September 14-18, 2015; Stockholm, Sweden; Day #1 Highlights – Draft

Executive Highlights

Hej hej (pronounced “hey hey”) from Stockholm, where EASD has kicked off with its day of corporate symposium festivities (a total of 18!) – we learned so much and have seriously cut through things for you in this report, bringing you the new and the newly contextualized and leaving ADA learnings that are being translated pretty directly here on the cutting floor. There was definitely new news mixed into the corporate symposia today and we love how much we found. Let’s get to it!

Today’s drug symposia featured topline results from the second phase 3 trial of Sanofi’s LixiLan (lixisenatide/insulin glargine) as well as announcement of an initiation of a small head-to-head trial of Novo Nordisk’s Tresiba (insulin degludec) vs. Sanofi’s Toujeo (insulin glargine U300). On the tech side, Dexcom announced that the company’s G5 mobile system has been approved in Europe, with a launch expected in coming weeks. Please see our top ten highlights and honorable mentions below, followed by detailed discussion and commentary from select sessions. And be sure to check out our preview if you haven’t yet to see what else is in store for the week. Get your skates on!

1. In Dexcom’s corporate symposium, we learned that the G5 mobile system has been approved in Europe (with a replacement claim) and will begin launching in select countries in the coming weeks. We also saw the first-ever picture of the Dexcom/Google sensor, and heard some details on Dexcom’s pipeline. On another positive note, Diasend announced a Dexcom G5 integration today, which will be ready at launch later this month. Dexcom was overt at this session on the power of MDI and CGM (vs. pumps and CGM) – see below for more.

2. Dr. Robert Henry (University of California San Diego, CA) shared hot-off-the-press positive topline results from the second phase 3 trial (LixiLan-L) of Sanofi’s LixiLan (lixisenatide/insulin glargine). While there wasn’t much in the press release, we definitely got the sense from those who know more on the outside are pretty psyched. Gosh how we would LOVE to see more patients GET and STAY on one therapy for awhile – we can see this working well for a long period of time and then patients taking on Afrezza to deal with the post-prandial rises that will come. No hypoglycemia – that’s definitely the word on the street and we hope it’ll be in the label by then.

3. Check it out. In a talk on novel insulins, Dr. Tim Heise (Profil, Neuss, Germany) noted that Novo Nordisk initiated a small head-to-head study of Tresiba (insulin degludec) vs. Sanofi’s Toujeo (insulin glargine U300) just last week (n=60).

4. Lilly/BI’s corporate symposium tantalized the audience with frequent references to the big reveal of the EMPA-REG OUTCOME full results on Thursday. It’s going to be really interesting to see what the risk reduction looks like – there’s a pretty wide spread in our office poll. If you participate, we’ll let you know the current thinking from our panel of ten under-25 associates who are among the smartest people I’ve ever met! Write to Sarah and me here to join. Winners get a SUPER special prize that we aren’t telling about yet.

5. Dr. Lars Rydén (Karolinska Institute, Stockholm, Sweden) offered a compelling take on the limitations of CVOTs during a talk on the relationship between diabetes and cardiovascular disease. Boy is it great to hear the diabeterati opine.

6. Abbott’s well-attended corporate symposium shared strong patient and clinician enthusiasm for FreeStyle Libre for the third straight year, along with new data from a 91-patient, ~9 month observational study of Libre users. Kudos to Abbott for putting patients on the podium to describe their experience – we learned a ton and saw so many nods of heads from clinicians in the EU who are obviously using Libre. That said – they want reimbursement and they want it now, and it’s coming, but not as quickly as everyone would like. What is there agreement on? This is a transformation product, full full stop stop. As my mom used to say, imitation is the sincerest form of flattery. We’re feeling more positive on reimbursement since Dexcom and Google made a plan to make a similar product – full speed ahead for all. Said one patient to me today (and a corporate leader who has diabetes who is using Libre) rather wistfully “Don’t you just love the sound? And the feel?) On a downer note, one of the patients on the panel disclosed, when asked about placement that “a friend” put the Libre on his bottom “and it works!” That is scanning we don’t need to hear about.

7. BD’s first corporate symposium dedicated to the FlowSmart infusion set gathered an impressive lineup of speakers, though there were no new major updates on FlowSmart’s commercialization (still slated for “2016” in the US, EU, and Canada). Exclusive commercial partner Medtronic was not mentioned during the 2.5-hour session.

8. Dr. John Buse offered a ringing endorsement of Novo Nordisk’s Xultophy (insulin degludec/liraglutide), suggesting that it may be more appropriate to conceptualize it as an entirely novel agent rather than a combination of existing drugs. Whoa. We hadn’t thought about that. We do love the idea (see above) of patients going on one therapy and staying on it a long time – sure there is a moderate difference in expense, but getting something that works over a long period of time for type 2 patients as their diabetes advances is hugely attractive. It’s not this sort of incremental expense that is driving costs, it’s the heart attacks, strokes, frequent flier ins and outs at hospitals. We’d love to see more testing on the value of therapies that work over the long run as diabetes advances. We do think both Novo Nordisk and Sanofi may need to consider

9. At Novo Nordisk’s packed corporate symposium, Dr. Niels Vrang (CEO, Gubra, Hørsholm, Denmark) discussed the growing research on obesity drug Saxenda’s (liraglutide 3.0 mg) mechanisms of action within the brain, followed by the always-great Dr. Donna Ryan’s (Pennington Biomedical Research Center, Baton Rouge, LA) presentation on how to personalize obesity treatment (there’s not nearly enough concrete discussion on how to do this in diabetes or obesity – we were very happy about the idea of this approach even if it was mainly “stop quickly if it isn’t working”).

10. Dr. Colin Dayan (Cardiff University, Wales, UK) opened a Sunday workshop on immunotherapy for type 1 diabetes with a pragmatic perspective on the most likely target populations and the biggest practical hurdles for the field. This was an excellent “type 1 cure” session for an audience that is always hungry for news and new insights.

