September 12-16, 2016; Munich, Germany; Day #1 Highlights – Draft

Executive Highlights

Hallo from the Bavarian capital of Munich, Germany, where our team has touched down at the 52^nd annual EASD meeting. With one day in the books, we already have SO much to share!

See below for our top 12 highlights (three in tech and nine in drugs) from the pre-conference days, be sure to check out our preview for a look at all that’s in store, and don’t miss our top picks for how to spend your down time (if you have any) in this historic city!

Diabetes Technology

1. A small, head-to-head, investigator-initiated study compared the hypoglycemia impact of Dexcom’s G5 (n=15) vs. Abbott’s FreeStyle Libre (n=17) in type 1s with very impaired hypoglycemia awareness. Dexcom’s G5 won handily on hypoglycemia, highlighting the importance of alarms in this specific population of hypo unaware patients. If someone is hypo-unaware, we’d certainly hope they would have access to CGM and that their HCP and they would choose to individualize their treatment with CGM with alarms! No surprises there. See below for more on why different devices will benefit sub-groups.

2. Roche presented the most details ever on its Accu-Chek Insight CGM, which is currently in CE Mark approval trials and on track to launch by the end of the year. Preliminary pivotal data (n=36) suggested an overall mean ARD of 10.5% over seven days with two fingerstick calibrations per day. The transmitter is Bluetooth-enabled and pairs with an Android app. In addition to their symposium, they hosted a patient gathering that should go down as a model for patient gatherings – amazing input, totally engaged group, very transparent. If you are interested in learning more on this, see Twitter (you don’t have to have a logon) and search #diabetesmeetup or write to Kelly for her list of learnings.

3. Abbott’s IMPACT study was published in the Lancet today, alongside a balanced Comment from Cambridge’s Dr. Roman Hovorka and colleagues. We also learned about FreeStyle Libre partnerships with mySugr and Social Diabetes – extending the sensor data to popular apps.

Diabetes Drugs

4. Dr. Juris Meier (Ruhr University of Bochum, Germany) advocated for a number of changes to CVOT study design in order to optimize the impact of these trials on diabetes care. He suggested (i) eliminating the glycemic equipoise design; (ii) investigating the CV effects of both established and newer therapies; and (iii) expanding the focus to include primary prevention. We’d like to see the FDA update its 2008 guidance on CVOTs since so much has changed in the last eight years – Dr. John Jenkins offered this in late 2014 and we hope to see news on this.

5. A heated debate featuring Dr. Julio Rosenstock (UT Southwestern, Dallas, TX) and Dr. Neil Skolnik (Temple University, Philadelphia, PA) unraveled the controversy over whether diabetes combination therapies should be implemented simultaneously or sequentially.

6. The always-insightful Dr. Daniel Drucker (Mount Sinai Hospital, Toronto, Canada) called attention to the role of glucagon and the alpha cell (often overshadowed by the beta cell) in diabetes and expressed enthusiasm for combination and bihormonal therapies around the corner.

7. AZ’s head of Cardiovascular and Metabolic Disease Development Dr. Marcus Schindler offered an exciting glimpse into AZ’s areas of focus in terms of promising early-stage diabetes therapies. Dr. Schindler highlighted five particularly promising avenues that AZ has invested in: (i) beta cell regeneration; (ii) thermogenesis; (iii) mimic bariatric surgery; (iv) heart failure; and (v) precision medicine. Specifically, Dr. Schindler expressed optimism on the potential of transforming normal human white adipose tissue into metabolically-active “beige” tissue by inducing upregulation of UCP1 and shared that AZ has identified a small molecule compound that is able to dramatically increase UCP1 in human adipose tissue in vitro and suggested that this compound could perhaps induce both potent insulin sensitization and weight loss.

