American Diabetes Association 78th Scientific Sessions

June 22-26, 2018; Orlando, FL; Day #3 Highlights – Draft

Executive Highlights

  • Diabetes Technology: Today was headlined by Dr. Roy Beck’s never-before-seen time-in-range analysis of DCCT (seven-point fingerstick) data – it turns out that the correlation is very strong between time in 70-180 mg/dL and microvascular complications, a big win in the fight to validate CGM metrics! It looks almost identical to the relationship with A1c, in fact, and you remember what a win that was back in Las Vegas in 1993, 25 years ago (nearly to the day). Meanwhile, we saw a trove of really valuable closed loop data: a compelling bihormonal study with pramlintide + insulin from McGill’s Dr. Ahmad Haidar (a strong case for coformulation), Insulet’s Omnipod Horizon five-day hotel data in adults (lots of patients wanted into this trial), Diabeloop’s 12-week home trial, a real-world analysis of 670G users that transition from MDI to the hybrid closed loop. And then there were posters. In CGM, Dr. Bergenstal shared his wisdom on decision-making with A1c vs. CGM and the launch of a new GMI (glucose management indicator) calculator on Jaeb.org; Medtronic demoed Guardian Connect/Sugar.IQ in a well-attended product theater (dosing advisor screenshots); and the JDRF-sponsored TIME trial showed the benefits of starting a CGM with a pump (vs. delaying the sensor). The exhibit hall was a treasure trove for new device news, including our first in-person look at Novo Nordisk’s NFC-enabled (near-field communication, explained inside) smart pen downloaded on Glooko’s Kiosk (super cool!); Companion Medical slick new smart pen+CGM reports; updates on Tandem’s about-to-start hybrid closed loop pivotal trial with TypeZero/G6 (the pumps have been shipped); more on One Drop’s 12-hour glucose prediction; SOOIL’s plan to submit for an iPump in the US; BD’s new Briight app for education and coaching in type 2; and more!

  • Diabetes Therapy:  On the type 2: Major findings from Janssen’s Invokana OBSERVE-4D study were that J&J’s SGLT-2 inhibitor Invokana did not increase amputation risk vs. other diabetes drugs or other SGLT-2s specifically and that SGLT-2s as a class demonstrate powerful risk reductions for heart failure. Our coverage of OBSERVE-4D below includes insights from Dr. John Buse (who seems to be everywhere) and Janssen’s Dr. Paul Burton. A late-breaking poster showcased full phase 3 oral-GLP-1 PIONEER 1 data from Novo Nordisk – oral GLP-1 looks good and it’ll be interesting to see what patients are selected for what delivery and how the two will differ in price and marketing strategy. Adjunct therapy for type 1 diabetes continued to steal the spotlight on day #3 of ADA, and a standing-room-only session featured one-year data from inTandem1 (Dr. Buse again presenting) and 24-week results from DEPICT-2 (Prof. Chantal Mathieu presenting). We’re so impressed with virtually every speaker at ADA, but these two are sure standouts and boy do they fill a major gap in type 1. Both Sanofi/Lexicon’s sotagliflozin and AZ’s dapagliflozin gave significant benefits on A1c, body weight, and time-in-range, while also confirming that DKA is a class effect of adjunct type 1 drugs – we knew that, of course, and we’re watching closely for how it’s being addressed (it’s so clearly how, not if risk can be mitigated and we know risk will be highest if this compound isn’t approved for type 1). On a very exciting note for type 1, Dr. Paresh Dandona authored a late-breaking poster showing ~0.6% placebo-adjusted A1c decline and ~6 lbs placebo-adjusted weight loss when GLP-1 agonist liraglutide was taken by type 1s on top of insulin. These results were much better than what Novo Nordisk saw in ADJUNCT back in 2015 … so does that mean revitalized interest from the field in adjunct GLP-1? YES, yes it does, and yet again, CGM use showed so much more detail than A1c alone ever did. On pre-diabetes, CDC’s Dr. Ann Albright provided an informative update on the National Diabetes Prevention Project (DPP) – we’d love to see about 10x the investment in prediabetes here, given how very much our country and world must be addressing this.

ADA 2018 is full-steam ahead, and today continued with 21 highlights from day #3 – 11 in diabetes technology and 10 in diabetes therapy. We also include our exhibit hall highlights, featuring 15 diabetes tech booths and 10 diabetes therapy booths.

See all of our previous day #1 and day #2 highlights on our ADA Resource Hub: www.closeconcerns.com/knowledgebase/ADA2018

Table of Contents 

Diabetes Technology Highlights

1. Using DCCT Data to Validate Time-in-Range! Dr. Roy Beck’s Compelling BeyondA1c Case for Time-in-Range Association with Complications

In a never-before-seen, compelling analysis, Jaeb’s Dr. Roy Beck showed the HIGH correlation between time-in-range in DCCT (taken from seven-point BGM profiles) and microvascular complications. It looked almost identical to the relationship with A1c! The pictures below tell the clear story: time in 70-180 mg/dl (>50%, 40%-50%, 30%-40%, <30%) had a stepwise correlation with retinopathy progression and development of microalbuminuria. Notably, each 10-percentage-point drop in time-in-range increased the hazard rate for retinopathy progression by 61% and for microalbuminuria by 53%. Wow! It is remarkable the correlation is this tight, given that seven-point daily fingersticks were only taken quarterly during DCCT (pre/post meals and pre-bedtime). If anything, Dr Beck pointed out, the correlation might be stronger with CGM, which would more accurately capture time-in-range after meals and overnight. Even still, he noted this data is a “strong association” and “gives a compelling case” to validate time-in-range as a predictor of long-term complications. Wow! It was also interesting to see time-in-range in the DCCT groups: 52% in the intensive group (A1c: 7.3%) vs. 31% in the conventional group (A1c: 9.1%). Dr. Beck added that since both A1c and time-in-range are primarily measures of hyperglycemia, they should correlate quite well with each other – we’re glad to see that played out here. The Jaeb team is in the process of looking at cardiovascular outcomes too; we’d guess the association would be weaker, but who knows! Dr. Beck emphasized that it would be costly and perhaps not possible to replicate the DCCT study to answer this question; perhaps this type of analysis will persuade regulators to accept time-in-range as an alternate efficacy endpoint. He also confidently noted the data already exists to validate time <70 mg/dl and <54 mg/dl – see the slide below, which we hope the FDA will take seriously as it considers CGM data and potential efficacy claims. (On this note, Dr. Beck mentioned the Beyond A1c group’s recent Diabetes Care paper, “Need for Regulatory Change to Incorporate Beyond A1c Glycemic Metrics.”) We look forward to seeing this fresh DCCT analysis formally published, hopefully soon!

    

 

2. Omnipod Horizon Closed Loop Over 5 Days: +2.7 Hrs/Day in Range (74% TIR), 63% reduction in hypoglycemia in 11 adults

Stanford’s Dr. Bruce Buckingham presented strong results from a five-day, free-living hotel study of Insulet’s Omnipod Horizon hybrid closed loop in adults (n=11, baseline A1c: 7.4%). The study compared 96 hours of hybrid closed loop with a tablet computer and Dexcom G4 CGM to seven days of patients’ standard therapy (27% MDI, 63% pump). Horizon drove a robust +2.7 hour/day improvement in the range of 70-180 mg/dl (74% vs. 63%, p=0.02), a dramatic 63% reduction in time <70 mg/dl (-46 mins/day: 1.9% vs. 5.1%, p=0.001), and a 47% reduction in time >250 mg/dl (-58 mins/day: 4.5% vs. 8.5%, p=0.01). Mean glucose was not significantly different between the groups – 150 mg/dl on closed loop vs. 156 mg/dl on standard therapy (p=0.46) – though with a larger study and broader population at baseline, perhaps this would have been significant. The same was true for time >180 mg/dl, which trended in the right direction: 25% on closed loop vs. 32% on standard therapy (p=0.12). Overnight glucose outcomes looked similar, with an even larger differential on time <70 mg/dl – an 88% reduction in hypoglycemia, from 5.7% to 0.7% (p=0.02). As seen in the picture below, closed loop narrowed glucose variability across the entire day, and coefficient of variation came in at a strong 33% overall (vs. 37% on standard therapy), including a very impressive CV of 26% on closed loop overnight. These results look great and compare quite favorably to the MiniMed 670G pivotal Horizon users were in closed loop 97.5% of time, outstanding and hopefully a good sign for the commercial product. It was great to see the study include 27% MDI users – key for Insulet to include, given its target market. This was also a pretty real-world challenge for the system, as the average meal size was 53 grams of carbs (largest meal was 200 grams of carbs!) and the 11 study participants engaged in a total of 43 exercise sessions averaging 54 minutes each (51% of which were moderate or high intensity). The algorithm targets 120 mg/dl, but participants could adjust their glucose set point temporarily anywhere between 100 mg/dl and 150 mg/dl – nice! A raised glucose set point was used for 37% of exercise sessions (mostly 140 or 150 mg/dl). Participants could also opt to use extended boluses, and 64% of participants chose to do so – a marker of how engaged this population is, perhaps even underselling the system’s benefit. Dr. Buckingham concluded that Horizon was safe and performed well over five days of use, and the team is planning further studies in 2-4 year olds. We’ll see the 6-12 year old and adolescent data from this study in poster form. It’s unclear when Insulet plans to do its pivotal, but we’d guess 2019 is likely at this stage.

  • To enable fast iteration, the team is still using a research platform: a tablet running the MPC algorithm and communicating to the Omnipod PDM and a separate Dexcom G4 receiver. The compelling commercial product vision remains an algorithm integrated into the tubeless pod and talking to the G6 directly – a full on-body closed loop ecosystem. The Dash PDM platform, adapted for Horizon, will allow users to interact with the system for meals, see G6 CGM values, view system status, etc.

  • “The system handled exercise reasonably well…We had a guy who could run a 4-minute mile, and he wanted to run a few miles at a 6.5 minute pace. We didn’t have anyone that could run that fast with the tablet to keep up, so we had someone follow him on a bike with the tablet.”

 

3. Impressive Bihormonal Insulin+Pramlintide Closed Loop Gives 86% TIR, +3 Hours/Day vs. Insulin Alone; No Sig Difference in Hypo Events or Side Effects; McGill/Lilly algorithm

McGill’s Dr. Ahmad Haidar presented some of the most compelling hybrid closed loop data of ADA (so far): use of pramlintide (amylin analog) on top of rapid acting insulin during a 24-hour, in-clinic, JDRF-funded study boosted time in 70-180 mg/dl by nearly three hours/day vs. insulin alone. There were no concomitant increases in hypoglycemia or side effects. 27 type 1 adults (mean age 39 years, mean A1c 7.8%) each used single-hormone closed loop (rapid insulin), dual hormone closed loop (rapid insulin + pramlintide), and dual hormone closed loop (Humulin R + pramlintide), in randomized order, for 24-hours in clinic. Basal-bolus pramlintide was delivered through a separate pump at a fixed ratio of 6 ug per unit of insulin to mimic co-formulation. On rapid insulin + pramlintide, patients spent a whopping 86% in-range, vs. 74% with rapid insulin alone and 68% with Humulin R + pramlintide. This translates to ~3 hours in-range per day than rapid insulin alone, and ~4.5 hours more than with Humulin R + pramlintide. Meals really drove the advantage, as shown in the quite compelling plots below. Mean glucose was also a significant 10 mg/dl lower on rapid insulin + pramlintide vs. insulin-alone and Humulin R + pramlintide (133 vs. 143 vs. 143 mg/dl). The same was true of coefficient of variation: 27% vs. 31% vs. 33%. Time >180 mg/dl was significantly reduced by 1.7 hours/day with rapid insulin + pramlintide compared to rapid alone (16.7% vs. 9.7%) There was no difference between rapid alone and rapid + pramlintide in terms of time <70 mg/dl. From an episodic perspective, there were 0.45 hypoglycemia events/day in the rapid insulin arm, 0.46 events/day with rapid insulin + pramlintide, and 0.7 events/day with Humulin R + pramlintide. It is still possible that pramlintide + rapid insulin caused greater time/depth of hypoglycemia than did rapid insulin alone, but the data presented is encouraging, as hypoglycemia is a risk with amylin. The swift PK/PD of the rapid acting insulin allows for what appears to be safe use in tandem with co-infused pramlintide, while the Humulin R-pramlintide combo seems less advisable. Regarding side effects (nausea, headache, vomiting, bloating, and heartburn), there were no observable differences between the three arms, and all reported events were noted to be mild. This preliminary data is highly encouraging, suggesting that amylin-insulin analog co-formulations could be very successful in closed loop for type 1s, especially because insulin is co-secreted with amylin in a non-diabetes beta cell. This study used the Class AP algorithm that Lilly licensed for its in-development hybrid closed loop – we can’t help but wonder whether Lilly will pursue this dual-hormone approach (after all, the company has said they are keeping an open mind with regards to closed loop system design). Lilly doesn’t have an amylin analog in its pipeline to our knowledge, but could well work with Adocia (who has an insulin/pramlintide coformulation), AZ (pramlintide, on the market), Novo Nordisk (long-acting amylin analog in phase 1), or Zealand/BI (long-acting analog). We’re not aware of other analogs in-development.

  • During the day, rapid insulin + pramlintide conferred a remarkable 82% time-in-range, compared to 60% in the rapid insulin arm. This makes sense, as one of pramlintide’s key attributes is its ability to blunt postprandial excursions). The improvement during the night was not significant (95% vs. 92%), though Dr. Haidar pointed out that there’s obviously not much room to improve from insulin alone. Daytime mean glucose with rapid insulin + pramlintide (143 mg/dl) bested that in the rapid insulin arm (155 mg/dl). At night, the rapid insulin + pramlintide arm had slightly greater mean glucose than rapid insulin alone (118 vs. 111 mg/dl), though this difference was not significant. The only significant difference with Humulin R + pramlintide was a ~2 hour decrease time-in-range overnight relative to rapid insulin alone. In Q&A, a physician noted that the improvements came during the day, so why not just use pramlintide at mealtime as it is currently indicated. Dr. Haidar responded that if he had a dual-chambered pump, he wouldn’t choose to deliver at night, but the advantage of co-formulation is the user only needs one infusion site, one cartridge, etc.  

  • Supplementing insulin with pramlintide in hybrid closed loop significantly improved postprandial response, particularly when the insulin was rapid-acting. The slide below depicts the responses in the cases when glucose at the start of the meal was <90 mg/dl (upper left), >180 mg/dl (lower left), and between 90-180 mg/dl (right). The figures demonstrate how pramlintide blunts postprandial excursions in all three scenarios, and even causes an immediate decrease in glucose following a meal when initial glucose is >180 mg/dl. 

  • In a post-trial survey, 19/26 (73%) individuals agreed or strongly agreed that they would use a co-formulation product of rapid insulin + pramlintide if it were on the market. Only three (~12%) disagreed or strongly disagreed. Further, 19/26 (73%) agreed or strongly agreed that rapid insulin + pramlintide made their sugar control more even or predictable (of course, this wasn’t exactly a placebo-controlled, blinded study). Meanwhile, 14/26 (54%) disagreed or strongly disagreed that they would use a co-formulation product of Humulin R + pramlintide, and 12/26 (46%) disagreed or strongly disagreed that Humulin R + pramlintide made their blood glucose more even or predictable.