Top 10 Highlights

1. In Dexcom’s corporate symposium, Senior VP of R&D Jake Leach shared that the G5 mobile system has been approved in Europe and will begin launching in select countries in the coming weeks, in tandem with the US launch. This was very unexpected, as Dexcom has never given an official timeline on EU availability of G5. Notably, the EU version of G5 has a replacement claim (!!) in the label: “The G5 Mobile System is designed to replace fingerstick blood glucose testing for diabetes treatment decisions.” Though it still requires two fingerstick calibrations per day, the move is important as Dexcom seeks to compete with Abbott’s factory calibrated FreeStyle Libre in the EU. The EU launch of G5 also brings the Share remote monitoring capabilities and the more accurate G4AP algorithm (MARD: 9.0%) to Europe for the first time (Share was never launched in the EU – smart from a resource perspective). In other major news, Mr. Leach showed a first-ever picture of the Dexcom/Google prototype sensor – it was the size of penny and a tiny bandage (see the picture below – actually smaller than we had imagined on the body). The partnership was only announced a month ago, though the pressure is certainly on to hit the goal of commercializing within ~ two to three years. On the data front, Mr. Leach revealed that Dexcom is working on real-time therapy support “like an insulin dosing calculator,” (sounds kind of like Sanofi’s COACH for Toujeo and Afrezza that is winning lots of praise) and a pilot is ongoing at Lucile Packard Children’s Hospital Stanford to seamlessly integrate Dexcom CGM data with the notoriously non-interoperable EPIC (how many times have we heard from clinicians off the record “EPIC is an EPIC failure!”?). More details below on the Google partnership, G5, the data management pipeline, partners, and a super-insightful Q&A. Dr. Claudia Graham gave an excellent talk on cost-effectiveness following Mr. Leach, pointing out the high cost of pumps and the lack of incremental clinical benefit over standalone CGM. This certainly speaks to the lack of good pump therapy economic data – we do think more pump data will be coming now that, ironically, CGM is a lot more accurate and can help point out the benefit.

• Outside of the session, Diasend announced integration with Dexcom’s G5 system today. Excellent timing - it will be available right when G5 launches this month. Dexcom CGM data will now seamlessly flow into Diasend (no cables!), allowing combination with insulin pump and activity data (Fitbit, Jawbone). It’s a strong integration: patients will link their Dexcom G5 Mobile account with their diasend Personal account (from within diasend) to establish a permanent link (cloud-to-cloud). This makes the diasend integration low hassle for patients, platform agnostic, and immediately ready for Android once G5 launches next year. Like Apple’s HealthKit, diasend will still come with a three-hour delay between the CGM data acquisition and posting. Patients will be able see their Dexcom data in the diasend app, but are not required to, since G5 will also synchronize to their web-based diasend patient account (and linked healthcare provider account). The news also marks the launch of diasend’s new mobile app, which will be on display here at EASD. We’ll take a look in the exhibit hall and be very interested to compare it to other diabetes apps.

2. Dr. Robert Henry (University of California San Diego, CA) shared hot-off-the-press positive topline results from the second phase 3 trial (LixiLan-L) of Sanofi’s LixiLan (lixisenatide/insulin glargine). The combination produced statistically superior A1c reductions vs. Lantus (insulin glargine) after 30 weeks in 736 patients with type 2 diabetes on basal insulin, with a safety profile reflecting those of the components. Secondary endpoint results were not shared, and we eagerly await details on LixiLan’s effect on weight, hypoglycemia, and GI side effects. We see basal insulin/GLP-1 agonist combinations as one of the most exciting type 2 diabetes drug classes on the immediate horizon and look forward to seeing how the detailed results for LixiLan compare to those for Novo Nordisk’s Xultophy (insulin degludec/liraglutide), which have been very impressive (even though of course “we can’t really compare”). The LixiLan-L results were included at the end of a broader presentation on intensification options for patients with type 2 diabetes whose blood glucose is not adequately controlled by basal insulin (see below for more on the engaging, insightful, and opinionated talk). We’re glad to hear about intensification since we need it so badly – the percentage of patients on basal only who are not hitting their glycemic targets is incredibly depressing.

• In its own announcement just hours before, Sanofi confirmed its expected timeline of 4Q15 for a US LixiLan regulatory submission and 1Q16 for an EU submission. This is consistent with Sanofi’s guidance since its 1Q15 update. While Xultophy has a significant head start in the European market, the two will likely launch in the US at around the same time (whoa), as we look for an FDA submission for Xultophy in 4Q15 as well (assuming a Tresiba [insulin degludec] approval in October as expected). Yeah. This is going to be a race that everyone wins. And some will win more – it’s all fantastic and we look very forward to seeing payer opinion on this class. The diabeterati sure seem to like it and we think it’ll expand the market for all GLP-1.

3. In a talk on novel insulins, Dr. Tim Heise (Profil, Neuss, Germany) noted that Novo Nordisk initiated a head-to-head study of Tresiba (insulin degludec) vs. Sanofi’s Toujeo (insulin glargine U300) just last week. The small trial (n=60 patients with type 1 diabetes; currently recruiting) aims to compare the pharmacodynamic and pharmacokinetic properties of the two products at steady-state conditions. The primary endpoint is area under the glucose infusion rate curve during a 24-hour period at day 6, 9, and 12. Primary completion is expected in April 2016. This study will provide the first direct comparison between the two products, which will likely be each other’s most direct commercial competitors in the medium-term future. Based on data from previous studies (including that presented during this talk), we would predict a slight edge for Tresiba in terms of duration of action and variability; we assume Novo Nordisk made a similar assessment to conclude that the study was worth the investment. From a clinical perspective the two products appear to be relatively comparable, both offering incremental improvements over their predecessors but potentially clinically meaningful advantages in terms of hypoglycemia and reduced variability. We assume reimbursement will be the main determinant of the products’ success, and positive results from comparative studies like this one could certainly be a useful tool in negotiations with payers. Overall, Sanofi should be very happy with the feedback on Toujeo – we have heard virtually no negatives on it outside the perennial pricing problem. While we definitely understand that, and sympathize, the value for getting patients to go faster is also worth a whole heck of a lot.

