit high to constitute “reasonable control” in our view), were randomized to receive either an automated bolus calculator or continue with standard care. All participants received instructions on carb counting and took an exam prior to randomization. Although glucose variability did significantly improve in the experimental group while it remained unchanged in the control, there were no observed significant differences in glucose levels, LBGI and HBGI scores, hypoglycemia frequency, and quality of life both within and between groups. It’s interesting that improvements in glycemic variability were achieved, yet this did not impact anything else – we can’t recall seeing that in a study before. This was a small study and both groups consisted of experienced pumpers with verified carb counting ability, so it’s perhaps not surprising that the calculator didn’t augment A1c or other parameters drastically. We expect that the meal dosing paradigm is going to change quite drastically in the coming years with automated insulin delivery – what’s the best way optimize the patient-automated algorithm interface to achieve maximum time-in-range? Meanwhile, how will bolus calculators benefit MDIs when they are more widely integrated into apps paired with smart pens? Interestingly, the researchers had originally intended to enroll type 2 adults as well, but they were only able to find two eligible participants and therefore decided to exclude them.

Corporate Symposium: Dexcom Continuous Glucose Monitoring: Clinical Outcomes and Next Generation Technology (Sponsored by Dexcom)

Introduction to the Next Generation Dexcom CGM Technology

Jake Leach (Dexcom, San Diego, CA)

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.

Corporate Symposium: Shaping the Future of Integrated Diabetes Management Solutions (Sponsored by Roche)

Features and Performance of the New Eversense Implantable CGM System

Tim Juergens (Roche, Basel, Switzerland)

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.

Features and Performance of the New Eversense Implantable CGM System

Lynne Kelley, MD (Senseonics Holdings, Inc., Germantown, MD)

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. 

Corporate Symposium: Focus on the Future: Scientific and Clinical Understanding of Type 2 Diabetes and the Role of the Endocrinologist (Sponsored by MSD)

Evolving Role of the Endocrinologist in the Care of Patients with Type 2 Diabetes in a Changing Digital Environment

Partha Kar, MD (Portsmouth Hospitals NHS Trust, Portsmouth,UK)

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).

Corporate Symposia: The Omnipod® System: Real World Use and Future Innovation

Trang Ly, PhD (Insulet, Billerica, MA, USA); Thomas Danne, MD (Kinderkrankenhaus, Hannover, Germany); Lalantha Leelarathna, PhD (University of Cambridge, Cambridge, UK); Shacey Petrovic (Insulet, Boston, MA, USA)

Insulet’s corporate symposium shared real-world Omnipod user data from over 38,000+ Glooko users, German/Austria DPV registry members, and outcomes with different pumps at Manchester Diabetes Center. The takeaway was clear – Omnipod outcomes and retention look similar to other pumps, if not slightly better. Overall, there was nothing truly compelling or shocking in the cross-sectional, retrospective, observational data (see key outcomes below), but it does show what is possible with direct device data downloads – characterizing real-world outcomes, understanding populations, and benchmarking. The Glooko partnership is clearly going to become a bigger Insulet asset over time, helping the company keep up with Medtronic’s CareLink. Indeed, Insulet-provided Glooko is now in 2,800+ clinics, with over 50,000 users uploading. There were no big pipeline updates, though the Horizon Automated Glucose Control system has now been tested in 113 patients (n=7,104 hours), up notably from 92 patients (n=4,584 hours) as of AADE in August. Medical Director Dr. Trang Ly did not give a timing update on Horizon, though did confirm that a pre-pivotal study is the next step after the ongoing five-day hotel study is complete. She did show a CGM trace from one 10-year-old participant in the hotel study, who entered with a mean A1c of 9.8%; on day #4, mean glucose had dropped to ~144 mg/dl, predicting an estimated A1c drop to ~6.7% (an impressive 82% time-in-range). No other days or participants were shown, though this was an encouraging n=1 plot in one user, and we look forward to full outcomes from this first outpatient study with Horizon. Presumably the previous timing is on track for a pivotal in 2018 and launch in 2019, though this was not confirmed. Otherwise, President Shacey Petrovic confirmed that Lilly U500 Omnipod clinical/development work is complete, data analysis is in progress, and Insulet is “preparing for submission” and running human factors studies. (A launch is expected in 2019, per 2Q17.)  As of AADE, Dr. Trang Ly hoped data from this phase 3 study (VIVID; n=416) could be shared at ADA 2018. U200 work remains in “technical development” and an FDA submission is expected in the “next 1-1.5 years,” in line with the planned 2020 launch. There was no update on the Dash PDM beyond what we saw at AADE and ADA; as of the 2Q17 call, FDA submission was expected in 4Q17. On the commercial front, there was definite excitement from Ms. Petrovic concerning Insulet’s move to directly distribute Omnipod in Europe, starting in mid-2018 with the Ypsomed agreement expiration (see our previous coverage).

