European Association for the Study of Diabetes (EASD) 51st Annual Meeting

September 13-18, 2015: Stockholm, Sweden – Full Report – Diabetes Technology – Draft

Executive Highlights

Dr. Lalantha Leelarathna’s presentation of results from Cambridge’s two three-month, at-home, unsupervised closed-loop studies – in tandem with a publication in the NEJM – was the biggest device highlight from EASD 2015. We learned that day and night time-in-range improved significantly in both studies, with a ~20-25 percentage point improvement at night and a ~9-11 percentage point improvement during the day. Mean glucose followed a similar pattern, with a ~19-30 mg/dl improvement at night and ~9-11 mg/dl improvement during the day. Also on the closed loop front, EASD brought yet another Bionic Pancreas vs. Cambridge debate on the merits of bihormonal vs. insulin-only closed-loop systems. The main argument for insulin-only is the complexity, burden, and higher cost of incorporating glucagon into the system, while bihormonal proponents believe that that a “fully” closed system will relieve patients of the demands of insulin-only systems (carb counting), and provide those who are less tech-savvy with automated glucose control. Ultimately, we felt that both sides raised valuable points – see below for the details.

Valuable results also came from a human factors study comparing Locemia’s instranasal glucagon powder to a standard emergency injection kit in a simulated episode of severe hypoglycemia (using a mannequin). In the analysis, 94% of caregivers correctly gave a full dose of glucagon with the intranasal device, and it took just 16 seconds on average. Conversely, only 13% of the same caregivers delivered a full dose with the injection kit and 38% gave a partial dose; the average time for these eight individuals was 1 minute and 53 seconds (seven times longer than intranasal delivery). Shockingly, 50% of diabetes caregivers failed to deliver any glucagon at all with the injection kit vs. just 6% that failed to deliver glucagon via the intranasal route. Even more frighteningly, two caregivers in the injection group mistakenly used insulin for the hypoglycemia rescue, as they were confused about which injection to use. The data seem like a slam-dunk for Locemia’s needle-free device, especially as it seeks regulatory approval and future reimbursement relative to existing devices.

On Monday’s stacked corporate symposia day, Dexcom stole the show by announced its G5 approval in Europe where the EU version of the G5 has a replacement claim in the label: “The G5 Mobile System is designed to replace fingerstick blood glucose testing for diabetes treatment decisions.” In addition, Dexcom showed a first-ever picture of the prototype sensor with partner Google – a tiny, penny-sized bandage.

Below is our complete coverage of Diabetes Technology from EASD 2015. Titles highlighted in blue are new additions that were not mentioned in our daily updates from Stockholm, and those highlighted in yellow represent what we felt were the most notable talks of the meeting.

Table of Contents 

Diabetes Technology

Oral Presentations: Devices Changing Treatment Paradigm

HbA1c Improvement with Less Hypoglycaemia in Patients with Type 1 Diabetes Wearing an Artificial Pancreas for Two Months from Dinner to Breakfast

Hans DeVries, MD (Academic Medical Center, Netherlands)

Dr. Hans DeVries presented encouraging results from a randomized, crossover AP@Home trial comparing two months of dinner-to-breakfast hybrid closed-loop (8 pm to 8am) with UVA’s DiAs to two months of 24/7 open-loop with sensor-augmented pump therapy (Dexcom G4, Roche Spirit). The trial enrolled 35 current insulin pump users, with three dropouts due to poor system acceptance. The headline finding was a significant reduction in A1c: -0.32% on overnight closed loop vs. -0.16% on open loop (baseline: 8.2%; p=0.04). Though that seems small, we see it as an encouraging finding given the sole use of the system at night; a near halving of nocturnal time spent <70 mg/dl (1.7% on HCL vs. 3.0% on open-loop); and use of pump+CGM as the comparator group (harder). Overnight time-in-range (70-180) significantly improved (67% on closed loop vs. 58% on open loop; p<0.0001), though not as much as we would have expected – perhaps the overnight DiAs algorithm was a bit conservative in this home study, or the comparison to pump+CGM simply made improvement more challenging to show. The study is in press in the Lancet Diabetes & Endocrinology, and an extension phase has tested 24/7 use.

  • Three of 35 patients discontinued use due to poor system acceptance. Dr. De Vries mentioned the hassle of alarms as a key factor, and one patient had a “trust issue” (a mathematics professor). It was a reminder that even among pump users, first-gen artificial pancreas systems are not going to be for everyone.
  • Read the diaTribe experience testing this system at night and 24/7. Kelly and Adam appreciated DiAs’ nighttime algorithm, ability to reduce hypoglycemia, and the power of waking up with a glucose of 120 mg/dl.

Medical Imaging for Performance Characterisation of a Novel Continuous Subcutaneous Insulin Infusion Set

Robert Pettis, MD (BD, Research Park Triangle, NC)

Dr. Robert Pettis presented an investigational study of the new BD FlowSmart infusion set (6mm, side-ported), first presented as a poster (1088-P) at ADA 2015. As expected, there were no new updates on FlowSmart’s commercialization, which is still slated for “2016” in the US, EU, and Canada. The objective of the study was to use medical imaging techniques to evaluate the in vivo flow and deposition performance of the investigational set against control commercialized sets (Medtronic’s Quickset). Dr. Pettis first shared the results of an in vivo fluoroscopy experiment in swine that provided visualization of device placement and depot patterning during a 10U bolus infusion of iodinated contrast media. Notably, two distinct depots were created by the investigation set in contrast to the smaller, condensed diffusion pattern created by the control set. Building on these findings, investigators sought to replicate the preclinical results in humans. A corollary human MRI study of the investigational set in non-diabetes individual (n=8) showed similar depot patterning across multiple saline bolus volumes (2-20U). Comparison of the 6mm investigational set vs. a control 9mm set also demonstrated that the shorter length increased diffusion in areas of thin subcutaneous fat where muscle can occlude single ports. Lastly, a feasibility experiment of intentionally poorly inserted devices demonstrated successful bolus delivery with the FlowSmart set even under “non-ideal,” “real-life” conditions. Ultimately, we continue to be impressed by the preliminary data, though the major question for BD remains whether these differences will translate meaningfully to the clinic: Better insulin absorption? Lower A1cs? Less hypoglycemia? Greater time-in-range?

Questions and Answers

Q: Have you considered adding multiple ports to the catheter?

A: Yes, but it did not provide any additional advantage. It actually provided a disadvantage because the catheter became less stable. We did investigate different versions, but settled on this one.

Q: if you had to choose a side port vs. a main port, which do you think is better?

A: Two is always better than one, and this is all about redundancy. I think that because of the unique delivery characteristics of the side port, I would go in that direction. But that is my opinion.

Q: Have you done studies in clinic?

A: No. We have not done those studies yet.

Oral Presentations: Optimizing the Insulin Treatment Paradigm

Insulin Pump in Difficult to Control Type 2 Diabetes Mellitus

Priyamvada Singh, MBBS (Beth Israel Deaconess Medical Center, Boston, MA)

An observational pilot study (n=13) investigating the utility of insulin pump therapy in type 2 diabetes demonstrated significant improvements in A1c associated with pump therapy (8.9% to 7.7%) over five years. While we would raise questions about the results – retrospective analysis, very small sample size – the findings are directionally interesting given the lack of reimbursement for pump therapy in this population in the US. The data represent the longest observation of the efficacy of pump therapy in type 2 patients that we can recall seeing to date, and the analysis was interesting from a real-world use perspective. (Of course, the Medtronic’s OpT2mise results are the gold standard in this field so far.) That said, we were a bit disappointed to hear some of the commentary during the Q&A from the investigator, who sounded confused regarding the difference between CGM and pumps (she suggested that pumps record glucose data … ) – a big reminder of the importance of education for all those that are in the field, even those that we think of as “on the cutting-edge.”

Questions and Answers

Q: How did insulin doses change when patients were switched from MDI to pump therapy?

A: The total insulin requirements did not change while patients were on pumps. However, the insulin requirements were only about 100 units relative to 200 units on MDI.

Q: Do you have data on glucose variability?

A: There were fewer excursions.

Q: Did you look at CGM data?

A: We did not have to because insulin pumps have a chip you can download to look at glucose data.