4. Lilly/BI’s corporate symposium tantalized the audience with frequent references to the big reveal of the EMPA-REG OUTCOME full results on Thursday (at 5:45 pm local time in Stockholm to be exact – we’ll all be there on the edge of our seats!) Upon entering the packed auditorium, attendees were immediately greeted by a huge screen flashing a continuous loop of the words “SGLT-2,” “CVOT,” and “CVD,” interspersed with EKG-style heartbeats and set to upbeat music. If that display had not already put attendees in the frame of mind to be thinking about the EMPA-REG OUTCOME trial, every seat in the room offered an invitation to the Lilly/BI-sponsored symposium on EMPA-REG OUTCOME immediately following the results presentation (really!). As a reminder, Lilly/BI released topline results from the trial last month stating only that Jardiance (empagliflozin) demonstrated cardiovascular risk reduction vs. placebo. Lilly and BI are definitely building up big interest up the full results – we certainly hope they live up to the publicity, though we believe even a fairly subtle effect, which may well be the result, would still be a big deal given the number of reduced deaths this would still indicate.

• In his presentation during the symposium, Dr. Naveed Sattar (University of Glasgow, UK) asserted that the diabetes field needs more CVOTs moving forward because they are the only way to understand drugs’ full effect on cardiovascular risk. In the case of SGLT-2 inhibitors, he pointed out that the class is known to decrease blood pressure and weight (good in terms of cardiovascular risk), but it also raises LDL cholesterol (for unclear reasons but potentially a concern).  During the ensuing panel discussion, fellow presenter Dr. Kausik Ray (Imperial College, London, UK) echoed this point, stating that superiority (rather than non-inferiority) trials require investigators to be absolutely sure there are no off-target harmful effects first. We agree that outcomes trials certainly provide invaluable information about products’ safety and efficacy but believe that the current FDA paradigm has important limitations that may prevent the trials from demonstrating the most clinically useful information (see below for more).
• During the panel discussion, Dr. Ray and Dr. Sattar speculated on the potential drivers of the positive EMPA-REG OUTCOME results. Dr. Ray was clear that he expects the blood pressure-lowering effect of SGLT-2 inhibitors to be the main driver of reduced cardiovascular risk, while Dr. Sattar suggested that it might be a composite effect of lower blood pressure, weight, and glucose.

5. Dr. Lars Rydén (Karolinska Institute, Stockholm, Sweden) offered a thoughtful take on the limitations of CVOTs during a talk on the relationship between diabetes and cardiovascular disease. He pointed to several commonly cited shortcomings (short duration, disproportionately high-risk populations, glycemic equipoise design) and mentioned others that have attracted less discussion, such as a lack of attention to postprandial glucose and use of primary endpoints that do not include clinically relevant events like peripheral arterial disease, heart failure, and stable angina. He also cautioned that the promising findings from UKPDS have limited applicability to the modern type 2 diabetes patient population because so few patients were on blood pressure- and lipid-lowering drugs – he said the heavy use of such medications is likely one of the main reasons why it is so difficult for current trials to demonstrate superiority (we wonder if it’s more a matter of just short timing). While the tone of Dr. Rydén’s critique was not as strident as some of the commentary we heard recently at ESC, the implication seemed to be that the information gained from these trials may not be worth the enormous investment of patient time and financial resources. As he aptly noted, the design of current trials is driven by commercial and regulatory factors rather than academic research goals – yeah, that’s pretty depressing given the potential impact on public health. We hope the FDA will feel compelled in the coming years to engage in a discussion about how the 2008 Guidance can be modified to encourage more cost-effective studies. We also hope that government, industry, academia, and private foundations can work together to develop creative ways to better answer the most important clinical questions about diabetes drugs and cardiovascular risk, such as through more robust large-scale databases or comparative effectiveness studies.

• Dr. Rury Holman (University of Oxford, UK) alluded to similar limitations during Q&A following his recap of the results from TECOS (CVOT for Merck’s Januvia [sitagliptin]). Dr. Holman said it would be a “very long time” before anyone can expect clinical outcome data on the neuro-, cardio-, and nephroprotective effects of sitagliptin or other DPP-4 inhibitors. He believes a truly informative study would have to incorporate the glucose-lowering effects of the drug, and it would be difficult to do this ethically as a placebo-controlled trial given the known relationship between glucose control and microvascular complications. He argued that even uncovering any protective glucose-independent effects would require a much longer trial than most companies would be willing to undertake – this is where we believe funding from non-industry sources can play a very useful role since once these agents are generic, it would of course be very useful to understand the true benefit. Given these concerns, he suggested that a head-to-head comparative outcomes study with agents from different classes are the most likely to reveal the true long-term benefits and harms of new drugs. We completely agree and see this as one of the ways in which more flexible FDA policy could enable more informative trials.
• On the other side of the coin, Dr. Marc Pfeffer (Brigham and Women’s Hospital, Boston, MA) stressed the importance of evaluating hard clinical outcomes rather than relying on surrogate markers like A1c. He joked that he did not intend to “pick on A1c,” offering a long list of promising hypotheses in cardiology based on epidemiological studies with surrogate endpoints that were later disproven in outcomes trials. However, he too offered some criticism of existing CVOTs for diabetes drugs, namely the fact that they do not include heart failure as a primary endpoint, a sentiment we have heard repeatedly over the past few years.

6. Abbott’s well-attended corporate symposium shared strong patient and clinician enthusiasm for FreeStyle Libre for the third straight year, along with new data from the company’s 91-patient, ~ nine-month observational study of Libre. The latter was an observational study of FreeStyle Libre in type 1 patients at a high risk for developing complications (baseline A1c = 10.1%). The data was strong for a device – especially in a tough and very real-world group – with three- to nine-month follow-ups from baseline demonstrating a mean A1c improvement of 1.4%. Hypoglycemia was not reported. Now one year following FreeStyle Libre’s EU commercialization, Abbott featured two conversations with current users and clinicians – the very entertaining and articulate Mr. Stephen Dixon (type 1) with diabeterati member Dr. Pratik Choudhary, and the fascinating Mr. Detlef Behring (type 2) with powerhouse user Dr. Oliver Schubert. The device’s convenience was a recurring theme, with speakers highlighting the speed (vs. BGM) and discretion (vs. CGM) as significant advantages. Interestingly, Mr. Dixon characterized his decision to choose Libre over traditional CGM as a “no-brainer,” highlighting the psychosocial benefits of the technology (“alarms are a nighmare!”) and information availability (“I swipe 15 times per day and get 20 times more information than I would with 15 fingersticks”). On accuracy too, type 1 Mr. Dixon provided a stirring endorsement of Libre, noting that he has not done a fingerstick in ~12 months: “People say you must check Libre values against SMBG, but real life is real life.” We’ve heard that from a lot of FreeStyle Libre users. There is still no timeline on a US submission of FreeStyle Libre; the blinded Pro version is currently under FDA review, with a launch expected next year. See the detailed commentary for the most quotable quotes from this session where one thing is clear – this is a truly transformational product and the best interest is in getting it to as many users who want it as possible (the patients literally couldn’t name any kind of patient who couldn’t benefit).