• Dr. Trang Ly shared data from 38,778 Omnipod patients in the US with at least three months of data downloaded using Insulet-provided Glooko. The average glucose level was 186 mg/dl, equivalent to an estimated A1c of 8.1%. Dr. Ly emphasized that this “compares favorably” to data from the T1D Exchange Registry, where A1c is 8.4%. The more interesting analysis showed data in a subset of Omnipod CGM users (n=3,394) vs. non-CGM users (n=35,384) – those using CGM had a slightly higher percentage of glucose tests in-range (52% vs. 48%), a slightly lower estimated A1c (8.1% vs. 7.8%), and a lower total daily insulin dose. Dr. Ly mentioned that this data likely underestimates CGM use in Insulet’s user base, since it does not include G5/Glooko integration. A separate slide showed a subset of Insulet users with self-reported demographic data, which included a notable n=496 type 2s– they were slightly older (mean age: 56 years), but had a lower estimated A1c (7.8%) and higher daily insulin dose (59 units per day) than the full cohort. This certainly bodes well for Insulet’s U500 and U200 work! We’ve include both slides below.
• Drs. Thomas Danne (DPV registry) and Lalantha Leelarathna (Manchester Diabetes Center) provided reassuring real-world Omnipod data from Europe – outcomes with Omnipod looked very similar to other pumps. The DPV registry showed increasing use of Omnipod since 2012, with the highest use in youth with type 1 diabetes (10-15 years). A1c of Omnipod users in DPV was an encouraging 7.2%-7.7% (depending on age group); it was not compared to other pumps. On average, <10% of patients stopped using Omnipod in the DPV, retention in line with what Insulet has shared historically. At the Manchester Diabetes Center, Omnipod retention at three years was an impressive 99%, better than Medtronic (96%), Animas (96%), and Roche (81%). Said Dr. Danne, “For people who say Omnipod has a delivery problem – we don’t see this with the data and with the retention rate. We can feel good about it.” Dr. Danne concluded that “switching to a tubeless pump appears to be an effective alternative to MDI.” 

Corporate Symposium: Changing Diabetes Care: From Glycaemia to Cardiovascular Disease (Sponsored by Novo Nordisk)

Prospects of Ultra-Fast Insulins in Pump Therapy

Bruce Bode, MD (Emory University, Atlanta, GA)

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.

Corporate Symposium: Innovating Beyond Glucose Control in Diabetes Care (Sponsored by Sanofi)

Enriching Diabetes Care: Technology and New Models for Intervention Strategie

Boris Kovatchev, PhD (University of Virginia School of Medicine, Charlottesville, Virginia)

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. 

Integrating Diabetes Care

David Kerr, MD (Bournemouth Diabetes and Endocrine Centre, Bouurnemouth, UK)

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.