8. Dr. William Cefalu discussed recent developments in diabetes to answer the questiton of whether we are on the verge of a revolution in diabetes treatment. In regard to "precision medicine", he suggested “not quite yet”, but with new technology, computational power, etc., small steps are being taken each year. He also went through an exercise as to what treatement guidelines would look like today if we "wiped the slate clean” and based only on recent evidence as opposed to changing current diabetes treatment guidelines for a true paradigm shift.

9. Dr. Clifford Bailey provided an overview of the positives and potential drawback of a wide range of upcoming diabetes treatments under investigation, offering a glimpse at what might be the next frontier of diabetes therapy. Dr. Bailey categorized the investigational treatments into six broad mechanisms of action: (i) support pancreatic beta cells; (ii) curb alpha cells; (iii) enhance incretin effects; (iv) counter insulin resistance; (v) induce glucosuria; and (vi) insulins.

10. Excitement over the emerging class of GLP-1 agonist/basal insulin fixed-ratio combinations permeated the discussion in several sessions.

11. Drs. Kamlesh Khunti (University of Leicester, UK), and Joao Raposo (Diabetes Education Study Group, Portugal) attributed less-than-ideal rates of adherence to a lack of high-quality diabetes education programs and suggested partnerships with pharma as an intriguing solution.

12. A Novo Nordisk-sponsored symposium provided an enthusiastic and comprehensive overview of the company’s next-generation basal insulin profile, highlighting the benefits of Tresiba (insulin degludec) beyond glycemic control, as evidenced by the recent SWITCH 1 trial.

Diabetes Technology Highlights

1. Dr. Nick Oliver presented preliminary data from a fascinating investigator-initiated head-to-head study comparing the hypoglycemia impact of Dexcom’s G5 (n=15) vs. Abbott’s FreeStyle Libre (n=17) in type 1s with very impaired hypoglycemia awareness (one severe event in the past 12 months or a Gold Score >4). Following a two-week baseline run-in with blinded Dexcom G4, CGM-naïve patients on MDI (baseline A1c: 7.5%) were randomized to use either G5 or FreeStyle Libre for eight weeks. Dexcom’s G5 won handily on the primary hypoglycemia endpoint, showing a significant reduction in time spent <60 mg/dl (3.3 mmol/l): from 6.1% at baseline to 3.3% in the last four weeks of the study (p=0.02). By contrast, the FreeStyle Libre group saw no significant change in hypoglycemia (from 7.4% to 8.2%; p=0.5), for a between-group difference of 3.6% (p=0.03). This translated to a clinically significant 52 minutes per day less time in hypoglycemia (<60 mg/dl) with G5 vs. Libre in a very high-risk group. All other hypoglycemia thresholds were also in favor of G5 (<70, <63, <50 mg/dl) and statistically significant. We loved seeing “time below zone” information and were struck by, although this is a small study, how helpful it would be to see these “zones” when various drugs and devices are tested! Notably, there were no significant between-group differences in time-in-range or time in hyperglycemia – both groups saw strong and nearly equal improvements, which was a positive for Abbott from our view (that despite alarms, the time in range was the same as with Dexcom). Dr. Oliver emphasized that the alarms really drove the greater hypoglycemia improvement in the G5 group, a key device feature for patients with a high degree of impaired hypoglycemia awareness. He characterized the FreeStyle Libre as “reflective” and the G5 as “reactive,” and noted that hypoglycemia measurement (frequency, severity) and awareness should be considered before commencing CGM – presumably to stratify patients to see if they need alarms.  We totally agree on this kind of individualization and personalization of devices and therapy – we think this is not happening in the US nearly to the extent it could and we believe it would help HCPs and patients and the system enormously. The study is not yet complete and will report more data in early 2017 – we note that although it’s small, there is some good learning.