7. BD’s first corporate symposium dedicated to the FlowSmart infusion set gathered an impressive lineup of speakers to discuss the “Achilles Heel” of insulin pumps and the company’s new set. There were no new major updates on FlowSmart’s commercialization, which is still slated for “2016” in the US, EU, and Canada. Interestingly, exclusive commercial partner Medtronic was not mentioned at all during the 2.5-hour session; this felt odd, since the set will be co-branded BD/Medtronic and sold exclusively by Medtronic. However, this session was about the science, so that may well have been expected. Notably, Dr. Larry Hirsch’s review of the set’s features did offer a new perspective on the advantages of the dual-port catheter: with insulin flowing out of two places, two distinct depots of insulin form (via imaging studies), potentially offering absorption advantages (better PK/PD must be confirmed in studies). The session was mostly an overview of infusion sets and the associated subcutaneous biology, and Drs. Bruce Buckingham, Lutz Heinemann, Thomas Danne, Hans De Vries, and Aaron Kowalski expressed a mix of outrage and enthusiasm – outrage at the underwhelming body of research on infusion sets, and enthusiasm for what BD’s new set could offer. Going forward, a big question is not whether the FlowSmart set reduces “flow interruptions” (that much seems clear from the data), but to what extent the design offers true clinical advantages – better insulin PK/PD, more time-in-range, fewer hospitalizations from DKA, etc. Those are tall orders for sure, and many of the product’s form factor improvements are meaningful from a patient perspective (smallest gauge insertion needle on the market, multi-position connector, sliding needle shield cover, etc.). More up-close details on the set are here.

• Drs. Buckingham, Danne, and Heinemann converged on similar points in their clinical experience and the overviews of the infusion set literature: (i) reliable sets matter tremendously from a patient perspective (for pump satisfaction, for insulin absorption, for DKA, for the artificial pancreas); (ii) patients experience many problems with sets (pain, lipohypertrophy, kinking, scarring, unexplained hyperglycemia); (iii) infusion set wear seems to be highly individualized, with a surprising number of patients able to tolerate seven-day wear without much of a problem (Dr. Buckingham said~20-30%); (iv) sensors are better tolerated than sets, suggesting it is insulin – and not the subcutaneous tissue – that is causing a biological response; and (v) there are a tremendous number of factors that affect absorption/action of subcutaneous insulin (23 were listed on Dr. Heinemann’s slide). Wow are these guys smart. We’re so happy that BD has worked on set development and we expect more innovation to come on this front – it’s a new day! We’ll be eager to watch the commercial launch, of course.

8. Dr. John Buse offered a ringing endorsement of Novo Nordisk’s Xultophy (insulin degludec/liraglutide), suggesting that it may be more appropriate to conceptualize it as an entirely novel agent rather than a combination of existing drugs. The majority of his talk was spent reviewing some of the less-cited data from the DUAL phase 3 program for Xultophy, including patient-reported outcomes, safety of switching from basal insulin, efficacy stratified by baseline characteristics, and GI side effects. The results favored Xultophy across the board, in most cases compared to its individual components. He closed by explaining that he is increasingly conceptualizing Xultophy as a novel drug that offers greater tolerability/quality of life enhancements than either component and unparalleled efficacy among type 2 diabetes drugs rather than simply as a combination of two existing drugs. He suggested that while cost could be a significant barrier for some patients, there does not appear to be any clinical reason why any subset of patients would be a poor fit – that’s a big deal. We believe this therapy could just result in less “noise” and patients doing better for a longer duration – that would be excellent from a public health perspective, personal perspective, health professional perspective, etc. He suggested that Xultophy would be well placed as a second-line treatment option after metformin in the ADA/EASD algorithm, either in addition to the six existing options or even as a replacement for basal insulin – a provocative but logical argument given the greater efficacy and reductions in hypoglycemia and weight gain compared to basal insulin in clinical trials.

• During Q&A following the session, Dr. Buse and Dr. Simon Heller (University of Sheffield, UK) expressed optimism that payers will look favorably on the clinical value of Xultophy and other such fixed-dose combinations. Dr. Heller noted the very small percentage of diabetes expenditures (at least in the UK) devoted to medications compared to complications and lamented the challenges involved in persuading NICE that new expensive drugs warrant robust reimbursement. However, he also offered some defense of the oft-criticized NICE, noting that the organization does value clinical efficacy and reduction in complications and predicting that it will ultimately come down in favor of such an appealing product. In the US, Dr. Buse acknowledged that “the gloves are off” in terms of pricing negotiations but argued that Xultophy has a uniquely impressive profile and expressed hope that its clinical value will be recognized and the price will not be exorbitant. We hope these predictions prove correct and largely share the speakers’ optimism, although we were very surprised to see the German IQWiG hand down a “no additional benefit ruling” for Xultophy last month – that seems like crazy talk.

