In Automated Insulin Delivery, a session on DIY and interoperable systems shared JDRF’s interoperable vision, compelling data from the DIWHY survey (n=671!), and news of an upcoming AndroidAPS multicenter study. It’s excellent to see this field moving to clinical validation and commercialization! We also heard from Harvard’s Dr. Frank Doyle on the bleeding edge of algorithm development, which is bringing in silico time-in-range up to 93% (clinical evaluation up next).
Also check out Dr. Bruce Bode on ultra-rapid insulins for closed loop, under Diabetes Therapy below.
In remote care and digital health, The Lancet’s big-time publication of Hygieia’s six-month RCT, demonstrating a greater A1c reduction with its d-Nav BGM with built-in insulin titration + HCP support (-1.0%) vs. HCP support alone (-0.3%). In back-to-back talks, UVA’s Dr. Boris Kovatchev and Verily’s Dr. Howard Zisser talked about the road to suggesting therapeutic adjustments based on in silico representations and connected care, respectively.
In a word, baseline blinded CGM data from the Helmsley-funded CITY study (n=153) of CGM in type 1s ages 14-25 years without recent CGM use is scary: Median time-in-range was just 35%, with a median of 60% spent >180 mg/dl. Hopefully CGM will prove useful in improving these metrics – results read out at ADA 2019.
In the exhibit hall, we have coverage of over 20 booths, including highlights from Biocorp (partnerships with AgaMatrix + DreaMed), Glooko (Annual Diabetes Report), and Novo Nordisk (NFC pen scan with smartphone demo).
And of course, we have bullets on the annual fan-favorite ATTD Yearbook session. 13 experts gave rapid-fire reviews of “the year that was” in 2017-2018 on topics from diabetes tech in pregnancy to immune intervention in type 1, and everything in between.
Hello from Berlin, where we’re bringing you our last daily highlights report from ATTD! Beyond AID, decision support/digital health, and big picture categories, we’re also bringing you our coverage of the fan-favorite ATTD Yearbook session and our coverage of some two dozen exhibits!
In case you missed it, take a gander at our coverage from Day #1 (Dr. Heinemann's diabetes 2025 predictions), Day #2 (Medtronic closed loop pipeline), and Day #3 (HUGE Abbott real-world data set)!
- Automated Insulin Delivery Highlights
- 1. DIY AID: JDRF’s Vision of Interoperable Systems; Compelling OPEN Project and DIWHY Survey; Multicenter Study to Soon Test AndroidAPS
- 2. PEPPER Decision Support System Reduces Severe Hypo, Increases TIR in Proof-of-Concept Study Using Cellnovo Pump + Dexcom G5 CGM; Phase 3 Clinical Results Expected by Year-End
- 3. Harvard’s Dr. Frank Doyle Explains Approach to Long-Term Closed Loop Adaptation; Up to 93% TIR in UVA/Padova Simulation
- 4. Prof. Barnard Presents INSPIRE Instrument for AID PROs, How to Improve PROs in Diabetes
- Remote Care and Digital Health Highlights
- 1. Hygieia d-Nav RCT Published in The Lancet!! 1.0% A1c Reduction in 6-months vs. 0.3% in Control Group; Dr. Bergenstal Underscores Benefit of Remote Care and Automated Insulin Titration in T2D
- 2. Dr. Kovatchev’s VIP (Virtual Image of the Patient) Approach Fleshed Out: CGM Daily Profile Clusters -> Transition Probabilities -> Optimizing Treatments –> Mapping Individuals onto Virtual Representations
- 3. Verily’s Dr. Zisser: “Information Has a Tremendous Power Once We Share It”; Nodes and Connected Networks, Lack of Endos, Tribute to Dr. Lois Jovanovic
- 4. Dr. Riddell Hints at New Exercise Support App for Type 1s – Undisclosed Industry Partner, Beta Version to Launch in ~Six Months
- CGM & Big Picture Highlights
- 1. Median 35% TIR, 60% >180 mg/dl Seen in 153 T1s Ages 14-25 without Recent CGM Use (Baseline Data from Helmsley-Funded CITY Study); Full Results to Report at ADA 2019
- 2. ISPAD 2018 Clinical Practice Consensus Guidelines Include Chapter on Diabetes Technology for First Time; Stronger Stance than ADA on Pumps, CGM, and AID
- Diabetes Therapy Highlights
- Exhibit Hall
- ATTD Yearbook Session
- Self-Monitoring of Blood Glucose
- Continuous Glucose Monitoring in 2018
- Insulin Pumps
- Decision Support Systems and Closed Loop
- New Insulins, Biosimilars, and Insulin Therapy
- New Medications for the Treatment of Diabetes
- Using Digital Health Technology to Prevent and Treat Diabetes
- Immune Intervention in Type 1 Diabetes
- Technology and Pregnancy
- Advances in Exercise, Physical Activity, and Diabetes Mellitus
- Diabetes Technology and Therapy in the Pediatric Age Group
- Diabetes Technology and the Human Factor
- Practical Implementation of Diabetes Technology: It is Time
Automated Insulin Delivery Highlights
1. DIY AID: JDRF’s Vision of Interoperable Systems; Compelling OPEN Project and DIWHY Survey; Multicenter Study to Soon Test AndroidAPS
An exciting session on DIY Automated Insulin Delivery shared JDRF’s vision and new research efforts to study systems more rigorously. To start, JDRF’s Dr. Daniel Finan provided a great overview of the DIY Landscape (Loop, OpenAPS, AndroidAPS), highlighting the goal of the non-profit’s open protocol initiative – to marry DIY innovation with safety, transparency, and access. Dr. Finan beautifully explained the regulatory advantages of the iCGM and ACE pump paradigms, which move to a component-based, mix-and-match model rather than a system-based model of AID – see the slides below. The open protocol, interoperable configuration defines and regulates the components separately (see red boxes), allowing them to be connected afterwards and to be swapped in/out. The new paradigm should be faster for companies that don’t own all the components, avoid some of the complicated business relationships that have slowed the field down, simplify regulatory submissions, allow AID system components to keep up to date with new models, and allow users to mix-and-match components that fit their needs. Dr. Finan closed with a summary of outstanding issues: (i) what does an iController look like, what kind of data will be required to approve it, and what will be the special controls? (ii) Can we achieve true plug-and-play interoperability, or will there still need to be agreements between companies? (iii) what are the business models in an interoperable AID ecosystem? (iv) what about customer tech support – e.g., if something is not working, who should I call?; (v) Where should the algorithm live – the phone or the pump (there are pros/cons to each). Dr. Finan said manufacturers have been “very willing” to participate in the open protocol effort so far, and we hope to see more take part – Tandem, Dexcom, Insulet, and Senseonics are the next-most-likely candidates, in our view. This session also included updates on DIY research in Europe – the new Open Project and Good News Project are discussed below Dr. Finan’s slides.
On the research front, Dr. Katarina Braune (Charité – Universitätsmedizin Berlin) shared results from the DIWHY survey, asking about DIY system use in a remarkable n=671 people from 27 countries (81% Europe; median age of 42 years; 76% adults and 24% children). The main (self-reported) outcomes are shown below, suggesting DIY systems improve A1c by 0.8% with an impressive +20%-gain in time-in-range (64% to 84%). The “Why do you DIY” question was equally interesting (orange slide), showing the myriad reasons why individual choose to use these systems. Dr. Braune highlighted improved sleep – especially among parents – as the most strongly endorsed reason. The survey is still open until the end of the month at https://open-diabetes.eu/
She also discussed The Open Project – open-diabetes.eu – an international collaboration studying DIY AID systems via prestigious EU Horizon 2020 funding (<1% acceptance rate!). Some of Europe’s leading research institutes are involved in the consortium, including Steno Diabetes Center. DIY systems (OpenAPS, AndroidAPS, Loop) will be studied on several fronts: clinical outcomes, quality of life, and barriers to scale. The consortium will even use machine learning to enhance systems’ predictive capacities.
Also on the research front, Dr. Lenka Petruzelkova (University Hospital Motol) mentioned the “Good News Project,” a soon-to-start multicenter international study of the DIY AndroidAPS. The goal is to confirm the DIY system’s effectiveness, following promising pilot data comparing AndroidAPS vs. MiniMed 640G in a three-day ski camp study (DT&T 2018). As the picture below shows, AndroidAPS was identical to the 640G on time-in-range, with a meaningful 11 mg/dl advantage on mean glucose.
2. PEPPER Decision Support System Reduces Severe Hypo, Increases TIR in Proof-of-Concept Study Using Cellnovo Pump + Dexcom G5 CGM; Phase 3 Clinical Results Expected by Year-End
Imperial College London’s Dr. Parizad Avari reported phase 1 proof-of-concept data on the PEPPER (Patient Empowerment through Predictive Personalized Decision Support) AID system. This project, funded by the EU’s Horizon 2020 program, is using Cellnovo’s pump and Dexcom G5 CGM to investigate algorithms for diabetes decision support. PEPPER collects CGM measurements, insulin bolus doses, meal information, and activity details to produce a 30-minute glucose forecast. The tool can then send alerts/alarms (direct notification to a phone and/or a text message), suspend basal insulin, recommend carbohydrate intake, put a dynamic constraint on insulin bolus, and offer insulin pump commands. The phase 1 study enrolled six participants with type 1 diabetes. Between baseline (weeks 1-2) and study end (weeks 7-8), there was a significant drop in time spent <54 mg/dl (p=0.02) and time spent in-range (p=0.03), but no significant difference in severe hypoglycemia or time spent in hyperglycemia. There was a significant decrease in total number of alarms between the first and last two-week windows (p<0.05), and alerts to caregivers also declined in frequency with PEPPER (p<0.01). Dr. Avari noted insignificant effects on quality of life as assessed by PAID (the Problem Areas in Diabetes scale) and DQOL (Diabetes Quality of Life). She emphasized that these findings should be interpreted as proof-of-concept, and suggested a positive proof-of-concept at that, given significantly reduced time in hypo and significantly improved time-in-range. We won’t be too critical of the lack of significant effect on quality of life metrics or milder hypoglycemia, as this was a relatively short and super small trial (n=6). Rather, we’ll look for meaningful improvements on these outcomes in later-stage investigations – after all, one of the main objects of automation should be to minimize errors and ease diabetes burden, thereby improving quality of life. Phase 2 of this clinical program analyzes not only the safety of PEPPER, but also its adaptive insulin dose calculator with AI; according to Dr. Avari, this trial is complete. Phase 3 is an open-label study comparing PEPPER vs. standard therapy, and Dr. Avari announced that full results will read out by the end of 2019. Per ClinicalTrials.gov, the phase 3 study is expected to complete by end of July. The primary endpoint is within-subject change in time-in-range between three months with PEPPER and three months without.