Posters

Needle-Free Nasal Delivery of Glucagon is Superior to Injectable Delivery in Simulated Hypoglycemia Rescue (867-P)

J Yale, C Piché, M Lafontaine, R Margolies, E Dissinger, A Shames, N Fink, M Egeth, H Dulude

This brilliantly designed human factors study compared use of Locemia’s intranasal glucagon powder to a standard glucagon emergency injection kit in a simulated episode of severe hypoglycemia (a mannequin; details below). The study included two groups to mimic realistic scenarios: (i) people with diabetes that taught a caregiver how to use the glucagon device a week prior to the simulation; and (ii) untrained participants with no connection to diabetes, who were shown the device and then asked to use it on the spot. In the key analysis, 94% of caregivers (15/16) correctly gave a full dose of glucagon with the intranasal device, and it took just 16 seconds on average. Conversely, only 13% of the same caregivers (2/16) delivered a full dose with the injection kit and 38% gave a partial dose (6/16); the average time for these eight individuals was 1 minute and 53 seconds, or seven times longer than intranasal delivery. Shockingly, 50% of diabetes caregivers (8/15) failed to deliver any glucagon at all with the injection kit vs. 6% (1/16) with intranasal. Even more frighteningly, two caregivers in the injection group mistakenly used insulin for the hypoglycemia rescue (cleverly included in the diabetes supply bag alongside the glucagon, to simulate a realistic hypoglycemia rescue situation), as they were confused about which injection to use. Whew. The results were equally strong for Locemia in the untrained acquaintance group: 93% success (14/15) with intranasal in an average of 26 seconds vs. 0% success for a full-dose (0/15) and 20% success for a partial dose (3/15) with the injection kit in an average of 2 minutes and 24 seconds. Overall, the results are a slam-dunk for Locemia’s needle-free device, especially as it seeks regulatory approval and future reimbursement relative to existing devices. We’ve always said that injected glucagon kits are burdensome for caregivers, but who knew it was this hard to use them correctly and quickly? The study also revealed an unexpected concern with an injected route of glucagon delivery that is easy to mix up with injected insulin – this could be a strong marketing advantage vs. competitors Xeris and Biodel. As a reminder, Locemia has now reported phase 3 adult and pediatric data, showing strong equivalence to injected glucagon; we assume a submission could happen sometime early next year.

  • The severe hypoglycemia simulation included a fully clothed adult mannequin representing a person with diabetes. Participants were told that the mannequin was having an episode of severe hypoglycemia and that they had to administer the rescue glucagon as quickly as possible. The glucagon rescue device was located in the patient’s backpack, which also contained a diabetes supply pouch (glucose meter and strips, alcohol swabs, lancing device, insulin vial, and syringe). Sound effects and distractions created a sense of urgency – a nice touch.
    • The trained caregiver arm included 16 adult insulin-using people with diabetes and their caregivers. Patients were taught how to use one of the glucagon devices (in random order) and then instructed their caregivers, replicating real-life transfer of information. One week later, caregivers were asked to treat a mannequin during a simulated episode of severe hypoglycemia. The procedure was repeated with the other device.
    • The untrained acquaintance arm included 15 adults with no diabetes connection, but who said they were willing to assist someone in distress. They were not trained on device use and only shown the device prior to the simulation. This group treated two episodes of severe hypoglycemia with the injection kit and intranasal powder in random order, with a delay of about ten minutes between each simulation.
  • Two caregivers in the injection group mistakenly used insulin for the hypoglycemia rescue attributed to “form factor confusion.” An additional two caregivers in the intranasal group and three caregivers in the injection group attempted to give insulin in addition to glucagon “due to misunderstanding of diabetes management” (i.e., “insulin helps the patient with their blood glucose, so I should give that too”). The data simply underscores the tremendous educational challenges related to glucagon, even amongst diabetes caregivers!
  • It was notable to see that untrained acquaintances were able to deliver intranasal glucagon successfully and at a similar rate as trained caregivers. We agree with the poster’s conclusion that it highlights the ease of use of Locemia’s needle-free nasal glucagon delivery system.
  • “Glucagon delivery using a different route and device form than those used for insulin may reduce the risk of confusion and accidental delivery of insulin.” This was a fascinating point we had never thought of, but a realistic one since insulin might be co-located with a glucagon kit. Certainly, this gives Locemia some marketing advantage for injected rescue glucagon competitors Xeris and Biodel.

Psychological Aspects of Evening and Night Closed-Loop Insulin Delivery Under Free Living Conditions: A 2-month Crossover Trial (988-P)

J Kropff, J DeJong, S del Favero, J Place, M Messori, B Coestier, A Farret, F Boscari, S Galasso, D Bruttomesso, C Cobelli, E Renard, L Magni, J DeVries

This multicenter, crossover trial from the AP@Home Consortium investigated the psychological aspects of overnight closed-loop control, finding that patients appreciate the benefits of artificial pancreas technology despite the existing human factors burdens. The study enrolled 35 patients with type 1 diabetes, exposing all to sensor-augmented pump therapy for eight weeks during a control period and overnight-closed loop therapy for eight weeks during an intervention period. Results demonstrated an overall positive attitude towards closed-loop technology (perspective score = 69/90) with many patients acknowledging “positive effects at work,” “improved blood glucose,” and “less worry.” On the other hand, frequent alarms, interference with sleep and social life, and technological issue (e.g., loss of connectivity) all came up as issues and continue to underscore the need to study closed-loop technology in the context of real-life. Clinical setting are instructive from an accuracy and efficacy standpoint, though these findings serve as a reminder that the “most successful” closed-loop devices may not be those that are “most efficacious” but those that offer the “most normalcy” for patients. Patients did not report differences in fear of hypoglycemia during their time on SAP vs. closed-loop technology, perhaps a reflection of how far low-glucose suspend/predictive low-glucose suspend technologies have come in patient’s eyes. We continue to believe that human factors work will be pertinent to artificial pancreas uptake/success and, despite the limited analyses in this study, are big fans of the push to understand the psychosocial aspects of closed-loop technology more closely. Indeed, we can’t hand patients an artificial pancreas and expect them to love it immediately – perhaps we can take a lesson from CGM (which was once heralded as a must-have) and learn to set expectations more appropriately.

Continuous Glucose Monitoring Improved Glycaemic Control in Patients with Type 1 Diabetes During 52 Weeks of Insulin Pump Therapy as well as with Basal-Bolus Insulin Regimen (983-P)

J Šoupal, M Fleka, L Petruelková, J Škrha Jr., J Škrha, M Prázný

This prospective study investigated the efficacy of long-term CGM use in patients treated with CSII and MDI. The trial enrolled 51 patients with type 1 diabetes, dividing patients into three groups: (i) those initiated on CGM (n=17); (ii) those initiated on pumps without CGM (n=17); and (iii) those initiated on MDI and SMBG only (n=17). [In the first group, ten patients were on pumps (i.e., sensor-augmented pump therapy) while seven were on MDI.] After one year, findings indicated that patients on CGM saw a significant improvement in glycemic control (A1c: 8.3% vs. 7.2%, p<0.0001) with both subgroups (patients on MDI and patients on SAP) showing similar improvement in A1c. Patients on insulin pump therapy alone also saw an improvement in glycemic control (A1c: 8.4% vs. 7.9%, p<0.05) – though, we would note, not as great as those on CGM – while those in the control group did not experience a significant improvement (A1c: 8.3% vs. 8.0%). The poster notes that a reduction in time spent in hypoglycemia was only observed in patients with CGM (8% vs. 6%, p<0.01) – however, we’d point out that it’s tough to compare time in hypoglycemia for patients on SMBG and CGM in the first place given the 24/7 data presented by CGM and lack thereof with SMBG. Regardless of this limitation, the findings speak to the value of CGM relative to pumps, suggesting that a combination of CGM + MDI and be just as effective as CGM + pumps in a subset of patients. We look forward to more rigorous studies investigating the relative benefits of pumps vs. CGM in the future.

Long-Term Accuracy Surveillance of a System for Self-Monitoring of Blood Glucose (930-P)

G Freckmann, A Baumstark, N Jendrike, T Leucht, P Wintergerst, D Rittmeyer, S Pleus

This poster examined the real-world accuracy of CE-marked SMBG systems, demonstrating that commercial devices often do not meet the standards by which they were cleared. The findings came as little surprise considering the attention BGM post-market surveillance has received in the past year (see our report on the 2014 AACE/ACE Consensus Conference on Glucose Monitoring). Four individual studies evaluated a total of eleven test strip lots for a single system’s accuracy over 1.5 years. Results were analyzed using both ISO 2003 (at least 95% of results have to fall within ±15 mg/dl at blood glucose values below 75 mg/dl and within ±20% at blood glucose values ≥75 mg/dl) and more stringent ISO 2013 (at least 95% of results must fall within ±15 mg/dl and ±15% for BG values ≤100 mg/dl) criteria. Findings indicated that nine out of the eleven test strip lots fulfilled the ISO 20013 criteria, while only five fulfilled the more stringent guidance. No clear trend in accuracy was observed over time. Ultimately, the findings drove home the need for consensus on issues of quality and safety. As a reminder, we heard much about the DTS’ post-marketing surveillance program last year, though it looks like the major outstanding question – who will fund it – continues to remain unanswered.