9. At Novo Nordisk’s packed corporate symposium, Dr. Niels Vrang (CEO, Gubra, Hørsholm, Denmark) discussed the growing research on Saxenda’s (liraglutide 3.0 mg) mechanisms of action within the brain. He first introduced the complexity of hunger signals, noting that hunger has hedonic aspects, humoral feedback signals from the fat and gut, as well as neural feedback signals from the gut. In explaining how peripheral liraglutide can affect food intake and weight control, Dr. Vrang highlighted that GLP-1 is not only a gut hormone, but also a neurotransmitter used by a small group of neurons in the caudal brainstem that project to the hypothalamus. Specifically, recent research has suggested that GLP-1 agonists influence receptors on appetite regulating neurons in the hypothalamus, activating the arcuate POMC/CART neurons (which are involved in appetite inhibition) and inhibits NPY neurons (which are involved in appetite stimulation). Additionally, Dr. Vrang walked attendees through brain imaging studies that have demonstrated that peripheral liraglutide administration is taken up into these specific brain areas in a receptor-dependent manner. Looking forward, he posed questions including how paraventricular nucleus activation (also in the hypothalamus) may affect energy expenditure as well as the roles of brainstem and vagal GLP-1 receptors and glucose regulation. A more in-depth look into the brain has appeared to become an increasingly hot topic of research for obesity, especially as more research has suggested GLP-1 agonists’ neural mechanisms – please see our coverage below for more details.

• Later in the symposium, Dr. Donna Ryan (Pennington Biomedical Research Center, Baton Rouge, LA) provided guidance on how to better personalize obesity treatment using weight loss medications. She opened by stressing the diversity of individuals with obesity as well as the heterogeneity of treatment effects, specifically pointing out “the trouble with averages” in obesity drugs’ clinical data as there are very few “average” patients (she noted that the majority of individuals will either derive less than or greater than the average net benefit or no clinically meaningful effect at all). Dr. Ryan thus highlighted the need to identify patient characteristics to best target treatments, providing four considerations based on the knowledge of heterogeneity of treatment effects: (i) do no harm, evaluating contraindications and warnings; (ii) consider the added benefits of therapies by understanding pre-treatment factors; (iii) manage concomitant medications and chronic diseases; and (iv) understand that the early weight loss response is the best predictor of ultimate success. This last consideration is the most common one we have heard. While early response seems to be a pretty reliable predictor, it still means needing to prescribe obesity drugs in a trial and error fashion to identify this early response.  She did stress that ultimately the trial is based on a shared decision between patient and physician and dosing characteristics (injection or oral), side effect profiles and cost are all important to patients. Until weight loss medications become more affordable, excitement of patients and providers will be dampened. For more on Dr. Ryan’s presentation, please see our detailed coverage below.

10. Dr. Colin Dayan (Cardiff University, Wales, UK) opened a Sunday workshop on immunotherapy for type 1 diabetes with a valuable and pragmatic perspective on the most likely target populations and the biggest practical hurdles for the field. He suggested that the ideal candidates for novel immunotherapies are (i) patients with very high A1cs and poor adherence to insulin (who are responsible for most of the morbidity and mortality still associated with type 1 diabetes) and (ii) those with tight control but frequent hypoglycemia. We heard a similarly pragmatic talk on cell-based type 1 diabetes therapies from Dr. Alexander Fleming (Kinexum, Harpers Ferry, WV) at GTC Bio earlier this year and believe that this strategy of defining narrow target populations is a very smart approach in such a challenging area. Dr. Dayan was frank about the complexity and difficulty of this field, pointing to the narrow target population, the lack of reliable biomarkers, the likely need for combination or at least sequential therapy, and a poorly defined paradigm for cost/benefit assessments as key challenges. As he aptly put it, it is not currently clear what price the healthcare system is willing to pay to cure type 1 diabetes. In his view, academia can help by creating more efficient recruitment networks for clinical trials, discovering better biomarkers, sharing assays, and better defining the highest-need population. For its part, industry can provide funding for later-stage trials, offer access to agents for earlier-stage trials, and engage in more sample sharing – the need for greater collaboration within and between the two sectors was a theme of the talk. The remainder of the session featured talks by Dr. Bart Keymeulen (Vrije University, Brussels, Belgium), Dr. Mark Peakman (King’s College London, UK), Dr. Mark Rigby (Janssen, Philadelphia, PA), and Dr. Mark Atkinson (University of Florida, Gainesville, FL) on four immune interventions that have already shown benefit in phase 2 studies of beta cell preservation (anti-CD3, CTLA4 blockade, alefacept, and ATG/G-CSF, respectively). 

Honorable Mention

• We also learned today that Dr. Kerstin Rebrin has been appointed Roche’s Head of Diabetes Management Solutions, a strong indication of the company’s commitment to CGM and a sign that no one should discount Roche on the CGM front. Dr. Rebrin has an impressive resume in diabetes technology, coming over from BD where she ran the CGM program prior to its discontinuation last year as well as early work at Abbott and in academia, where she was very highly respected. We view the signing as a major win for Roche and look forward to seeing how her expertise can translate to R&D progress. Indeed, given the increasingly competitive CGM landscape, we are curious to see how the company can differentiate its product from the market’s more established players – her job won’t be easy! As a reminder, Roche disclosed at its 2Q15 Diagnostic Division Analyst Event that it plans to bring its novel CGM to the market in the “next 18 months” (as of this past July). We were also impressed to learn today from the Roche session that there won’t be any problems with Roche’s CGM and interferents like Tylenol – so excellent they figured out how to address ths.
• During the AstraZeneca-sponsored symposium, Dr. Jochen Seufert (University of Freiburg, Germany) advocated the use of combination therapy as a first-line treatment. He characterized as many have the traditional stepwise approach to type 2 diabetes a “treat to fail” strategy, emphasizing that diabetes is a progressive disease requiring therapy intensification over time as beta-cell function decreases. He suggested that combination therapy, rather than monotherapy metformin, may allow for faster achievement of A1c targets. Combining treatments with different mechanisms of action may also increase clinical benefit by improved target achievement, weight and blood pressure reduction, reduced risk of hypoglycemia, delayed disease progression, improved long-term glucose control, and reduced long-term complications. Furthering the argument that early use of combination therapy is beneficial for patients with type 2 diabetes, Dr. Seufert showcased data from the UK Clinical Practice Research Datalink of medical records showed that a 6-month delay in therapy intensification increased the risk of cardiovascular disease by 20% and heart attack by 26% when compared with immediate therapy intensification. We have heard a number of conference speakers make similar arguments in favor of earlier, more aggressive combination therapy. Dr. Ralph DeFronzo (University of Texas, San Antonio, TX), one of the most vocal proponents of this idea, will make his case during a debate titled “Do we need triple and quadruple therapies?” on Thursday.