To our knowledge, Cellnovo is the only medical device company sponsoring the PEPPER project (see all the partners here), although Dexcom CGMs were apparently used in phase 1. Dr. Avari did not disclose which products are being used in phase 2 or phase 3 (nor is this information listed on ClinicalTrials.gov).
3. Harvard’s Dr. Frank Doyle Explains Approach to Long-Term Closed Loop Adaptation; Up to 93% TIR in UVA/Padova Simulation
Harvard’s Dr. Frank Doyle gave a masterful overview of the cutting edge of AID controller development, highlighting his group’s latest in silico data (up to 93% time-in-range) with a multivariate learning framework for long-term adaptation. The approach, known as Bayesian optimization, “underlies a lot of the more effective algorithms,” said Dr. Doyle, “it’s the engine underlying many machine learning approaches.” Explained in colloquial terms, the concept isn’t so complex: The framework is based on a normal controller algorithm with feedforward control (calculates meal and correction boluses) plus the variable basal rate; to this basic algorithm, multivariate learning framework adds long-term parameter adaptation. One loop of this module intends to automatically identify the correct parameter to adjust, and the other optimizes that parameter safely and efficiently. The first loop determines which parameter should be updated on a weekly basis in an intuitive manner: If the user has recurrent hypoglycemia/hyperglycemia overnight, it selects the basal rate to optimize; if the user has recurrent postprandial hyperglycemia/hypoglycemia, it selects the insulin:carb ratio (ICR); and if the user has overall hyperglycemia/hypoglycemia, it selects the controller algorithm. It ceases performing evaluations when glycemia has returned to normal, or if the data suggests there’s no way to better eliminate variability with further tuning. The second loop adapts the selected parameter through linear programming. Dr. Doyle et al. have challenged the algorithm with two scenarios in the UVA/Padova type 1 diabetes simulator: In the first scenario, the starting ICR is twice what would be optimal, and the basal rate is half optimal. In the second, both ICR and basal rate are doubled. As seen in the slides below, parameters in both scenarios self-adjust in predictable manners (given their erroneous starting points), causing time-in-range to climb dramatically while mean glucose decreases dramatically. Up next, this’ll be put to the test in clinical evaluation.
The Doyle group at Harvard maintains a database of artificial pancreas studies, mapping each study onto a plot of hypoglycemia vs. time-in-range. We enjoy seeing this figure transform each time Dr. Doyle presents, reflecting the latest trials – will the long-term adaptation approach begin to bring points in the red box at the top left?
4. Prof. Barnard Presents INSPIRE Instrument for AID PROs, How to Improve PROs in Diabetes
In a high-level talk on patient-reported outcomes (PROs), Professor Katharine Barnard plugged the INSPIRE measures as a way to evaluate a type 1 diabetes patient’s psychological experience with automated insulin delivery. A paper establishing the validity of INSPIRE was very recently published in Diabetic Medicine. The assessment involves a series of questionnaires (17-22 items each) gauging quality of life, fear of hypoglycemia, diabetes distress, and glucose monitoring satisfaction. Separate questionnaires are given to parents and partners of type 1s. This initial study found INSPIRE to be internally consistent, and Prof. Barnard suggested it could have important applications in the next generation of diabetes technology RCTs. A major challenge with PROs today, she explained, is that we have insufficient evidence correlating them to clinically-relevant outcomes in diabetes, such as change in A1c or time-in-range. She claimed that INSPIRE could show an association with A1c and other outcomes, and we hope to see more data on this going forward; at the very least, it may correlate with adherence, which may be in and of itself sufficiently compelling for payers. Prof. Barnard lamented the lack of standardization in how PROs are collected, analyzed, and reported (framing INSPIRE as one potential standard assessment), and she argued that we need more robust PROs than what the diabetes technology field is currently using. She discussed GOLD scores as one example: With a number between 1-7, we know with some certainty if a patient is aware or unaware of the onset of hypoglycemia, but we don’t capture how hypoglycemia is actually impacting their life, whether it’s exacerbating stress, fear, or other negative emotions. INSPIRE takes a more holistic approach, getting at “life impact” by evaluating someone’s diabetes distress right alongside their treatment satisfaction. Prof. Barnard shared enthusiastically that many clinical trials globally are starting to incorporate the INSPIRE measures, which will soon lead to data reported in a standardized fashion on individual experiences with diabetes technologies.
Moreover, Prof. Barnard advocated for more RCTs with PROs as a primary outcome. Another current challenge with diabetes PROs is that most studies are under-powered on these endpoints, she explained (sample size is too small, measurements are inaccurate, etc.). Where we have ample real-world experience with diabetes tech, say in the CGM category, Prof. Barnard argued that it’s high-time to focus clinical trials around user experience and psychosocial impact. See the Q&A below for her full take.
Prof. Barnard celebrated the fact that we’re now debating how to use PROs and not if. As she put it, “I’m thrilled to be giving this talk, because it means we’ve moved away from ‘should we assess PROs’ to ‘how should we best measure and report PROs.’” We’ve certainly seen substantial progress in how different stakeholders – including FDA/other regulators – look at PROs and factor them into decision-making. We’re strong proponents of more standardization across trials so that PROs can be useful in clinical decision-making as well; Prof. Barnard commented that it’s still impossible to reliably judge who will do best on a given technology, and she pointed in this direction as the path forward for diabetes PROs.
Questions and Answers
Dr. Korey Hood (Stanford University, CA): What happens when there’s a separation of clinical outcomes vs. psychosocial outcomes, e.g. when there’s an efficacious and safe clinical outcome but there’s a psychosocial side that’s falling behind, or maybe there’s a negative psychosocial effect? What should regulators and device companies do in those cases?
Prof. Barnard: This is perhaps an example of when to discontinue a device, and it shows that if we don’t understand the psychological impact of technology before we give it to a patient, it could cause harm – especially if there’s a prior expectation that the new device will be great. Take CGM, for example. We have lots of evidence now that CGMs improve time-in-range and biomedical outcomes, that they’re safe and efficacious. So maybe CGM trials should now be around usability and fitting into everyday living to meet individual user needs. There’s a point where you say: Insulin pumps are safe and beneficial; CGM is safe and beneficial. What we need to research now is psychological impact. Let’s step up and adequately assess this. Let’s power trials on psychosocial outcomes.
Q: I wanted to ask about the social determinants of health, and how that influences your interpretation of PROs?
Prof. Barnard: Social determinants (for example, socioeconomic status or gender) have a direct impact on people in terms of healthcare access, health literacy and numeracy, their ability to engage with care. A lot of devices are still very difficult to use if you have low numeracy or low literacy skills. So I think social determinants are very important, and we do actually look into some of these things in the INSPIRE measures. For now, this information usually comes from the demographic part of a study rather than the patient-reported outcomes part.
Remote Care and Digital Health Highlights
1. Hygieia d-Nav RCT Published in The Lancet!! 1.0% A1c Reduction in 6-months vs. 0.3% in Control Group; Dr. Bergenstal Underscores Benefit of Remote Care and Automated Insulin Titration in T2D
Dr. Rich Bergenstal threw a curveball on the final day of ATTD, announcing that a six-month RCT (n=181) of Hygieia’s d-Nav Insulin Guidance System (BGM with built-in insulin titration plus remote HCP support) had just been published in The Lancet. See Hygieia’s press release on the publication. The study found a statistically significant A1c reduction of 1.0% with the d-Nav system, compared to 0.3% in the control group of only HCP support (p<0.0001); baseline A1cs were 8.7% and 8.5%, respectively. It is worth noting that, the intervention arm had significantly higher mean glucose (185 vs. 166 mg/dl) and mean fasting glucose (185 vs. 157 mg/dl) at enrollment, and mean glucoses were not significantly different at study’s end (though the d-Nav group certainly saw a bigger decline). Frequency of SMBG-measured hypoglycemia (<54 mg/dl) was low and similar in both groups (~0.3/month), and there were three and two severe hypoglycemia events in the d-Nav and control groups, respectively. Achieving A1c <7% without a severe hypo was ~7x more common in the d-Nav group; achieving A1c <8% without a severe hypo was ~2x as common. Total daily insulin dose increased by 0.48 units/kg in the d-Nav group (0.77 -> 1.24 units/kg) and only 0.05 units/kg in the control group (0.71 -> 0.76 units/kg), with the average d-Nav participant making 1.1 adjustments per week, 20% of which were down-titrations (compare to the majority response of 1 insulin dose adjustment per year reported in a baseline questionnaire). As expected with increased insulin dosing, average weight gain was higher in the d-Nav group than the intervention group – 2.3 kg (~5 lbs) vs. 0.7 kg (~1.5 lbs), respectively – though Dr. Bergenstal noted that a few pounds (~3) is a small trade-off for a 1.0% A1c decline. As he put it: “This is what it takes… You can’t just call once a week and ask ‘how are you doing?’ then adjust… You have to go up, then down, then up, then down.” Indeed, his “key slide” – a case study of dynamics in insulin needs displaying the immense variability between all doses of insulin (see below) – underscored that there is no one “right” dose of insulin, even for each person. These titrations, while necessary, are extremely difficult to accomplish on one’s own but much more manageable with an algorithm and care team behind you. People in the study seemed to trust the recommendations: 70% reported that they were “comfortable” or “very comfortable” with d-Nav adjusting doses, while only 10% were “not comfortable” – we’d be curious to see outcomes split along this variable. This manuscript is probably the highest-profile publication for the remote diabetes care/insulin dosing titration landscape ever – we sincerely hope that it drives greater consideration of these technologies in the eyes of patients, providers, and payers. Regardless, Dr. Bergenstal seemed sure that conversation of technology in type 2 will be escalated sooner rather than later, quoting Dr. Mark Evans’ accompanying editorial for the paper: “Faced with increasing pressures and demands on primary care, a substantial niche seems likely for technology to help in type 2 diabetes.” To be sure, simple algorithms like those on the d-Nav device carry tremendous potential to improve the outcomes of countless people who are not using insulin optimally/safely and for those who are not yet using insulin due to fear on their or a caregiver’s/HCP's part.
Hygieia received FDA 510(k) clearance for a type 2 insulin titration app capable of supporting “all types of insulin regimens” just three days prior to this publication. The d-Nav device with built-in titration that was used in this study, however, has still yet to be cleared (to our knowledge).