  • Close Concerns Questions: Was there a reduction in insulin dose during the pramlintide arms (Dr. Haidar tells us the data is not fully analyzed yet)? If so, by how much? How cost effective is pramlintide when used in a co-formulation? Will any company pursue this to market? How much time did participants spend <70mg/dl? <54 mg/dl? Was there an overall reduction in time <180 mg/dl? Will Lilly pursue a pramlintide + rapid insulin algorithm? Would this have greater efficacy over insulin + glucagon?

  • Details on methods and logistics: The study used Dexcom sensors and Medtronic pumps with the patients’ usual rapid-acting insulins. Algorithms for basal deliveries were identical, while bolus deliveries were different across interventions – meals and carbs were announced to the algorithms. Each intervention was preceded by a two-week run-in to titrate dosing, after which the participant came into the clinic for 24-hour evaluation including three self-selected meals and one snack.

4. Diabeloop 12-Week Data: ~3 Hr/Day Increase in Time 70-180 mg/dl vs. Open Loop (+~2 Hrs/Day Adjusted for Disparate Baseline A1c)

12-week home data from Diabeloop’s WP7 (n=67) randomized crossover trial of its AID system (Cellnovo patch pump + Dexcom CGM + algorithm on handset) were very positive, with time in 70-180 mg/dl increasing by 2.9 hours/day vs open loop (69% vs. 57%). Due to a discrepancy in baseline A1c (7.9% in the open loop group, and 7.3% in closed loop), the authors also presented mean adjusted data, which still suggested a ~2 hour mean increase per day in time 70-180 mg/dl vs. open loop (67% vs. 59%). Because this is just an interim readout of the first segment of a real-world crossover trial – as requested by the French Health authorities – the difference in initial A1c levels will come out in the crossover period. Adjusted for baseline A1c, the closed loop group spent 50 minutes less per day <70 mg/dl (1.6% vs. 4.9%), 10 minutes less per day <50 mg/dl (from a low base; 0.1% vs. 0.8%), and 30 minutes less per day >300 mg/dl (2.6% vs. 4.5%). Efficacy in the overnight period was very similar to that seen in the 24-hour data. From a safety perspective, the open loop group experienced two severe hypoglycemias, while the closed loop group had zero “due to the Diabeloop device,” and three “not linked to the Diabeloop device” – this was not further clarified. There was no DKA in either group. The slide below shows tightening and slight lowering of the glucose profile compared to the open loop control during both day and night, though differences in mean glucose and coefficient of variation (CV) were not significant: Mean glucose was 165 mg/dl in open loop vs. 161 mg/dl in closed loop; the improvement in CV from 33.8% in open loop to 31.8% in closed loop trended toward, but did not reach significance (p=0.062). The second “crossed-over” arm of WP7 is still ongoing.

  • Up next, Diabeloop aims to obtain CE marking, complete the second half of WP7, commence WP8 (a study for European reimbursement), and evaluate the system in kids. As a reminder, the first iteration of Diabeloop’s automated insulin delivery system is set to roll out in France, the Netherlands, and Sweden in late 2018 – though Cellnovo’s pump was used in WP7, we’re not sure if Cellnovo’s, Kaleido’s, or both patch pumps will be used in the initial launch. This system could be the first hybrid closed loop on the EU market, depending on when 670G launches. (Tandem has not given Basal.IQ timing for Europe.) We also learned yesterday from Ms. Dana Lewis that Diabeloop will incorporate features inspired and at least partially designed by the OpenAPS community in its second-generation closed loop, expected to begin rolling out in early 2019.

  • The French Health authorities required Diabeloop to offer the telemedicine services of dedicated nurses for the purposes of the trial. A skeptical audience member asked if the improvements were due to the remote support or the closed loop, though we would assume both groups had access to the nurses. In the future, not all Diabeloop systems will come with the telemedicine contacts. 

5. Stanford/UVA/Mt. Sinai Poster: 27% of Meals Are Accompanied by Late or Missed Bolus in Adults and Adolescents on MDI (n=24) – with G5 and Connected NovoPens

A Stanford/UVA/Mt. Sinai poster showed that adults and adolescents (n=24) using  smart pens in a study regularly miss or are late with mealtime boluses. While previously this kind of data would have been rendered largely “invisible,” by using CGM (Dexcom G5) and connected pens (Novo Nordisk NovoPen Echo Plus or NovoPen 5 Plus) the investigators filled in the gaps in insulin dose history. Seven days of data were analyzed upon initiation of the devices followed by an additional seven days one month later. 1,173 meals in total were evaluated, identified by either the subject manually recording the meal through the TypeZero InControl Decision Support System app, or if the CGM read >70 mg/dl and there was a >70 mg/dl rise within two hours. A late meal bolus was defined when CGM increased >50 mg/dl from baseline prior to the insulin dose, and a missed meal bolus was defined by no insulin dose within two hours before the start of the CGM rise (see picture below). In total, 27% of meals had either a late or missed meal bolus, with 13% of total meals accompanied by a late bolus, and 14% of total meals with no bolus whatsoever. We’re willing to be that the rates of missed or late boluses in the general population – particularly when type 2 is included – is higher than in this study. Importantly, although not surprisingly, there was a positive correlation between the percentage of missed meal boluses and A1c levels (p=0.02); there was no significant correlation between late boluses and A1c. It would be interesting to calculate how many missed/late boluses it would require for an individual to have any given A1c – this data was not provided, but has been shared in publications on pumps (Burdick et al., Pediatrics 2004).  We’d be interested to see how missed boluses affects other outcomes like time-in-range and PROs like diabetes distress and treatment satisfaction. No significant differences were observed when comparing results between the first and last weeks of the study. We think this is an incredibly important trial, clearly demonstrating the value of connected pens and digital dose capture for injection users. Hopefully, as more connected pens launch, MDI data will facilitate more informed conversations between providers and patients and drive more efficient/effective insulin use. A late breaker on Monday will explore a similar topic – the degree to which patients actually prime insulin pens prior to injection. (Our guess: They don’t.)

6. Dr. Rich Bergenstal on A1c vs. CGM: What Action Do I Need to Take to … New “GMI” Calculator at Jaeb.org/GMI/ (formerly “eA1c”)

In a way that only he could, IDC’s Dr. Rich Bergenstal summed up the beyond A1c with a simple statement: “A1c answers the question, ‘Do I need to take action to prevent long-term complications?’ CGM answer the question, ‘What action to I need to take to prevent long-term complications, prevent short-term complications, and reduce the burden of diabetes and improve quality of life?” What a great way to phrase it! We think these questions should be written into textbooks TONIGHT – if diabetologists and GPs are trained to think this way, the beyond A1c movement will be the norm. However, we might suggest one minor modification: A1c answers “Might I need to take action to prevent long-term complications.” A high A1c doesn’t necessarily mean a patient is at high risk of complications if they have a condition artificially raising their A1c beyond that which would be reasonably expected from their mean glucose.

  • After introducing the concept of GMI (Glucose Management Indicator) to replace the confusing term “eA1c,” Dr. Bergenstal unveiled a brand-new GMI calculator on the Jaeb Center’s website: https://www.jaeb.org/gmi/. Nice! The formula for this calculator is slightly different from that used in eA1c calculation, since it is derived solely from CGM data from five recent studies, but it is the same idea. Hopefully this will be published soon and companies can get it back in their reports. We particularly like that the calculator comes with the disclaimer: “The GMI may be similar to, higher than, or lower than the laboratory A1c. Differences between the GMI and laboratory measured A1C may reflect differences among individuals in the lifespan of red blood cells or how glucose binds to hemoglobin in red blood cells or could occur do to a recent, short term fluctuation in glucose control.” Nice!

  • Dr. Bergenstal also listed the top four reasons, in his mind, that A1c is limited:

    • (i) Using A1c alone to guide improvement in care isn’t working – “it hasn’t gotten us too far.” 52% of people are still not down to 7% A1c, and only 30% of people on insulin have reached an A1c of 7%, he cited.

    • (ii) There is not broad agreement on A1c targets. Is it ≥6.5%? (AACE) ≥7%? (ADA) 7%-8%? (ACP) ACP recently stirred up controversy, ‘everyone should be between 7%-8%, and if you’re older than 65, we don’t care about you anyway,’” he joked. A recent article, he noted, suggested that experts convene and agree on A1c guidelines. And if A1c is used to guide treatment, set rational targets by age, comorbidities, etc.

    • (iii) A1c tells only part of the story of glucose control/management. He showed a series of AGPs with vastly different profiles and identical A1cs, then asked: “Do you really want to use A1c alone? I think we want to know what A1c is for complications, but not for treatment.”

    • (iv) Complications: More than long-term vascular disease. A1c misses short-term complications (hypoglycemia), diabetes-related distress and burden of living with diabetes, and sleep.

Questions and Answers

Dr. Nicholas Argento (Maryland Endocrine and Diabetes Center, Laurel, MD): For Abbott Libre Pro, the population mean glucose for an A1c of 7% was 143 mg/dl, whereas the population mean for an A1c of 7% on other CGMs was 155 mg/dl. Is that an outlier?

Dr. Bergenstal: The formula we have currently was a mix of new generation – Dexcom, Libre – and from several thousand patients. Over time, I think with the scrutiny of how tight you have to be and how accurate you have to be, they’ll be squeezed in, and they’ll be pretty equivalent. But maybe there’s a slight variation. We haven’t changed the formula [for different sensors] at this point.

Dr. Argento: Best I can tell, Libre is 12 points different from Medtronic and Dexcom. That’s a half point of A1c.

Dr. Bergenstal: Let’s see more data. Treating the profiles gets you to where you need to be – how much you rely on this exact metric is up to you.

Dr. Sue Kirkman (UNC): Just to play devil’s advocate, did we ever rely only on A1c, especially for type 1 diabetes management? I agree with what you’re saying, but it’s a bit of a strawman, don’t think anyone would say we shouldn’t use only A1c?

Dr. Bergenstal: Ah, type 1, 5% of the population…I don’t think we only relied on it, but we never got enough SMBG data, and we sure missed a lot of hypoglycemia, especially overnight, no matter what we did.

Dr. Kirkman: Also, why bring back the number [eA1c] and call it GMI, when the units are exactly the same as A1c? How is that less confusing?

Dr. Bergenstal: Well the expectation is not there that the two should agree. The expectation shouldn’t be that it’ll agree with the lab value. There are good reasons it shouldn’t agree, and you can decide which to trust. If you have a good two weeks of CGM, and your eA1c is 0.6% lower than your lab A1c of 7.2%, then I’d argue you have to be careful.

Dr. Kirkman: Why not just use average glucose then?

Dr. Bergenstal: Well they already know the A1c, now we’re saying be careful when making A1c targets, because the number is always running higher or lower than expected.

7. Medtronic 670G Real-World Data – Similar Change in Former MDIs Between Manual and Auto Mode; No-Baggage Advantage?

Medtronic’s Dr. Scott Lee shared interesting real-world data from former MDI users who transitioned to the MiniMed 670G (n=241), comparing their CGM data on 670G in Manual Mode vs. Auto Mode. As the table below shows, relative to the pivotal trial and a bigger real-world 670G data set from 30,337 users, these 241 former MDI users had similar Auto Mode outcomes on the MiniMed 670G: 73% time-in-range (70-180 mg/dl), 2% time <70 mg/dl, and 25% time >180 mg/dl. The change from manual mode was also similar to the other groups: a +1.9 hour improvement in time-in-range (73% vs. 65%), no change in hypoglycemia, and an 8 mg/dl improvement in mean glucose. Notably, the MDI users spent 82% of the time in Auto Mode, slightly higher than the real-world users (79%) and closer to the pivotal’s 87%. Dr. Lee clarified in Q&A that these are not pre-670G outcomes on MDI vs. 670G Auto Mode outcomes – the real question we’d want to see answered. Instead, these data reflect how someone on MDI did after transitioning to 670G, both in Manual and Auto Mode. The bigger question will be answered in Medtronic’s currently-recruiting outcomes study (goal of n=1,000). As a reminder, the 670G pivotal study required patients on a pump for at least six months (± CGM) – it’s great to see positive outcomes in MDI users, even if it’s a small fraction of users to start.

  • Dr. Lee commented on his own practice, noting that many MDI users have had an easier time transitioning to the 670G than many pump patients: “In some ways, they have less luggage from wanting to control every single blood sugar and every single insulin delivery.” This is a great point and something we had not appreciated – and a sign closed loop might actually expand the pump market more than others thought. The real homerun closed loop product for MDIs will be Insulet’s Horizon, though over time Medtronic could get there with smaller and more intuitive versions of the 670G.

8. Medtronic Guardian Connect Product Theater: Emphasis on Sugar.IQ as Key Differentiator; Plans for HCP-Facing Decision Support, MDI Dosing Assistant

Medtronic’s Guardian Connect CGM product theater focused mostly on the paired Sugar.IQ app’s insights and next-gen pipeline – including a look at future plans for healthcare provider insights and an MDI dosing assistant powered by IBM Watson. The dosing insight noted very specifically, “Your next dose is going to be 2 units at 5:50 PM. Input carb: 80G. insulin type: Short-acting.” Said Medtronic Head of Digital Health Solutions/AI Dr. Huzefa Neemuchwala, “We were first to bring hybrid closed loop to market, and we plan to be the first to bring closed Loop to MDI users.” Now that’s a line in the sand! This would of course provide a Medtronic answer to what Bigfoot and Lilly (among others) are doing to close the loop for people on injections with apps, CGM, and smart pens. (Medtronic has not announced what its hardware plans on the smart pen front.) It also aligns with Medtronic’s new business unit, MDI Solutions, led by Laura Stoltenberg. No timing was shared today on the dosing assistant, though we know from the early June Analyst Meeting that it is targeted to launch within two years (by April 2020). Meanwhile, our first-look at Sugar.IQ-driven healthcare provider insights looked fantastic. Near-term, a provider dashboard would show similar insights as patients will see on Sugar.IQ (i.e., unique days, unique repeated habits, meal responses, rapid glucose changes, bolus habits). However, next-generation HCP insights will give clinical decision support driven by IBM Watson, advice that a provider can simply “Deliver” to the patient from their dashboard or “Skip”– e.g., “increase insulin sensitivity factor from 2 to 2.2” or “Increase Bolus Wizard target glucose value from 90 to 95 mg/dl.” Nice! (No timing shared, but this could be the “intelligent therapy recommendations” expected to launch within two years.) Dr. Neemuchwala also mentioned the “Inner Circle” CGM gamification/engagement app a few times in quick passing, but didn’t share more details or specific timing; as of the Analyst Meeting, this is expected to launch within the next year (by April 2019), allowing users to redeem points for more time-in-range. Dr. Neemuchwala shared two other notes on Sugar.IQ: (i) the company’s goal to push a new version of Sugar.IQ every three months; and (ii) plans for Sugar.IQ to fit into its larger strategy on value-based diabetes care. Otherwise, most of the product theater was review from Friday’s oral presentation, what we saw at ATTD on Guardian Connect, and things we’ve previously seen on Guardian Connect/Sugar.IQ – see our report on the launch from a few weeks ago.