Is The Pump Bolus Calculator a Useful Tool or The Man Behind The Curtain? (920-P)

K Miller, D Maahs, J Wong, S Adi, R Beck, A Peters

This human factors study of T1D Exchange data examined the utility of bolus calculators in insulin pumps. Analysis included 1,944 T1D registry patients on pumps who were age ≥ 13 years. Findings suggested that a majority of patients who use an insulin pump frequently report using a bolus wizard/calculator (79%); this was more common in adolescents, females, patients with shorter duration of T1D, and patients with a lower education level (see table below). None of these findings were particularly unexpected. What was surprisingly was that frequent use of the wizard/calculator was NOT a significant factor in the safe and effective use of pumps – e.g., there were no significant differences between frequent vs. infrequent bolus calculator users in terms of the numbers of boluses per day (5.4 vs. 5.3, p=0.23), glycemic control (A1c 8.0% vs. 8.1%, p=0.04), occurrence of DKA in the prior 3 months (2% vs. 1%, p=0.18), and occurrence of SH in the prior 3 months (6% vs. 7%, p=0.56). Indeed, the findings support the notion that bolus calculators are valuable for patients of lesser diabetes literacy (or newly diagnosed), but also underscore the room for human factors/validation studies that could bring improvements in design/feasibility/utility. We assume that in shorter-term, less educated users, the benefits of accuracy outweigh the hassles of the calculator, though with a certain level of literacy, it appears that this added value dissipates. Moving forward, we would love to see a similar study done in a different population – those using BGMs with built-in bolus calculators on MDI, particularly given how many these patients would not otherwise have access to the benefits. We have to imagine that bolus advice would be associated with safer and more effective self-management.

  • Adolescents, females, patients with shorter duration of T1D, and patients with a lower education level were more likely to use insulin pump-integrated bolus calculators/wizards.

Product Demos

Dexcom Clarity

Dexcom silently launched its new web-based Clarity downloading software today, an outstanding upgrade over its previous data interpretation offerings. Clarity retains the high and low pattern recognition features from Studio/Portrait on the Web, but has added a much-improved dynamic web user interface, a better one-page snapshot with key information, and our absolute favorite, a “Best Glucose Day” report – we love the focus on the positive, which is too often overlooked for understanding what is working well. The refreshingly minimalist Clarity interface includes just four pages (Overview, Patterns, Data, and Compare), which show key information, mostly rely on graphics, and allow for manageable customization in all the right places. Pattern recognition is the major focus of the software, which should lay a foundation of what will hopefully come in the future – dosing advice. Details below!

  • The “Overview” report is the one-pager for the busy patient/clinician, showing estimated A1c, average glucose, hypoglycemia risk (low, medium, high), time-in-range, calibrations per day, and identified patterns during the specified date range (high, low, and Best Glucose Day, with associated time buckets – super useful for problem identification). Dexcom has clearly been thoughtful about including only the most important things on the Overview page, and for once it’s not an overwhelming spaghetti chart or tables full of statistics. Clicking on a pattern gives a deeper dive into the events that triggered its identification.

  • The “Data” page shows an AGP-like modal day report with bands to indicate the 15th/75th percentile range of values in a particular time slot – the spirit of AGP is there, though Dexcom has not entirely adopted the look and feel of AGP. The 15th percentile choice is a definite departure from AGP’s 25th percentile – we assume the goal is to really hone in on low outliers in a time slot.

  • “Compare” is a nice screen for examining quarter-to-quarter changes, giving key side-by-side Overview statistics and modal day reports for two specified periods of times.

  • The exported PDFs are equally well-designed and clear (pun intended), and we give the upload process high marks too – once we downloaded the uploader program (Mac and PC compatible), it sat in the background, auto-detected the plugged in Dexcom receiver, and uploaded the data to the web-based report in less than 10 seconds.
  • Clarity offers the same view for patients and clinicians (Yes!), and will pull data from both G4 Platinum and G5; we assume G5 data will automatically go to Clarity for those using the mobile app.
  • According to the user manual, Dexcom Clarity will also be offered in a separate mobile app. Notably, users can generate a code to allow others to view the data – that will be a big asset to caregivers and healthcare providers. 
  • The big next step, of course, is EMR integration … some of that is happening in a pilot at Stanford with EPIC.

Diasend Mobile App

We had a chance to play with CGM data in Diasend’s new Mobile app, which has just two main screens: “Scorecard” (a one pager showing average glucose, standard deviation, time in range, and activity levels via popular trackers like Fitbit and Jawbone) and “Reports” (timeline, modal day, and time-in-range). See pictures below. Like Dexcom’s approach with Clarity, the Scorecard view gives a terrific topline look at what’s happening with someone’s glucose levels – the four statistics diasend chose are great selections. The highlight of the “Reports” view is actually coming in two weeks, where Diasend plans to add AGP to visualize CGM data; Abbott has gotten a lot of patient praise with this output, and the app’s current modal day report is a spaghetti chart. We like the super clear time-in-range pie chart at the bottom of the Reports page – the glanceability of color pie charts is really something we hope to see more of. The app’s scrolling timeline view is not particularly useful for identifying patterns. A third tab, “Upload Data,” can only read from an NFC-enabled A. Menarini meter for now, though presumably more devices will come in the future (FreeStyle Libre?). We got data into the Diasend app via a Dexcom receiver downloaded to diasend.com; like Dexcom’s Clarity, this took ~10 seconds with diasend’s uploader. Diasend’s mobile app is really headlined by its disciplined restraint, and it’s hard to discount the platform’s tremendous compatibility (including Dexcom’s G5 at launch). We hope to see the company do more on the pattern recognition front, and to make the web interface more intuitive for problem identification – there are still too many of the overwhelming CGM graphs and statistics right now.

EASD/ADA Symposium: Devices

The Artificial Beta Cell: European Research

Lalantha Leelarathna, PhD (University of Cambridge, UK)

Dr. Lalantha Leelarathna began with unexpected news – two three-month, at-home, unsupervised closed-loop studies were published today in NEJM (a big day for diabetes indeed!). The single publication combines two crossover, randomized studies: 24/7 hybrid closed-loop in 33 adults and overnight closed-loop in 25 children and adolescents. Both used Cambridge’s MPC algorithm and compared closed loop to sensor-augmented pump therapy (Abbott Navigator 2, Dana R pump). Day and night time-in-range improved significantly in both studies, with a major ~20-25 percentage point improvement at night and a ~10-11 percentage point improvement during the day. Mean glucose followed a similar pattern, with an ~19-30 mg/dl improvement at night and ~10-11 mg/dl improvement during the day. This translated to an A1c reduction of 0.3% in adults (baseline: 7.6% post run-in; p=0.002) and a 0.3% advantage in children (baseline: 7.8% post run-in; p=0.17). Time spent in hypoglycemia (<50 mg/dl) was very low in both studies, though was still halved in children and adolescents (0.3% CL vs. 0.6% OL) and declined ~25% in adults (0.3% CL vs. 0.4% OL). See the pictures below, which really underscore the tremendous nocturnal gains (plus reduced variability) in this study. The multicenter trials were very scientifically rigorous and included long run-in periods (four weeks and 2-8 weeks), did not have remote monitoring or dietary/activity/geographic restrictions, used sensor-augmented pump therapy as the comparator (harder), and represent the longest at-home data published to date. The reduction in mean glucose plus less hypoglycemia is an important finding for an insulin-only system. This also marks three straight years of automated insulin delivery trials in NEJM, following the Bionic Pancreas in 2014 and DREAM and ASPIRE in-home in 2013. We salute the Cambridge team, who has really blazed a trail of ambitious, at-home, free-living closed-loop studies. We’re not sure what the team’s commercialization plans are, though hope there is something in the works!

  • The modal day plots below really highlight the advantage of the Cambridge system at night – there’s a clear reduction in mean glucose and a dramatic reduction in variability.

  • Total daily insulin dose were not significantly different between open and closed-loop in either study. This is consistent with prior Cambridge studies; insulin delivery was clearly more variable, an advantage of closed loop.
  • Closed-loop was used for a median of 20 hours per day in the adult study and 9 hours per day in the children/adolescent study. This was excellent considering the device burden, which entailed a smartphone + pump + CGM receiver + transmitter in the adult study, and a receiver + pump + CGM receiver + transmitter in the children/adolescent study.
  • Three severe hypoglycemic episodes occurred during the closed-loop phase, though the system was not in use in these cases. One episode of severe hypoglycemia occurred in an adult participant when the closed-loop system was not in use because of loss of connectivity (low battery); the participant was receiving insulin at the rate supplied by the study insulin pump. One adolescent participant had two severe hypoglycemic episodes (seizures) during the intervention period; the closed-loop system was not in use (not turned on and lack of pump connectivity), and the participant was using sensor-augmented pump therapy. It will be interesting to see what severe hypoglycemia looks like once larger artificial pancreas pivotal studies get under way.
  • The paper has a balanced criticism about dual-hormone systems: “Dual-hormone systems may provide additional protection against hypoglycemia, but are currently limited by the need to reconstitute glucagon daily and by the use of a second pump to deliver glucagon through a separate infusion set, which increases the burden and complexity.”