Despite guidelines suggesting GLP-1 agonists as first-line injectables and insulin’s resulting demotion within these algorithms, the real-world effectiveness of insulin is undoubtable. Based on NHANES database analyses, ~50% of people with type 2 taking insulin achieve an A1c <7% in clinical trials, while only ~30% reach that same goal in the real-world, conferring a real-world-to-clinical-trial effectiveness ratio of 60% (30/50). For GLP-1 agonists, that ratio is 42%, based on an average A1c change of 1.25% in clinical trials vs. 0.52% in the real world (0.52/1.25). Dr. Bergenstal’s point was not to compare the effectiveness of these two agents – which would be impossible given that the endpoints are different – but rather to assert that demotion of insulin within a treatment algorithm does not preempt its efficacy or preclude its use. His point was that we must find a way to use insulin more effectively. To this end, he provided his criteria for effective type 2 insulin management trials and devices, which must: (i) provide effective and safe insulin management; (ii) provide timely insulin adjustments; (iii) get the patient involved in their own management; and (iv) allow HCPs to play a critical but supportive role. As examples, Dr. Bergenstal highlighted both Hygieia’s d-Nav and CeQur’s bolus patch (formerly Calibra’s Finesse bolus patch); for the latter, he presented a trio of posters originally seen at ADA 2018 demonstrating patient and provider preference for the patch over standard insulin pen delivery.
2. Dr. Kovatchev’s VIP (Virtual Image of the Patient) Approach Fleshed Out: CGM Daily Profile Clusters -> Transition Probabilities -> Optimizing Treatments –> Mapping Individuals onto Virtual Representations
UVA’s Dr. Boris Kovatchev provided the most detailed explanation of his VIP (Virtual Image of the Patient) concept to date, clarifying how a therapeutic suggestion could be made based on in silico representations. The process begins by generating clusters of daily CGM profiles. He showed how the ~9,000 CGM daily profiles generated from the 126 IDCL Protocol 1 participants during the course of the study fell nicely into three general clusters: 1) tight control/intensive treatment (77% time-in-range, 5.6% time <70 mg/dl); 2) glucose volatility/hyperglycemia (27% time-in-range, 1.2% time <70 mg/dl); and 3) intermediate/average control (55% time-in-range, 1.8% time <70 mg/dl). [It’s worth noting that the clusters were roughly the same for the control group (SAP) and the closed loop group, though SAP participants had 4% less time-in-range and 3.2% more time below 70 mg/dl while in cluster 1.] Next, each participant's clusters were linked in a chain – i.e., an individual’s day one profile fell into cluster 1, day two fell into cluster 3, etc. – and their transition probabilities were calculated. Transition probabilities reflect the likelihood that an individual will fall in each of the three clusters the day after her profile matches a given profile. For example, one person in the closed loop group has a 67% chance, following a day in the ~77% in-range bin, of repeating this same sort of day; meanwhile, this probability for one individual in the SAP group was 0%. The next step is to map an individual’s CGM profile to a representative virtual image of the cluster they currently fall in, and then to use in silico experiments to optimize treatment for each daily cluster (“for a cluster 1 day, do XX”). This procedure can be automated, applied daily, and adapted for either MDI support or closed loop, and then applied to individuals. The overall objective is to maximize the probability that individuals will transition to cluster 1.
3. Verily’s Dr. Zisser: “Information Has a Tremendous Power Once We Share It”; Nodes and Connected Networks, Lack of Endos, Tribute to Dr. Lois Jovanovic
Verily’s Dr. Howard Zisser delivered a dynamic talk on connectivity, best summarized up by his closing line: “Information has a tremendous power once we share it.” In the course of his talk, we found most notable his discussion and examples of nodes and connected networks (specifically connecting a node to itself, and connecting a node to others), a visualization of the sheer lack of diabetes specialists in Arkansas, and a touching tribute to the late, great Dr. Lois Jovanovic.
“The first thing we can do with connectivity is connect patients with themselves. The first patients who put the Dexcom on, it was like ‘I was blind, now I can see.’” He showed a before and after trace of a type 2 who used CGM. At baseline, A1c was 8.1% and nearly every strand of the spaghetti plot danced above 180 mg/dl; just eight weeks later, A1c had fallen to 6.4%, 20 pounds of weight had been shed, and nearly all of the spaghetti was flat in the range of 80-180 mg/dl. “They quickly change behavior…just by connecting the patient to themselves, you’ll see remarkable things.” Dr. Amit Majithia presented a pressure test of this idea on Friday, showing the change in mean blood glucose of participants 14 days before vs. 14 days after CGM in Onduo – most people saw minimal change, but Dr. Majithia noted that Onduo coaches encouraged people to “go crazy” with their CGM initially, treating it as an “exploratory time” (presumably test the limit of what they can eat, etc.). The next step beyond self-to-self connectivity is, of course, self-to-other; i.e., sending information to the healthcare team and back to the patient, and to family members. Dr. Zisser reminisced back to his days in a Sansum lab with Dr. Eyal Dassau, where the two found a way to get Dexcom information out of a patient’s Dexcom and onto a laptop, thus marking the start of Dexcom Share.
The picture below of people with type 2 in Arkansas vs. the endocrinologists in Arkansas says 1,000 words about the rationale for connectivity and remote care.
Dr. Zisser concluded with a touching tribute to one of his mentors, the late Dr. Lois Jovanovic: “I’ve never known anyone to love a patient so much.” He recalled how in 1985 she tried to make a “pocket doc,” to “get Lois into a RadioShack TRS-80 PC-1 program for type 1s on pumps.” “Most of these sessions [at ATTD] can trace directly back to Lois.” He also shared that Dr. Jovanovic’s grandmother was one of Dr. Frederick Banting’s first patients. See warm thoughts on Dr. Jovanovic from a handful of the myriad people in and with diabetes who were so lucky to have known her.
4. Dr. Riddell Hints at New Exercise Support App for Type 1s – Undisclosed Industry Partner, Beta Version to Launch in ~Six Months
Dr. Michael Riddell gave a rundown of available exercise apps for type 1s, and announced a new app – in development with an undisclosed industry partner – that will recommend basal, bolus, and carb intake based on activity; he expects a beta version to launch within six months. Needless to say, we’re intrigued. Dr. Riddell didn’t share many concrete details, beyond that the backend of the app will follow the logic of the decision tree from the 2017 consensus statement on exercise management in T1D. We’ll be looking to see how this app distinguishes itself from others already in the App Store, because as Dr. Riddell himself stated, there are quite a few. This is not to say that the field is saturated with exercise management support for type 1s – on the contrary, we see significant unmet need, and Dr. Riddell displayed data to this end. A small minority of people with type 1 diabetes who exercise regularly use apps today, but they say they would rely on an app if they found the right one, which suggests growing demand. From the same survey, Dr. Riddell highlighted that patients want more exercise-related support from peers with diabetes. He gave a nod to Team Novo Nordisk, and recommended incorporating social media communities into these apps; we wonder if this will be a component of the mystery up-and-coming app. Moreover, different platforms bring different offerings. Dr. Riddell reviewed that Engine1 and DiaBits feature active coaching, while Glucose Buddy and Bant give personalized feedback and reminders, but no coaching. Most of the apps he discussed have a free intro version, with the exception of Engine1. Since patient preferences and needs are particularly unique around exercise, we’d love to see this new app fill gaps in the market.
CGM & Big Picture Highlights
1. Median 35% TIR, 60% >180 mg/dl Seen in 153 T1s Ages 14-25 without Recent CGM Use (Baseline Data from Helmsley-Funded CITY Study); Full Results to Report at ADA 2019
Joslin’s Dr. Lori Laffel presented disheartening baseline glycemic data from the Helmsley-funded CITY study of CGM in young type 1s ages 14-25 years old (all either CGM-naïve or not active users in the past three months). The 153 participants are wearing blinded Dexcom G4 (with software 505) for two weeks, followed by six months of CGM. The sad story here is the baseline:
Mean A1c is 8.9% (25% of participants had A1cs above 9.6%).
Median time-in-range (70-180 mg/dl) is just 35% (8.5 hours/day). Half of the sample spends less more than 15.5 hours per day out of range, and only 17% of participants spent ≥50% time-in-range.
Median time >180 mg/dl is 60% (14.5 hours/day)! Half of the group spends ≥7.9 hours per day above 250 mg/dl.
Only 21% of participants had “stable” glycemic variability as determined by CV ≤36%.
Median time <70 mg/dl (3%) and <54 mg/dl (1%) are in line with recommendations, but only because hyperglycemia is so pronounced.
Obviously, there is a lot of room for improvement in this cohort, adding fuel to the fire exacerbated just last month by the latest T1D Exchange Registry data. CITY will read out at ADA 2019, and our fingers are tightly crossed for a positive outcome – the study population is pretty much exactly the hump in the canonical T1D Exchange graph of A1c by age that needs the most help. But as the Registry shows, improving time-in-range and A1c is not as easy as just giving more people CGM; Dr. Bergenstal explained on Day #2 of ATTD that patients have to be supported in effectively using CGM.
Dr. Laffel noted that the exclusion criteria of current/recent CGM use resulted in a very heterogeneous population where 38% are of minority race/ethnicity, and 41% are not privately insured. Interestingly, however, there were no demographic or clinical factors associated with baseline CGM metrics. Said Dr. Laffel, “This is a population with uncontrolled diabetes, and we’re not finding causal factors easily – there must be behavioral or psychosocial factors we’ve yet to measure. This work is so important on so many levels.
2. ISPAD 2018 Clinical Practice Consensus Guidelines Include Chapter on Diabetes Technology for First Time; Stronger Stance than ADA on Pumps, CGM, and AID
In line with ADA’s 2019 Standards of Care, ISPAD’s 2018 Clinical Practice Consensus Guidelines included a chapter on diabetes technology for the first time. The chapter consists of recommendations for insulin pumps, CGM, sensor-augmented pump therapy (SAP), closed loop systems, digital health (i.e., apps, decision support, bolus calculators), downloading technologies (e.g., Glooko, Tidepool), telehealth, and impact on quality of life. In today’s session, Yale’s Dr. Jennifer Sherr presented on insulin pumps, University of Otago’s Dr. Martin de Bock on CGM, and University of Cambridge’s Dr. Martin Tauschmann on SAP and closed loop. See below for the top takeaways.
On insulin pumps: ISPAD took a stronger stance than the ADA in favor of pump therapy in pediatrics, claiming that pump therapy “can be used safely and effectively in youth with type 1 diabetes to assist with achieving targeted glycemic control (B)” and “can assist with reducing episodes of hypoglycemia (B).” Moreover, pump therapy was found to be “appropriate for youth with diabetes, regardless of age (B)” and to “reduce chronic complications of T1D in youth, even when compared to those with similar A1c levels on MDI therapy (B).” To compare, ADA guidelines were more conservative, noting that pump therapy “may be considered as an option for all children and adolescents, especially in children under seven years of age. C”
On CGM: We were pleased to see a strong statement (A-level evidence) in favor of CGM to “effectively” lower A1c, reach target A1c, reduce glucose variability (for pumpers and MDI-treated patients), and increase time-in-range in the pediatric population. Once again, ISPAD was stronger than the ADA, which recommended that CGM “should be considered in children and adolescents. B” ISPAD guidelines also included the possibility for CGM to evaluate “clinically meaningful outcomes beyond HbA1c (E),” including time-in-range (70-180 mg/dl), time in hypoglycemia (Level 1: <70-54 mg/dl; Level 2: <54 mg/dl) and time in hyperglycemia (Level 1: >180 mg/dl; Level 2: >250 mg/dl). As Dr. de Bock noted, it’s a bit strange this recommendation was graded with only E-level evidence, given that it seems obvious CGM would be necessary to evaluate CGM metrics like time-in-range. Similar to the ADA guidelines, FreeStyle Libre received a separate recommendation: “Use of intermittently scanned/viewed CGM (isCGM), also known as flash glucose monitoring, in the pediatric population is safe (C).” Other notable recommendations are included below:
“Real-time CGM can be used effectively for reducing mild to moderate hypoglycemia and shortening the time spent in hypoglycemia in the pediatric population with T1D (B).”