9. Pediatric Overnight Time-in-Range Increases 1.3 Hours with MiniMed 670G; Post-Market Pediatric Study Investigating CGM-Naïve and Pump-Naïve Patients

Barbara Davis Center’s Dr. Gregory Forlenza shared unpublished data on overnight to early-morning glycemic outcomes in pediatrics (7-13-year-olds) with the MiniMed 670G/Guardian Sensor 3 hybrid closed loop. The results (n=105) are broken out from the three-month pediatric pivotal study presented at ATTD in February. The single-arm, multi-center investigation found the 670G significantly increased overnight (10PM – 7AM) time-in-range (70-180 mg/dl) from 57% to 71% (+1.3 hours). Overnight time <70 mg/dl also improved significantly, dropping from 5% to 2% (-16 minutes), and overnight time >180 mg/dl decreased from 39% to 27% (-1.1 hours). To us, these data sound like many more uninterrupted nights of sleep for child and parent, which is easily one of the most compelling outcomes of hybrid closed loop. Mean glucose declined from 166 mg/dl to 155 mg/dl. Impressively, the time during which no insulin was delivered increased a whopping 108 minutes – that’s nearly two hours! As Dr. Forlenza pointed out, this alone clearly demonstrates the benefit of matching insulin delivery to physiologic demand, which is impossible with a single set basal rate every night. We were delighted to see the 670G obtain FDA approval for 7-13 year-olds on Thursday, becoming the first hybrid closed loop system indicated for pediatric use. Dr. Forlenza mentioned during Q&A that a post-market study is currently underway to investigate outcomes in CGM-naïve patients, as well as those transitioning from MDI – see it here (goal of n=1,000 participants). He expects the next round of post-market studies to focus on patients with a higher baseline A1c (baseline A1c in the pediatric pivotal was 7.9%). The seven-site, three-month 670G study (n=50) in children ages 2-6 is still ongoing.

10. JDRF-Sponsored CGM TIME Trial: Greater CGM Adherence in Pediatrics when CGM is Initiated Simultaneously with Pump Therapy vs. After Six-Month Delay

Dr. Margaret Lawson (Children’s Hospital of Eastern Ontario) presented results from the JDRF-sponsored CGM TIME trial, demonstrating higher CGM adherence in pediatrics when CGM is initiated at the same time as pump therapy as opposed to after a six-month delay. The five-site, randomized controlled trial (n=144) evaluated the number of hours per 28 days that pump-naïve children (5-18 years) with type 1 diabetes used CGM over a span six-months. The study excluded those who had used CGM for more than 50% of the time during the six months prior to the study. Those randomized to simultaneous initiation of CGM and pump therapy spent an additional 2.8 hours/day wearing CGM during the final month of the study than those in the delayed group. Significant differences in wear-time between the two groups were observed consistently and (modestly) increasingly, beginning in month one. There were no significant differences in A1c, despite better CGM adherence in the simultaneous start group (though it’s possible hypoglycemia and hyperglycemia might have been lower in this group). Females exhibited significantly higher adherence overall. Dr. Lawson noted that there were unexpected differences in adherence by study site. In fact, she mentioned during Q&A that in two of the five sites, “CGM was not used very well at all,” despite implementing standardized education and initiation protocols. Dr. Lawson is interested in further investigating the differences between sites to potentially identify predictors of CGM success. We wonder how CGM adherence might change if pump therapy was initiated six months later – especially as the field is shifting toward a “CGM-first” mindset. Wearing a sensor would theoretical give pump-naive patients a better understanding of their diabetes before handing them a tool to fine tune insulin delivery.

  • We’re not entirely sure why the investigators decided to include participants who had used CGM in the past, rather than a completely naïve population. Was it to investigate the behavior around trying CGM for a second time after low initial adherence? Of course, behavior in an RCT is inherently flawed, so researchers might be better off studying real-world observational data. Perhaps it also had to do with a shortage of enrollment with stricter exclusion criteria – CGM is increasingly common in young children with type 1, at least in the T1D Exchange.

11. CDC Partnership with Google to Adjust Type 2 Diabetes Google Health Card; CDC to Host Telehealth Think Tank Next Week to Address Regulatory, Payment, Tech DPP Barriers;

The CDC’s Dr. Ann Albright described several exciting ways in which the National Diabetes Education Program (NDEP) is incorporating technology to drive diabetes prevention. The CDC is currently partnered with Google to adjust the Google Health Card that appears when users search for “type 2 diabetes.” Currently, the card includes some information on prediabetes, but Dr. Albright believes it can be optimized to connect users to resources and increase participation in the CDC’s diabetes risk test. A new version of the card has been developed and is currently being tested. Dr. Albright also highlighted a new digital tool for DPP coaches to share with their patients. The modules, which are currently being tested in the field, have helped patients feel more engaged, as well as reinforced their commitment in the program.

  • Dr. Albright strongly asserted that the National DPP can be delivered effectively both in-person and virtually (not surprising, as the CDC has fully recognized at least six digital DPPs). She stressed that head-to-head studies comparing the two modalities aren’t useful, as the main goal is to create as much access as possible – programs should instead be compared to the CDC standards. Dr. Albright encouraged the use of technology, noting that virtual DPP delivery can reduce behavioral and structural barriers that might otherwise prevent individuals from participating in in-person programs. While she highlighted Medicare reimbursement of DPPs as a potential “big win for all of us,” she recognizes that there is still much to be done in expanding access. To this end, the CDC is hosting a Telehealth Think Tank next week to address regulatory, payment, and technology barriers for the DPP. The results will be made publicly available – we’ll be eager to hear any discussion on Medicare reimbursement for digital DPPs, which many were frustrated to see not included in CMS’ decision last summer.

Diabetes Therapy Highlights

Adjunct Therapy for Type 1 Diabetes

1. DEPICT-2 Confirms Farxiga’s (Dapagliflozin) Potential in T1D: SGLT-2 Inhibitor Lowers A1c, Body Weight, Insulin Doses; DKA Story Continues

Prof. Chantal Mathieu shared the first public results from DEPICT-2, investigating AZ’s SGLT-2 inhibitor dapagliflozin in patients with type 1 diabetes. ADA published a press release on this data simultaneous with the start of her oral presentation. DEPICT-2 (n=813) largely matched DEPICT-1 (n=833) in terms of major efficacy results, although there was an imbalance in DKA events which wasn’t seen in the first trial. After 24 weeks, patients randomized to 5 mg dapagliflozin as adjunct to insulin (n=271) saw placebo-adjusted A1c decline of 0.37%, while those randomized to 10 mg dapagliflozin (n=270) saw placebo-adjusted A1c decline of 0.42% (both p<0.0001). Baseline A1c was 8.4% across the trial. Weight loss was 3% greater in the 5 mg arm vs. placebo and 4% greater in the 10 mg arm vs. placebo (both p<0.0001). Baseline body weight was ~174 lbs (BMI 28 kg/m2). Total daily insulin dose fell 11% regardless of dose relative to placebo (p<0.0001), and at baseline, participants were taking 0.7 units/kg. Prof. Mathieu paused to emphasize the composite endpoint of ≥0.5% A1c reduction without severe hypoglycemia, achieved by 40% of the lower dose group and by 42% of the higher dose group vs. only 20% of the placebo group. DKA occurred in seven and six people from the 5 mg and 10 mg dapagliflozin arms, respectively, which corresponds to event rates of 2% and 3%. There were no instances of DKA reported in the placebo arm. Prof. Mathieu reviewed data on DKA events in pump users vs. MDI, episodes caused by pump failure vs. missed insulin dose, ultimately concluding that there was no clear pattern and DKA is a risk inherent to dapagliflozin and to adjunct type 1 diabetes therapies more generally. She continued, these events were sporadic throughout the 24 weeks of DEPICT-2; they weren’t concentrated toward the beginning of the study, when patients have just started their SGLT-2 prescription. These results and Prof. Mathieu’s comments confirm our sense that DKA is a class effect of adjunct therapies for type 1; even after DEPICT-1, DKA was still a concern for this molecule, and Prof. Mathieu clarified that events were balanced in that earlier study because of a higher rate in the placebo group – this is not surprising from our view, and our focus is still on how the field minimizes the chance of DKA. Now that AZ has submitted dapagliflozin for a type 1 indication to EMA (FDA filing planned for 2H18), and now that Sanofi/Lexicon have submitted sotagliflozin for type 1 to both FDA/EMA, the field needs to establish best practices for DKA risk management. There’s no question in our minds that the benefits far outweigh the risks, and we hope for more answers on DKA risk mitigation in the coming months: How often should patients taking an adjunct SGLT be asked to check ketones? By how much should their insulin dose be adjusted? Basal or bolus reduction? See our coverage of the ATTD Consensus meeting (hosted in conjunction with ADA 2018) for more.

  • Prof. Mathieu gave a preview of the CGM data from DEPICT-2 – more granularity on these results will come on a late-breaking poster (125-LB). Time-in-range (>70-180 mg/dl) increased 6% in six months with 5 mg dapagliflozin – that’s 1.5 hours per day that a patient spends feeling well, not working to correct hyper or hypoglycemia. In the 10 mg dapa arm, time-in-range grew 8% – that’s nearly two hours (both p<0.0001 vs. placebo). In the placebo group, time-in-range actually decreased 3% (this may not sound like a lot – it’s ~45 minutes/day, which is nearly five days a year!). We cannot emphasize enough the value of time-in-range as an outcome, because of how closely it’s correlated with quality of life (direct relationship) and with diabetes work (inverse relationship). Prof. Mathieu also reported a 10 mg/dl reduction in MAGE with 5 mg dapa (p<0.0001) and a 9 mg/dl reduction with 10 mg dapa (p=0.0001), highlighting the postprandial improvements with this adjunct treatment on top of insulin. There was no significant difference in hypoglycemia across groups.

  • DEPICT-2 was a global study enrolling patients from 136 centers across 13 countries. Prof. Mathieu noted that the trial population was in pretty poor control at baseline: Inclusion criteria included A1c between 7.5%-10.5%, and one in five participants entered the study with an A1c >9%. Prof. Mathieu also highlighted the “remarkable retention” of DEPICT-2, explaining that 90% of patients starting on dapagliflozin continued through the six-month mark compared to 88% of placebo-treated patients – good patient selection, of course, and they love it as it fills a gap.

Select Questions and Answers

Q: Did you find that people with higher baseline A1c had more DKA? What was the effect of education?

A: In DEPICT-2, patients were educated to measure ketones when they felt sick. They were also instructed to eat carbs, give bolus, contact a medical team, etc. We looked at all 13 events but couldn’t find a pattern with higher A1c. Most events were random, not only happening at the beginning, but just throughout the six months.

2. inTandem Trial Extensions Support Sustained Benefits of Sanofi/Lexicon’s Sotagliflozin in T1D; Data Reinforces DKA Risk, Suggests Interesting Dose-Dependent Effects; Full 24-Week Pooled CGM Results

In an absolutely packed oral session, Dr. John Buse presented 52-week inTandem1 results (n=793), reinforcing the glycemic and weight loss benefits of sotagliflozin in adults with type 1 diabetes, while also confirming the DKA risk associated with all SGLT inhibitors in type 1. See the full results in Diabetes Care and the 24-weeks results here. At 52 weeks, sotagliflozin 200 mg gave a 0.25% drop in A1c vs. placebo (p<0.001) and 400 mg gave a 0.31% drop vs. placebo (p<0.001). This compares to placebo-adjusted A1c reductions of 0.36% and 0.41%, respectively, at 24 weeks. There was a noticeable rise in A1c during the trial’s extension period, but still a significant reduction overall. The net benefit endpoint of A1c <7% with no severe hypoglycemia or DKA was observed in 26% of sotagliflozin 200 mg participants vs. 19% of placebo participants, just missing significance (p=0.05). Sotagliflozin 400 mg gave net benefit in 32% of participants, and this was statistically significant compared to placebo (p<0.001). We remain very curious about the relative risk/benefit with respect to dose: Overall, higher doses have been associated with greater risk of DKA, but they also seem more effective on glucose and weight loss. Other endpoints also revealed dose effects of sotagliflozin: 200 mg was associated with a ~4 mg/dl drop in fasting plasma glucose (p=0.028 vs. placebo) vs. ~11 mg/dl with 400 mg (p<0.001 vs. placebo); this compared to a ~9 mg/dl rise in the placebo group. Dr. Buse also shared CGM data from inTandem1, noting a superior effect on 400 mg sotagliflozin vs. the 200 mg dose on pre-meal glucose in the context of overall increases in time-in-range with both doses. Notably, these results were presented alongside DEPICT-2 at the end of an oral presentations session otherwise dominated by tech trials, and Dr. Buse made a point to comment that the time-in-range benefits seen in inTandem1 were “on par with those discussed by speakers earlier in this session.” Exact numbers were not given but pooled CGM data from inTandem1 and 2 showed +1.3 hours and +2.8 hours more time-in-range with 200 mg and 400 mg sotagliflozin. Sanofi/Lexicon have filed sotagliflozin with FDA and EMA for a type 1 indication, and regulatory decisions are anticipated in 1Q19.

  • On the all-important safety endpoint of DKA: 11 participants on 400 mg sotagliflozin experienced DKA (4.2% of the group), as did nine participants on 200 mg (3.4%) and one on placebo (0.4%). For a comprehensive take on DKA risk management, see our report on Friday’s SGLT/DKA consensus meeting. These DKA data include events adjudicated as (i) definite DKA and (ii) probable DKA. There were 22 events overall, in 21 patients. For 15 of 22 events, blood glucose at the time of DKA was >250 mg/dl; for the remaining seven, blood glucose was ≥150-250 mg/dl. As such, no truly euglycemic DKA occurred, and Dr. Buse himself has previously identified this as the real challenge, because blood sugar levels don’t alert a patient to anything being wrong. That said, blood glucose between 150-250 mg/dl wouldn’t necessarily cause alarm in most patients with type 1 diabetes. While exact data were not shared, Dr. Buse noted during Q&A that proportionally more DKA events occurred in patients on pumps. He also clarified that participants were instructed to check ketones when feeling unwell; in his practice, they were also told to check intermittently as general practice, though we understand that this was not part of the official inTandem1 protocol. Participants were given both blood and urine ketone testing supplies. Genital mycotic infections were also increased in the 200 mg (9%) and 400 mg (13%) groups vs. placebo (3%), as is to be expected for an SGLT inhibitor.

  • Weight loss continued through 52 weeks, and there was a significant benefit with 400 mg over 200 mg sotagliflozin. From a baseline ~192 lbs, participants in the 200 mg group lost a mean ~7 lbs vs. placebo, while those on 400 mg of the drug lost a mean ~10 lbs vs. placebo. This represents a respective increase over ~5 lbs and ~8 lbs at week 24, driven by both weight loss in the sotagliflozin groups and ~2 lbs weight gain in the placebo group. Based on the graph in Dr. Buse’s presentation, it was clear that weight loss in the sotagliflozin groups did not level off over the 52 weeks, reflecting what Lexicon sees as one of the key benefits of the dual SGLT-1/2 inhibitor mechanism.