Questions and Answers

Dr. Robert Ratner (ADA, Alexandra, VA): What do you think is the additive advantage of a second hormone over insulin alone? Is it cost-effective?

A: I think the single hormone can reduce hypoglycemia burden, and in most studies the actual burden is fairly small. For the majority of patients, we can do a very good job with a single hormone closed loop. I agree with Steven that there are some scenarios where a single hormone alone cannot stop hypoglycemia – exercise, a large enough dose of insulin. There may be some selective groups of people where dual hormone is useful: those with hypoglycemia unawareness or significant hypoglycemia burden. But we haven’t done comparative studies in Europe of single vs. dual-hormone. There was one study from Canada – Dr. Haidar – which showed a further small increment in hypoglycemia reduction with glucagon.

Dr. Steve Russell (MGH, Boston, MA): Do you think it’s possible to do fully closed loop with insulin only? These insulin-only systems require accurate carb counting and bolusing in the way patients typically do. Can insulin-only reduce that burden to the point of not having to do it?

A: In that scenario, dual hormone may have an advantage. You could dose insulin aggressively and treat with glucagon. Perhaps there’s an advantage with a fully closed-loop system. But you have to balance that with additional cost and complexity.

Dr. Russell: Who are the appropriate people to use these systems? Is the larger population of type 1 diabetes sophisticated enough to use insulin only systems, to do carb counting? In our pivotal trial, we will have MDI patients who have no experience with diabetes technology. We believe our system is easy enough that they can use it effectively. Will that be true for an insulin-only system?

A: The cost of these things is important. If you are taking patients who don’t use MDI correctly, there’s a question on reimbursement. What are the long term benefits and reductions in A1c?

Dr. Ratner: The T1D Exchange has documented an enormous degree of burnout among patients on CGM and even on pumps. Clearly all of the volunteers in the study are enthusiastic about participation. What have you seen in terms of discontinuations due to burnout? What do you anticipate in more generalized use?

A: I don’t know the honest answer. I suspect it’s broadly similar to CGM discontinuation rates. Possibly 10-20% of patients? Possibly more. I think it will all depend on the benefit they perceive and see. With early CGMs, patients were pretty frustrated. That’s why they didn’t want to use them. With more accurate devices, patients are telling us they love and want to use them. But there is the inconvenience of having to wear all these things.

The Bionic Pancreas: When Will The Dream Come True?

Steven Russell, MD, PhD (Massachusetts General Hospital, Boston, MA)

Dr. Steven Russell’s (MGH, Boston, MA) talk on the Bionic Pancreas summarized results from the team’s glucagon-only study (first presented at AADE 2015) and mentioned the possibility of using Lilly’s U200 Humalog (insulin lispro) in the dual-chamber iLet device. This was the first we had heard of this prospect, which would theoretically enable a smaller reservoir size. Timing-wise, it sounds like the team’s pivotal is still on track to begin in late 2016 and run through early 2017 with an FDA submission slated for 2018 and commercial launch in late 2018-early 2019. This could be accelerated based on the results of the ongoing glycemic target studies, as Dr. Russell noted that a single hormone iLet is a possibility pending encouraging insulin-only results. He told us after the session that the FDA would only require a three-month pivotal for insulin-only vs. 12 months for bi-hormonal (given the need for a chronic indication for glucagon). The team could then offer glucagon as an upgrade following an FDA chronic use indication (and commercialized stable glucagon).

  • The usual verbal jousting on bihormonal vs. insulin-only closed-loop came during Q&A, when Dr. Russell and Cambridge’s Dr. Lalantha Leelarathna debated the merits of full automation vs. higher complexity/cost. Dr. Leelarathna conceded that future bihormonal systems may offer greater control and the potential to achieve “fully” closed systems, though questioned the tradeoffs, namely greater cost and complexity. Dr. Russell countered that insulin-only designs have a ceiling as hybrid systems that will always put some onus on patients to carb count accurately. Both sides have valid points and this is not an either-or situation – patients and their providers will ultimately decide what’s best for them … See the Q&A from this session below.

Questions and Answers

Dr. Robert Ratner (ADA, Alexandria, VA): You mentioned using concentrated lispro moving forward. What about a faster-acting insulin?

A: Yes. Everyone wants a more rapid-acting insulin. After all, the delay is a challenge. We can achieve very good control with currently available insulin, but we can achieve better control with more rapid insulin.

Q: With more rapid-acting insulin, can the algorithm adapt?

A: We have a parameter in the algorithm that is the expected time to the peak of the insulin in blood. We have experimented in our early studies with two settings, and the more aggressive setting worked well for many people. However, there was lots of variability between subjects. For people with slower absorption, we saw some stacking and hypoglycemia. We are currently assuming that the slower insulin for everyone is safe. We could turn the parameters down a bit and could get significant gains in terms of reduction in mean glycemia. We may be able to use less glucagon.

Q: What would the application filing look like for that? Would you need to do more trials?

A: We would have to do an additional trial to do an ultra-rapid-acting insulin. I think it would be significantly shorter and smaller. The size and duration of the current trial relates to obtaining a chronic use indication for glucagon, since it is only approved for an acute indication.

Q: The glucagon-only data looks pretty impressive, particularly at night. Is there any difference in efficacy at the beginning vs. the end of the night?

A: No, we have never seen any differences in the effectiveness of glucagon at beginning or end of the night. Our assumption is that given the amount of glycogen storage in liver and the amount of glucagon that we’re using, we’re not depleting glycogen enough. We do anticipate that if one went long enough – such as during an extended duration of exercise – one could deplete the stores. This would reduce the effectiveness, but not entirely eliminate it.

Q: What is the battery life of your device? What do you advise patients to do in terms of battery failure?

A: That hasn’t been finally determined. What has been determined is that the system will use AA batteries. Those will provide at least a week of battery life, perhaps more. The life will be determined by the ultimate configuration in terms of optimizing it, shrinking it, changing the display to an electronic paper display, and using less power. We have yet to know what it will be. In terms of failure, we have thought about giving every patient two devices. We haven’t decided what the appropriate approach should be. The system could provide advice for self-treatment with syringes or pens based on the behavior of the Bionic Pancreas while on line.

Q: Have you considered a portable battery-charging device?

A: We do use that in current studies with the device. We advise charging every day. For the iLet device and the one we intend to use in the pivotal studies, it will use disposable AA batteries that are available everywhere and easily replaced. They’re cheaper than lithium ion batteries.

ADA/EASD Statement on the Evaluation of Insulin Pumps

Lutz Heinemann, PhD (Science & Co., Düsseldorf, Germany)

Dr. Lutz Heinemann presented an overview of the rationale behind and takeaways from the ADA/EASD Position Statement on Insulin Pumps, first presented in February at the EASD Diabetes Technology Meeting. As he noted previously, his remarks focused on the need for more pre- and post-marketing surveillance and for a more systematic and transparent regulatory process. See our February report for all the details from the statement; below, we summarize a few of the more nuanced points that Dr. Heinemann added to his previous commentary.

  • “Publishing the manuscript is nice, but what will be the impact of it?” Dr. Heinemann stressed that recognizing the currently flawed system is only the first step in the reform process. We would agree – the Working Group is valuable only as far as the recommendations are acted upon. We continue to wonder how the publication of this statement will actually affect the broader industry. The recommendations are not binding, and it is tough to say how manufacturers in particular will respond. Much of the utility may be determined by how regulatory bodies react: Will the FDA and EU Commission follow up on the statement? Will the ADA and EASD play a role as the Working Group has requested?
  • Dr. Heinemann cautioned that a thoughtful approach to regulating insulin pump therapy could pay off and have relevance for the future of artificial pancreas systems. After all, some of the most common errors seen in pump therapy are associated with user error – something that is sure to creep up with closed-loop systems. In this sense, he stressed that proactive thinking about the human factors design of pumps could pay off in a big way down the road.
  • We learned that the Working Group is currently discussing a second statement that will examine the performance, safety, and clinical outcomes of CGM.