“The effectiveness of CGM in children and adolescents with T1D is significantly related to the amount of sensor use (A).”
On SAP and AID: ISPAD’s strong recommendation for SAP therapy in children and adolescents was similar to that included in the ADA guidelines. ISPAD advises: “Sensor augmented pump (SAP) therapy is superior in children and adolescents over MDI with self-monitoring of blood glucose (SMBG) in reduction of HbA1c without an increase in hypoglycemia or severe hypoglycemia (A). However, this benefit is mediated by adherence to sensor therapy, with at least 60% use being associated with these findings.” ISPAD’s guidance on AID systems was much stronger than the ADA’s. ISPAD recommends: “Automated insulin delivery (closed loop) systems improve TIR, including minimizing hypoglycemia and hyperglycemia (A).” ADA’s recommendations advised: “Automated insulin delivery systems may be considered in children (>7 years) and adults with type 1 diabetes to improve glycemic control. B” See below for more notable ISPAD recommendations:
“Automated insulin delivery systems have proven to be especially beneficial in attaining targeted control in the overnight period (A).”
“Predictive low glucose suspend (PLGS) systems can prevent episodes of hypoglycemia and have been shown to reduce hypoglycemia exposure (B).”
“Low glucose suspend (LGS) systems reduce the severity and duration of hypoglycemia while not leading to deterioration of glycemic control, as measured by HbA1c (A).”
Diabetes Therapy Highlights
1. Dr. Bode Enthusiastic About Potential of Ultra-Rapid Insulin in Closed Loop, Despite Lack of Available Data
Dr. Brude Bode covered ultra-rapid insulin in closed loop systems, offering insight on the potential of Novo Nordisk’s Fiasp, Lilly’s URLi, and Adocia’s BioChaperone Lispro and concluding that in a closed loop, ultra-rapid insulins should lower A1c and improve time in range. Read on for the latest on the three most advanced ultra-rapid insulins:
Fiasp is currently under investigation in two closed loop studies, including one using Medtronic’s 670G (phase 4, n=20, expected completion May 2019) and another using Beta Bionics’ iLet system (phase 2, n=24, expected completion April 2019). The former comes from Stanford’s Dr. Bruce Buckingham, has a 2-week double-blind crossover design comparing NovoLog to Fiasp, and lists time in range and time <70 mg/dl as co-primary endpoints. To our understanding, ~20 patients have completed the trial, and Dr. Bode was optimistic that results would be presented as a late-breaker at ADA 2019 in San Francisco. And while Dr. Bode admitted that we have no robust dataset yet supporting a benefit with Fiasp in closed loop systems, he did present highly compelling data from a single patient of his: A 33-year old male with over 20 years of type 1 had an A1c on 7.3% and 70% time in range (70-180 mg/dl) on the 670G, but he was frustrated with postprandial spikes. Dr. Bode switched him from NovoLog to Fiasp with no other changes or intervention, and his A1c fell to 6.7% with a 4% gain in time in range (though also with a 1% gain in <70 mg/dl) in ~four months. He also noted a slight increase in bolus insulin and decrease in basal with this patient, arguing against the notion that HCPs need to increase basal insulin when switching to Fiasp – rather, he says, observed nighttime highs with Fiasp are a result of patients compensating for lower post-dinner values than they’re used to. When a patient has always gone to sleep at 150 mg/dl and is now seeing 120 mg/dl at bedtime, they often bring themselves up, leading to higher nighttime values: “It’s a behavioral issue, not an insulin issue.”
Regulatory submission for Lilly’s URLi (ultra-rapid lispro) is expected in 2019, and Dr. Bode highlighted that phase 3 PRONTO-T1D, PRONTO-T2D, and PRONTO-Pump results will all be presented at ADA 2019. Topline results from the first two were released October 2018, and Lilly has also – as expected – started a second, larger pump study (PRONTO-Pump 2) enrolling 526 type 1s. In terms of closed loop, he pointed to a phase 2 study comparing URLi to Humalog in 670G (n=50, expected completion September 2019), which he said two patients had entered as of last week and has a primary endpoint of time between 70 and 180 mg/dl. Lilly hasn’t yet released any phase 3 data on URLi (see phase 2 data in type 1 and type 2), and though PK/PD show improvements, it remains to be seen if this will translate to improved outcomes in 670G and other closed loop systems for type 1.
Finally, on Adocia’s BioChaperone Lispro, Dr. Bode commented that the company has gone back and forth on whether to do a study in closed loop. For context, Adocia recently decided to advance BC Lispro into phase 3, though the company is still open to partnerships for this highly promising candidate. Management has stated that the first phase 3 study will be in pumps, but, to our knowledge, no studies have been posted to ClinicalTrials.gov. Dr. Bode seemed particularly optimistic about BC Lispro, highlighting a 61% reduction in postprandial AUC in a phase 1/2 study and commenting that benefits are seen in both type 1 and 2. On the closed loop front, Beta Bionics is running a study comparing BC Lispro, NovoLog, and Humalog in a single-hormone configuration on the iLet pump in up to 30 type 1s; according to Dr. Bode, the trial is already underway (though not listed as such on ClinicalTrials.gov) and we could see results “at ADA or even before.”
2. Dr. Skyler Sweeps Over Beta Cell Replacement Landscape: Enthusiastic about Industry Commitment, Immune-Evasive Stem Cells
Wrapping up ATTD 2019, the venerable Dr. Jay Skyler gave an optimistic, sweeping overview of beta cell replacement landscape. Primarily driving his optimism was the increased industry interest and investment in the field in recent years, including most of the major pharmaceutical companies in diabetes (see below) – a key theme we identified in 2018. In his words, “When industry gets this involved, success can be predicted to be coming.”
In allogeneic stem cell research (cells are from a different host), Dr. Skyler highlighted the work of Semma Therapeutics and ViaCyte – two companies near the top of our competitive landscape. The former has garnered considerable attention for its “conformal coating” encapsulation device, which they hope will eliminate the need for immunosuppression and surrounds each naked islet cell to allow for better implantation and functionality (but remains preclinical). ViaCyte has brought two programs into the clinic, and the lead candidate right now is PEC-Direct, a device that allows for direct vascularization of graft cells to avoid the negative impact of foreign body response but requires immunosuppression. Proof-of-efficacy data from a phase 1/2 trial are expected as early as mid-2019. PEC-Encap – fully-enclosed beta cells in an implantable, semi-permeable membrane – is set to return to the clinic as early as mid-2019, with a revamped encapsulation device to reduce foreign body response developed in collaboration with W.L. Gore. The “last” generation, PEC-QT – immune-evasive stem-cells in a vascularized device – is being developed in partnership with gene-editing giant CRISPR Therapeutics and is currently preclinical. Dr. Skyler did, however, seem particularly bullish on the potential for hypoimmunogenic stem cells in the near future, pointing to a paper published in Nature Biotechnology only four days earlier suggesting that hypoimmunogenic cell grafts can be engineered for universal transplantation – wow! Moreover, another paper published just three weeks earlier in Stem Cell Reports proposed a new method for preprogramming cell death into cancerous cells forming during stem cell induction and selecting for pancreatic beta cells, potentially allowing for cleaner, safer cell differentiation. Both of these papers chip away at what the Diabetes Research Institute’s Dr. Cherie Stabler called the greatest hurdle in beta cell replacement therapy at the 2019 JDRF Mission Summit: producing a fully-functional stem-cell derived beta cell.
As Dr. Skyler explained, another major hurdle for beta cell replacement is producing the appropriate microenvironment mimicking a functional islet – neural cells, endothelial cells, pericytes, and many other types of cells – not just the beta cell – all interact to create a functioning islet. Session chair Dr. Des Schatz was noticeably nodding along with this assessment. On this note, we point to recent research from UCSF’s Hebrock Lab on the creation of “enriched beta clusters,” a more advanced cell type than other insulin-secreting stem cell-derived products – while these aren’t fully functional islets, researchers do seem to be making strides toward better stem-cell derived products, as well as on the best environment to house them.
Orgenesis was the only company mentioned conducting autologous stem cell research (cells coming from the same host) – a multi-step process that requires the modification of multiple cellular processes. The idea here is to revert liver cells to a suggestible stem-cell state, induce pancreatic differentiation, then fine tune the signaling pathway to allow generation of cells which secrete insulin – certainly no small feat. We haven’t heard much from the company in recent years and the project remains preclinical.
We confirmed with Abbott that the recently announced integration of insulin dosing data from Novo Nordisk’s connected pens directly into the FreeStyle LibreLink app and LibreView diabetes management systems will become available between late 2019 to early 2020, providing more specific timing than that originally noted (“as soon as possible”). The booth representative confirmed that the FreeStyle Libre 2 has only launched in Germany (in line with October’s CE Mark), making it clear that the upcoming “gradual European rollout” has not yet commenced. We last heard during Abbott’s 4Q18 call in January that the company expects FreeStyle Libre 2 to “come to the US shortly.” No updates on this front were shared.
Arecor brought a small, three-person booth to showcase preclinical results for its ultra-concentrated (U1000) rapid-acting insulin and ultra-rapid-acting prandial insulin. Of note, the ultra-rapid-acting candidate is set to enter a European phase 1 trial in “the next few months.” This is a delay from Arecor’s original timeline estimating 2018 human clinical trials, and it has been updated on Arecor’s product page. The U1000 candidate is on a slightly longer timeline and will likely enter the clinic in “late 2019 or early 2020”; we note that Arecor also originally slated the candidate for 2018 clinical development, so this is a substantial delay. Should it meet this new timeline, the candidate would likely be the first-ever U1000 mealtime insulin to advance into clinical development. Worth noting, representatives mentioned that they were meeting with major insulin manufacturers Sanofi, Lilly, and Novo Nordisk at ATTD to talk about micro-pump concepts for the U1000 insulin, expressing stronger enthusiasm for this candidate than the ultra-rapid molecule. Representatives did not mention Arecor’s liquid-stable glucagon or preclinical combination products for diabetes referenced in a recent, ~$8 million round of fundraising.