  • Sotagliflozin was associated with a numerical benefit on severe hypoglycemia (no significance given). In the placebo group, 26 people (10%) experienced an episode of severe hypoglycemia, which was reduced to 17 (7%) in the 200 mg group and an identical 17 (7%) in the 400 mg group. In our view, this trend is quite clear (we’ll be interested to see full data from the rest of the inTandem program), and indeed, Lexicon has expressed its intention to make hypoglycemia data a key component of the overall sotagliflozin risk/benefit profile. While the company has yet to release data on whether or not this difference is statistically significant, we do think it seems clinically meaningful so far and believe that this could be a genuine benefit of the overall flatter glucose profile that sotagliflozin treatment offers.

  • inTandem1 also found significant improvements in patient-reported outcomes with both sotagliflozin doses, maintained at 52 weeks. Participants completed the Diabetes Distress Scale, and both 200 mg (p=0.003) and 400 mg (p<0.001) were associated with significant drops in diabetes distress score vs. placebo. 

  • Dr. Buse showed that bolus insulin was reduced more than basal insulin in participants on sotagliflozin. In inTandem1, basal dropped 2% and 6% (p<0.001 vs. placebo) while bolus rose 2% (p=0.23) and dropped 9% (p<0.001), with 200 mg and 400 mg respectively. In inTandem2, basal dropped 4% in both sotagliflozin groups (p=0.006), while bolus fell 4% (p=0.08) and -8% (p=0.06). Reduction of basal vs. bolus insulin is becoming an increasingly hot topic in terms of minimizing DKA risk (see an in-depth discussion of this issue here), and it seems like the best methods for reducing insulin might differ based on which SGLT is being used. For a deeper dive on insulin reduction in inTandem, see 5-LB from Dr. Jeremy Pettus, to be presented on Monday; this analysis shows that ~70%-80% of total insulin reduction in these two studies came from bolus insulin. For inTandem1, total daily insulin dose (TDD) fell by 4% with 200 mg and by 9% with 400 mg (both p<0.001 vs. placebo). For inTandem2, TDD fell by ~6% with 200 mg (p=0.002) and ~8% with 400 mg (p<0.001). TDD rose by 4% and 1% in respective placebo groups.

  • Pooled CGM data from inTandem1 and 2 were presented in another poster, showing that sotagliflozin offers 1.3 to 2.8 more hours per day in-range (70-180 mg/dl) vs. placebo, according to a 278-person blinded CGM sub-study. On a primary endpoint of percent time-in-range at week 24, 200 mg sotagliflozin gave an additional 1.0 hr/day in range vs. baseline and 1.3 hrs/day vs. placebo (p=0.026), while 400 mg sotagliflozin gave an additional 2.5 hrs/day vs. baseline and 2.8 hrs/day vs. placebo (p<0.001). While time-in-range for the placebo group (n=93) remained constant at 52%, it rose from 52% to 58% with 200 mg (n=89) and from 51% to 64% with 400 mg (n=96). Mean daily glucose fell an average of 6 mg/dl in the 200 mg group (p=0.09 vs. placebo) and 17 mg/dl in the 400 mg group (p<0.001 vs. placebo), rising 2 mg/dl in the placebo group. Postprandial glucose also declined ~35 mg/dl and 50 mg/dl in the sotagliflozin groups compared to placebo (p<0.001 for both), a very compelling effect that the authors attribute to SGLT-1 inhibition in the proximal intestine. MAGE results followed a corresponding pattern, dropping 16 mg/dl (p=0.022) and 25 mg/dl (p<0.001), respectively, in the sotagliflozin groups and 3 mg/dl in the placebo group. Lexicon released topline data on this sub-study last September, and these data offer a fuller picture of the time-in-range and dose dependent benefits to sotagliflozin. Notably, time spent in hypoglycemia was not significantly affected, though small reductions were observed (i.e. the effect trended in the right direction); thus, the time-in-range benefit occurs almost entirely through reduced time spent >180 mg/dl. We remain convinced that time-in-range is perhaps the most important benefit type 1s get from SGLT inhibitors, and Lexicon has confirmed that this pooled CGM data is included in the regulatory submissions for Zynquista (the intended brand name, which we love!). Still, it’s unclear whether and how FDA/EMA might consider these data. We truly hope that FDA takes CGM findings into account when weighing the risk/benefit profile of these agents; spending an additional ~1-3 hours per day not worrying about or trying to correct hyperglycemia or hypoglycemia should translate to a serious quality of life benefit for patients.

3. In Type 1s, GLP-1 Liraglutide Lowers A1c by 0.6%, Body Weight by ~6 lbs Over 52 Weeks; Improved Glucose Control w/o Excess Hypoglycemia

Is there still hope for GLP-1s as adjunct therapy in type 1 diabetes? Novo Nordisk declined to move forward with liraglutide for type 1 after modest phase 3 results, but Dr. Paresh Dandona conducted another year-long trial in which the agent showed promise. We note that this was a much smaller study (n=46) than Novo Nordisk’s ADJUNCT ONE (n=1,398), but we were nonetheless struck by the 0.6% placebo-adjusted A1c decline with liraglutide (p=0.006), from a baseline 7.9%. For context, liraglutide gave a placebo-adjusted A1c reduction of only 0.2% in ADJUNCT ONE, and Dr. Dandona’s RCT found glycemic benefit on par with SGLT inhibitors in type 1 diabetes (e.g. 0.4% estimated treatment difference with dapagliflozin in DEPICT-2). Placebo-adjusted weight loss was ~6 lbs on average with adjunct liraglutide (baseline ~185 lbs, p=0.041). There was no significant difference in total daily insulin dose between the two treatment arms at the end of the trial. Moreover, hypoglycemia events and time spent <70 mg/dl were balanced across groups; however, CGM was only used for four weeks total, and we wonder what the time-in-range data would look like across all treatment exposure. Importantly, these findings all trend in liraglutide’s favor, whereas results in ADJUNCT ONE were more mixed. That liraglutide (branded as Victoza for type 2 diabetes) could offer type 1s additional glucose-lowering without additional hypoglycemia risk is an exciting prospect, and we wonder if there’s lingering interest in pursuing a type 1 indication for this drug. Victoza’s patent expiry is somewhat imminent (expected around 2022/2023). Perhaps generic liraglutide could be an effective and highly-affordable adjunct to insulin for people with type 1 diabetes, if further clinical trials corroborate what we saw on this late-breaking poster. ADA also issued a press release alongside. One thing’s for sure: There is so. much. enthusiasm. for adjunct type 1 diabetes therapy at this meeting.

  • In a call with our team, Novo Nordisk's CMO in North America Dr. Todd Hobbs said it's unlikely the company will revive the type 1 program for Victoza. He elaborated on the ADJUNCT study results, explaining that investigators saw a lot of heterogeneity. Some people with type 1 diabetes experienced meaningful A1c-lowering and weight loss, while others didn't respond as positively, leading to underwhelming mean values. Dr. Hobbs acknowledged the tremendous enthusiasm around SGLT inhibitors in type 1 diabetes as a defining theme of ADA 2018, but reiterated that this "won't make it more likely for us to re-open our situation with liraglutide as an adjunct in type 1."

4. EMERALD Study Suggests CV Benefit to Metformin in T1D Youth

Dr. Kristen Nadeau presented new data from the EMERALD study revealing potential CV benefits of adjunct metformin therapy in youth with type 1 diabetes. Type 1s between age 12-21 (n=49) were randomized to metformin or placebo as adjunct to basal/bolus insulin for three months. Compared to those on placebo, participants on metformin experienced significant improvements in insulin resistance (p<0.01), aortic pulse wave velocity (-1.1 m/s vs. +4.1 m/s, p<0.04), aortic wall shear stress (-0.03 N/m2 vs. +0.2 N/m2, p=0.03), and carotid intima media thickness (cIMT), a common surrogate marker for CV risk (p=0.04). Additionally, metformin had marked effects on body composition, reducing body weight by ~1 lb vs. +3 lbs with placebo (p=0.004), BMI by 0.19 kg/m2 vs. +0.44 kg/m2 (p=0.005), and fat mass by ~1.5 lbs vs. +1.2 lbs (p=0.01). Metformin use was associated with no significant changes in A1c, blood pressure, LDL, HDL, triglycerides, or peripheral measures of arterial stiffness and function in this population. Dr. Nadeau hinted that the research team is still analyzing data on cardiac, renal, and mitochondrial function with metformin in type 1 diabetes, and we’re looking forward to learning the fuller picture.

  • Dr. Nadeau suggested that these results bode well for the use of metformin as a cardioprotective intervention in youth with type 1, though we’d note that metformin has a rather mixed history when it comes to CV effects in this patient population. One year ago at ADA 2017, the JDRF-sponsored REMOVAL trial failed to show metformin’s CV efficacy on the primary endpoint of decreased mean cIMT over three years. While the tertiary outcome of maximal cIMT increased at a significantly slower pace in the metformin-treated group (0.012 mm/year) vs. the placebo group (0.25 mm/year, p=0.0093), our sense is that most thought leaders consider REMOVAL to be a resoundingly neutral study. REMOVAL comprised an adult patient population, and perhaps there are meaningful underlying differences of youth type 1 diabetes. In any case, the present findings add more data in favor of a beneficial CV effect for metformin in type 1 (albeit in a small study population). What we really need to reach conclusions on this question is a larger, longer study investigating hard CV outcomes with metformin (as opposed to these CV biomarkers), but the issue of funding remains (we’d love one of the three traditional funders – NIH, JDRF, or the Helmsley Charitable Trust). In the meantime, since many type 1s do take metformin off-label in the real world (for additional glucose-lowering, weight loss, etc.), it’s encouraging to see continued clinical research on this front and to get confirmation of safety with possible CV efficacy.

  • Dr. Nadeau stressed that the primary rationale for adjunct therapy in type 1 diabetes is improvements in beyond-A1c outcomes, e.g. the vascular benefits observed in this study. These are especially important in light of the fact that people with type 1 diabetes, even youth, have elevated CV risk factors. In this study, participants with type 1 had greater vascular dysfunction (elevated aortic pulse wave velocity and aortic wall shear stress) compared to age- and BMI-matched controls without diabetes. In addition, the elevated insulin resistance seen in people with type 1 diabetes has a well-established relationship with CV morbidity.

5. Phase 2 Results for Kamada’s Alpha-1 Antitrypsin (AAT) “Inconclusive” on Delaying Progression of New-Onset Type 1 Diabetes

Dr. Yael Lebenthal presented full phase 2 data on Kamada’s serine protease inhibitor alpha-1 antitrypsin (AAT), in development to arrest the progression of newly-diagnosed type 1 diabetes. Topline results were released by the company in November 2017. Given the anti-inflammatory and anti-apoptotic properties of this serine protease inhibitor, the hope is that AAT could prevent or delay the autoimmune destruction of beta cells, thereby slowing the progression of type 1 diabetes. Newly-diagnosed type 1s between the ages of 8-25 (n=70) were randomized to either 60 mg/kg AAT, 120 mg/kg AAT, or placebo, administered via 22 IV infusions over the course of one year. The trial failed to meet its primary endpoint, with a significant reduction in C-peptide area under the curve (AUC) from baseline, measured by a mixed-meal tolerance test. While there was significant reduction in C-peptide AUC for the AAT 60 mg/kg and placebo groups, there was no significant reduction in C-peptide AUC in the specific cohort of participants between the ages of 12-18 with the 120 mg/kg AAT dose (-0.18 pmol/ml, p-0.20). Additionally, there appeared to be a dose-dependent relationship between AAT and A1c-lowering: After one year, participants on 120 mg/kg AAT had a mean A1c of 6.7% vs. 7.8% with 60 mg/kg AAT and 8.2% with placebo. Also in this vein, a higher proportion of participants who received the higher dose of AAT attained an A1c <7% (75%) vs. lower dose AAT (27%) and placebo (25%). Overall, AAT was safe and well-tolerated, with the exception of two adverse events involving allergic reactions. Dr. Lebenthal characterized these results as “inconclusive,” positing that further studies should probe whether AAT could be effective in newly-diagnosed type 1s 12-years and up. This seems plausible given the subgroup analysis, though it’s difficult to imagine a business model for a future drug that’s only effective in such a narrow population. We look forward to learning whether Kamada will continue the development program for AAT. Dr. Lebenthal alluded that future studies will determine whether the drug has impact on beta cell preservation.

Type 2 Diabetes and Prediabetes Therapy

6. Novo Nordisk’s Oral GLP-1 Semaglutide Shows Remarkable Efficacy in PIONEER 1; 73% of Patients on Highest Dose Achieve A1c <7% w/o Hypoglycemia or Weight Gain; 44% Experience ≥5% Weight Loss

Building on the topline results released in February, Novo Nordisk presented full data from PIONEER 1 (oral semaglutide vs. placebo) on a late-breaking poster. Adults with type 2 diabetes (n=703) started on either 3 mg oral semaglutide, were up-titrated to 7 mg or 14 mg over eight weeks, or were randomized to placebo. The total treatment duration was 26 weeks. In the on-treatment analysis, A1c declined by 0.8% in the 3 mg group, -1.3% in the 7 mg group, -1.5% in the 14 mg group, and only -0.1% in the placebo group, leading to estimated treatment differences of 0.7%, 1.2%, and 1.4%, respectively (all p<0.001). Baseline A1c was 7.9% (3 mg, placebo) or 8.0% (7 mg, 14 mg). Oral semaglutide stimulated very meaningful weight loss – ~4 lbs with the 3 mg dose, ~6 lbs with the 7 mg dose, and ~9 lbs with the 14 mg dose after just 26 weeks. Mean weight loss was ~3 lbs in the placebo group, leading to estimated treatment differences of 1 lb (non-significant p-value), ~3 lbs (p<0.05), and ~6 lbs (p<0.001). The decline in body weight started immediately and continued steadily over these 6+ months, without major plateauing, and we’ll be curious to see if the oral GLP-1 agonist confers even more weight loss with longer exposure time. Novo Nordisk is also exploring injectable semaglutide as an obesity drug, and we’re cautiously optimistic that an oral formulation could ultimately help many people with type 2 diabetes/obesity. Baseline body weight was ~194 lbs across PIONEER 1, which means patients on 14 mg oral semaglutide lost ~5% body weight on average (experts say 5%-10% weight loss is needed for metabolic benefits, though the obesity field is now striving to break through this threshold with drugs that offer 15%-20% weight loss). In addition, the poster mentions that 44% of people on 14 mg semaglutide experienced at least 5% weight loss vs. 16% of individuals taking placebo (p<0.001). The composite outcome of A1c <7% without weight gain or hypoglycemia was achieved by 73% of participants on high-dose semaglutide vs. 27% of those on placebo (p<0.001), and the composite of at least 1% A1c decline + at least 3% weight loss was seen in 54% and 11%, respectively (p<0.001). Fasting plasma glucose fell 12 mg/dl with the lowest dose of oral semaglutide, -27 mg/dl with the medium dose, and -37 mg/dl with the highest dose vs. +4 mg/dl with placebo (all p<0.001). Baseline fasting glucose was ~159 mg/dl. Lastly from the on-treatment principle, 59%, 72%, and 80% of semaglutide-treated patients (3 mg, 7 mg, and 14 mg, respectively) achieved A1c <7% after 26 weeks, while only 34% of placebo-treated patients reached this ADA-recommended target (all p<0.001 vs. placebo).