Corporate Symposium: Dexcom Continuous Glucose Monitoring in 2015 – Clinical Practice, Technology Innovations and Market Access (Sponsored by Dexcom)

Current and Future Dexcom CGM Technology Innovations

Jake Leach (Senior VP of R&D, Dexcom, San Diego, CA)

Dexcom’s Senior VP of R&D Jake Leach started with big news out of the gate: Dexcom’s G5 mobile system has been approved in Europe and will begin launching in select countries in the coming weeks (in tandem with the US launch). This was very unexpected, as Dexcom has never given an official timeline on EU availability of G5. Notably, the EU version of G5 also has a replacement claim in the label: “The G5 Mobile System is designed to replace fingerstick blood glucose testing for diabetes treatment decisions.” Though it still requires two fingerstick calibrations per day, the move is a major one for Dexcom and makes G5 more competitive with Abbott’s factory calibrated FreeStyle Libre. The EU launch of G5 also brings the Share remote monitoring capabilities and the more accurate G4AP algorithm to Europe for the first time (Share was never launched in the EU). In other major news, Mr. Leach showed a picture of the Dexcom/Google prototype sensor for the first time – it was the size of penny and a tiny bandage (see the picture below – smaller than we had imagined on the body). The partnership was only announced a month ago, though the pressure is certainly on to hit the goal of commercializing within ~2-3 years. On the data front, Dexcom is working on real-time therapy support “like an insulin dosing calculator,” and a pilot is ongoing at Stanford Children’s Hospital to seamlessly integrate Dexcom CGM data with notoriously non-interoperable EPIC. More details below on the Google partnership, G5, the data management pipeline, pump partners, and an insightful Q&A.

  • Mr. Leach showed a picture of the Dexcom/Google prototype CGM sensor, highlighting the ambitious goals: “develop a simple, low-cost, disposable, body-worn sensor system integrated into an advanced data analytics platform to drive entry into [the] type 2 market and to expand CGM use in [the] type 1 market.” Succinct and lofty – the best kind of goal. In August, the product was envisioned as a bandage the size of a couple of dimes stacked on top of each other, and this looks roughly the same size. Still, seeing it on a human abdomen for the first time really reinforced how small this form factor will be. We wonder if Abbott’s real-time version of FreeStyle Libre will be out at that point in the US.

  • “We expect to have a portfolio of multiple products for different groups. The best example is the type 2 product we’re focused on with Google.” Mr. Leach admitted that these products might require tradeoffs on cost and performance. Indeed, we wonder what level of accuracy/reliability the Google/Dexcom product will achieve – could the sensor attain a MARD ~10%? Is 15% more likely? What is the necessary MARD for a type 2-focused product? What is the right accuracy/reliability tradeoff to substantially improve the form factor? Hard decisions!
  • “A MARD of 10% is the safety threshold for CGM to replace SMBG.” Mr. Leach highlighted a new modeling paper (Kovatchev et al., DT&T 2015) to underscore this point. The newly acquired replacement claim in the G5 EU label is a major win for Dexcom, and we wonder how such a label will be phrased in the US – per Dexcom’s 2Q15 call, such a claim is expected sometime in 2016 in the US. This has major implications for Medicare coverage, for doctors to prescribe CGM, for the patient experience of using CGM, and perhaps for payer discussions.
  • In new news, remote software updating the Share receiver to G5 will be possible on both Mac and PC. This overcomes frustration with the PC-only upgrade from the G4 Platinum algorithm to the G4AP algorithm (Software 505) last fall.
  • Fingerstick calibrations entered on the G5 app will be sent directly to the new smart Bluetooth transmitter. We assume from there they would also be sent to the receiver, should a patient opt to use one. This is impressive smart transmitter technology that retains the same form factor as the existing G4 Platinum transmitter. The tradeoff is a shorter battery life, as we have previously covered (three month indication).
  • Mr. Leach highlighted the G5 app’s discrete alerts and alarms, which show up on the iPhone lock screen similar to any other notification (e.g., text message). Swiping the notification opens the Dexcom app and shows the alert. The notification sounds can be customized, correcting a long-stated frustrated of CGM users (“I’m used to the alarms!”). Alarms can also be set to vibrate for discretion. Overall, it seems like the mobile interface is going to offer a substantial customization and user experience upgrade over the standalone receiver.

  • Dexcom is currently working on real-time therapy support “like an insulin dosing calculator.” The company has historically focused on retrospective data – and that will continue – though Mr. Leach said in Q&A that improved real-time analytics are also in the works. The hope is to add these straight into the G5 app. We could imagine several potential offerings: a bolus calculator that incorporates CGM values and trend information; analyzing insulin pump data from partners Insulet, Tandem, and Animas; projecting CGM values into the future; real-time exercise dosing/eating advice; etc.
  • Stanford Children’s Hospital is piloting seamless Dexcom integration with EPIC, the notoriously non-interoperable electronic medical record. Dexcom users’ CGM data will post to HealthKit (via the Share app now, and G5 in the future), and an EPIC app takes the glucose data from HealthKit and puts it into the EMR. “The user and doctor don’t have to do anything at all.” Physicians can log in and see the CGM data within the EPIC program, eliminating the need to go to separate Dexcom software. Stanford plans to roll the pilot out more widely. Mr. Leach urged attendees to contact EPIC for more details on this seamless integration with HealthKit.
  • Mr. Leach emphasized Dexcom’s “ecosystem” approach and showed the growing list of data management, app, and pump partners: diasend, EPIC (new!), Glooko, SweetSpot, Tidepool; Databetes (Meal Memory) and Training Peaks; Animas, Insulet, and Tandem. Apple’s HealthKit platform was shown on the slide as the hub of all these partnerships – it will be interesting to see if Android lags behind on this front. 
  • Dexcom CGM data currently posts to HealthKit with a three-hour delay. Mr. Leach said it might be reduced over time. Three hours was established as a safe limit with the FDA, preventing real-time use of CGM data by other apps (i.e., making those apps class III medical devices). It’s a nuanced and tricky debate – what constitutes real time data? Is a 20-minute delay sufficiently retrospective? We hope this window declines over time, since there is so much potential to improve care with real-time, contextual feedback. Other apps could do more if the data flowed to HealthKit closer to its acquisition – Mr. Leach acknowledged as much, but it sounds like Dexcom’s classic interim steps regulatory approach will be the strategy here.
  • Dexcom is “working towards” G5 integration with its pump partners Animas, Insulet, and Tandem. At this stage, it’s hard to know who will be first-to-market with an integrated pump:
    • Insulet’s next-gen OmniPod PDM is expected to launch in 2016, though we don’t think it will include G5 data on the handheld to start – Insulet has maintained that the PDM will be submitted for 510(k) clearance, meaning non-CGM-integrated. Perhaps the next-gen PDM will launch with integration on the app side, allowing the Dexcom mobile app to display Insulet pump data sent through an Insulet app and HealthKit. That is complete speculation on our part, and an open question is whether HealthKit can even handle insulin dose data (it does not have such an entry field to our knowledge).
    • Tandem announced an updated agreement in its 2Q15 call to integrate G5 in the future, but there is no timing on when it could launch.
    • Animas has never talked about a G5 integration publicly, though we assume one is in the works for automated insulin delivery.

CGM: Cost Modeling and Reimbursement

Claudia Graham, PhD (Dexcom, San Diego, CA)

Dr. Claudia Graham provided a 30,000-foot perspective on CGM, arguing that the technology provides greater and more cost-effective benefits vs. pump therapy. Drawing from the literature (e.g., JDRF CGM trial; Soupal et al. [Abstract #983], EASD 2015), she pointed out that A1c reductions for patients on CGM + MDI are actually comparable to (or better than) those on CGM + pump. Dr. Graham supported the clinical assertion with convincing cost-effectiveness data – in her analysis (tables 1A and 1B below), CGM + MDI, saved ~$10,000 vs. sensor-augmented pumping over four years. She also shared a CORE analysis (i.e., a validated cost-effectiveness model) demonstrating that CGM + MDI therapy can be highly cost-effective (“dominant”) from a payer’s perspective in a one-year time frame– see the analysis below, which used pretty conservative values that should improve with more modern CGM devices. The talk continued a Dexcom theme of “CGM first” (i.e., before pumps), along with management’s recent remarks that the pump partnerships won’t be transformative for the company. It makes sense strategically, given the size of the MDI market and the increasingly cost-conscious payer environment. Dr. Graham’s concluding slide was greeted by nods and laughter: “Is using a pump before beginning a CGM like putting the cart before the horse?” In her eyes, investing in CGM before pumps is a no-brainer decision, though the real challenge is getting payers to buy in. In Europe, that seems to be slowly changing, per her country-by-country update – see below.

  • In a slide titled “Simple Math,” Dr. Graham compared the four-year cost of sensor-augmented pump therapy (without considering the cost of insulin) vs. CGM + MDI therapy. The results suggested a ~$10,000 savings with CGM + MDI. The data on this front are clearly estimates, and Dexcom has already made moves with the DiaMond study to evaluate this more fully.
    • Assumptions: Transmitters = 1.5/year; Assumes CGM sensor use of 80% at an average selling price of $72 per sensor.