Corporate Symposium: Can Connectivity Drive Sustained Behavior Change? (sponsored by Ascensia)

Ascensia Announced Global Innovation Competition – €200,000 for Winning DIgital Solutions that Address Type 2 Diabetes

Michael Kloss (Ascensia, Parsippany, NJ)

At the end of an excellent Ascensia symposium on behavioral change, CEO Mr. Michael Kloss took over the mic to announce a global innovation competition (The Ascensia Diabetes Challenge) – €200,000 in cash prizes are available for digital solutions that improve the lives of people with type 2 diabetes. He began by thanking the panelists for “pointing out that our technology is frustrating for patients,” and cited this fact as the reason for the competition. Submissions will be welcome from Europe, the Americas, and Asia Pacific with entries opening on October 1 for Europe and November 6, 2017 for Asia Pacific and the Americas. Finalists will then be announced in early 2018, with a finalist event in spring 2018 and winner announced in June 2018. The expert panel of judges will include UCSD’s Dr. Bill Polonsky, Dr. Masood Nazir (a GP from the UK), and Robin Swindell (a person with type 2 and on the board of Diabetes UK) – nice! Criteria includes user experience, innovation, efficacy, sustainability, and scalability. The challenge is done in partnership with yet2, an innovation and technology consultant that has run several similar efforts. We’ll be interested to see who applies, what ultimately wins, and whether it comes to market or stimulates further innovation inside Ascensia. Prize competitions create nice financial incentives for applicants, though we wonder how entrepreneurs think about them – Do they worry about making their ideas public? Are they excited by the chance to bring an idea to a big company and do something with it? Of course, this also sends a big message to Ascensia’s internal team that innovation can come from anywhere, including outside of the company’s walls. In a press conference on the challenge, we asked whether the competition and associated cash prize bring any strings attached. We were referred to the challenge's terms and conditions (fine print), which do seem pretty hands off – “the winner will also have the opportunity to work with Sponsor on the development of their solution, using the expertise and resources from the company to help towards bringing their solution to market.  Such collaboration is subject to a mutually agreed upon business relationship with mutually agreeable terms.” Ascensia does not automatically get any IP from ideas, which is great to see. We’re glad to see the standalone company trying to broaden and think differently, as relying on the BGM+strips market will not prove sustainable long term.  

• Will we see more of these innovation challenges moving forward? These seem like a great deal for companies to crowdsource innovation, assuming the ideas are solid and applicant quality is high. Amazon/Merck launched the Alexa Diabetes Challenge in April, and we’ll be at the Demo Day to see the finalist voice-enabled solutions for type 2 diabetes. We wonder what the IP parameters are for contests like this – does the winning content automatically belong to the funding company? Or is the winner independent, just with some extra cash in pocket? Or somewhere in between?

Driving Sustained Behavioral Change: Digitizing an Evidence Based Diabetes Program

Osama Hamdy, MD, PhD (Joslin Diabetes Center, Boston, MA); William Polonsky, PhD (UCSD, San Diego, USA)

The respected Dr. Osama Hamdy gave an overview of Healthimation’s weight management program (using animation, gaming, and leveraging Joslin’s Why WAIT program), which he co-founded, sharing that the platform now integrates with device data. Pictured on the slide were a connected scale, a smartwatch, and a series of Ascensia meters. An Ascensia rep later told us that the picture did not denote an exclusive relationship, though the talk did come in an Ascensia symposium. We’re glad to see Healthimation pushing forward with connectivity, and of course, to see Ascensia embracing up-and-coming digital tools that expand its addressable market. Based on Dr. Hamdy’s remarks, the company aims to create an ecosystem, in which “every part of a day is connected.” The original WhyWAIT intervention has shown encouraging data, driving average weight loss of 6.4% at five years, 21% of enrollees stopping insulin, and 50%-60% experiencing a reduction in their diabetes medications. The question is, can this program translate to the digital setting with the help of machine-learning assisted personalization, Hollywood style animation and gaming, and coaching? How will it stack up to Virta’s approach? No outcomes were shared today, which was disappointing following the beta launch in December. According to the website, the product is available as a free seven-day trial, with a steep direct-to-consumer price of $49.99 per month. Many attempts to turn weight management virtual have fallen short because the programs aren’t sticky, but Dr. Hamdy firmly believes that “Lena,” the fit, young, quirky avatar that guides users through the course and the Hollywood magic (surprises, new games, etc.) will keep people from getting bored – we like the out-of-the-box thinking and hope he is right. Following the presentation, UCSD’s Dr. William Polonsky plainly said that “most apps we see in type 2 diabetes are pretty darn boring.” He (naturally) didn’t seem as positive about Healthimation as its founder did, but if it can provide the right mix of cheerleading, connectivity, and support to make sense of data, then Dr. Polonsky believes it can be successful.