Detailed Discussion and Commentary

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

Current and Future Dexcom CGM Technology Innovations

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

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

• Mr. Leach showed a picture of the Dexcom/Google prototype CGM sensor, highlighting the ambitious goals: “develop a simple, low-cost, disposable, body-worn sensor system integrated into an advanced data analytics platform to drive entry into [the] type 2 market and to expand CGM use in [the] type 1 market.” Succinct and lofty – the best kind of goal. In August, the product was envisioned as a bandage the size of a couple of dimes stacked on top of each other, and this looks roughly the same size. Still, seeing it on a human abdomen for the first time really reinforced how small this form factor will be. We wonder if Abbott’s real-time version of FreeStyle Libre will be out at that point in the US. 
• “We expect to have a portfolio of multiple products for different groups. The best example is the type 2 product we’re focused on with Google.” Mr. Leach admitted that these products might require tradeoffs on cost and performance. Indeed, we wonder what level of accuracy/reliability the Google/Dexcom product will achieve – could the sensor attain a MARD ~10%? Is 15% more likely? What is the necessary MARD for a type 2-focused product? What is the right accuracy/reliability tradeoff to substantially improve the form factor? Hard decisions!
• “A MARD of 10% is the safety threshold for CGM to replace SMBG.” Mr. Leach highlighted a new modeling paper (Kovatchev et al., DT&T 2015) to underscore this point. The newly acquired replacement claim in the G5 EU label is a major win for Dexcom, and we wonder how such a label will be phrased in the US – per Dexcom’s 2Q15 call, such a claim is expected sometime in 2016 in the US. This has major implications for Medicare coverage, for doctors to prescribe CGM, for the patient experience of using CGM, and perhaps for payer discussions.
• In new news, remote software updating the Share receiver to G5 will be possible on both Mac and PC. This overcomes frustration with the PC-only upgrade from the G4 Platinum algorithm to the G4AP algorithm (Software 505) last fall.
• Fingerstick calibrations entered on the G5 app will be sent directly to the new smart Bluetooth transmitter. We assume from there they would also be sent to the receiver, should a patient opt to use one. This is impressive smart transmitter technology that retains the same form factor as the existing G4 Platinum transmitter. The tradeoff is a shorter battery life, as we have previously covered (three month indication).
• Mr. Leach highlighted the G5 app’s discrete alerts and alarms, which show up on the iPhone lock screen similar to any other notification (e.g., text message). Swiping the notification opens the Dexcom app and shows the alert. The notification sounds can be customized, correcting a long-stated frustrated of CGM users (“I’m used to the alarms!”). Alarms can also be set to vibrate for discretion. Overall, it seems like the mobile interface is going to offer a substantial customization and user experience upgrade over the standalone receiver.
• Dexcom is currently working on real-time therapy support “like an insulin dosing calculator.” The company has historically focused on retrospective data – and that will continue – though Mr. Leach said in Q&A that improved real-time analytics are also in the works. The hope is to add these straight into the G5 app. We could imagine several potential offerings: a bolus calculator that incorporates CGM values and trend information; analyzing insulin pump data from partners Insulet, Tandem, and Animas; projecting CGM values into the future; real-time exercise dosing/eating advice; etc.
• Stanford Children’s Hospital is piloting seamless Dexcom integration with EPIC, the notoriously non-interoperable electronic medical record. Dexcom users’ CGM data will post to HealthKit (via the Share app now, and G5 in the future), and an EPIC app takes the glucose data from HealthKit and puts it into the EMR. “The user and doctor don’t have to do anything at all.” Physicians can log in and see the CGM data within the EPIC program, eliminating the need to go to separate Dexcom software. Stanford plans to roll the pilot out more widely. Mr. Leach urged attendees to contact EPIC for more details on this seamless integration with HealthKit.
• Mr. Leach emphasized Dexcom’s “ecosystem” approach and showed the growing list of data management, app, and pump partners: diasend, EPIC (new!), Glooko, SweetSpot, Tidepool; Databetes (Meal Memory) and Training Peaks; Animas, Insulet, and Tandem. Apple’s HealthKit platform was shown on the slide as the hub of all these partnerships – it will be interesting to see if Android lags behind on this front. 
• Dexcom CGM data currently posts to HealthKit with a three-hour delay. Mr. Leach said it might be reduced over time. Three hours was established as a safe limit with the FDA, preventing real-time use of CGM data by other apps (i.e., making those apps class III medical devices). It’s a nuanced and tricky debate – what constitutes real time data? Is a 20-minute delay sufficiently retrospective? We hope this window declines over time, since there is so much potential to improve care with real-time, contextual feedback. Other apps could do more if the data flowed to HealthKit closer to its acquisition – Mr. Leach acknowledged as much, but it sounds like Dexcom’s classic interim steps regulatory approach will be the strategy here.
• Dexcom is “working towards” G5 integration with its pump partners Animas, Insulet, and Tandem. At this stage, it’s hard to know who will be first-to-market with an integrated pump:
  
  • Insulet’s next-gen OmniPod PDM is expected to launch in 2016, though we don’t think it will include G5 data on the handheld to start – Insulet has maintained that the PDM will be submitted for 510(k) clearance, meaning non-CGM-integrated. Perhaps the next-gen PDM will launch with integration on the app side, allowing the Dexcom mobile app to display Insulet pump data sent through an Insulet app and HealthKit. That is complete speculation on our part, and an open question is whether HealthKit can even handle insulin dose data (it does not have such an entry field to our knowledge).
  • Tandem announced an updated agreement in its 2Q15 call to integrate G5 in the future, but there is no timing on when it could launch.
  • Animas has never talked about a G5 integration publicly, though we assume one is in the works for automated insulin delivery.

CGM: Cost Modeling and Reimbursement

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

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

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

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

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

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

CGM + MDI: Cost-Effectiveness Modeling

*Assuming only half of patients buy a receiver in the future, due to G5.