1A. Four-Year Cost of Sensor-Augmented Pump Therapy

Year

Pump

Pump Disposables

Transmitter

Sensors

1

$1,150

$1,455

$675

$2,995

2

$1,150

$1,455

$675

$2,995

3

$1,150

$1,455

$675

$2,995

4

$1,150

$1,455

$675

$2,995

 

$4,600

$5,820

$2,700

$11,980

Total Cost

$25,100

1B. Four-Year Cost of CGM + MDI Therapy

Year

Receiver

Transmitter

Sensors

1

$400

$675

$2,995

2

$0

$675

$2,995

3

$400

$675

$2,995

4

$0

$675

$2,995

 

$800

$2,700

$11,980

Total Cost

$15,480

 
  • Dr. Graham also analyzed how much benefit CGM + MDI therapy would have to deliver in order to be cost-effective over a one-year period. Under relatively conservative conditions (an A1c reduction of 0.5%, two fingersticks/day; patients using the sensor for ~10 days, 50% reduction in hypoglycemia), Dr. Graham suggested that CGM + MDI would be highly cost effective. Her analysis spoke to the value of CGM under pretty minimal assumptions, though we were also reminded of the need for longer studies examining A1c reductions/severe hypoglycemia/quality of life – indeed, she noted that with current data it is impossible to look past one year.

CGM + MDI: Cost-Effectiveness Modeling

A1c Reduction

# SMBG/Day

# sensors/ month

Hypoglycemia (moderate and severe)

Receiver Cost

Quality of Life

ICER/QALY

0.5%

5.5

4

No reduction

$450

0

$130,403

0.7%

5.5

4

No reduction

$450

0

$94,823

0.5%

2.5

3

50% reduction

50% reduction*

+

$16,613

0.5% (and include indirect costs)

2

3

50% reduction

50% reduction*

+

Dominant

*Assuming 50% of patients don’t buy a receiver in the future, due to G5

  • Dr. Graham concluded her talk with a valuable summary of general reimbursement status of CGM worldwide.
    • She strongly critiqued Medicare’s unwillingness to cover CGM in patients > 65 years: “Medicare’s ruling on CGM is the bane of my very existence. It’s the most asinine thing I have heard of in my life. One out of five seniors are having hypoglycemia and blacking out in a year, but because they ‘rely’ on a SMBG confirmatory fingerstick, Medicare won’t cover it.” While it continues to irritate, she did offer optimism for the future, suggesting the coverage is not a question of “if” but “when.” See our recent coverage of the bills in Congress here.

CGM Reimbursement Status

Country

Type

CGM?

US

T1D Commercial Payers

Yes

US

T1D Medicare

No

UK

NICE Diagnostic Assessment

Pending for SAP

Sweden

Tenders; regional

Yes, majority

Norway

Tenders; regional

Yes, majority

France

HAS; national

In review

Germany

GB-A; national

In review

Switzerland

National

Yes

Slovenia

National

Yes - pediatrics

Netherlands

Regional

Partial

Czech Republic

Patient capitation

Partial

Israel

Regional

Yes - pediatrics

Using Dexcom CGM in Clinical Practice – Education and Medical Management

Peter Adolfsson, MD, PhD (University of Gothenburg, Sweden)

Dr. Peter Adolfsson provided a practical overview of the clinical use of CGM. To be frank, his talk was far too long and lost the audience about halfway through. From optimizing alarms to understanding lag time, Dr. Adolfsson led attendees through the many intricacies involved in proper education, summarizing the highlights of a CGM start guide utilized in Sweden and to be published globally in the near future. Using these guidelines, Dr. Adolfsson’s Kungsbacka clinic has seen impressive CGM penetration (and benefit) in recent years – CGM use has increased from 52% in December 2014 to 70% currently (55% on real-time CGM + 15% on FreeStyle Libre). It was quote notable to see FreeStyle Libre already at 15% in such a short time after commercialization. According to his estimates, glycemic control has improved in 78% of patients and 87% have had a positive experience on the technology. This is exactly the kind of real-world data that lend credibility to a device, and we hope much more of it comes with Big Data from platforms like diasend, Glooko, and Tidepool.

Panel Discussion

Q: What is the lag time for Dexcom G5 mobile?

Mr. Leach: It’s the same as for G4 Platinum – on average 5-7 minutes. There has been lots of study on it. There’s been interesting work on the physiologic lag between venous and interstitial fluid. That ends up being sub-five minutes. There is a little lag based on our system averaging data over five minutes. That’s why you get the 5-7 minute lag time.

Q: Do you see more cost effectiveness in pediatric patients?

Dr. Graham: I haven’t looked at it. However, I would think that the lifetime cost-effectiveness is better in pediatric patients than for adults … especially when we’re talking about hypoglycemia in the moderate and severe range. Plus, when you add in the cost of hospitalizations associated with hypoglycemia, this is huge.

Q: What about acetaminophen and the interaction with G5? Is this unique to Dexcom’s technology?

Mr. Leach: The G5 system can get erroneous readings with high doses of Tylenol. It’s not specific to Dexcom. Other commercial devices have the same potential error if you are taking large doses of acetaminophen. If you are using CGM, we recommend you don’t take Tylenol.

Q: What about non-invasive sensors?

Mr. Leach: We are constantly reviewing them. We love the idea. The reality is we haven’t seen anything that can the meet performance and reliability to manage diabetes properly. It’s a great dream, but we haven’t seen anything we would consider.

Q: Can you talk about the new ISO standards and how those apply to your CGM?

Mr. Leach: There are new ISO standards. As background, that particular method is performed in a laboratory, and it’s a very analytical test. It’s not actual life. Our CGMs are actually measured in patients where we take venous blood and compare the results to the CGM values. The performance you get from a properly run CGM study is very indicative of the performance of a CGM. We don’t believe the ISO standard is really applicable here.

Q: Can you talk about privacy issues?

Mr. Leach: This is a question we asked ourselves when we began working with smartphones. We spent a significant amount of time thinking about how data is transferred. For example, our Bluetooth protocol is proprietary to Dexcom, and we spent time with security consultants ensuring that this is safe. After all, there are a number of different ways people can try to hack your system. We are confident that our system is very secure. In the iOS system, the information is sandboxed and information is not transferred between apps unless we’re using something like HealthKit where it is controlled. The reasons we’re doing Android G5 second is that we’re still working on mitigating these issues with Android. After all, this is a different system. We believe we can fulfill all the requirements, but this is why Android is slightly behind.

Q: What is your confidence of using Dexcom CGM for treatment decisions?

Dr. Adolfsson: We have already started with G4. We use the value together with trends. We do not do it if there is a large difference between the last calibration, or if you don’t have the trend values. But we are using the CGM for treatment decisions.

Q: In your experience, what additional values do you see from low glucose suspend in pump treatment when used with CGM?

Dr. Adolfsson: If the sensor is correct, it’s the perfect system. Previously, we have always longed for a system with a brake instead. The sensor previously worked much better in a normal range. You need to have quite a good sensor to make this work. I really think this is something for the future. We want a brake as well as speeding up.

Q: Can you talk about the timeline for eliminating fingersticks in the US?

Mr. Leach: We are working on it. However, regulatory timelines in the US are hard to gauge.

Q: Do you have plans for a dose advisor?

Mr. Leach: Yes, we are working on real-time therapy support like an insulin dosing calculator – there are lots of things we can do to optimize insulin therapy with CGM, both retrospective and real-time. We hope to add that to the app, so it’s a component of what users already have.

Q: How will the portfolio evolve over time for different patient segments? What future tradeoffs will you make?

Mr. Leach: We expect to have a portfolio of multiple products for different groups. The best example is the type 2 product we’re focused on with Google. That’s a different product. We may need to make tradeoffs on cost and performance to make the right product for the right patients. I see our portfolio becoming larger with different products

Q: Will Dexcom reduce the three-hour delayed post of CGM data to HealthKit? If it cannot be real-time, could it get to an hour or 20 minutes?

Mr. Leach: As background, Dexcom data downloaded to HealthKit currently has a three-hour delay. We established that as a safe limit when we were working with the FDA so that the data could not be used for real-time decision-making. In the future, that could be changed. That was something we mutually agreed to. It’s going to depend on how people get used to real-time data. In the US, real time data is Class III, which is given a strict review. We’ll see what happens over time. We might be able to reduce the time period. I’d love to be able to have real-time data going into HealthKit, but we’ll have to see.

Dr. Ramiro Antuna: In Spain, we have highly motivated patients using CGM, since they pay out-of-pocket. We are having a hard time with patients downloading the system regularly. What is the percentage at your clinic? In my experience, less than 20% are downloading regularly. How do you empower patients to keep downloading?