Corporate Symposium: Real-World Challenges in Type 2 Diabetes: Why a Paradigm Shift is Needed

Luc Van Gaal, MD, PhD (Antwerp University Hospital, Antwerp, Belgium); Steven Edelman, MD (UCSD, San Diego, USA); Richard O’Brien, MD, PhD (University of Melbourne, Melbourne, Australia); William Polonsky, PhD (UCSD, San Diego, USA); Eduard Montanya, MD, PhD (University of Barcelona, Barcelona, Spain)

Melbourne’s Prof. Richard O’Brien, UCSD’s Dr. William Polonsky, and Barcelona’s Prof. Eduard Montanya discussed real- world challenges in type 2 diabetes, identifying adherence as the primary driver for the gap between outcomes observed in clinical trials versus real life. Dr. O’Brien cited a recent study (from Dr. Polonsky’s group) demonstrating that 75% of the differences in A1c reductions seen in clinical trials for GLP-1 agonists vs. real-world data can be explained by non-adherence. For DPP-4 inhibitors, the paper suggests that 72% is due to non-adherence. Dr. O’Brien urged physicians to discuss adherence with their patients, citing that one third of prescriptions for diabetes medications are never filled. Dr. Polonsky took adherence a step further, diving into critical patient beliefs surrounding medication. The issue, he said, is that diabetes medications lack short-term, tangible benefits, while cons such as burden and real/imagined adverse effects are plentiful – we wonder if VR, simulation, and higher tech education might help close this gap. For example, here’s what happens to the body when glucose levels are high, here’s how you will age when glucose levels are high, etc. Dr. Polonsky provided the telling example of an exercise he performs with type 2 patients, in which he shows them the profiles of two hypothetical patients, one of whom has at-goal A1c but takes two medications and is on insulin, while the other has a high A1c, but is not on any medications. When asked which patient is doing better, the vast majority say it’s a tough question. In other words, some people with diabetes equate more medication with failure. Yikes! The onus for this misconception is largely on providers, who sometimes threaten patients with more medication if they don’t improve behavior. Dr. Polonsky emphasized working on the patient-provider relationship, citing several studies demonstrating that improved trust is associated with greater adherence. So how do we shift the paradigm? Dr. Montanya mentioned a study demonstrating that triple combination therapy immediately following diagnosis (instead of a step-wise add-on approach over four months) conferred a greater A1c improvement. His argument was in favor of early combination therapy, but this could also tie in to adherence: Presumably, a stepwise approach is perceived as consecutive failures, while the immediate intensification is simply a medication regimen that drives right to success, so patients are more likely to stick to it. Dr. Montanya also suggested telemedicine as a potential approach to improve adherence, although acknowledged that meta-analyses yield mixed results and tend to demonstrate only short-term efficacy. He, and many thought leaders we’ve heard from recently, are particularly excited about ITCA 650, the six-month implantable exenatide pump from Intarcia. He discussed the FREEDOM-1 and -2 trials demonstrating significant reductions in A1c and body weight, and sees real potential in the pump to drive adherence. Once implanted, it works! We also see very high potential in novel ways to take and track medication, such as the super brilliant Pill Pack(“Pharmacy Simplified”). Poor adherence is a complicated affair, one that costs the health system huge sums of money – addressing it will take a carefully-crafted combination of support, technology, and design.

Questions and Answers

Q: What is the best way to approach a patient about being adherent?