  • Novo Nordisk management explained to us recently that FDA requires an intention-to-treat analysis wherein all patients are considered, even those who discontinued from the study or who used rescue medication. Participants in the placebo group are more likely to need rescue therapy, and including them thus mutes the apparent efficacy of the study drug. Presumably, excluding dropouts in the on-treatment analysis would have the opposite effect, amplifying the apparent efficacy of oral semaglutide, but the discontinuation rate in PIONEER 1 was about what’s expected for any GLP-1 agonist. Four people (2%), seven people (4%), and 13 people (7%) prematurely discontinued 3 mg, 7 mg, and 14 mg semaglutide, respectively, vs. four people (2%) from the placebo group. In PIONEER 4, 11% of individuals taking 14 mg semaglutide dropped out (this was a longer, 52-week study) vs. 9% of those taking injectable GLP-1 Victoza (liraglutide). Rates of GI side-effects, including nausea, vomiting, and diarrhea, were also as expected for a GLP-1 agonist (18%-31% of oral semaglutide patients vs. 17% of placebo patients). In any case, Novo Nordisk’s first-in-class oral GLP-1 met its primary endpoint within the intention-to-treat principle, in that all three doses showed superior A1c-lowering vs. placebo. We’ll be keeping our ear to the ground for more on these two different statistical approaches (intention-to-treat vs. on-treatment), listening for any clues as to which analysis non-FDA regulators will use.

  • We’ve heard some speculation that the fasting requirements around oral semaglutide will impose undue burden on patients. As stated on the poster, PIONEER 1 participants were instructed to take their dose in a fasting state every morning and to refrain from eating for another 30 minutes thereafter. While this could be perceived as a nuisance by some patients, we think that many others will decide the glucose-lowering and weight loss are well worth it; plus, oral semaglutide is an appetite-suppressant, which could ease the post-dose fasting. Non-adherence to this protocol would undercut the efficacy of oral semaglutide. Based on the compelling efficacy data from PIONEER 1, we suspect adherence was fairly strong, but we’d love specific details on this. Moreover, since adherence is always lower outside the context of an RCT, we’ll be curious to see if Novo Nordisk invests in any support tools – digital or otherwise – to aid real-world engagement.

  • Which dose(s) will Novo Nordisk choose for commercialization? Management has previously shared plans to submit an NDA for oral semaglutide in 2019. Apparently, the company used mathematical modeling to find an optimal dose of the oral GLP-1, settling on 14 mg once-daily. Given the higher rates of nausea and dropout associated with the higher dose, will Novo Nordisk opt for 7 mg instead, or for both? On the other hand, it’s important to note that glycemic improvements and weight loss were also greater in the higher dose group, and nausea is usually mild to moderate and tends to subside over time.

  • The phase 3 PIONEER program for oral semaglutide features 10 trials in total. Four of these have reported topline data (1, 2, 4, and 7), and this late-breaker offered the first full PIONEER dataset. We look forward to many more readouts on oral semaglutide in the remainder of 2018 – it’s shaping up to be “the year of oral GLP-1.” We spoke to Dr. Todd Hobbs (Novo Nordisk's CMO in North America) about the PIONEER program, and he shared that he's most excited for the PIONEER 6 CVOT results, which will be informative for our clinical understanding of oral semaglutide as well as the company's commercialization efforts. To be sure, it's becoming increasingly difficult for a new diabetes drug to gain traction on the market without CV benefit, now that multiple GLP-1s and SGLT-2s have shown cardioprotection, and now that patients/providers are looking for more than A1c reduction from their pharmacotherapy.

  • Dr. Hobbs affirmed that Novo Nordisk is committed to providing high-quality educational materials to help real-world patients adhere to the oral semaglutide fasting requirements. He acknowledged that participants in a clinical trial typically have more support in their diabetes management and overall health engagement vs. patients in the real world; to keep adherence rates strong so that oral semaglutide's efficacy is preserved outside of RCTs, he alluded to replicating support materials from the PIONEER program for the real world. He also emphasized that adherence to oral semaglutide in PIONEER 1 was as high as you'd expect for a GLP-1 agonist. And, he pointed to the longer duration of follow-up in PIONEER 3 (78 weeks), describing how participants were able to stick to their oral semaglutide regimen (dose timing/fasting) for a lengthy period of time.

Phase 3 PIONEER Program

Trial

Estimated Enrollment

Comparator/Design

Timeline

PIONEER 1

704

Placebo

Completed December 2017; Topline results announced February 2018; Full results coming on ADA poster (2-LB)

PIONEER 2

816

Lilly/BI’s Jardiance (empagliflozin)

Completed March 2018; Topline results announced May 2018

PIONEER 3

1,860

Merck’s Januvia (sitagliptin)

Completed March 2018, Topline results expected by June 30, 2018

PIONEER 4

711

Novo Nordisk’s Victoza (liraglutide)

Completed March 2018; Topline results announced June 2018

PIONEER 5

324

Moderate renal impairment

Expected to complete May 2018

PIONEER 6

3,176

CVOT

Expected to complete September 2018

PIONEER 7

504

Flexible dose escalation

Completed March 2019; Topline results announced June 2018

PIONEER 8

720

Insulin add-on

Expected to complete August 2018

PIONEER 9

230

Placebo and liraglutide in Japan

Expected to complete August 2018

PIONEER 10

336

Lilly’s Trulicity (dulaglutide) as an add-on to oral agents in Japan

Expected to complete July 2018

7. OBSERVE-4D Finds No Increased Amputation Risk with Invokana or SGLT-2s, but Median Exposure <6 Months (A Win for Canagliflozin?); Reaffirms Heart Failure Benefits of SGLT-2 Class

J&J’s OBSERVE-4D study was featured on a late-breaking poster: >700,000 real-world US patients were analyzed, and SGLT-2 inhibitor Invokana (canagliflozin) was not associated with an increased risk of below-knee amputations vs. non-SGLT-2 inhibitor diabetes therapies, except metformin (intent-to-treat HR=1.01, 95% CI: 0.93-1.10, p=0.71; on-treatment HR=0.75, 95% CI: 0.40-1.41, p=0.25). Amputations were also balanced between Invokana and other SGLT-2s (intent-to-treat HR=1.13, 95% CI: 0.99-1.29, p=0.06; on-treatment HR=1.14, 95% CI: 0.67-1.93, p=0.48). See the full paper here. These are reassuring results for Invokana, since one year ago at ADA 2017, CANVAS showed a nearly two-fold risk for lower limb amputations with canagliflozin vs. placebo (HR=1.97, 95% CI: 1.41-2.75, p<0.001). Questions linger about the safety of canagliflozin (especially since a black box warning for amputations is on the product label), and some thought leaders have endorsed switching patients onto another SGLT-2 inhibitor; said Dr. Jay Skyler at CMHC 2017, “why deal with this concern if you don’t have to?” Dr. John Buse explained in a press conference that while he was very reassured by the results, given a choice of SGLT-2 inhibitors he would not prescribe Invokana to patients with risk factors for amputation (prior amputation, severe neuropathy, peripheral vascular disease, and very high A1c). Notably, OBSERVE-4D found similar results in the subset of patients with established CV disease vs. the total study population (on-treatment HR=0.72, 95% CI: 0.34-1.51), suggesting that CV disease did not confer additional amputation risk in this real-world sample. We’ve heard some speculation that the high-risk patient population in CANVAS may have contributed to the amputation finding. For reference, in CANVAS, baseline CV disease independently conferred a 50% increased risk of amputation in a multivariate analysis of risk factors (HR=1.50, 95% CI: 1.0-2.3), though this did not explain away the correlation between cana and lower-extremity amputations (i.e. in cohorts with and without baseline CV disease, amputations were more common with Invokana vs. placebo). In an interview with Dr. Paul Burton (VP Scientific Affairs, Janssen), we learned that roughly 25% of people in OBSERVE-4D had established CV disease, coming in far below the 66% of participants in CANVAS who had prior CV events at randomization. It’s possible that evaluating a greater proportion of patients without baseline CV disease had a bearing on OBSERVE-4D’s positive safety results, although it’s reassuring that data from the highest-risk quartile matched overall data.

  • Dr. Burton emphasized that sample size in OBSERVE-4D was much larger than a CVOT. That said, we also point to results from EASEL, another real-world study (n=25, 258) from J&J that linked SGLT-2 inhibitors with a ~doubled risk of lower limb amputations (HR=1.99, 95% CI: 1.12-3.51, p=0.018); 58% of observed patients in EASEL were on Invokana, 26% on Lilly/BI’s Jardiance (empagliflozin), and 16% on AZ’s Farxiga (dapagliflozin). We asked Dr. Buse how he views OBSERVE-4D and EASEL in relation to each other, and he too highlighted the order-of-magnitude difference in population exposed. While he did acknowledge that it’s difficult to pinpoint why the two trials reached different conclusions, he also pointed out that the trials’ confidence intervals readily overlap with one another (though on the wrong side of 1.0). Dr. Buse also mentioned that, when OBSERVE-4D is published, there will be a tool that allows any reader to do whatever they want with the dataset – this is now available here.

  • Perhaps the most significant limitation of OBSERVE-4D was that median on-treatment exposure time was <six months, raising questions as to whether the study was long enough to detect an amputation signal. In CANVAS, the amputation curves continued to widen over the duration of the trial. Dr. Burton affirmed that J&J will continue to look at this real-world data over time, and he noted that in CANVAS, an amputation signal would have actually been detected even at six months. Moreover, he shared that OBSERVE-4D found no signal for amputations in patients with longer duration of exposure to canagliflozin, up to one-two years. Dr. Buse reiterated this finding, adding that there’s no hint of amputation rates changing over time and the six-month HR in CANVAS would have been 1.81.

  • Ultimately, we don’t think that OBSERVE-4D will completely negate the amputation signal seen in CANVAS (even though it should given the experts to whom we’ve spoken), but it should serve as a reminder to HCPs that canagliflozin is a potent, efficacious drug (more on specific clinical benefits below), that base rate of amputations is very low even in diabetes, and that this risk is manageable with careful monitoring of the feet. Dr. Burton described how providers have come to understand that the absolute increase in amputations seen in CANVAS was quite low (0.2%-0.3%). Moreover, he underscored that HCPs can identify patients at-risk for amputations (e.g. those with prior amputations, those with peripheral arterial disease) and decide against prescribing Invokana (or prescribe it, but monitor extremely closely). We’re not totally sure about the first point, because our sense is that the average (busy) PCP sees the black box warning for amputations and pivots away from Invokana (to another SGLT-2, or to another therapy class altogether); in fact, Dr. Buse touched on the need to help PCPs understand the risk/benefit profile of Invokana. Invokana sales have been falling since the black box was added in May 2017, although J&J has always cited pricing pressure as the primary reason for this (and indeed, the company offers one of the best Patient Assistance Programs according to diaTribe’s analysis). We think there’s a major opportunity here for J&J to double down and really invest in the class but we don’t see J&J CEO Alex Gorsky doing this – too bad, and we hope we’re wrong.

  • On a very exciting note, OBSERVE-4D also confirmed the heart failure benefit of the SGLT-2 inhibitor class. On-treatment analysis identified a 61% risk reduction in hospitalization for heart failure with Invokana vs. non-SGLT-2 therapies (HR=0.39, 95% CI: 0.26-0.60, p=0.01), and no difference on this heart failure endpoint with Invokana vs. other SGLT-2s (HR=0.90, 95% CI: 0.71-1.13, p=0.22). In the subgroup with established CV disease, the reduction was 56% (HR=0.44, 95% CI: 0.36-0.54). These findings corroborate the positive heart failure outcomes from both CANVAS and EMPA-REG (for Lilly/BI’s Jardiance), as well as findings from the real-world, AZ-sponsored CVD-REAL program. A 61% risk reduction strikes us as remarkably robust, though Dr. Burton attributed this to the nature of real-world evidence; he acknowledged that he would not expect this to actually be significantly greater than the risk reductions seen in CVD-REAL. Moreover, heart failure results were again similar in the overall cohort and the subgroup with established CV disease. In the future, we’d be interested to see results from the primary prevention cohort only. The role of SGLT-2s in primary vs. secondary CV prevention remains a key area of investigation, as CANVAS and EMPA-REG OUTCOME enrolled predominantly participants with baseline CV disease. DECLARE, AZ’s CVOT for Farxiga slated to read out later in 2018, has enrolled a 59% primary prevention cohort. On the whole, we’ve noticed tremendous thought leader enthusiasm for SGLT-2s, particularly from cardiologists, who are very focused on the heart failure benefit these agents offer; to this end, Lilly/BI and AZ have initiated the dedicated EMPEROR and Dapa-HF trials to investigate Jardiance and Farxiga, respectively, in patients with heart failure with or without diabetes. Dr. Burton shared that while J&J has considered conducting a dedicated heart failure trial, management feels that CREDENCE, the renal outcomes trial for Invokana, will be a good approach to the heart failure question, since that study is enrolling patients with stage 2-3 CKD who should experience a fair number of heart failure events. CREDENCE is expected to complete in June 2019.

    • It’s worth noting that the intent-to-treat analysis was not completed for Invokana vs. non-SGLT-2 therapies because of heterogeneity (I2=0.59) between the four databases used. Though these all trended in the right direction (HRs=0.63, 0.94, 0.83, 0.73), only two were statistically significant on their own. However, we understand this heterogeneity to be an issue of statistical power and we imagine that very few would argue against a class effect for SGLT-2s on reducing heart failure hospitalizations at this point. The intent-to-treat analysis of Invokana vs. other SGLT-2s revealed no difference (HR=1.07, 95% CI: 0.95-1.20, p=0.16).

  • OBSERVE-4D pulled data from four US claims databases, evaluating new users to SGLT-2s and other glucose-lowering therapies with propensity score matching and other sensitivity analyses. In total, 142,000 new users of canagliflozin, 110,000 new users of other SGLT-2s, and 460,000 new users of other therapies were included in the study. For reference, the intent-to-treat period was defined as one day following exposure to the last day of observation in the database, while the on-treatment period was one day following exposure through the period of persistent exposure, allowing for ≤30-day gaps between exposure. If patients started a non-metformin diabetes drug (other than SGLT-2 inhibitors), they were censored from the sample. Databases included Truven’s Commercial Claims and Encounters, multi-state Medicaid and Medicare Supplemental Beneficiaries, and OptumInsight’s Clinformatics Datamart.