Dr. Adolfsson: I always download when they come to the office. I never have written logs. I sit in front of the computer with patients, analyzing together and giving advice on what to look for. “These are the pages that are the most interesting for you to look back at home.” Try to motivate them, try to find the positive things about using the data back home. Comparing it to having a knee surgery, the physiotherapist comes to the bed, and tells you to do 15 squats. You do the 15, and it hurts. Then she tells you to do it every morning, lunch, and dinner. When she comes asking, you say, “Yes, I’ve done it,” when you really haven’t. But then she says, “Doing this will prevent you from having a thrombosis, make you go home earlier, etc.” – she’s pointing out the positive things, which makes it much more interesting. Don’t mention A1c; talk about other things like not needing to go into the office, having visits less frequently, doing visits by Face Time or phone. Of course, we also need to make the technology easier to use.

Dr. Ramiro Antuna: What percent of your patients input carb intake and insulin dosing daily into the CGM system?

Dr. Adolfsson: It’s rare.

Corporate Symposium: One Year with Flash Glucose Monitoring – Perspectives From Different Stakeholders in Diabetes Care. What’s Next? (Sponsored by Abbott)

Clinical Experience with FreeStyle Libre

Katarina Eeg-Olofsson, MD (University of Gothenburg, Sweden)

Dr. Katarina Eeg-Olofsson shared new data from a 91-patient observational study of its factory calibrated FreeStyle Libre system. The trial sought to investigate the real-world benefits of Libre in type 1 patients at a high risk for developing complications (baseline A1c = 10.1%). The data was strong for a diabetes device – especially in a tough and very real-world group – with 3-9 month follow-ups from baseline demonstrating a mean A1c improvement of 1.4%. Hypoglycemia was not reported. Dr. Eeg-Olofsson did note that 1% of patients had serious skin reactions forcing them to discontinue use of the sensor, while ~5-7% continued with extra precaution and care. [The numbers are presumably similar to those wearing other adhesive-using devices.] Ultimately, she noted that further investigations into the human factors (e.g., patient satisfaction, skin reactions) are critical and ongoing. Of course, the studies we REALLY want to see are the ongoing reimbursement trials – REPLACE and IMPACT – which have completion dates in December and September 2015, respectively.

The Impact of AGP and FreeStyle Libre on the Patient-Clinician Dialogue in T1 Diabetes

Stephen Dixon (Type 1 patient, UK) and Pratik Choudhary, MD (King’s College Hospital, London, UK)

A conversation between Dr. Pratik Choudhary and Mr. Stephen Dixon (an on-air reporter in Britain and type 1 patient) shared valuable insight into how FreeStyle Libre is being used in the real world. Mr. Dixon spoke in glowing terms about his year on FreeStyle Libre, describing the experience as a “game-changer” for his diabetes. Indeed, the convenience of Libre was a recurring theme throughout the interview with Mr. Dixon, who highlighted the speed (vs. BGM) and discretion/lack of alarms (vs. CGM) as significant advantages. Mr. Dixon called his decision to choose Libre over classical CGM as a no-brainer, emphasizing the oft-overlooked psychosocial benefits of the technology – e.g., not being “tethered” to a receiver, being able to leave the receiver behind and not lose data (assuming it is swiped within eight hours). On accuracy too, Mr. Dixon provided a stirring endorsement of the technology, noting that he has not done a confirmatory fingerstick (as is indicated in certain situations) in ~12 months: “People say you must check Libre values against SMBG, but real life is real life.” Indeed, the remarks echo commentary on the excellent hypoglycemic accuracy we heard at ATTD 2015 and ultimately speak to what continues to be tremendous real-world enthusiasm for Libre.

  • Below, we bring you some of our favorite quotes from Mr. Dixon during the session:
    •  “I swipe 15 times per day and get 20 times more information than I would with 15 fingersticks. It’s hugely impressive. The amazing thing is that I can take over my own management much more than before. Normally, you go to clinic once a year to get told how to improve your life. Now, you can do that yourself on a daily basis.”
    • “The alarms on CGM are awful. I haven’t met anybody yet on Libre that wishes for alarms. They always seem to be overly sensitive. Not having an alarm is a benefit.”
    • “Having glucose information with Libre has been a game-changer. I’ve always been very careful about my diabetes management. But with Libre, my attitude has changed. I almost feel like I’ve got a different condition.”
    • “Libre can empower those that do not even want to be empowered.”
    • “There is a huge difference on Libre. The key is not where I am, but where I have been and where I am going. I used to have my hands tied behind my back with SMBG. The fact that I’ve got all this information at my fingertips in a few seconds is incredible.”

The Impact of AGP and FreeStyle Libre on the Patient-Clinician Dialogue in T2 Diabetes

Detlef Behring (Type 2 patient, Germany) and Oliver Schubert, MD (Diabetes Care Center Buxtehude, Germany)

“I was asked earlier, ‘Who should use FreeStyle Libre?’ That’s the wrong question. The real question is who should not use it,” said Dr. Oliver Schubert. It was a compelling introduction to yet another enthusiastic interview with a FreeStyle Libre user – Mr. Detlef Behring – who presented Libre and the accompanying Ambulatory Glucose Profile software as valuable tools for patient education and pattern recognition. [We continue to be fans of AGP’s simple output and pattern identification, and as we understand it, other manufacturers are in line to integrate it too. ] Mr. Behring spoke at length about the positive impact Libre has had on his type 2 diabetes, though he admitted to initial reservations about using the device (e.g., too complex, confusing interpretation). He has been surprised by the technology’s ease-of-use and its accessible data has further motivated him to more frequently check his blood glucose. As he concluded, “I learned from Libre that it’s not my doctors’ job to work on my glucose levels. It’s my job.” Indeed!

Corporate Symposium: How Much Can Technology Support Personalized Diabetes Management? (Sponsored by Roche)

First Results of the Accu-Chek Insight EU Study

Julia Mader, MD (Medical University of Graz, Austria)

Dr. Julia Mader presented results of the Accu-Chek Insight EU study, which found that users were mostly satisfied with the pump though some device malfunctions occurred. In this study, people with type 1 diabetes (n=91) on MDI or CSII were switched to the AccuCheck Inishgt insulin pump (which is a pump with an integrated glucose meter and bolus advice) after one or two training sessions. The results found that over six months, there was no significant change in body weight or insulin dose. Participants were able to maintain glycemic control with the system: at six months, the CSII-experienced group saw an A1c reduction of ~0.1% (baseline A1c of ~7.8%) and the MDI group saw an A1c reduction of ~0.5% (baseline A1c of ~7.9%). The study’s most frequent pump malfunctions were electronic errors while few mechanical/rewind errors were recorded. Survey results regarding hypoglycemia fear and well-being appeared to remain relatively stable throughout the study. Notably, the user acceptance analysis showed that participants liked the system’s ease of use, small size, and screen information provided on the pump and handheld; on the other hand, users least liked the speed of the handheld, the large size of the carrying cases provided, and the small size of the cartridge.

  • We also learned that Dr. Kerstin Rebrin has been appointed Roche’s Head of Diabetes Management Solutions, a strong indication of the company’s commitment to CGM and a sign that no one should discount Roche on the CGM front. Dr. Rebrin has an impressive resume in diabetes technology, coming over from BD where she ran the CGM program prior to its discontinuation last year as well as early work at Abbott and in academia, where she was very highly respected. We view the signing as a major win for Roche and look forward to seeing how her expertise can translate to R&D progress. Indeed, given the increasingly competitive CGM landscape, we are curious to see how the company can differentiate its product from the market’s more established players – her job won’t be easy! As a reminder, Roche disclosed at its 2Q15 Diagnostic Division Analyst Event that it plans to bring its novel CGM to the market in the “next 18 months” (as of this past July). We were also impressed to learn today from the Roche session that there won’t be any problems with Roche’s CGM and interferents like Tylenol – so excellent they figured out how to address this.

Questions and Answers

Q: Have you been using this for patients in clinic? What is their response?

A: Some patients wanted to keep the insulin pump. There appears to be fewer errors than before but this is also probably because the patients are trained.

Comment: We’ve been using it and people like the pump and cartridge. The feedback is similar. The communication between the handset and pump needs some work. But it definitely offers a lot to our patients.

Corporate Symposium: Optimizing Insulin Pump Therapy: Infusion Set Failures and Silent Occlusions (Sponsored by BD)

Summary

Aaron Kowalski, PhD (JDRF, New York, NY), Bruce Buckingham, MD (Stanford University, Palo Alto, CA), Larry Hirsch, MD (BD Diabetes Care, Franklin Lakes, NJ), Thomas Danne, MD (Kinderkrankenhaus, Hannover, Germany), Lutz Heinemann, PhD (Science & Co., Düsseldorf, Germany), Hans DeVries, MD, PhD (Academic Medical Center, Amsterdam, The Netherlands)

BD’s first corporate symposium dedicated to the FlowSmart infusion set gathered an impressive lineup of speakers to discuss the “Achilles Heel” of insulin pumps and the company’s new set. There were no new major updates on FlowSmart’s commercialization, which is still slated for “2016” in the US, EU, and Canada. Interestingly, exclusive commercial partner Medtronic was not mentioned at all during the 2.5-hour session; this felt odd, since the set will be co-branded BD/Medtronic and sold exclusively by Medtronic. The session provided a valuable overview of infusion sets and the associated subcutaneous biology, and Drs. Bruce Buckingham, Lutz Heinemann, Thomas Danne, Hans De Vries, and Aaron Kowalski expressed a mix of outrage and enthusiasm – outrage at the underwhelming body of research on infusion sets, and enthusiasm for what BD’s new set could offer.