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

CGM Reimbursement Status

Using Dexcom CGM in Clinical Practice – Education and Medical Management

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

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

Panel Discussion

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

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

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

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

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

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

Q: What about non-invasive sensors?

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

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

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

Q: Can you talk about privacy issues?

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

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

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

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

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

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

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

Q: Do you have plans for a dose advisor?

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

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

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

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

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

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

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

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

Dr. Adolfsson: It’s rare.

Corporate Symposium: Different Patients, Different Needs – Towards an Integrated Care Approach to Diabetes (Sponsored by Sanofi)

When It’s Time to Intensify: What are the Options?

Robert Henry, MD (University of California San Diego, CA)

Dr. Robert Henry presented an informative and opinionated view of options to intensify insulin therapy in type 2 diabetes, reviewing the data behind rapid-acting insulin and GLP-1 agonists in postprandial glucose lowering and presenting hot-off-the-press positive topline results from the second phase 3 trial of Sanofi’s LixiLan (lixisenatide/insulin glargine). Dr. Henry opened with a discussion of when intensification is necessary, noting that more than half of patients who initially achieve an A1c <7% can’t sustain it; the average time to failure is about 400 days. While these patients may be at target in terms of their fasting plasma glucose (FPG), their postprandial plasma glucose (PPG) may be high and using basal insulin is not sufficient. Dr. Henry demonstrated a clear preference for adding a GLP-1 agonist rather than rapid-acting insulin in such situations, noting that in head-to-head comparisons between GLP-1 agonists and rapid-acting insulins, the GLP-1 agonist arm demonstrated non-inferior A1c reductions, superior PPG changes, weight loss instead of weight gain, and less hypoglycemia. Dr. Henry concluded his talk by giving attendees a sneak peek at the GLP-1 agonist/basal insulin combinations on the horizon (LixiLan and Novo Nordisk’s Xultophy [insulin degludec/liraglutide)..

• Dr. Henry shared positive topline results released just hours earlier from the phase 3 LixiLan-L trial. The combination produced statistically superior A1c reductions vs. Lantus (insulin glargine) after 30 weeks in 736 patients with type 2 diabetes on basal insulin, with a safety profile reflecting those of the components. Secondary endpoint results were not shared, but we eagerly await details on LixiLan’s effect on weight, hypoglycemia, and GI side effects. We see basal insulin/GLP-1 agonist combinations as one of the truly exciting type 2 diabetes drug classes on the immediate or near to medium term horizon and look forward to seeing how the detailed results for LixiLan compare to those for Novo Nordisk’s Xultophy (insulin degludec/liraglutide), which have been very impressive.
• The positive LixiLan-L results follow the announcement of positive topline results from the phase 3 LixiLan-O trial, announced in July. LixiLan-O compared A1c reductions with LixiLan vs. Lyxumia or Lantus in 1,170 patients with type 2 diabetes on background metformin. As with LixiLan-L, the announcement shared only that the combination produced statistically superior A1c reductions compared to the individual components and did not comment on the secondary endpoints. Full results for the trials will be presented at a future conference.
• In its announcement, Sanofi confirmed its expected timeline of 4Q15 for a US LixiLan regulatory submission and 1Q16 for an EU submission. This is consistent with Sanofi’s guidance since its 1Q15 update. While Xultophy has a significant head start in the European market, the two may well launch in the US at around the same time, as we expect an FDA submission for Xultophy in 4Q15 as well (assuming a Tresiba [insulin degludec] approval in October as expected).

Corporate Symposium: Getting to the Heart of Type 2 Diabetes (Sponsored by Lilly/BI)

Panel Discussion

Kausik Ray, MD (Imperial College London, UK), Naveed Sattar, MD (University of Glasgow, UK), and Nikolaus Marx, MD (University Hospital Aachen, Germany)

Q: Should future CVOTs demonstrate superiority rather non-inferiority?

Dr. Nikolaus Marx: From a cardiologist’s point of view: of course, we’d love to see that and lots of cardiologists can’t understand why these aren’t being performed. But it’s important to remember what is required by regulatory bodies. In future I hope to see superiority trials.

Dr. Kausik Ray: It really depends on what it is you want to do. One way to look at this is in terms of on-target benefits and on-target harm. Lower glucose has a cardiovascular benefit. If you change glucose levels, you might get a benefit, but it will take 25 years. On-target harm are things related to hypo. With any new class, we’re worried about the off-target effects, like heart failure. If you’re absolutely sure there are no off-target effects, then you can go straight to superiority trials. That’s the big question, is it safe?

Dr. Naveed Sattar: Glucose and microvascular risk go hand in hand. Glycemic control is used to prevent microvascular complications. If a diabetes drug can also decrease macrovascular risk, that’s an added bonus. That’d be fantastic. But the key issue is if it can do it without other safety issues and long term CVOTs help find that out.

Q: As a professor of public health, what are the most important messages we should be putting across?

Dr. Ray: Probably preventing diabetes in first place. Once you’ve got it, its progression is inevitable. Education is important, starting particularly in childhood - we’re seeing anthropometric measures that are abnormal in the first decade of life.

Dr. Sattar: I think Dr. Ray is completely correct. The big public health battle is to reduce the number of excess calories in the environment. In addition, picking out people with diabetes early or at high risk to instigate lifestyle changes helps. If I can recognize somebody at high risk and I can encourage and help that individual make small sustainable lifestyle changes to delay diabetes for 5, 10 years, that’s significant.

Dr. Marx: I have one simple sentence: don’t forget about blood pressure and lipids.

Q: CVOTs vary considerably in length. Is there likely to be any difference in short-term vs long-term trials?

Dr. Marx: It depends on the intervention. If you look at statin trials, short-term trials already reduce risk. It’s important to see the design of the trial. If the primary objective is non-inferiority, short-term may be appropriate.

Q: Are the effects of SGLT-2 inhibitors on blood pressure and weight reduction likely to account for superiority in CVOT?

Dr. Ray: From data I showed you, we’ve seen such consistent data on blood pressure and lipids that for me, the blood pressure-lowering effect, even if it’s only 5 mmHg, is going to translate to a reduction in CV events. With regards to weight loss and CV risk, we have not really seen major trials that show this relationship. For me, the blood pressure effect is really going to be what’s driving it.