BD’s “Diabetes Personal Assistant” app, Briight, released at ADA, now has “over 30,000” users, reflecting a steady increase from 20,000 users as of AADE in August. BD’s Digital Diabetes Product Leader Mr. Ed Liebowitz shared that the minimal viable product for the app has now been validated, demonstrating that optimized structured education can increase engagement. Bright currently has 4.1/5 stars on Google Play (30 ratings) and 4.3/5 stars on the App Store (12 ratings). The Digital Health team is working on version 2.0 of Briight, which he expects to be live this calendar year. Mr. Liebowitz noted that Briight is still intended to support both BD’s injection and infusion patients, alluding to the type 2 patch pump. Last we heard on BD’s 4Q18 call earlier this month, the pump was submitted for US and EU regulatory approval, with an initial “early product introduction” still slated for “late in calendar year 2019.”
This ATTD, Biocorp unveiled new branding for its two-piece dose capture pen attachment (“Mallya”; formerly “Easylog”) and announced its first two diabetes partnerships (to our knowledge) with AgaMatrix and DreaMed. AgaMatrix will be the non-exclusive distributor of Mallya in the US, EU, and UK, and the two companies also signed a co-development agreement to develop “a breakthrough innovation.” Given AgaMatrix’s work in closed loop (WaveForm), we wouldn’t be surprised if Mallya is used to inform open loop insulin delivery. On the commercialization front, reps told us that they expect AgaMatrix to begin distributing the CE-marked pen attachment in Europe – starting with UK, France, and Germany – beginning in 1H19. As for the DreaMed collaboration, Biocorp will provide insulin dosing data to inform the MDI/basal-only versions of DreaMed’s Advisor Pro clinical decision support, with clinical trials set to begin this year.
Cam Med – developer of the ultra-thin, flexible, bandage-like Evopump capable of delivering multiple drugs at minimum cost – showcased its interim 1 ml prototype device (see below) and gave timing updates at its one-person booth. CEO Mr. Larry Alberts shared that the 2 ml beta prototype of the device, will be done in March, then tested in a preclinical model for two months. Provided positive results are achieved, the product will progress through human factors studies and device evolution to support an IDE application by the end of 2020. Boasting accuracy within ±5% at individual NovoLog doses of 5 mL and 1 mL and built-in pressure and temperature measurements to ensure proper delivery under varying environmental conditions, Cam Med has inspired investor confidence to-date. When we were first introduced to the company at ATTD 2017, it had won several competitions and secured $440,000 in non-dilutive funding; now, it has received ~$1.6 million in prizes and grants and $1.5 million in Seed equity funding. Notably, the project is currently being funded in part by JDRF, with potential continuation of the partnership after preclinical studies. Of note, the eight distinct reservoirs within the patch enable potential multi-drug delivery (e.g., insulin + Symlin, GLP-1, and/or glucagon), and Mr. Alberts noted that he had struck up conversations on this topic before and during ATTD with developers of these formulations JDRF’s funding announcement also explicitly stated artificial pancreas development as an end-goal. On cost, he asserted his hope for the Evopump to compete with pens. Currently, he said, each Insulet Omnipod costs roughly $12 to make; Evopump can currently be manufactured for less than $2, with the hope to get down to $1 through volume – wow! This is in part due to the electronic controller – which will have a simple UI containing a light, bolus-button and vibration in addition to having a Bluetooth module enabling communication with a handheld device – being reusable between patches. There are many barriers to entry in patch pumps, but among the biggest is extremely high-quality manufacturing and scale. Can Cam Med make it happen, where others have struggled?
We learned at Capillary Biomedical’s booth that the company no longer anticipates launching the wire-reinforced, multi-ported (three side holes) SteadiSet infusion set in 2019. On the other hand, while the 2019 launch was going to be for three-day wear, Capillary now expects to leapfrog straight to a 2020 launch of seven-day wear. See our August coverage for a deep dive on Capillary Biomedical and the SteadiSet. Also new at this booth was a picture of the sleek, one-handed inserter, which has a similar feel to FreeStyle Libre, Mio Advance, and G6. Nice!
A Cellnovo booth representative confirmed that the Gen 3 system was submitted to the FDA “early this year,” aligning with timing shared on the 3Q18 call in October. The Cellnovo booth touted its once-refillable cartridge, which launched last month. The booth representative hopes this feature will make Cellnovo’s pump more attractive to type 2 patients. Currently Cellnovo is integrated with two Bluetooth-enabled BGMs (Roche AccuChek Guide and Fora). CGM integration is in the pipeline, and Cellnovo is in discussions with Dexcom “and others.” However, users can view their CGM data via Apple Health in Cellnovo’s newly launched Cellnovo Monitoring app. We also received updates on two out of the three AID studies in which Cellnovo is involved. Per the booth representative, TypeZero will “propose a product” in 2021. Last we heard at EASD in October, Cellnovo was “getting ready for a trial” with TypeZero. Cellnovo and Diabeloop are currently working together on the business details of including Cellnovo in Diabeloop’s commercial system. Although the first arm of the Diabeloop study was completed with the Cellnovo pump, the second arm was completed with the Kaleido pump. As of CES in January, Diabeloop plans to launch its CE Marked adult hybrid closed loop system (DBLG1) in early 2019 in France ahead of a broader European scaling in 2Q19, using Dexcom G6 CGM and Kaleido’s patch pump.
Unomedical showed a number of brand-new infusion set concepts in its booth, including sets for dual-hormone delivery, a patch pump base plate design leveraging the all-in-one Mio Advance inserter, and a combined set-CGM sensor design. Pictures are included below. A poster also showed encouraging data from the ongoing Stanford study (n=24) testing up to 10-day wear with the coated Lantern set that includes slits along the sides. Interim outcomes (n=10) look encouraging, as 100% of sets have lasted seven days or more (mean: 8.9 days) and half of sets have gone for 10 days. There is still unexplained hyperglycemia (see table below), and clearly quite a bit of variability between different people. A follow-on, larger crossover study (masked, randomized) will compare the coated Lantern catheter against commercially available infusion sets. Based on these interim outcomes, we’d guess the company will go for seven-day wear and not ten. As noted on Day #2, Unomedical is also working with Medtronic on a separate seven-day wear set that uses a different technology; a launch is ambitiously expected in one year, according to Medtronic’s presentation. We also asked about a Mio Advance launch in the US – the excellent inserter has been available OUS since last ATTD and FDA cleared for nearly a year – and the team told us it is still building capacity to support a US launch. This is prudent, as Mio Advance is such a tremendous upgrade and we know demand will be sky high. Medtronic does have an exclusive deal on Mio Advance for an unspecified amount of time, a downside for Tandem.
Coated Lantern study at Stanford – interim data from n=10 patients, with two patients excluded in red:
Unomedical also debuted some never-before-seen infusion set concepts: (i) dual hormone delivery (Beta Bionics?); (ii) a dual CGM sensor/insulin catheter set with a side-by-side design and Mio-Advance-like insertion (2+ years away, per Medtronic’s pipeline); (iii) a patch pump base plate that uses the Mio Advance insertion device (looks ideal for Roche’s Solo); (iv) an all-in-one inserter like Mio Advance, but with the tubing bundled into the lid; and (v) an all-in-one inserter like Mio Advance, but with an angled insertion.
Dexcom’s booth advertised G6 at its first ATTD, along with the Clarity mobile app that launched internationally last fall. The Clarity team in the booth shared excitement for the upcoming launch of “On the Bright Side” notifications (see Day #2), allowing users to set time-in-range goals and be notified (via automated push notification) when the goal is achieved – a beautiful way to bring a Bright Spots focus to CGM data! (Historically, CGM has been focused on the opposite: notifying users when they’ve done something wrong or made a mistake.) The rep explained the tough balance between notifications and nuisance, and the team spent a lot of time deciding what time window to look back on for the “Best Day” notification – seven days was the right balance. See the slide below, taken from Dexcom’s Day #2 symposium:
ATTD start-up grant winner Dianovator promoted its proprietary insulin algorithm (patent pending), which not only doses insulin but also predicts the PK/PD profile of different insulins within the body. CEO Dr. Fredrik Ståhl founded the company based on his dissertation work on insulin algorithms, which is now incorporated into a beta system with a CE mark application coming in the next few months. Most notably, the ability to predict the PK/PD profile of insulins has the potential to enable earlier hypoglycemia alarms than current systems. A retrospective analysis to test this hypothesis is currently underway, with an RCT planned if this first step i successful.
According to reps at the DreaMed booth, Advisor Pro hasn’t actually started rolling out in the US or Europe through Glooko’s Population Tracker. Why? It’s mostly due to IT departments at clinics, who have a lot of say regarding software and are apparently proving to be a “big obstacle.” That said, there are a dozen or so clinics who are interested, and DreaMed is speaking with them one-by-one to see if they can clear all necessary hurdles and get their clinical decision support tool in front of providers. We’re hoping they’ll share their negotiation best practices with the rest of the field so that each new company doesn’t have to reinvent the wheel in terms of pitches to IT crews and figuring out the right business model. On that end, it sounds like DreaMed is looking to offer clinics a three-month trial, followed by a three-year discounted rate. For clinics that use Glooko, that probably means a premium monthly subscription fee on top of that paid for Glooko (we’ve even heard of a possible Glooko Gold, Glooko Silver, and Glooko Bronze setup); through Tidepool, which is free to clinics, DreaMed would still likely charge a set monthly fee depending on the number of patients (i.e., one fee for clinics with 0-200 patients, a higher fee for clinics with 201-500 patients, and so on). As with almost all adoption curves, this one sounds like it’s going to take time, but we’re glad DreaMed is on the front lines making headway.
Glooko’s 2018 Annual Diabetes Report (single-page infographic) was the primary focus of its exhibit hall booth. The report analyzes one of the largest bodies of combined diabetes data in the world: nearly 15 billion data points collected from over 2 million people with diabetes in 17 countries – up ~6.5 billion points, half a million people, and two countries from 2017! Once again, Belgium had the best glycemic metrics across the board, with an average blood glucose of 156 mg/dl; the highest was 198 mg/dl, in New Zealand, once again displaying great disparity in glycemic control across geographies. Belgium also had the lowest rates of hypoglycemia (5.8%) and hyperglycemia (35.4%) – both lower than last year – while Spain (21.8%) and New Zealand (77.4%) occupied the top spots for each, respectively. The most common times for hypoglycemia and hyperglycemia were Thursday at 2 am (8% of readings <70 mg/dl) and Saturday at 11 pm (48% of readings >200 mg/dl), respectively. The most common time to check blood glucose was 7 am, and the least frequent was 2 am.