  • Drs. Buckingham, Danne, and Heinemann converged on similar points in their clinical experience and the overviews of the infusion set literature: (i) reliable sets matter tremendously from a patient perspective (for pump satisfaction, for insulin absorption, for DKA, for the artificial pancreas); (ii) patients experience many problems with sets (pain, lipohypertrophy, kinking, scarring, unexplained hyperglycemia); (iii) infusion set wear seems to be highly individualized, with a surprising number of patients able to tolerate seven-day wear without much of a problem (Dr. Buckingham said~20-30%); (iv) sensors are better tolerated than sets, suggesting it is insulin – and not the subcutaneous tissue – that is causing a biological response; and (v) there are a tremendous number of factors that affect absorption/action of subcutaneous insulin (23 were listed on Dr. Heinemann’s slide).

New Insulin Infusion Set Technology: BD FlowSmart

Larry Hirsch, MD (VP Global Medical Affairs, BD Diabetes Care, Franklin Lakes, NJ)

Dr. Larry Hirsch’s review of FlowSmart summarized previous presentations (ATTD, Keystone), but did offer a new perspective on the advantages of the dual-port catheter: with insulin flowing out of two places, two distinct depots of insulin form (via imaging studies), potentially offering absorption advantages (better PK/PD must be confirmed in studies). Going forward, a big question is not whether the FlowSmart set reduces “flow interruptions” (that much seems clear from the data), but to what extent the design offers true clinical advantages – better insulin PK/PD, more time-in-range, fewer hospitalizations from DKA, etc. Those are tall orders for sure, and many of the product’s form factor improvements are still meaningful from a patient perspective (smallest gauge insertion needle on the market, multi-position connector, sliding needle shield cover, etc.). The set is still slated for a launch in “2016” in the US, EU, and Canada. FlowSmart will be available through exclusive commercial partner Medtronic for Paradigm and Luer Lock reservoirs (the slide only showed Medtronic, Roche, and Animas pumps, though we assume Tandem pumps will also be compatible).

  • Dr. Hirsch reviewed FlowSmart data first shown at Keystone 2015 and presented in poster form at ADA. The expanded study compared BD’s new infusion set to Medtronic’s Quick-set in 60 healthy participants (ADA 2015 Poster: 1071-P) – the previous pilot study shown at ATTD was only in 25 participants. As a reminder, the study had each participant wear two of each set; diluent was used and pressure was tracked for basal and bolus infusion. Consistent with results from the pilot study, the BD set significantly reduced the amount of time with flow interruptions (p=0.002) and reduced the risk of pressure events by ~75%. There were no observed statistical differences in set site leakage upon removal compared to the Quick-set (1 vs. 0 events, respectively).
  • A single slide succinctly summarized FlowSmart’s key product features. We got an up-close look at BD’s headquarters earlier this year.

FlowSmart Product Features

Compatible with Paradigm and Luer Lock connections

Compatible with Quick-Serter insertion device

Proprietary side-ported catheter

30G inserter needle and 28G catheter

10mm hub width and flexible base

8 different points of attachment of tubing to infusion hub

Auto-deployed needle shield

Unit package environmentally friendly

 

New Research: What the Future Holds

Aaron Kowalski, PhD (Chief Mission Officer/VP of Research, JDRF, New York, NY)

Dr. Kowalski provided an overview of JDRF”s near-term, mid-term, and long-term research priorities. Most notable was his summary of artificial pancreas efforts, which has now moved to the commercialization stage. His slide listed nine organizations developing systems: Medtronic; Animas; Bigfoot Biomedical; Type Zero; Boston University; Inreda; Tandem; Insulet; Roche. That was the order they were listed on the slide, though only Medtronic had a timeline attached to it (April 2017, consistent with the JPM timeline). See below for the most recent timelines and updates on all the organizations. Dr. Kowalski devoted a slide to the use of type 2 therapies in type 1, acknowledging that Novo Nordisk is not moving forward with Victoza; still, he is optimistic about SGLT-2s in type 1 and believes the DKA risk can be overcome. In the medium term research pipeline (“7-12 years”), Dr. Kowalski highlighted Merck/SmartCells Smart Insulin (still in phase 1, expected to wrap in December) and ViaCyte’s encapsulation device (still in phase 1/2, expected to wrap in 2017). Similar to his talk at ADA, Dr. Kowalski summarized his “Diabetes Scorecard (Diabetes Care 2015) to judge the value of future therapies and technologies. He commended BD for the new FlowSmart set, which does bring meaningful value in his view.

  • “AP systems Are Coming...” – Dr. Kowalski listed nine organizations on the slide in the following order. We found the order highly instructive, and wonder if it was intentional.
    • Medtronic: hybrid closed-loop (meal-time bolusing): April 2017 (Editor’s Note: It was encouraging to see Dr. Kowalski include the “April 2017” timeline, which we first heard at JPM 2015. Though Medtronic historically misses its timeline, the 670G is already in a pivotal study slated to wrap up in May 2016)
    • Animas, Hypoglycemia-Hyperglycemia Minimizing System (Editor’s Note: J&J/Animas has never given a timeline on its AP, but said in 2Q15 that it is working on a next-gen CGM-integrated pump. Bigfoot plans to be in a pivotal trial in 2016)
    • Bigfoot Biomedical: hybrid closed-loop (Editor’s Note: Per the June Dexcom agreement, Bigfoot still plans to be in a pivotal study in late 2016.)
    • Type Zero: hybrid closed-loop (Editor’s Note: Type Zero hasn’t given a launch timing, but does have major studies planned for this year and 2016.)
    • Boston University: Dual-hormone with glucagon (Editor’s Note: The Bionic Pancreas team hopes to be in a pivotal study in late 2016 through early 2017.)
    • Inreda: Dual-hormone with glucagon (Editor’s Note: This is a lesser known European group working with Dr. Hans DeVries. We don’t know any study details or timing.)
    • Tandem (Editor’s Note: Per the 2Q15 call, plans to file an IDE by the end of 2015 for its first clinical study.)
    • Insulet (Editor’s Note: No specific details, but definitely committed to a product given remarks in recent quarterly calls.)
    • Roche (Editor’s Note: No artificial pancreas timing. CGM to be commercialized in next 18 months, per July Analyst Event)
  • Dr. Kowalski devoted a slide to the use of type 2 therapies in type 1, acknowledging that Novo Nordisk is not moving forward with Victoza. He highlighted potential type 1 label extensions for SGLT-2s dapagliflozin (AZ) and canagliflozin (J&J) – on a positive note, he believe the concerns over euglycemic DKA can be overcome.
  • In the medium term pipeline (“7-12 years”), Dr. Kowalski highlighted Merck/SmartCells Smart Insulin and ViaCyte’s encapsulation device. Merck is still in a 74-patient phase 1 PK/PD trial expected to wrap up in December (the page was updated last month). ViaCyte is still in a 40-patient phase 1/2 feasibility trial that recently expanded into Canada and will wrap up in August 2017.
  • Longer-term, JDRF is focused on restoration and prevention.
    • Restoration: Many people with type 1 diabetes retain residual C-peptide production, even with a long disease duration. Dr. Kowalski hopes that with a very specific immunotherapy and the right stimulation, insulin production could be restored in some people.
    • Prevention: Dr. Kowalski called prevention “a high priority area,” and noted the now-published joint statement with ADA on defining the early stages of type 1 diabetes. Now that type 1 diabetes has been staged, Dr. Kowalski believes there is a framework to think about prevention and proper risk/benefit.
  • Similar to his talk at ADA, Dr. Kowalski summarized his “Diabetes Scorecard (Diabetes Care 2015) to judge the value of future therapies and technologies. Scorekeepers are people with diabetes (and loved ones), clinicians, and payers, and the categories are glycemic control, “burden”, and value. Future advances, said Dr. Kowalski, will only be successful if they add value across all three stakeholders. He commended BD in addressing some of these issues with the new infusion set.
  • Dr. Kowalski highlighted a new JDRF call for proposals to improve infusion set duration of wear, with ultimate goal to match CGM wear. We first heard of this in August. Expressions of interest were due by September 22, and JDRF will get back to applicants by October 21. More information is here.

 

-- by Melissa An, Adam Brown, Varun Iyengar, Ava Runge, and Kelly Close