8. Negative Results from VADT Follow-Up – No Significant Micro or Macrovascular Risk Reduction; Engaging Panel Discussion Considers Relevance of A1c vs. Cardioprotection in Diabetes Decision-Making

A Sunday afternoon symposium offered new data from the VADT follow-up (VADT-f) out to 15 years, meaning it’s been 10 years since the intervention (intensive glucose control vs. standard care) was stopped. Results were negative overall, in that neither microvascular nor macrovascular risk were significantly reduced in the intensive control arm at 15 years (intensive control being an aim to lower A1c by 1.5% from baseline). As a reminder, the original VADT (n=1,791) found no significant benefit on the primary CV endpoint, either; some attribute this to low event rate. Dr. Peter Reaven took the stage to discuss macrovascular results from VADT-f. The hazard ratio for the primary composite CV outcome was 0.91 trending toward intensive control (95% CI: 0.78-1.06, p=0.23). The Kaplan-Meier curves show a gradual separation between groups, followed by a gradual re-joining of the curves. At 15 years, intensive glucose control did not meet any secondary CV, diabetes, or mortality outcomes; there was no evidence of a legacy effect. For reference, the primary endpoint of VADT was a composite of MI, stroke, CV death, new or worsening heart failure, amputation for ischemic gangrene, surgery (for cardiac, cerebrovascular, or peripheral vascular disease), and inoperable CAD. For the interim and final VADT-F analyses, the primary endpoint included MI, stroke, new heart failure, CV death, and ischemic amputation. Dr. Nicholas Emanuele followed Dr. Reaven with a presentation of microvascular effects, and again, risk was well-balanced across groups at 15 years. For the renal composite outcome of eGFR <45 ml/min/1.73m2, sustained macroalbuminuria, or end-stage renal disease, the hazard ratio was 0.90 trending toward intensive control (95% CI: 0.63-1.27, p=0.55). For eye events, the hazard ratio was 0.84 (95% CI: 0.70-1.00, p=0.053). Importantly, mean A1c rose in the intensive control arm in the interim 10 years, so that it closely matched A1c of the standard control group. In providing independent commentary, Dr. Hertzel Gerstein asserted that achieving tight glycemic control and maintaining tight control are both important in avoiding diabetes complications.

  • Ultimately, some of the greatest learning from this session came during the panel discussion with audience Q&A. An overly simplistic interpretation of VADT-f would be that current A1c targets are invalidated, and there’s nothing special about reaching A1c below 7%. Dr. Gerstein refuted this immediately. He put these results in context with ACCORD, ADVANCE, and UKPDS – when all four are analyzed together in one meta-analysis, there is a significant microvascular benefit overall to A1c <7%. Moreover, Dr. Gerstein emphasized the importance of personalized targets. “Please put your hand up if you’re average. Nobody is average!” he asserted, continuing “clinical trials do not tell you how to treat the patient in front of you, because they just say what works on average.” Indeed, when asked what A1c goal they set for their patients today, none of the panelists could give a clear answer – because it always depends. This discussion also featured a nod toward outcomes beyond A1c and outcomes-based medicine, when Dr. Reaven noted that treatment decisions today should consider cardioprotection as seriously as glycemic effects. GLP-1 use was incredibly low in the VADT, and SGLT-2s weren’t even available yet, which further calls into question how relevant this is to modern diabetes practice. “Speaking as a VA physician,” Dr. Reaven remarked, “SGLT-2 and GLP-1 use is still very low today.” And we believe, we will look back upon this and see this as shameful.

9. Dr. Fonseca: Basal Insulin/GLP-1 “Should be the First Injectable We Use in T2D, but We Need FDA Approval for that Indication”

Tulane’s Dr. Vivian Fonseca suggested that fixed-ratio combination therapy with basal insulin/GLP-1 should be the first injectable drug used in type 2 diabetes – and he argued that FDA should update the Xultophy and Soliqua product labels to allow for this. Novo Nordisk’s Xultophy (insulin degludec/liraglutide) and Sanofi’s Soliqua (insulin glargine/lixisenatide) were both approved for the US market on the same day in November 2016. Here we are a year and a half later, and commercial uptake of these products has been disappointingly low. Dr. Fonseca attributed this in part to the restrictive indications on both drugs: FDA stipulated that Xultophy can only be used after basal insulin or liraglutide (Victoza) in any given patient, while Soliqua can only be used after basal insulin or lixisenatide (Adlyxin). This precludes fixed-ratio combination therapy from being used as a first injectable, it unnecessarily delays treatment intensification and exposes patients to more hyperglycemia (and possibly hypoglycemia), and it’s been especially challenging for the Soliqua franchise since standalone Adlyxin is prescribed so infrequently. Dr. Fonseca characterized this as a “limitation in the packet insert that creates issues in patient access” to fixed-ratio combination products, and he noted that there are already enough barriers to optimal diabetes care without this one. We’ll keep an eye out for the label updates Dr. Fonseca proposed, and in the meantime, we hope to see continued efforts from Novo Nordisk and Sanofi to educate providers about this new therapy class. Our sense is that many HCPs (and especially PCPs) aren’t entirely comfortable with the concept of a fixed-ratio combination, and we owe it to patients to spread more awareness of medicines that profoundly lower A1c without weight gain or excess hypoglycemia risk. For more on basal insulin/GLP-1, see our coverage of DUAL IX results (Xultophy vs. Lantus) from ADA day #2.

10. National DPP Enrollment Up 37% from Jan. 2018, Still Only Reaching ~0.3% of US Population with Prediabetes; CDC’s Dr. Ann Albright on Supply & Demand, Reimbursement Prospects, and What HCPs Can Do

CDC’s Dr. Ann Albright provided a status update on the National Diabetes Prevention Program (NDPP), seeming upbeat about progress to-date and expressing enthusiasm for what lies ahead. Supply of the NDPP has grown steadily, and as of this month, CDC recognizes nearly 1,800 programs (1,786, to be exact). Demand has grown as well, with nearly 220,000 individuals enrolled in the NDPP as of this month (219,156). The number enrolled has climbed 37% from January 2018 (160,378) and has more than doubled from last summer (106,219). As for reimbursement, Dr. Albright explained that >3.4 million US adults (in 18 different states) have access to the DPP through their employer. We like this momentum, but we’d love to see a steeper incline – the NDPP is still only reaching ~0.3% of the 84 million Americans with prediabetes, based on these latest figures. Dr. Albright has the same ambition, and she announced that CDC will open an NDPP Operations Center within its diabetes division, much like there’s an operations center for emergency outbreaks. While it’s too early to tell exactly what this NDPP Operations Center will accomplish (in Dr. Albright’s words, “we are in initial phases of development”), we see this as a signal of CDC’s commitment to addressing the public health crises of prediabetes and diabetes. Furthermore, she mentioned that launch is imminent for an NDPP Customer Service Center, created because public interest in these programs is becoming overwhelming (another positive sign!). While it’s hard to be optimistic when 84 million people in the US have prediabetes, 88% of them unaware, and it’s been this way for ages, we appreciated Dr. Albright’s motivating words. She urged providers in the audience to get engaged and get their patients engaged. One of CDC’s goals is to increase referrals to the DPP for people with prediabetes, and Dr. Albright added that HCPs should have their patients watch the CDC/Ad Council prediabetes awareness campaign. She also directed everyone to the NDPP website, Facebook page, and Twitter. To date, CDC has invested hugely in social media, like FDA or CMS or other government agencies have – CDC’s got a million followers on Twitter (though under 8,000 followers on @CDCdiabetes) whereas FDA has 200,000 followers and CMS has just under 150,000.   

Exhibit Hall

Diabetes Technology

Abbott

Abbott boasted a very large booth advertising the FreeStyle Libre as “the #1 CGM worldwide.” We noticed there was an entire section devoted to the FreeStyle Libre Pro – we still can’t get over the incredible data presented from day #1, showing a single diet/pharmacotherapy intervention during one 14-day Libre Pro session massively improves time-in-range(s) in an Indian type 2 population. Booth representatives were understandably unable to comment on timing for a US pediatric indication, which we know is at or near the top of many US providers’ and patients’ wish lists. Last we heard during Abbott’s 1Q18 call in April, the company plans to file a FreeStyle Libre pediatric claim with the FDA in 2018 – great to see, as the device is indicated down to four years old in Europe. Sub-analyses of SELFY and IMPACT data in adolescents and young-adults respectively were presented last night at an Abbott-sponsored symposium and revealed additional evidence of FreeStyle Libre efficacy in these populations. Abbott currently has three US pediatric FreeStyle Libre trials in the works: (i) an accuracy study (n=85 6-17-year-olds) slated for an August completion; (ii) a post-approval safety study (n=400 4-17-year-olds) slated for February 2021 completion; and (iii) an accuracy study (n=100 4-17-year-olds) slated for a July completion. All three studies are currently recruiting. The other big priority for Abbott must be getting the FreeStyle LibreLink apps approved in the US, as it’s the only US CGM without a smartphone option stateside.

Ascensia

Ascensia’s booth highlighted the Contour Next BGM as “the only meter to connect via Bluetooth with the Omnipod,” an important move since Roche will be taking over the Medtronic BGM partnership once the 670G adds Bluetooth. Indeed, at Ascensia’s product theater today, the main topic was the need for a highly accurate BGM to drive outcomes in CGM and hybrid closed loop. The booth also advertised the newly updated Contour Diabetes app, which identifies 14 glycemic trends and provides users with contextual prompts. Booth representatives noted that initial feedback has been “very good,” resulting in a positive bump in app ratings – currently a still-rough 2.4/5 stars in the App Store (151 ratings) and 2.7/5 stars on Google Play (277 ratings). Representatives shared that future iterations will look at more patterns as the algorithm advances. Ascensia is also looking to incorporate other digital offerings into the app, such as the recent Ascensia Diabetes Challenge winner Whisk (AI-driven nutrition platform) to enhance the kinds of recommendations the algorithm might provide. To this end, a booth representative gave the theoretical example of the algorithm noticing a user’s glycemic pattern associated with a particular meal and directing the user to a healthier recipe through Whisk – nice! Currently, Ascensia is collaborating with Whisk in a pilot program. See our Day #1 coverage of Whisk here.

BD

BD’s booth featured its free “Diabetes Personal Assistant” app, Briight, which initiated a preview release on Monday. Read our just-published report on our demo of the app. Version 1.4 of Briight is a mix of a chat-based digital assistant, diabetes data collection, education/support, recipes, and food logging, although the emphasis for now is on educating patients on proper injection technique – a banner at the BD booth read: “Structured injection technique training may transform diabetes care.” While it’s still very early days for Briight, we’re delighted to see BD Diabetes moving into digital health app-driven education, and there was certainly substantial buzz surrounding Briight in the exhibit hall. BD’s Digital Diabetes Product Leader Ed Liebowitz noted “great reception” from ADA attendees. BD also had a second, unbranded booth, Type 2.0, in the exhibit hall to raise awareness of the burden experienced by type 2 MDI patients. As with past conferences, the booth asked providers to select features that they believe to be important for the insulin delivery device of the future. When we stopped by, 22% of respondents had selected wireless controller for discreet basal/bolus dosing, 17% had selected flexible and adjustable basal/bolus dosing, and 14% had selected real-time dose capture reports. At the bottom of the list were a patient lifestyle app (8%) and a large insulin reservoir for longer wear (3%).

Companion Medical

At a bustling backlit booth, Companion Medical showed off its new reports – “Insights by InPen” – which we believe to be the first page in the US to show providers data from a smart pen in conjunction with an AGP-like glucose profile (the reports were announced earlier this week). The design of the report is very intuitive, with glucose insulin, and carbs front and center, time-in-ranges and insulin doses (broken up into basal/bolus if the patient utilizes the app’s basal reminders) flanking the title at the top, bolus calculator usage behavior at the bottom left, and missed doses at the bottom right – we love this take on the uncharted territory! The report is really slick looking! The second page has daily traces, which could be game-changing for providers trying to help people on MDI, if Common Sensing/Joslin data from last year’s ADA is any indication. Notably, these reports can be emailed/faxed to providers with very little hassle in the app.

  • The limited launch – through mail-order pharmacies – has not yet expanded to retail pharmacies. Android app clearance is expected in Q3, so we wouldn’t be surprised if the company waited until that came through to launch in ~70,000+ retail pharmacies.

  • Companion has closed a Series C, and though it won’t comment on the size or investors yet, an SEC Form D filed on May 3rd suggests that the total offering amount was ~$18.5 million. At the time, the company had already sold ~$14.1 million.

  • CE marking is expected “in the near future,” though the company intends to “support the US” before launching in the EU.

Dexcom

Dexcom’s tall, modern booth was appropriately sleek for marketing the newly launched G6, no-calibration 10-day sensor, slimmer transmitter, one-button applicator, and iOS/Android apps. The tall booth was dotted with smartphones showing the apps, alongside a line of desktop screens highlighting Clarity on the web. The reps said things are “very busy” and “demand is very strong” following the G6 clearance in March and launch prior to ADA. We’ve anecdotally heard some patients are lined up to get on G6 later in the summer – presumably many have to wait for G5 transmitters to expire before getting the new slimmer transmitter and required receiver purchase. (We also assume Dexcom has a fair amount of production scaling to do, given the dramatic manufacturing change.) On the international side of the booth, reps mentioned the CE Mark and launch in the UK this month (“about to ship”), with other European countries in 4Q18. We’d expect the biggest Dexcom presence ever at EASD! A rep told us many attendees were entering the booth having heard of G6 and wondering when it would be available –unlike prior ADAs, where Dexcom had to do more education. We see this as a big win, as it reflects rising awareness of the category and new products, something providers can easily struggle with. Around the booth were flyers advertising the 9.0% MARD (based on the auto applicator study; see our day #2 report), a growing list of studies supporting the benefits of Dexcom CGM (DiaMonD, GOLD, HypoDE, COMISAIR).  WE asked about a profession version of G6 – as Ms. David Kruger implied yesterday – and the rep certainly did not deny it. 

Glooko

We passed through Glooko’s booth as the DreaMed team demoed its recently-FDA-cleared Advisor Pro, which is integrated into Glooko’s Population Tracker. Many attendees crowded around, including many familiar KOL faces. Glooko reps said they did not yet have firm launch plans for the software. As for the other major decision support launch on the horizon, Glooko’s MIDS (Mobile Insulin Dosing Support) is expected to enter pilots at a small number of clinics next month, with more commercialization by the end of the year, confirming what we heard at the AACE booth. All Glooko sites have now reportedly converted to the new touchscreen, NFC-enabled, much more user-friendly transmitter. The booth highlighted population management, emphasizing Glooko’s ability to help stratify, correlate, learn, understand, streamline, and collaborate. What’s NFC-enabled, by the way? Tech Radar explains it really well: it’s a method of wireless data transfer that “detects and then enables technology in close proximity to communicate without the need for an internet connection”.

 

Good Measures

Good Measures is forging ahead with a subscription diabetes management bundle, complete with free meters and strips, 24/7 coaching, and Common Sensing’s GoCap to capture insulin dose data, for ~$600/year. We don’t know much more about the program, but will be keeping a close eye on it. The website touts a limited time offer for a full year of coaching for $425.

  • In other exciting news, Good Measures’ digital DPP has obtained full CDC recognition, just the sixth online DPP to do so (see the list here). Notably, full recognition is a prerequisite for CMS reimbursement. Good Measures’ DPP provides weekly digital lessons, virtual support groups, and a wireless scale, which syncs with the Good Measures app and website, for 12 months. The software tracks food intake, physical activity, and weight, and gives participants meal recommendations based on their preferences, nutrition needs, and progress. Each user is also connected with a coach (an RD, CDE, or RN), who provides customized meal and snack suggestions and is available 24/7 via text, email, video, or phone. Good Measures Index (GMI), a single number on a scale of 0-100, summarizes how well individuals are meeting their nutrient needs (weighted for importance, given present medical conditions). A high GMI denotes recent success in meeting near-term nutrition needs, as logged in the Good Measures app or website. The company has enrolled “thousands” of people so far, demonstrating an average weight loss of 6.8% at 12 months.