Dr. Sattar: When they report full results, I suggest looking to see if they’re going to show data by baseline blood pressure - that’s going to potentially informative. I think benefits could be mix of glucose, weight, and blood pressure benefits. But let’s see. There may be a surprise in there.

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

Clinical Experience with FreeStyle Libre

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

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

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

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

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

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

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

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

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

Corporate Symposium: Evolving Perspective in Treating Diabetes and Obesity (Sponsored by Novo Nordisk)

Mode of Action of Liraglutide 3.0 mg in Weight Management

Niels Vrang, MD, PhD (CEO, Gubra, Hørsholm, Denmark)

Dr. Niels Vrang discussed the research surrounding the mechanisms of action of Novo Nordisk’s Saxenda (liraglutide 3.0 mg), specifically within the brain. In identifying the various GLP-1 receptors within the brain, Dr. Vrang explained how peripheral liraglutide can affect food intake and weight control. He introduced the complexity of hunger signals, noting that hunger has hedonic aspects, humoral feedback signals from the fat and gut, as well as neural feedback signals from the gut. He highlighted that GLP-1 is not only a gut hormone, but also a neurotransmitter used by a small group of neurons in the caudal brainstem that project to the hypothalamus. In understanding where and how peripherally circulating GLP-1 acts, Dr. Vrang reviewed research demonstrating that the GLP-1 receptors on vagal afferents and area postrema are not important for the weight loss mediated by GLP-1 agonists, but that the receptors on the hypothalamus play a significant role within this mechanism. Specifically, GLP-1 receptors on appetite regulating neurons in the hypothalamus are influenced, as GLP-1 activates the arcuate POMC/CART neurons (which inhibit appetite) and inhibit NPY neurons (which stimulate appetite). Additionally, Dr. Vrang walked attendees through brain imaging studies that have shown that peripheral liraglutide administration is taken up into these specific brain areas in a receptor-dependent manner. Looking forward, he posed questions including how paraventricular nucleus activation (also in the hypothalamus) may affect energy expenditure as well as the roles of brainstem and vagal GLP-1 receptors and glucose regulation. A more in-depth look into the brain for weight management has become an increasingly hot topic of research for obesity – for more on this, please see our coverage from ECO of Novo Nordisk’s symposium on Saxenda in the brain as well as our interview with Dr. Kevin Grove (Novo Nordisk, Seattle, WA) on the brain as a new target within obesity.

The SCALE Phase 3a Clinical Trial Program – Benefits on Secondary Outcomes

Luc Van Gaal, MD (Antwerp University Hospital, Belgium)

Dr. Luc Van Gaal reviewed data from the four different SCALE trials (SCALE Obesity and Prediabetes, SCALE Diabetes, SCALE Sleep Apnea, and SCALE Maintenance), with a specific focus on the benefits on secondary outcomes. He opened by highlighting that 5% to 10% weight loss can improve many obesity-related comorbidities and demonstrated from SCALE data that Novo Nordisk’s Saxenda (liraglutide 3.0 mg) was similarly associated with clinical benefits such as glycemic status, blood pressure, and cardiovascular risk factors. In addition, he reviewed the SCALE post-hoc analysis that showed that improvement in these various secondary endpoints were driven by both weight-loss dependent and independent effects of Saxenda. For a more in-depth look at this analysis, please see our coverage of the data at ECO earlier this year.

Personalizing the Choice of Anti-Obesity Medication (Responder Analyses)

Donna Ryan, MD (Pennington Biomedical Research Center, Baton Rouge, LA)

Dr. Donna Ryan walked attendees through four considerations for prescribing weight loss medications in the goal of better personalizing obesity treatment. She opened by stressing the diversity of patients with obesity as well as the heterogeneity of treatment effects. Dr. Ryan specifically pointed out “the trouble with averages” when discussing obesity pharmacotherapies’ clinical data since there is no “average” patient as many individuals will either derive less than or greater than average net benefit or no clinically meaningful effect. She thus pointed to the need to identify characteristics of patients to best target treatments, providing four considerations based on the knowledge of heterogeneity of treatment effects. First, Dr. Ryan stated the importance of “doing no harm” to carefully evaluate each drug’s contraindications and warnings to exclude certain medications. Second, she encouraged providers to consider the added benefits of therapies (such as effects of glycemic improvement and LDL lowering, which are independent of those benefits mediated by weight loss per se). Some pre-treatment factors, including gender and racial differences as well as response differences based on the presence of type 2 diabetes or insulin therapy will predict weight loss response, but they aren’t modifiable. Dr. Ryan also briefly touched on genetic predictors of weight loss, noting that the research here is interesting and promising but not close for prime time – we would agree that genetic understanding for diabetes and obesity remain far behind that of other disease areas such as cancer. Third, she highlighted the value of managing concomitant medications and chronic diseases to ensure that these are not sabotaging weight loss efforts and medication efficacy, as well. She also stressed the importance of supporting approaches to make adherence to lifestyle intervention easier (more use of meal replacements, using tools such as wearables and apps for self-monitoring of food intake, physical activity and weight. Lastly, Dr. Ryan stressed that patients must play a role in choice of medication, so cost, tolerability and dosing methods are considerations.

• Acknowledging these considerations, Dr. Ryan noted that the actual prescription of medications is still more of an art than a science and early response is the best predictor of ultimate success. She reviewed the drugs’ stopping rules and clinical data surrounding responders. This last consideration is the most common one we have heard and while early response seems to be a pretty reliable predictor. She showed liraglutide as an example and for the two out of three patients who met the EU stopping rule, more than 80% will have 5% weight loss at one year and nearly a third will have 10% weight loss at one year. The challenge to prescribers of obesity drugs is a trial and error system. In the case of obesity medications, the efficacy of the drug may be fine, but other factors may thwart weight loss, thus the recommendation to manage medications, chronic diseases, stress, sleep deprivation and other factors that sabotage weight loss. Until cost considerations are addressed by third party payers and more physicians are trained in weight management, uptake of these medications will be slow.

-- by Melissa An, Adam Brown, Helen Gao, Varun Iyengar, Sarah Odeh, Emily Regier, and Kelly Close