A: Dr. Polonsky: What we see is healthcare providers will say, “I don’t know this data regarding adherence, I don’t see that.” That probably has to do with how we ask the question. It’s common for providers to say: “Look you haven’t had any problems managing your meds, have you?” The patient is almost guaranteed to answer no. There’s an opportunity to normalize the situation. Instead say, “I know people struggle taking medication, what kind of trouble do you have with your medication?” It’s important to open up the door to normalize the issue. Bravo!

Posters

Positive Clinical Outcome of Belgian Reimbursement of Real-time Continuous Glucose Monitoring for Type 1 Diabetes Patients on Insulin Pump Therapy

S Charleer, C De Block, R Radermecker, E Weber, C Vercammen, L Crenier, Y Taes, F Nobels, B Keymeulen, C Mathieu, P Gillard

A very compelling poster shared 12-month healthcare outcomes from a national Belgian reimbursement of CGM in 515 insulin pump users (RESCUE). The hospitalization and work absenteeism outcomes were outstanding and a tremendous win for CGM. This academic study tracked outcomes in the 12 months prior to CGM initiation and then in the 12 months following CGM in a population of type 1 adults on pumps. Most notably, the percentage of patients experiencing a hypoglycemia/DKA hospitalization declined by a striking 75% following CGM initiation (16% of patients without CGM to 4% with CGM; p<0005). Meanwhile, CGM drove a 64% decline in the percentage of patients experiencing a work absence (25% to 9%; p<0005). From these data, the poster estimates a nationwide cost reduction of €345,509 – assuming this was calculated from the sub-set of 379 users with 12-month CGM data, it implies €911 saved per person. We’re not sure if this cost estimate included the price of CGM, but saving this many days from work and hospitalizations is very encouraging for CGM’s cost-effectiveness. Notably, the observed A1c reduction of approximately 0.3% (baseline: 7.6%) with CGM over 12 months would have significantly understated these outcomes. As we’ve seen in other CGM studies, the benefit was slightly larger for those with higher A1c levels at baseline. CGM drove an improvement in quality of life (SF-36, though numerical numbers were not given), and both fear of hypoglycemia (HFS-Worry) and emotional burden due to diabetes (PAID-SF) improved significantly. It was not clear from the poster or the ClinicalTrials.gov page what CGM device(s) were used in this study. What a victory for the field and something we hope to see repeated in other countries and health systems!

• This was a real-world, observational study of CGM, meaning there are some limitations. First, there seemed to be some patient dropout between the pre-post evaluation – n=515 were enrolled, n=496 had 12-month data before CGM, and then n=379 had 12-month data post-CGM. (This is why we focused on percentage of patients and not number of events in the above.) We’re not sure if this was a lost data issue or if people actually stopped wearing CGM. There is likely some selection bias from no inclusion criteria or randomization – patients for CGM were “selected by the diabetes teams.” Last, the study only enrolled pumpers at specialized diabetes centers, meaning generalizability is a question. We’re not sure how these limitations would influence the impressive results.
• The ClinicalTrials.gov page notes that Belgian CGM reimbursement was granted for an initial period of three years, with this study serving as an evaluation of the decision. This trial will continue out to 24 months, meaning we should see follow-on data at some point. If outcomes are positive, we’d have to assume reimbursement will be extended.

Insulin Treated Patients Titrated to HbA1c Target Require Insulin Dose Titration Every 39 Days on Average to Maintain Glucose Control

Andrew Rhinehart, MD (Glytec, Waltham, MA, USA), John Clarke, RN, CDE (Glytec, Waltham, MA, USA), Robby Booth (Glytec, Waltham, MA, USA)