As a reminder of just how little patients rely on data to manage their diabetes, fingerstick frequency ranged from 2.7 readings/day in South Africa to 4.4 readings/day in the Netherlands – the exact same as last year. (This could partially reflect growing CGM adoption, especially in Glooko users.) Yet, perhaps unsurprisingly, the number of blood glucose tests and average blood glucose during the week correlated inversely, as the two days of the week with the lowest number of blood glucose tests (Saturday and Sunday) were the two that looked to have the highest average blood glucose.
Christmas Day leap-frogged Valentine’s Day and Halloween as the holiday with the highest average blood glucose values. However, average blood glucose on all of the holidays seen in the figure below rose considerably in 2018; left to right, 2017 values were 168 mg/dl, 158 mg/dl, 140 mg/dl, and 131 mg/dl. What accounted for these changes? More stress and less vigilance on these days than last year? Shifts in the population studied that reflect more or fewer users celebrating these holidays? Likely the latter. Intriguingly, the report notes that the best and worst days (highest and lowest percentage of readings between 70-144 mg/dl) were September 28 and New Year’s.
The two countries with the highest average blood glucose – Australia and New Zealand – were also the two countries with the least number of sleep interruptions (1.4% and 3.2%, respectively; measured by having at least one glucose BGM measurement between midnight and 6 am). France came in third but also had the second lowest average blood glucose, suggesting that the higher blood glucose values sign in Oceania might be more related to geographical or cultural differences than sleep patterns.
Altogether, we cannot wait to see more analyses like these, and we salute all companies working to publish real-world data. In the future, we’d love to see an even further expanded report including details of device distribution over geography and time, demographic breakdowns, and situational context for results (e.g., what are clinics/providers/countries with good outcomes doing to manage patients on a population level?)
This was Insulet’s third major European exhibit hall appearance – following ATTD 2018 and EASD 2018 – and the second after taking European distribution over from Ypsomed last July. The new Omnipod Dash PDM was on display in a corner of the booth, though the focus was clearly on the current Omnipod – no surprise, given Monday’s remarks delaying a Dash international launch to late 2019/early 2020. In fact, the reps were not even aware the Dash has a CE Mark!
LifeScan’s exhibit touted the relatively new OneTouch Reflect BGM, featuring the Blood Sugar Mentor that provides trend analysis and tips on both the meter and phone app. According to reps at the booth, the meter has launched in both Germany and France, Italy is on deck, and Belgium and Austria will see the product soon thereafter. As of October, OneTouch Reflect is with both FDA and Health Canada, with FDA clearance potentially expected by this fall. We learned about some more of the insights on Monday at a LifeScan symposium.
Medios Technologies housed a small, corner booth to showcase its AI retinopathy detection device and app; an iPhone 6 attachment (looks like a nail gun, see below; both are shipped together – small modifications have been made to the phone’s camera to promote better fundus photography) allows photos of the retina to be taken without the need for pupil dilation. The whole process takes about 15 seconds – ~10 to place the device to the eye and align it properly, ~5 to analyze the image. The app assesses both image quality (prompting for retake if need be) as well as probability of having retinopathy – it was 96% sure that one of our esteemed associates had healthy eyes. However, if she had been diagnosed, a detailed report would have highlighted areas of concern in the fundus photo. Altogether, we found the process quite quick and pleasant, at least compared to the traditional ophthalmoscope which requires dilation, a severely bright light, and uncomfortable chin placement. When asked about timing, representatives told us that the device part of the system is approved in the US, but the algorithm is currently being investigated with “a few more months” to go. That said, the display boards of the booth touted the algorithms specificity – 93% sensitivity, 92% specificity in a 900-patient sample from Diacon hospital (data currently under submission), although to our understanding, the diagnoses made aren’t prescription level. The idea instead would be to have the device in PCP offices as a way to quickly identify those who need referral to an ophthalmologist, similar to the way Verily/Google are proceeding in India and Thailand. Doubtless, a shortage of specialists and lack of referrals – issues multiple companies are currently working to remedy through AI-based systems that can be utilized by PCPs – play a role in eye exam uptake, and we are thrilled to see another company producing such a quick and simple device.
Medtronic’s expansive booth advertised the MiniMed 670G at its first ATTD following the international launch at EASD. Unlike the US, the outstanding Unomedical Mio Advance infusion set inserter was advertised alongside the 670G – we are highly anticipating this to be available stateside following under-the-radar FDA clearance nearly a year ago. In the iPro2 professional CGM section, a new Medtronic brochure advertised results from the very cool Adjust study (see Day #3): after quarterly blinded CGM applications over one year, each with a follow-up visit (in-person or by phone), A1cs dropped by a mean of 1.3% (baseline: 9.4%). In real-time CGM, the Guardian Connect app was on display for Apple iOS, and we confirmed with Medtronic that it has had select availability on some Android phones internationally. The Google Play listing for Guardian Connect, however, has tragically low reviews – 1.3/5 stars, 268 reviews, 5,000+ downloads – criticizing poor performance and compatibility with the latest Android OS and models. Medtronic told us (via email) an upcoming update will expand availability. Guardian Connect Android will be key for Medtronic’s international CGM expansion, as Android is more dominant OUS and competitors all have Android compatibility (Abbott FreeStyle LibreLink, Dexcom G5/G6, Senseonics Eversense). As of JPM, Guardian Connect on Android is expected to launch between April 2019-April 2020.
Shanghai-based Medtrum boldly advertised three integrated patch pump and CGM products, including a predictive low-glucose-suspend system reportedly available in six European countries and with ~200 users so far (Germany, Denmark, Sweden, UK, Spain, Italy). The current A6 system includes a semi-disposable tubeless patch pump, a handheld controller, a seven-day CGM (two calibrations/day), and predictive low glucose suspend. The A7 system adds a secondary display mobile app and improves the CGM to 14-day wear and one calibration/day, with an expected launch this year in Europe and “2020” in the US (seems highly ambitious). The P7 system, currently in R&D, adds direct smartphone control (no handheld) and a no-calibration CGM. Like Roche’s Solo, Medtrum’s tubeless patch pump is semi-disposable – in this case, the reusable part (colored) reportedly lasts four years, while the disposable part is replaced every three days. The company also offers its Bluetooth-enabled S7 CGM as a standalone product (countries unclear). This was Medtrum’s largest booth following smaller and less-confidence-inspiring EASD exhibit hall appearances (e.g., 2018, 2015). We’re not convinced of the CGM’s accuracy nor the ability to reliably scale the patch pump’s manufacturing. Still, it is notable that Medtrum owns its own tubeless patch pump and CGM – a combined offering that no other company has at this point.
FDA-cleared and CE-marked clinician-facing dose titration software Insulin Insights was the focus of Mellitus Health’s one-person display. The software, which showed highly robust reductions in A1c at three (-1.9%) and six months (-2.4%) from a high baseline (10%) in six month data presented at ADA 2018, is based on the ADA standards of care and equipped to process “all approved insulins.” Connected BGM readings with an associated mobile app are analyzed with respect to eight different insulin regimens, generating a recommended insulin adjustment. Most recently, the company announced a partnership to integrate Insulin Insights with Smart Meter’s cellular-enabled iGlucose BGM, though this partnership was not mentioned in our discussion with representatives.
Novo Nordisk’s ATTD booth, emblazoned with bold blue text, “Digital + Health,” was all about the CE marked, NFC-enabled NovoPen 6 and NovoPen Echo. Crowds gathered around a small table to watch reps perform a sham insulin injection with a NovoPen 6, and then hold the pen against the surface of a Sony smartphone, thereby transferring the injection history directly to the Diasend app. The app tells the user when the upload is complete (just a few seconds), and then gives a menu of insulin options for the user to indicate what was just injected. We imagine future pen-app pairings will be able to distinguish between types of insulin doses; this feature will be especially an especially useful risk mitigation consideration, particularly when these apps adjust/recommend insulin doses based on past glucose and insulin data. On day #1 of ATTD, Abbott and Novo Nordisk both announced a partnership to integrated connected insulin injection device data into FreeStyle Libre software “as soon as possible”; Novo Nordisk already had similar partnerships with Dexcom, Roche, and Glooko.
Percusense – headed by CEO Mr. Brian Kannard and Dr. Rajiv Shah – is developing a multi-analyte sensor platform for diabetes: glucose, ketones, oxygen (at the infusion catheter to assess infusion set viability), and lactate and oxygen (to detect worsening comorbidities). From a CGM perspective, the company intends for a 14-day wear, factory-calibrated device. A poster in the ATTD booth also gave more details on a three-day integrated sensor and infusion set (picture below). The poster touted: (i) Low-cost sensor manufacturing through high volume microelectronics processes; (ii) a 30-minute warmup period; and (iii) innate interference rejection (insulin, glucagon, acetaminophen), precluding the need to rely on costly membranes.
The Roche booth displayed its highly-anticipated Accu-Chek Solo patch pump, which has launched to ~200 people in Austria, Switzerland, Poland, and the UK. Roche expects the pilot launch will stay fairly limited and “definitely” will not exceed 10,000 patients in 2019. A booth representative shared that a pre-submission of Solo to the FDA is “running.” The rep added that Solo has received “excellent feedback” from patients so far. We were impressed by the very sleek on-body form factor, but the demo confirmed our view that the insertion process is more burdensome and complicated than Omnipod (see multiple components below). Solo consists of: (i) a plastic baseplate with adhesive; (ii) a 200-unit disposable reservoir – the representative emphasized that patients do not have to fill up the entire 200U so as to mitigate insulin waste; (iii) the reusable pump itself, consisting of the electronics, which last 120 days; and (v) a touchscreen, Bluetooth-enabled handheld controller with an integrated BGM. Solo is recommended for 3-4 days of use, although the representative underscored that this is not due to adhesive wear or battery life, but instead related to insulin absorption and utilization. The inserter is reusable (it looks like a computer mouse) and lasts for two years, and the pump holder and cannula (available in 6 mL and 9 mL) come together as a sterile package. Users are guided through the insertion process on the handheld controller. The handheld also includes a camera to scan a unique code located on the pump base for pump activation and pairing. The booth representative expects that the “last phase” of Solo will include pump control via a smartphone app, which will also integrate CGM data. We wonder if Roche may wait for this final version to launch in the US – the current controller doesn’t come close to Insulet’s excellent user experience on Omnipod Dash. The booth representative also anticipates “several cloud-based platforms,” including Glooko and Roche’s “in-house solution,” to be compatible with Solo.
In addition to the section on Solo, the Roche booth also had portions dedicated to mySugr and Senseonics’ 180-day Eversense XL CGM. Notably, “Roche” and “mySugr” were printed at equal size beneath “Accu-Chek” on the booth banner, reflecting Roche’s commitment to its digital ecosystem. At the Eversense XL section of the booth, representatives performed sensor insertion/removal demonstrations. We learned that Eversense XL just received reimbursement from three major insurance companies in Germany – a big win, which the booth representative believes will help to increase adoption. As expected, Senseonics recently renewed its distribution agreement for Eversense XL with Roche, adding 17 new countries.