Insulet

ADA 2018 brings Insulet’s biggest product launch in five years: Omnipod Dash, the Bluetooth-enabled pod, touchscreen PDM (locked-down Android phone), secondary display iOS apps, and paired Ascensia Contour Next One BGM. Following the FDA clearance three weeks ago, Insulet put together an expansive booth showcasing the new PDM and other goings-on at the company. I gigantic screen offered a self-guided tour of the PDM around the booth - we really like the final interface Insulet came up after hundreds of interviews and thousands of hours of market research. The company has done a great job pulling out complexity, leaving the essentials on the home screen (insulin-on-board, last bolus, last BG, large bolus button), moving the rest to other menus and screens. It’s definitely a less-is-more design, not unlike what Dexcom did with the G5 and G6 apps. The six-month limited market release is getting underway soon (limited number of endocrinologists), followed by a full market release in early 2019. For the provider audience, Insulet-provided Glooko was a focus of demos too – it will be exciting at full launch when the Dash PDM automatically uploads pump data to Glooko whenever it is connected to Wi-Fi (eliminating the high=hassle cable downloading process, as Adam mentioned in his talk on apps yesterday). Reps also noted the upcoming European transition on July 1 to take over direct Omnipod sales from Ypsomed. The company is focused on continuity of care and a smooth transition, so there is no Dash timing to report. Globally, Insulet has surpassed 140,000 users.

  • At Insulet’s VIP Dash launch event, we enjoyed the screen below on the PDM iteration process. President Shacey Petrovic noted the complex design of the original Phoenix PDM – our ADA 2015 write-up was kind of generous in retrospect, as it was a truly tragic design compared to where Dash ended up. We liked her point that the Phoenix PDM moved further from users’ true desire: phone control. Dash, on the other hand, is basically an app on an Android phone – a clear precursor to where Insulet is going with smartphone control at some point in the future.

LifeScan

The dedicated LifeScan booth solely featured the OneTouch Verio BGM and OneTouch Reveal app, as it did at ATTD. Representatives could not comment on J&J’s recent acceptance of Platinum Equity’s binding offer to acquire LifeScan for ~$2.1 billion besides reassuring that everything will be “business as usual.” We’re cautiously optimistic that LifeScan may recover, given the right investment: the OneTouch Reveal app is very high-rated on the App Store (4.7/5 stars; 15,600 ratings) and Google Play (3.9/5 stars; 5,973 ratings), and the OneTouch Verio Flex integration with WellDoc’s Bluestar could bring valuable education and support to type 2s. Regarding WellDoc, the BGM-app integration launched last March, allowing wireless blood glucose data entry into BlueStar via Bluetooth. We also learned that patients who get BlueStar through a health plan are eligible for a free Verio Flex meter.

  • As a reminder, OneTouch Via, the bolus-only patch insulin delivery device was not included in the sale to Premium. J&J continues to pursue strategic options for Calibra Medical and the OneTouch Via – we see this as a potentially highly valuable asset in the right hands. We’ll return with our coverage of the OneTouch Via late-breaking poster here at ADA.

Medtronic

Medtronic’s expansive, open booth in the center of the hall focused on the MiniMed 670G hybrid closed loop (approved on Thursday for 7-13 year olds), newly launched Guardian Connect/Sugar.IQ, and a new iPro 2 professional CGM food report powered by Nutrino. Reps said Guardian Connect was a definite draw, with many attendees stopping by and asking questions (see product theater above). We learned from a rep that the separate Sugar.IQ app will run analytics in the background and push insight notifications to the user – even if the Sugar.IQ app is not opened. (Sugar.IQ actually pulls CGM data from the CareLink cloud, with an ~two-minute delay after it appears in the real-time Guardian Connect app.) Of course, a user won’t get as much value out of Sugar.IQ if they never open it (e.g., no food insights), but we like that the glucose-related notifications won’t require opening the app constantly – much like Dexcom’s Clarity mobile weekly notifications. The rep also told us people are asking for Sugar.IQ outside the US; Medtronic has never given timing on an OUS launch, but obviously Guardian Connect has been available for some time now with the Enlite Enhanced sensor. It will be fascinating to see how Medtronic builds out Sugar.IQ – could it be a platform for the company’s various products for type 1, type 2, providers, employers, etc.? It certainly is moving in that direction.

In playing with the Guardian Connect iOS app on display, we liked the ability to scroll backwards in time (e.g., to the previous day) – this is more interactive than Dexcom’s static 6/12/24 hour display when tilting the phone sideways. One MDI user that works at Medtronic said she loved the ability to log insulin and see her combined CGM and dosing history within the app. Guardian Connect’s user interface is quite dark, which makes it recognizably different from Dexcom’s brighter G6 display.

The new Nutrino/iPro 2 pairs CGM data and meal photos taken in the myLog app to give greater context to a professional CGM wear session (see below). Medtronic and Nutrino actually assign a letter grade from “A” through “F” to each meal photo based on the postprandial CGM trend (AUC, time-in-range, average glucose), with the “F” appearing in dark red and “A” in green. On the plus side, we are glad to see photo-based food logging paired with CGM, as this will be a huge driver of behavior change in our view. That said, we’re concerned about using glucose values for explicit grades, especially in a type 2 audience that already feels very judged and stigmatized around food. See Adam’s diaTribe column on this very topic, which has been viewed over 15,000 times. This is tricky – providing people specific feedback on what meals keep them in range vs. not, but not making users feel like a failure (e.g., a page filled with F’s and a finger-wagging provider stating, “what did you eat here?!”). We wonder what is possible with “in range” vs. “out of range” or other ways to intelligently share a proper ratio of positive:negative insights – “Oh wow, I actually have many meals in range, and here are a couple I could improve on…”

Novo Nordisk

Sometimes Close Concerns’ tech writers like to meander into pharmaceutical company booths, and sometimes it has a big payoff: On the international side of the Novo Nordisk booth, we stumbled across the NFC-enabled reusable NovoPen 6! Last we heard, the pen is currently piloting at ~10 Swedish clinics (~1,000 patients), and the rep said it will expand “soon,” in part due to provider demand! The pen enables providers to upload insulin usage data to their Glooko/Diasend NFC pad (see picture below – we think it’s kind of cute how it stands on its backside as it uploads to Glooko within seconds). Providers can then visualize blood glucose values vs. insulin dosage, filling a gap in MDI therapy, to help them to better guide treatment. The pen’s dial also has a low-tech display on it, giving the size of the last dose and the time since the last dose. The reusable pen requires cartridge refills. The US side of the booth was unfamiliar with the smart NovoPen 6. As an aside, we expect Novo Nordisk will eventually build Bluetooth into these pens so that they can communicate directly with the patient app 24/7. Reps also told us about a new smart pen cap under development with an undisclosed digital partner ­– possibly Glooko? – called “Revival.” See our smart pen/cap competitive landscape here.

  • The booth also showed off Novo Nordisk’s “Cornerstones4Care powered by Glooko” diabetes management app. Graphics highlighted the app’s meal-planning tool, interactive tracker app, and digital AI guide (“Sophia”), who can answer questions about diabetes care 24/7. Interestingly, the AI guide was not demoed in the Diabetes Mine presentation on the app on Friday.

One Drop

We caught up with Head of Data Science Dr. Dan Goldner, who discussed the company’s automated decision support 12-hour forward-looking glucose prediction (for type 2s not on insulin), first shown on Thursday at D-Data Exchange. We learned that predicting weather patterns – which Dr. Goldner did for a number of years – is simpler than predicting blood glucose in people with diabetes. That helps to put into perspective just how difficult managing diabetes can be. Dr. Goldner also confirmed that predicting the glucose of people on insulin (which will likely require regulatory involvement) and people on CGM are both on the roadmap. When asked about more traditional decision support, he noted that “our spirit isn’t really prescriptive,” implying that decision support will remain along the lines of predicting glucose and feeding trends and insights to the user.

  • One Drop is in the process of wrapping up data collection for three RCTs: A-One, Fit-One, and another (undisclosed). A-One is investigating the effect of integrating Afrezza and the One Drop Premium (unlimited strips + 24/7 in-app support from CDEs) vs. One Drop Premium. Fit-One has three main arms, each comparing a One Drop program with a Fitbit watch/tracker to a One Drop coaching program without a Fitbit. The three arms study the One Drop +/- Fitbit combination in type 2 diabetes, type 1 diabetes, and excitingly, prediabetes (the One Drop “Revive” DPP!). We are excited for outcomes – measured in A1c at three months – across the spectrum, particularly in the prediabetes segment, where participants also receive Fitbit Aria Wi-Fi scale!

Senseonics

The US Senseonics sales team was out in full force after receiving FDA approval for Eversense a mere 48 hours prior to the exhibit hall’s opening. The booth was packed with interested attendees who gathered to watch live demonstrations of the 90-day sensor insertion/removal procedure on fake arms, by way of a monitor relaying the video feed from a camera placed over the head of the demonstrator. Booth representatives admitted that some conference-goers have been intimidated by the device initially but for the most part are quickly reassured upon learning of Eversense’s fantastic accuracy and observing the simple insertion/removal procedure. Representatives highlighted how Eversense dramatically reduces the hassle associated with managing CGM supplies – no need to bring multiple sensors on a trip or to worry about carrying a receiver (smartphone-only display). In addition to the booth, Senseonics also boasted a large “mobile clinic” bus, where providers can learn how to perform the insertion/removal procedure. Senseonics actually plans to drive the clinic across the country, for the most part following diabetes conferences and events – the upcoming Keystone conference is on the list! This is brilliant grassroots training. We’re absolutely thrilled to see such excitement surrounding Eversense, which we hope will expand the CGM segment by offering a differentiated feature set. Currently, the 180-day Eversense XL is available in all OUS markets (except South Africa) with very promising accuracy data in a primarily pediatric population shared at ADA on Friday.

SOOIL

SOOIL’s Justin Walker shared bold goals at the company’s booth, “guaranteeing” the launch of an open protocol, smartphone-controlled insulin pump in the US by ADA 2019. Notably, the company plans to submit a de novo request to be registered as an integrated pump (iPump), building on the new integrated CGM category paved by Dexcom’s G6. Per Mr. Walker, SOOIL was approached by the FDA at the JDRF/HCT interoperability workshop in April and asked to write the iPump protocol. Given Mr. Walker’s assertion that a launch will be feasible in June 2019, SOOIL must be quite far along in the regulatory and testing phases of the product. (As noted on Day #1, SOOIL has been building pumps since 1979, so it has been in the game for a while.) If SOOIL can pull this off – smartphone control and iPump registration – it could send waves through the US diabetes community and drives meaningful sales through the . Mr. Walker also mentioned SOOIL’s collaboration with OpenAPS to license an algorithm for the pump as an integrated algorithm (see day #1) – timing and feasibility for this project is a bit more uncertain, as SOOIL has not yet engaged in discussions with the FDA. Lastly, we learned that SOOIL signed an agreement with Dexcom earlier this week to integrate G5 data with SOOIL apps. We’ll be looking to see if the company executes on this bold plan… As a reminder, there are currently no regulatory-cleared pumps besides SOOIL’s Dana that can be controlled on a smartphone, although many are trying to get there at some point it: Bigfoot, Insulet, Lilly, Medtronic, Roche, and Ypsomed.

Tandem

Tandem didn’t have a full Basal-IQ-themed booth prepared for ADA – we can’t blame them after they got burned preparing last year’s booth for the t:slim X2-G5 integration, which didn’t get approved until August 2017 – but they did have small posters trumpeting Thursday’s FDA approval around the booth. And boy was there a buzz regarding the zero-calibrated G6 sensor, the pivotal PROLOG results, and exceptional subjective usability data from a late-breaking abstract (86-LB). As a reminder, the system will be available in August, including as a free software upgrade to current t:slim X2 users.

  • Protocol 3 of the US IDCL trial – the pivotal study of Tandem’s hypo-hyper minimizer (Control–IQ) with Dexcom G6 and TypeZero –will begin “very soon,” as early as within a week. Reps confirmed that pumps have shipped. As a reminder, the study will enroll 147 subjects randomized 2:1 closed loop vs. SAP. The primary outcomes are superiority in time <70 mg/dl plus non-inferiority in time >180 mg/dl. Secondary outcomes are A1c & technology acceptance. At ATTD, Dr. Boris Kovatchev hoped to commence the study in May, finish at the end of the year, and continue on with an extension phase – timing has slipped slightly, but the study could still feasibly finish before 2019. As of late April, a US launch was expected in 1H19.

    • In the protocol 3 pilot (pre-pivotal study of the Tandem/Dexcom embedded system), n=5 participants spent an excellent ~87% time in 70-180 mg/dl overall, with 94% time-in-range overnight. Time in hypoglycemia was “minimal,” with ~3% overall and just 1% overnight. Notably, there was no time spent >250 mg/dl, and time >180 mg/dl was limited to 5% overall. 

  • See the image below for Tandem’s 2018 international expansion progress. As a reminder, Tandem will launch with G5-integrated t:slim X2 in Europe, followed by Basal-IQ (PLGS with G6). t:slim X2 with Dexcom G5 integration received a CE Mark in April, with the first international sales expected in 2H18. Tandem has also signed distribution agreements in Australia, New Zealand, Italy, Sweden, Norway, and Denmark.

 

 

Diabetes Therapy

Amgen

Amgen hosted a commanding booth at the front of the exhibit hall, dedicated almost entirely to PCSK9 inhibitor Repatha (evolocumab) and its new CV indication for the prevention of heart attack, stroke, and coronary revascularization in patients with established CV disease. Prominent standing displays showed the Kaplan-Meier curves from the FOURIER CVOT, and messaging underscored Repatha’s ability to “help your patients escape high LDL,” overlaid with imagery of a person escaping a crumbling building to represent MI and stroke. Also underscoring the importance of cardioprotection, large infographics lining the wall of the booth delineated the troubling statistics that one in three people with a previous MI will have another CV event (one in four for peripheral artery disease). The booth was staffed by representatives showcasing sample SureClick pens. Furthermore, an entire wall of the booth was dedicated to discussing access for Repatha. We particularly appreciated the helpful list of documentation requirements for providers to help improve the chances of reimbursement for a Repatha prescription (including diagnosis details, a recent lipid panel, and a history of other lipid-lowering therapy).  The company’s commitment to improving access for this currently very pricey drug is commendable, and to this end we learned that 29% of US payers in 2017 streamlined their PCSK9 inhibitor requirements as a result of these negotiations. Reps emphasized that six in 10 patients could pay <$10 for Repatha thanks to patient assistance programs, and the product currently has 45% commercial coverage and 8% Medicare coverage.

AstraZeneca

AZ brought a sprawling, spacious booth to ADA, dedicated primarily to Bydureon BCise (the new exenatide autoinjector) and to SGLT-2 inhibitor Farxiga (dapagliflozin). Sample BCise autoinjectors were available throughout the booth; a pair of virtual-reality headsets took attendees “inside” BCise, demonstrating how the pen works – this was very cool. Reps shared that the single-use Bydureon reconstitution kits will be “phased out” in September (presumably, that’s when AZ will cease production – the end of an era), though they also noted that some patients/providers still actually really like them – they’re comfortable with the kits, they say. We do believe that in the long run, AZ will benefit from joining the movement toward patient-friendly autoinjectors for GLP-1 agonists.