12-month data from Glytec’s outpatient Glucommander decision support system demonstrated a significant A1c drop, sustained with adjustments every ~57 days after goal was reached. 74 patients with insulin-dependent diabetes (baseline A1c: 10.3%; 78% type 2; average age = 56 years) were included in the non-randomized, uncontrolled study. At three months, A1c had dropped 2.3% points to 8.0%; at six months, A1c stayed flat at 8.0%; at nine months, A1c crept up to 8.3%; and at 12 months, A1c fell to 7.8%, representing a 2.5% absolute drop from the high baseline of 10.3%. The magnitude of this drop closely resemble that shown in six-month data from a separate study (presented at ATTD 2o17). Over the course of the study, mean blood glucose dropped from 214 mg/dl to 162 mg/dl. Impressively, the median time to goal (three consecutive days with average blood glucose <180 mg/dl) was just seven days. These rapid and sustained improvements in glycemia came at a very low risk of SMBG-detected hypoglycemia. The percentage of readings <54 mg/dl was o.37%, and the percentage <40 mg/dl was 0.05% – no episodes required assistance. These values were captured in a mean 3.0 fingersticks per day in the first three months, and 2.5 per day in the final three months. It’s impressive that Glytec can titrate insulin with so little glucose data; how would it look with CGM? After the first three months of treatment, Glucommander recommended a dose update every ~57 days – the poster reasons that the best-case three-to-four months between in-person clinic visits doesn’t meet the titration needs of most patients, and we would add that software is likely better at adjusting insulin than a provider with limited time. Average total daily dose per kg rose by 38% (0.66 U/kg to 0.91 U/kg), reflecting a failure to intensify prior to the intervention. Interestingly, the percent of daily dose coming in the form of basal fell from 50% to 31% - this ratio of basal:bolus continues to vary widely in studies and we hope the field moves away from one-size-fits-all expectations for 50%/50%. The poster notes that larger prospective RCTs are needed to confirm these results – great to hear since a number of studies have shown solid data but with no control group – and also that Glucommander will be used to treat over 100,000 patients in 2017.

• We would have loved to see CGM in this study, at least in a subset of participants, to truly capture time spent in hypoglycemia (especially overnight). Richer CGM data could also be leveraged to guide the titration software more precisely. Glytec has existing BGM integrations with Roche, Livongo, Agamatrix, and Telcare.
• Participants were given a Telcare cellular-enabled meter and asked to check four times a day. Blood glucose data was automatically sent to the clinic, where patients due for titration were flagged in the Glytec software so that a nurse could make the recommended adjustment, which appeared either on the patient’s meter or via text message.

A Prospective Pragmatic Clinical Trial in Type 2 Diabetes to Compare the V-Go Insulin Delivery Device with Standard Treatment Optimisation

M Cziraky, S Abbott, M Nguyen, P Strange, T Wasser, L Nowalk, K Larholt

In a four-month, multicenter, pragmatic clinical trial, use of the V-Go insulin delivery device induced significant reductions in A1c amongst adults with type 2 diabetes (n=415), alongside significant decreases in total daily dose of insulin (TDD). 52 participating clinical sites across the US were randomized to offer either the V-Go or continue offering standard care to their patients (we’re not sure how enrollment was determined within a clinic assigned to V-Go). Overall, the V-Go group saw a significantly greater A1c decrease than the control group (0.95% vs. 0.46%; P=0.002), though from a higher baseline A1c (9.9% vs. 9.3%). Presumably, this reflects some selection bias in prescribing – those given V-Go were more likely to be having a harder time with their diabetes. There was a 32% decrease in the number of V-Go patients with A1c greater than 9% vs. a 17% reduction in the control group, though the higher baseline A1cs with V-Go makes comparative conclusions challenging. Indeed, by the study’s end, the control group actually had lower average A1cs than did the V-Go group (8.8% vs. 9.0%). Average TDD decreased significantly in V-Go patients by 0.2 U/kg (baseline: 71.3 units), while TDD in the control group remained unchanged. Similar results were achieved in a sub-population of MDI users, with V-Go patients achieving significantly larger decreases in A1c (-1.0% vs -0.4%; p=0.006) alongside declines in TDD. Again, baseline A1c levels were significantly greater in the V-Go group. An interesting A1c vs. TDD density plot for the overall study population (below) shows leftward and downward shifts in the solid blue line (V-Go group at end of the study) compared to the dotted blue line (V-Go at the beginning of the study) – this indicates a lower A1c with less insulin. Meanwhile, the control group only saw the red dotted line (pre-study) shift down slightly (to the solid red line), reflecting improved A1c without decreased TDD. Promisingly, a questionnaire administered to patients at the end of the study indicated that 94% of patients used V-Go as directed, and 85% intend to continue using V-Go. Valeritas has published a number of positive posters and studies in the recent past showing declines in A1c and TDD, and we’ll be interested to see if the newly public company can scale adoption and reimbursement. 