Photo-based meal-logging app developer Snaq demoed its beta version at a small booth with fake food. Based on a photo, the app can identify food, count nutrients, and estimate weight, with the last being the product’s differentiating selling point. For example, in our demo, Snaq correctly identified 37 g of fake risotto and allowed the user to add the mushrooms and tomatoes present in the concoction that the camera couldn’t pick up. Given how difficult carb counting can be, especially with meals not prepared by the person themselves, this ability to estimate weight could significantly improve the accuracy of carb counting and insulin dosing, and the company is currently looking for partnerships to investigate titration and bolus calculation in the long-term future. Eventually, representatives are hopeful that insulin dosing recommendations could be made based on an iterative learning process – how a particular user responded to a specific food and insulin dose previously informs their next dose – an exciting concept for sure!
At the SOOIL booth, we learned that the company is no longer planning on bringing its smartphone-controlled Dana RS insulin pump to the FDA with a version of the open source OpenAPS algorithm as previously announced at ADA. Instead, SOOIL plans to submit as an ACE insulin pump (referencing FDA’s newly created pathway for interoperable pumps) and develop its own proprietary algorithm. It’s not clear if SOOIL still plans to submit with an open communication protocol in addition to registering as an ACE pump; given that Loop will be submitted to the FDA, it may be a bit redundant, although we would have liked to see a pump designed specifically around the needs of the DIY community. SOOIL has a six-month clinical trial planned in the US and ambitiously expects to launch by the end of 2019. The booth representative was uncertain as to whether the pump will be submitted as a standalone device or with SOOIL’s proprietary algorithm. Following ADA 2019, SOOIL plans to register its own algorithm and CGM within four months. This is the first we are hearing that SOOIL plans to develop its own CGM and it’s possible we could have misunderstood the representative’s comments – no further details were provided.
Tandem appeared in its first ATTD exhibit hall following the first international sales in 3Q18. Reps told us the t:slim X2 is now in 10 countries (currently with Dexcom G5 integration OUS), far more than we realized. The booth advertised Tandem’s Basal-IQ with Dexcom’s G6, which is expected to launch outside the US throughout 2019; timing will vary by country, and we expect to hear more in Tandem’s 4Q18 call today. Reps told us the PROLOG pivotal trial for Basal-IQ (presented at ATTD last year) has “really changed the conversation in the field” – no surprise, given the strong 31% hypoglycemia reduction, excellent user experience, and no fingersticks. We also asked about the upcoming Control-IQ hybrid closed loop with automatic correction boluses – reps were very excited about the fully enrolled US pivotal study (n=168), which has not had a single dropout and has seen very high time in closed-loop (see the update on Day #2).
The Ypsomed booth featured a map of planned YpsoPump expansions, including US and Canada in its anticipated launches for 2019. At EASD in October, a booth representative confirmed that the YpsoPump is still under FDA review following submission in May. A Canadian YpsoPump launch was initially expected in October 2018, now reflecting a notable delay. YpsoPump’s Canadian launch will come firmly behind Tandem’s t:slim X2, which was expected to begin Canadian shipments by end of 2018. On the pipeline front, the booth representative shared that pump control will be on the Ypsomed mylife app “in the near future.”
ATTD Yearbook Session
Self-Monitoring of Blood Glucose
Reporting on his and Dr. Irl Hirsch’s last ATTD Yearbook SMBG chapter, Dr. Satish Garg underscored the importance of this technology due to the mass unaffordability of CGM. He highlighted a number of abstracts, this year focusing on more on the efficacy of various strategies around BGM, not the technology itself. For example, he cited studies showing: (i) the importance of behavioral self-monitoring implementation in veterans; (ii) financial incentives had no improvements in A1c in teens; and (iii) blood glucose testing resulted in cost savings. Ultimately, he emphasized that decision support is where the field needs to go; “Whether with CGM and/or SMBG, only time will tell depending on cost. There’s no doubt in my mind that clinical decision support systems are effective in people with diabetes. However, it is time now to consider that mobile apps need to be standardized – there are many zillions of apps, and people get lost. There are significant reductions in medication errors when people use these apps. And they’ve been shown to reduce hypoglycemia.” Read the full chapter here.
Continuous Glucose Monitoring in 2018
Dr. Tadej Battellino reviewed three key studies highlighted in the CGM chapter, which has seen 18,000 downloads and is the fifth most downloaded chapter. He featured Dexcom’s DIaMonD type 2 MDI results, showing a benefit of CGM at 24 weeks. We were also particularly excited to see CONCEPTT and RESCUE included in his selection. In the 12-month RESCUE study, national Belgian reimbursement of CGM for 515 insulin pump users drove a striking 75% decline in hypoglycemia/DKA hospitalization. In total, the intervention resulted in an estimated nationwide cost reduction of €345,509. Patients achieved a significant 0.3% reduction in A1c (baseline: 7.6%) and improvements in time <70 mg/dl (11% to 5%; -1.4 hours) as well as quality of life metrics. RESCUE was published in The Journal of Clinical Endocrinology & Metabolism last March. Dr. Battellino characterized CONCEPTT as “completely landmark,” emphasizing that participants achieved time-in-range (68%) very close to that proposed as the consensus goal in pregnancy (70%) – of course, the consensus recommendations were made in part based on the CONCEPTT Data. He also noted the very encouraging newborn health outcomes and pointed out that the NNT were “rather low” to achieve the strong newborn reductions in large for gestational age (LGA), hypoglycemia requiring dextrose, and NICU admission >24 hours. CONCEPTT was published in The Lancet in November 2017. Read the full chapter here.
Dr. John Pickup highlighted six themes in the insulin pump chapter: (i) acute diabetes complications in CSII vs. MDI; (ii) infusion set and site problems; (iii) pumps in practice; (iv) sensor-augmented pump therapy; (v) pump therapy for type 2 diabetes; and (vi) use of fast-acting insulin in pumps. Providing just a taste of what we’re sure is quite a comprehensive chapter, Dr. Pickup shared two real-world studies. A large study (n>30,000) using registry data from type 1 patients >20 years across 446 centers in Germany, Austria, Luxembourg, and Switzerland examined outcomes with pump therapy vs. MDI. A1c (8.04% vs. 8.22%; p<0.001), insulin (0.84 U/kg vs. 0.98 u/kg; p<0.001), and severe hypoglycemia (9.55 events/100 patient-years vs. 13.97 events/100 patient-years; p<0.001) were significantly improved on pump therapy. DKA events were also significantly lower in pumpers compared to patients on MDI (3.64 episodes/100 patient-years vs. 4.26 episodes/100 patient-years; p=0.04), which may sound surprising due to the prevalence of occlusions/kinking in infusion sets, though Dr. Pickup added that this trend is surfacing in more and more registries. We suspect this might be a correlation – people who are more likely to go on pumps are less likely to go into DKA at baseline. In The second highlighted article was a retrospective study in type 1 adults (n=503) comparing long-term A1c changes over 10 years with different pump types (Medtronic, Animas, Roche, Omnipod). A1c benefits were maintained over 10 years and there was no difference in A1c changes between pumps, including patch vs. tubed pumps. Read the full chapter here.
Decision Support Systems and Closed Loop
DreaMed’s Dr. Revital Nimri kicked off her review of the decision support and closed loop chapter with a dose of perspective: While there were only two closed loop studies evaluated in the very first ATTD Yearbook in 2009, this number has climbed to 37 in a decade. She first outlined three themes for closed loop in 2019: (i) “Expanding the loop” – bringing closed loop to non-traditional populations, such as type 2s hospitalized for non-critical care (Dr. Roman Hovorka’s Cambridge group) and adults with hypoglycemia unawareness; (ii) addressing physical activity; and (iii) addressing postprandial hyperglycemia (including automated meal detection). Next, three themes (verticals) in decision support: (i) retrospective decision support (automated pump settings adjustment; DreaMed Advisor Pro); (ii) real-time insulin dosing advisors (shown to reduce hypoglycemia and glycemic variability for both pumps and MDI); and (iii) and predictive glucose advisor (enables participants to modify their initial dosing decision). Finally, she overviewed a couple of studies that leverage closed loop with additional inputs and/or periodic adaptations, positing that these methods will “probably be the next-generation closed loop…as long as (the former) will not add to the patient burden.” The studies she cited were from Dr. Jessica Castle et al. (glucagon, exercise detection) and Eyal Dassau et al. (zone-based MPC algorithm with adaptation). Read the full chapter here.
New Insulins, Biosimilars, and Insulin Therapy
Dr. Lutz Heinemann focused on biosimilars in his presentation on new insulins – last year’s most-downloaded chapter – which, despite a relative lack of interesting and novel publications, he identified as a newly-matured area of research. Indeed, he chose to focus more on the commercial/regulatory landscape than the science, simultaneously expressing enthusiasm over how many companies are currently working to develop biosimilars (he cited >20) and questioning how many candidates will actually come to market. Specifically, he cited Merck’s decision to pull Lusduna (biosimilar insulin glargine) commercialization (October 2018), a decision Dr. Heinemann attributed to Sanofi’s litigation against the candidate (Merck cited an unfavorable commercial environment). This is balanced against other wins: 2018 saw the entry of the first-ever biosimilar mealtime in with Sanofi’s Admelog (lispro). Dr. Heinemann also raised the issue of insulin quality – a conversation Dr. Alan Carter’s and his 2017 DTM presentation and subsequent publication has driven. As more insulins hit the market, this will only become more important, and he criticized the fact that companies are not required to report data on insulin batch quality. In the coming years, Dr. Heinemann anticipates “drastic changes” in the insulin market, particularly with regard to cost, and he predicted “5 to 10 insulin glargines on the market in a number of years.” Read the full chapter here.
New Medications for the Treatment of Diabetes
Dr. Satish Garg chose biosimilar insulins and SGLT inhibitors for type 1 as the two therapy classes that made the biggest splash in the past year. There’s no denying that SGLTs for type 1 have stepped squarely into the spotlight. Dr. Garg summarized key findings from inTandem, DEPICT, and EASE (focusing only on EASE-2 and skipping any mention of EASE-3 or the 2.5 mg dose of empagliflozin). He gave a nod to the positive CHMP opinion on dapagliflozin for type 1 in Europe, and announced that this indication just received a positive opinion in Japan following AZ’s submission in May 2018, though we haven’t found this news or a press release online. FDA hosted an Advisory Committee on Sanofi/Lexicon’s sotagliflozin for type 1 earlier this year, and a decision on that novel molecule is expected in late March. Dr. Garg acknowledged that SGLTs increase relative risk for DKA in type 1 patients, but emphasized the power of education to counteract this. He explained that DKA was less common in the placebo arm of many of these trials than it is in the real-world T1D population (~5% incidence in the T1D Exchange), which suggests that careful patient education can “reduce the background risk and the risk associated with SGLT inhibitors.”