Additionally, AZ continues to advertise the idea of starting diabetes treatment off strong with Farxiga, suggesting the use of the SGLT-2 as first-line therapy. At the front of the booth, a few AZ reps spent hours each day setting up an intricate series of dominoes beneath a sign that read “Join the Momentum.” This display was set up to represent the endless series of healthy choices that patients have to make each and every day. By all accounts, it makes sense for AZ to be putting the bulk of its commercial resources behind Farxiga, as the product drove 100% of growth in the company’s diabetes portfolio in 1Q18. With the DECLARE CVOT reading out late this year, we only expect things to get better for the dapagliflozin franchise, pending positive results (which, to our understanding, are expected). There is certainly lots of hallway chatter at this ADA about the upcoming DECLARE data, the long-term effects of GLP-1 on heard disease.

We spoke to AZ management about Qtern, the fixed-dose combination of Farxiga with DPP-4 inhibitor Onglyza (saxagliptin) – we’ve heard patients who can get this drug love it and we’d love to see more patients receive it. According to Mr. Wooten, Qtern is reimbursed about as well as Farxiga: That is, most formularies that cover Farxiga also cover Qtern, with a few exceptions since the standalone SGLT-2 has a longer history on the market. In addition, AZ offers a copay card that covers up to $150/month of a patient copay for Farxiga, Xigduo (dapagliflozin/metformin), or Qtern. Because Qtern is generally more expensive than Farxiga ($720/month vs. $510/month at our local CVS in San Francisco), we can imagine some patients face very steep out of pocket costs for the combo even with the copay card –this is our speculation, and we’d love more color on these pricing dynamics. We were also reminded by Mr. Wooten that providers in the US continue to favor single agents, in part because they can be titrated separately – an inherent limitation of fixed-dose combinations and one that we’d love to see docs “get over”. It was noteworthy that AZ management revealed this growing focus on Qtern, and we are looking forward to data comparing Qtern vs. Lantus (insulin glargine) and vs. sulfonylureas (both orals on Monday morning).

J&J (Janssen)

J&J occupied a spacious booth with four identical displays at each corner. Video monitors showed prescribing information for SGLT-2 inhibitor Invokana (canagliflozin) and for fixed-dose combinations Invokamet (canagliflozin/metformin) and Invokamet XR (once-daily instead of twice-daily pills). Messaging was focused on Invokana’s first-to-market status in the US, and to this end, reps highlighted that we have ~6.5 years of real-world safety data on the drug (FDA approved in 1Q13). It was interesting that reps mentioned safety ahead of efficacy, and we imagine this was a slight nod to the black box warning for lower limb amputations, to HCP concerns about this risk. A poster presented at ADA, covering the OBSERVE-4D study, showed no imbalance in amputations between Invokana and other SGLT-2s, or between Invokana and other non-SGLT-2 diabetes drugs in a large real-world database (see our write-up above). Also notable, J&J’s booth remains pretty constant from conference to conference as far as we can tell, but we’re eagerly awaiting an FDA decision on Invokana’s CV indication – this is expected in 4Q18, and we’ll be curious to see if/how the booth changes afterward. Following the CV label updates for Jardiance and Victoza, Lilly/BI and Novo Nordisk revamped their respective booths to put cardioprotection center stage. Note that LifeScan isn’t now part of the booth but does have a small presence here – it feels odd to have that now up to the private equity people to figure out (they themselves never seem to come to the meetings).

Lilly/BI

One entire wall of Lilly/BI’s booth was dedicated to fixed-dose combinations Glyxambi (SGLT-2 empagliflozin/DPP-4 inhibitor linagliptin) and Synjardy (SGLT-2 empagliflozin/metformin), which stood out to us because the companies have not historically highlighted Glyxambi in their exhibits or appeared to prioritize it commercially. The eye-catching display advised “put Jardiance at the core of their treatment with Glyxambi and Synjardy.” Reps emphasized that all three of these empagliflozin products have a patient savings card available. According to the sample cards we picked up, commercially-insured patients can get up to $250 in copays covered per month on Jardiance and Synjardy, and can get up to $400 covered per month on Glyxambi. We were pleased to see this, since the list price of Glyxambi is substantially higher than that of Jardiance ($660/month vs. $510/month at our local San Francisco CVS) though we imagine that many patients face a copay higher than $250 or $400 per month based on their insurance, and these individuals would still have to pay out of pocket to get these drugs. For comparison, we learned at Merck’s booth that the company is offering a $460/month copay card for both Steglatro (ertugliflozin) and Steglujan (ertugliflozin/sitagliptin), which more than covers the standalone SGLT-2 prescription (~$319/month) and falls short of the Steglujan prescription (~$520/month) – this is great for patients and we’re not too surprised given diaTribe’s analysis on who has policies most favorable to patients – Merck and J&J won that contest earlier this year (see “How to Get Diabetes Drugs for Free”). Overall, reimbursement is much stronger for Lilly/BI’s SGLT-2 franchise compared to Merck/Pfizer’s SGLT-2 franchise, which is newly-launched – and reimbursement influences strongly, of course, what price the patient sees at the pharmacy counter. It’s noteworthy to see all these manufacturers thinking carefully about patient access, and we’d actually love for the companies to work collaboratively in expanding education on fixed-dose combination therapy, as this is still tragically underutilized in our view though we’re not sure this would be allowed.

Notably, Lilly did not host its own booth at ADA (a major departure), which means there was nothing in the exhibit hall on GLP-1 agonist Trulicity (dulaglutide) or Humalog (rapid-acting insulin lispro). The company hosted a very small booth at both ENDO and AACE earlier this year, a significant downsize from the spacious booths we’re accustomed to seeing from Lilly – clearly a change in strategy.

MannKind

MannKind’s booth was almost an exact replica of the exhibit put up at AACE 2018, with one exciting addition – interviews with Drs. Anne Peters and Satish Garg played on loop. Dr. Peters described how mealtime insulin is one of the most challenging aspects of diabetes care for patients and providers alike. She endorsed Afrezza for the flexibility it offers, and also encouraged CGM use when possible so that patients can receive and respond to feedback, tailoring their post-meal boluses to minimize glucose excursions and hypoglycemia risk. MannKind has framed CGM as a tool that goes hand-in-hand with Afrezza, and indeed, the ultra-rapid-acting nature of the inhaled insulin allows for faster, more narrow adjustments to mealtime insulin dose. In addition to the several mentions of CGM scattered throughout this booth, MannKind is presenting the STAT study at this ADA, which used Dexcom CGM to evaluate postprandial glycemia and time-in-range with Afrezza vs. Novo Nordisk’s NovoLog (insulin aspart) in type 1s. We’ll be back with more on those results. The emphasis on CGM seems like a smart strategy to us in many ways, especially because of what Dr. Peters referred to as “learning how to use your mealtime insulin.” We certainly see potential for CGM to help optimize outcomes in patients using Afrezza. We do wonder, however, if this approach might stimulate more penetration in the type 1 market but not type 2, and if it could deter any patients not on CGM who might otherwise have preferred Afrezza.

Merck

Merck’s ADA booth was much larger than we’ve seen from the company before. Half was dedicated to DPP-4 inhibitor Januvia (sitagliptin), and half showcased new marketing on Pfizer-partnered SGLT-2 inhibitor Steglatro (ertugliflozin). Bold yellow and purple banners read “Powerful A1c-Lowering with Steglatro.” A rep highlighted that Steglatro’s list price is ~42% lower than that of other standalone SGLT-2 inhibitors (J&J’s Invokana, Lilly/BI’s Jardiance, and AZ’s Farxiga) – we love that they are clearly trying to be the SGLT-2 easiest to access. Last we checked, the list price for Steglatro at our local San Francisco CVS was $319/month or $10.63/day, compared to ~$17/day on average for Invokana, Jardiance, and Farxiga. List price only means so much without taking reimbursement and patient discounts into consideration (and the same rep mentioned that payer coverage for all ertugliflozin products is next-to-nothing right now, as is typical for new drugs), but we’re nonetheless impressed by Merck/Pfizer’s pricing strategy here.

Although fixed-dose combination Steglujan (ertugliflozin/sitagliptin) wasn’t featured in the booth, which was very surprising, Merck reps emphasized that this SGLT-2/DPP-4 combo is what really makes the franchise unique. We’ve been surprised by the limited promotion of Steglujan since the ertugliflozin family of products launched in early 2018, but increasingly, it seems like Merck is smartly waiting to ramp up until reimbursement for the fixed-dose combination improves, which makes a lot of sense. We learned at AACE 2018 that the wholesale price for Steglatro is $270/month, while that for Steglujan is $520/month. Merck has issued a copay card valid on all ertugliflozin products, but it only covers up to $460 per month. That means a commercially-insured patient can pick up Steglatro at a pharmacy and pay $0 out of pocket, depending on her health plan; Steglujan would cost the same patient ≥$60/month, after a pharmacy markup on the wholesale price. A rep we spoke to at ADA confirmed these numbers, and suggested that Merck will build up commercialization efforts around Steglujan as payer coverage grows. To be sure, real-world uptake of SGLT-2/DPP-4 fixed-dose combos has been disappointingly low so far (the class also includes Lilly/BI’s Glyxambi and AZ’s Qtern) – we’re going to hope that the field doubles down on education. One thing we’ve noticed in talking to more doctors this year – although everyone acknowledges that patients could do much better, patients themselves are overwhelmed. We’re hopeful that commitment from Merck will get Steglujan into more patient hands in 2019 and beyond.

Novo Nordisk

Ozempic (semaglutide) was the main focus of Novo Nordisk’s sprawling booth, and interestingly, SUSTAIN 7 was the first thing reps talked about. This head-to-head study of two once-weekly GLP-1 agonists – Ozempic vs. Lilly’s Trulicity (dulaglutide) – has been published in the Lancet Diabetes & Endocrinology. The results aren’t yet reflected on the Ozempic product label. However, we learned at ENDO 2018 that sales reps have received special permission from FDA to discuss the findings with healthcare providers anyway – that’s quite something! As a reminder, SUSTAIN 7 found a ~0.4% A1c treatment difference favoring semaglutide over dulaglutide (p<0.0001), and weight loss was greater with semaglutide vs. dulaglutide (p<0.0001). Dr. Richard Pratley outlined SUSTAIN 7 results by baseline A1c subgroup in an oral presentation on Saturday. From our view, we think the power is in describing the class more than comparing two agents – even though it’s a multi-billion enterprise, the class is still woefully underused in our view. It was great to see focus on Victoza, of course – the GLP-1 is now the company’s largest commercial product. There was great professionalism at the booth as usual – very confidence-inspiring.

Sanofi/Lexicon

Sanofi/Lexicon’s joint booth made its second-ever appearance in the ADA exhibit hall, after its debut at AACE 2018 last month. Following the March submission of Zynquista (SGLT-1/2 dual inhibitor sotagliflozin) for type 1 diabetes to FDA and EMA, Sanofi/Lexicon have taken initiative to begin familiarizing the diabetes community with the concept of adjunct therapy for type 1 diabetes, without directly promoting Zynquista. Regulatory decisions on the candidate are expected in 1Q19.

In our opinion, this booth was very well-done and well-staffed, featuring eye-catching quotes about going “beyond insulin” and emphasizing “glycemic control beyond A1c.” The booth was crowded with attendees every time we looked. An interactive 10-question quiz reinforced the unmet need in type 1 diabetes (75% don’t meet an A1c goal of <7%,  even patients at that target might spend up to nine hours per day out of range, etc.). These quiz questions reaffirmed our sense that time-in-range benefit will be a key promotional piece for Sanofi/Lexicon. Patient perspectives also remain a big focus in the booth, and a live illustrator added attendee thoughts on diabetes management to a wall of quotes from patients with type 1 diabetes on the physical, emotional, and mental difficulty of managing this chronic disease. We’re very enthusiastic about the prospect of SGLT inhibitors being approved for type 1 diabetes, and believe that  the regulatory path will be smoother if unmet need is emphasized – while DKA risk associated with these agents exists whether they are regulated or unregulated, education will be far higher if they are regulated. There is clear consensus that patients and providers alike absolutely love the time-in-range, A1c, and weight loss benefit associated with these drugs, and we’re excited to see that the field is already working proactively on how to best manage the DKA risk. To that end, we’re glad to see substantial interest from both Lexicon and Sanofi, and we’re excited to see additional promotion of the beyond A1c movement generally. All this said, the field has to figure out how to move forward, on questions like frequency and type of ketone testing, etc.

Sanofi/Regeneron

Sanofi/Regeneron hosted the largest booth at ADA, as you can see on this exhibit hall floor plan. The space was divided more or less evenly between basal insulin Toujeo (a major improvement to many patients), fixed-ratio GLP-1/basal insulin combination Soliqua, and PCSK9 inhibitor Praluent, with Lantus, Apidra, and Admelog clustered into the fourth corner. We were very excited to see so much focus on Soliqua and hope fervently that more patients will be able to benefit from this combo drug whose data over time has been so motivating. Since we had thought that Sanofi would be launching Toujeo Max SoloStar at ADA, we were slightly disappointed in the attention given to this new highest-capacity basal insulin pen (it holds 900 units – such a positive for patients that take so much more insulin daily). Information on Max SoloStar was housed in one of multiple tabs on the Toujeo touch-screen panels, and there were no display pens to be seen. That said, a representative shared that the “real push” for Max SoloStar will be in a few weeks; the product is already in pharmacies and the salesforce has been giving copay cards to endocrinologists. On Soliqua, the same rep offered that uptake has been slow but that he is seeing some increased interest from providers – we think massively more education could be done on this front and also believe that the “class” needs a name, other than “basal insulin GLP-1 combo”. The hard work is done – creating the compound – now the real work is upon the field to make sure patients and doctors understand that this is available. We remember so much excitement on seeing the original data and hope more work can be done to prove the point about how much easier this is to prescribe and take (along with Novo Nordisk’s Xultophy, which uses even more potent base products, Tresiba and Victoza, and which is considerably more expensive).

On the CV side, reps continued to express excitement about the recent positive readout of ODYSSEY Outcomes, the CVOT for Praluent, and they were perhaps even more enthusiastic about Sanofi/Regeneron’s efforts to expand PCSK9 access. The companies have agreed to lower list price in exchange for simplified utilization management criteria and prior authorization processes from PBMs/payers, and they’ve already entered a deal with Express Scripts to this end. Onward! We’d so love to see many more patients get access.

Xeris

Xeris’ exhibit was a small, single-man booth promoting the company’s broad efforts in glucagon development, including its phase 3 liquid-stable glucagon autoinjector. Given the company’s ongoing IPO, we were glad to get a chance to speak with a Xeris representative, who explained that taking the company public was never a specific goal of management. Rather, it was seen internally as a better way to continue funding pipeline development than traveling around to fight for venture capital dollars. We were a bit surprised to hear this, but this could explain why the IPO came so seemingly early, before the company has even commercialized a product. Regardless, we’re excited for Xeris’ glucagon autoinjector and other products in the glucagon competitive landscape to reach the market, as we strongly feel that these products – which are markedly easier to use than current reconstitution kits – will improve both perceived and actual patient safety. Xeris hopes to file an NDA for the G-Pen (official name to follow) in 3Q18.

 

-- by Adam Brown, Ann Carracher, Abigail Dove, Martin Kurian, Brian Levine, Payal Marathe, Peter Rentzepis, Maeve Serino, and Kelly Close