Performance of a Non-invasive Glucose Monitoring Device for People with Prediabetes and Type 2 Diabetes

T Lin, E Naidis, A Rozner, A Gal, A Drexler, K Bahartan

A single-arm study (n=32) sponsored by Integrity Applications found that there were no significant differences in the accuracy of the GlucoTrack, the company’s non-invasive blood glucose monitoring device, between people with prediabetes (n=7; MARD=18.3%), people newly diagnosed with type 2 diabetes (duration 5 years; n=9; MARD=15.6%), and people with long-duration type 2 diabetes (duration >5 years; n=16; MARD=16.6%). Participants wore the ear-clip GlucoTrack for a “calibration day,” comprised of three measurements every 10 minutes, followed by a trial day consisting of a pre-prandial measurement, standardized breakfast, and six additional measurements every 30 minutes. All groups demonstrated similar proportions of measurements in the A and B zones of the Consensus error grid (at least 92% of the measurements were in Zone A across all groups). The sample sizes are small, so we’re not sure how results would look in a more robust pivotal study. If the main application is for people with prediabetes and those on orals, is this accuracy good enough? GlucoTrack is already CE marked and has launched in China, South Korea, Turkey, and some European countries, according to a rep in the exhibit hall. There is still a lot to prove here. The product’s non-invasive aspect is appealing (after a few calibration fingersticks twice a year), but the ear clip is bulky and attached to an industrial-looking handheld by a wire, and each reading takes one minute to register. The form factor and user friendliness aspects are lacking at the moment (save for the lack of fingersticks), while the likes of Dexcom and Abbott continue to move quickly on innovating subcutaneous sensors – slimmer on the body, less painful to insert, more integrated with consumer electronics, and lower cost. Until GlucoTrack becomes more discreet and less time-consuming to use, adoption will likely be difficult.

The Effects of Local Subcutaneous Inflammation on Insulin Pharmacokinetics

M Novak, R Radford, K Riley, J Alarcón, A Harvey, R Pettis

A BD poster showed that local inflammation, mimicking that seen from extended infusion set wear and insulin excipients, alters insulin PK profile in a large animal model. Swine (n=5) were given bolus subcutaneous injections of lipopolysaccharide (LPS; a documented activator of inflammatory cascades) or saline. 24 hours later, four units of U100 insulin lispro was injected into the same site. Plasma measurements recorded over the following six hours demonstrated significantly less total circulating insulin over the first 60 minutes, significantly lower peak plasma insulin concentration, and significantly slower time to peak in the LPS condition. This means that local inflammation may cause decreased and slower insulin absorption into the vasculature. The poster claims that this is the first time that local subcutaneous inflammation has been shown to significantly alter insulin PK, and BD is interested in looking more representatively at the effects of device- and insulin excipient-induced insulin. This has obvious implications in extended infusion set wear, often called the Achilles heel of pump therapy. A number of groups, including BD with funding from JDRF, are currently looking at ways to extend set wear time to seven days or beyond. JDRF is also funding TJU/Capillary Biomedical’s efforts ($1.5 million) to develop a novel seven-day wear set,  and last June, Medtronic shared that it is also working on an extended wear set that it is hoping to launch “in the next three years.” Addressing this issue with novel mechanical or molecular approaches will greatly reduce hassle associated with pump wear, and make a single-site CGM/pump closed loop system more realistic.

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