Dr. Garg highlighted Sanofi’s Admelog as the first-to-market biosimilar mealtime insulin. This biosimilar formulation of insulin lispro showed comparable efficacy/safety vs. Lilly’s Humalog in the SORELLA studies. Dr. Garg lamented the fact that in the basal category, biosimilar insulin glargine (Lilly/BI’s Basaglar) hasn’t been dramatically discounted from its predecessor (Sanofi’s Lantus). He shared his hope that rapid-acting biosimilars prove significantly cheaper for patients. Read the full Yearbook chapter on new medications for diabetes here.
Using Digital Health Technology to Prevent and Treat Diabetes
Schneider Children’s Dr. Tal Oron, stepping in to at the last second to present, reviewed the digital health technology chapter of the yearbook (first-authored by Canary Health’s Dr. Neal Kaufman). The chapter breaks “digital therapeutics” into three verticals: (i) digital services – aim to modify patient behaviors to improve health outcomes; (ii) adjunctive digital therapeutics – support the use of traditional therapies such as medications, devices, and monitors; and (iii) digital drug replacements – seek to provide a clinical benefit as a replacement for a traditional treatment. We’re not sure we’d parse the landscape in this manner, since almost every digital health tool does both (i) and (iii), though any taxonomy in this nascent field is useful. The authors reviewed 19 articles from the year, including those from/about Canary Health, Welldoc, Glooko, Livongo, One Drop, and Omada. A separate paper that Dr. Oron highlighted found that a simple self-management website was cost effective at ~$25,000 per QALY gained – under pretty much any cost-effective threshold – and the number needed to treat to make the technology cost-saving relative to usual care was just 363. We’re hoping for far more reimbursement, uptake, and economic analyses of these apps/services, which have the potential to address the problem of scale in diabetes and general wellness. Read the full chapter here.
Immune Intervention in Type 1 Diabetes
- On immune interventions for type 1, Dr. Desmond Schatz focused on oral insulin and methyldopa as advances in diabetes prevention, rather than on cure efforts. In his words, “until we can prevent, there will never be a cure. Even if we implant cells or replace islets, the disease is likely to come back because of its autoimmunity aspect.” To this end, he started by reviewing the TrialNet Oral Insulin trial, which found no overall effect with oral insulin on type 1 prevention in autoantibody-positive relatives of people with type 1. However, there was a benefit in the secondary stratum of participants with mIAA and ICA or both GAD65 and ICA512 antibodies, in which type 1 onset was delayed by an average of 31 months – in his assessment, highly meaningful. As such, Dr. Schatz believes oral insulin could be part of a cocktail or combinatorial agent in the future, for a certain endotype (that is, multiple prevention/treatment strategies will likely be needed). To this end, three studies are currently ongoing for oral insulin: (i) another TrialNet trial (immune effects and safety in stage 1/2 t1d); (ii) the Pre-POInT-Early (dose-ranging study in genetically at-risk children following beneficial immune effects in a pilot study); and (iii) GPPAD’s POInT trial (primary prevention of autoimmunity).
- On methyldopa, Dr. Schatz pointed to a 2018 JCI study showing that the common blood pressure drug reduces inflammatory T cell response to insulin in people with type 1 diabetes and blocks the DQ8 antigen, a known source of disease risk. Based on these results, a study of methyldopa in autoantibody-positive individuals (also conducted by TrialNet) has been approved and was recently posted to ClinicalTrials.gov. As we’ve come to appreciate (and expect) from Dr. Schatz, we left his talk more inspired and optimistic than we entered. Oral insulin and methyldopa are only two of a plethora of agents under investigation for type 1 prevention, and his enthusiasm gives us hope over the many irons in the fire – particularly as combination therapies become more of a reality. To be sure, our competitive landscape signals increasing interest, even if widespread prevention and cure remain a long way off. Read the full chapter here.
Technology and Pregnancy
Out of an impressive 2,300 papers on diabetes technology and pregnancy, Dr. Helen Murphy chose 10 to include in the ATTD Yearbook chapter. She provided a sobering reminder of the need to focus on improving outcomes in pregnancy: the rate of stillbirths in type 1 diabetes and type 2 diabetes remains significantly higher than that in the background population. The rate of large for gestational age (LGA) has also increased; in fact, the proportion of LGA babies born to type 1 mothers has increased over the last decade by almost 10%. In addition to showing the strong CONCEPTT results evaluating CGM in pregnancy, Dr. Murphy also shared a cost-analysis of CGM in pregnancy presented as a poster in this meeting. She was particularly excited by the significant reduction in duration of NICU stay with CGM vs. SMBG (6.6 days vs. 9.1 days). NICU admission is quite expensive, and Dr. Murphy hopes the data will be compelling for payers. In total, Dr. Murphy estimates real-time CGM used by all type 1 pregnant women in the UK could save £10,077,958 million/year as compared to no CGM use. Read the full chapter here.
Advances in Exercise, Physical Activity, and Diabetes Mellitus
Dr. Michael Riddell picked out four intriguing, emerging findings/research areas in exercise and diabetes management: (i) significant, pancreatic fat content reduction after just 2 weeks of exercise; (ii) exercise volume, intensity, frequency, and duration are all associated with reduced premature mortality regardless of kidney function; (iii) mini-dose glucagon for hypoglycemia prevention in type 1 during exercise; and (iv) single- and dual-hormone artificial pancreas systems in exercise. On the third, Dr. Riddell noted that necessary snacks prior to exercise to avoid hypoglycemia often preclude net calorie expenditure during exercise, making glucagon a much more attractive option not only for improved glycemic control but also for achieving weight loss. Regarding AID systems, which he posited may have begun to “crack the nut” of exercise in type 1, Dr. Riddell extolled their adaptability in difficult situations (e.g., on the ski slope or in unannounced exercise) as well as in returning agency and improving quality-of-life. Read the full chapter here.
Diabetes Technology and Therapy in the Pediatric Age Group
Dr. David Maahs shared several papers examining use of diabetes technology (pumps, sensor-augmented pump therapy, and hybrid closed loop) and diabetes therapies (ACE inhibitors, statins, and metformin) in pediatrics. A large DPV registry study (n=30,579) comparing pump vs. MDI in children found pumps to confer lower rates of severe hypoglycemia, DKA, and lower A1c (8.04% vs. 8.22%). A six-month RCT (n=154) comparing the 640G with sensor-augmented pump therapy found the 640G to reduce time <70 mg/dl from 2.6% to 1.5% (-16 minutes). Looking at hybrid closed loop therapy with the 670G, Dr. Maahs presented a sub-analysis from the three-month 670G pivotal looking at just 14-26-year-olds (n=31). Time-in-range increased an “impressive” 14% and A1c decreased by 0.75%, and a significant linear relationship was observed between time-in-range and time in auto mode. On the therapy side, Dr. Maahs described a paper published in NEJM (n=443) finding use of ACE inhibitors and statins in adolescents with type 1 diabetes to result in no difference in the change in ACR (urine microalbumin). ACE inhibitors were associated with lower incidence of microalbuminuria (HR=0.57) but were not considered significant in the context of the primary outcome. Dr. Maahs pointed to a 12-month RCT (n=90) investigating metformin (1 g twice daily) in children with type 1 diabetes in which vascular function was found to improve independent of A1c and insulin dose decreased. Difference in adjusted A1c between groups over the 12-month study period was a significant 1.0%. We were pleased to hear Dr. Maahs end his presentation by honing in on the main goal – helping patients to stop worrying about highs and lows so that “kids can get on with what they’re trying to do.” Read the full chapter here.
Diabetes Technology and the Human Factor
Schneider Children’s Dr. Alon Liberman summarized the diabetes tech and human factor chapter, which he co-authored with Prof. Katharine Barnard. He expounded upon two of the articles that were included in the chapter, each with a focus on parenting and pediatric diabetes: One UVA paper detailed the perspectives of patients and physicians on how to improve the safety and functionality of an artificial pancreas system for younger children. Both parents and pediatricians emphasized that there are several risks associated with the application of system’s developed for adults/adolescents in children; to mitigate risk of injury, they recommend, among other things: (i) simple instructions/pictorials accompanying alarms to make the correct response easier for young patients and their care providers; (ii) a modified/flexible system to help children assume more responsibility of their diabetes management; and (iii) a messaging feature in artificial pancreas systems. The second article, a paper from Yale, looked at CGM and remote monitoring practices for children in school. Dr. Liberman emphasized the tremendous reported utility of remote monitoring, which the study found to ease parental concerns about overnight hypoglycemia and school-day safety. “One clear area for improvement,” said Dr. Liberman based on the data, is in augmenting the amount of retrospective glucose review to make insulin dose adjustments (i.e., Dr. Bergenstal’s “Thinking Fast and Slow”); 62% of respondents upload their data quarterly or less. Read the full chapter here.
Practical Implementation of Diabetes Technology: It is Time
In her Yearbook debut, Barbara Davis Center’s Ms. Laurel Messer took on the ambitious task of summarizing the current state of the “practical implementation” of diabetes technology, emphasizing that “it’s time we start looking at these devices…in the real world.” Her chapter, which concerned itself with aspects such as clinical utility, patient education, real-world use, economics/access, and benefits/barriers, zeroes in on three themes: (i) Use of technology in the real world (e.g., DIY, remote monitoring in school, and results of expanding access); (ii) practical challenges and solutions with diabetes technology (e.g., skin issues, insulin set failures, and targeted pump education); and (iii) access and cost-effectiveness of technology. She highlighted two articles from the year: The Belgian RESCUE study of CGM, in which the national health authority offered to reimburse CGM use in a subset of pump users (n=515) to see what the economics looked like in the real-world setting. We covered the highly impressive results in a poster at EASD 2017: People in the study saw A1cs decline alongside impressive reductions in hospitalizations and absenteeism. “I applaud them for finding a unique way to use payers to test a technology in the real-world. It’s not just about A1c or time-in-range, it’s also about the individual and societal benefits of technology.” On the opposite end of the spectrum, Ms. Messer highlighted a small Danish study (n=143 children/adolescents from two clinical sites) showing tremendous prevalence of skin reactions to pumps and CGMs. At the very moment of the study, 63% of pump users and 46% of CGM users were currently experiencing a skin reaction, and 90% of pump and 80% of CGM users reported having ever experienced a skin reaction. Ms. Messer concluded with three calls to action. We need: (i) better surveillance and tracking of skin reactions needed; (ii) more disclosure from industry about adhesive agents; and (iii) more clinical practice guidelines recommending skin assessment for chronic device use, like there is for statins/niacin, foot care, and peripheral neuropathy. Read the full chapter here.
-- by Adam Brown, Ann Carracher, Brian Levine, Payal Marathe, Peter Rentzepis, Maeve Serino, and Kelly Close