• Though these were preliminary results from a small trial, we were glad to see a very strong study design (randomized, parallel group, strong parity, latest devices), an investigator initiated study, a test of these two great technologies head-to-head, and an important study in a high-risk patient group. These comparative effectiveness studies must happen to give providers, payers, and patients better data – who is most likely to benefit from a particular technology?
• Some may say the temptation is to say “G5 > Libre,” but this misses the more interesting point: when should one glucose sensing technology be used vs. another? High-risk patients with significant hypoglycemia unawareness should have the benefit of CGM alarms – this small study provides clear data on that front, assuming equal access and patient preferences. Of course, access and patient preferences are rarely equal between two options, which is why both of these technologies exist in the first place – offering a broader spectrum of device form factors, cost, and features to target different patient populations. This is not an “either-or” but a “both-and” – how can we bring glucose sensing to the masses in the most cost-effective way? CGM has not been accessible to nearly enough people to date, which is what motivated Abbott to rethink the design with FreeStyle Libre. We’re happy to see Dexcom/Verily doing the same and we believe both companies can expand the market significantly beyond those studied in this trial, who will most certainly benefit from traditional CGM, and for whom reimbursement should be a no-brainer.
• See below for more details, including Dr. Claudia Graham’s insightful and encouraging talk on CGM reimbursement.

2. Roche presented the most details ever on its Accu-Chek Insight CGM, which is currently in CE Mark approval trials and on track to launch by the end of the year – we learned today that the initial launch will be limited to “specialized diabetes centers” in the Netherlands, Norway, Denmark, and Sweden. Preliminary pivotal data in 36 patients wearing two sensors each (abdomen) suggested an overall mean ARD of 10.5% over seven days with two fingerstick calibrations per day (n=6,403 paired fingerstick BGM-CGM points). The accuracy was similar across the different glucose ranges (see below), though we’d note very few (3.7%) points in the <70 mg/dl range. Consistent with other CGMs, accuracy was slightly worse on day one (13%) and improved by day seven (9%). The Insight’s accuracy was similar during induced glycemic excursions (10.9%), and a section of the talk highlighted the short five-minute CGM-blood glucose time delay – we assume that is equal to or within a few minutes of other systems and are not sure if it is a clinically meaningful advantage though we do hear a range of complaints from certain patients about delays. The sensor has a two-hour warm-up time and seven-day wear. We also saw the first pictures of the commercial system today (see below), which has a round adhesive, a fairly large on-body transmitter (roughly two thumb drives in size; see second picture for a sense of thickness), and a syringe-like insertion device that isn’t unlike the Dexcom insertion device (like the Dexcom, one insertion device comes with each sensor). The Bluetooth-enabled transmitter sends data directly to an Android smartphone app, and no receiver is necessary – this is great to see at launch and could be a key competitive advantage. The app has the standard Roche design – nothing flashy, utilitarian, and roughly similar-looking to the Accu-Chek Connect BGM app. See below for more details and pictures, including how the Insight CGM stacks up against the competition on accuracy and other parameters. Roche gathered dozens of European patient advocates at a session in downtown Munich today and we found the session most valuable and truly the most transparent session we’d ever attended – lots of advice was going back and forth and the interaction was really valuable among all the patients. See Kelly’s Twitter handle (@kellyclose) for highlights and write her if you’d like best practices that she learned at today’s session. She recalled the 2009 Roche patient gathering in Indianapolis in her Twitter feed – that was a pioneering gathering and today’s was as well – the advocates gave extensive advice on product planning for future versions of CGM and the app.

3. Data from Abbott’s IMPACT study (presented in poster form at ADA) was published in the prominent UK medical journal The Lancet today, alongside a very balanced (but mostly positive) accompanying Comment from Cambridge’s Dr. Roman Hovorka and colleagues. Although this publication was mentioned only briefly in today’s symposium, it represents in our view a major victory for the company and hopefully a positive for eventual reimbursement. There were not major new details in the paper over the ADA poster, but getting the dramatic 38% hypoglycemia reduction (~74 minutes fewer per day) published in such a prestigious journal helps build the evidence base and reduces the noise factor around “no alarms.” We also learned today that a new integration agreement between Abbott and mySugr will allow Libre users to automatically and passively upload data to their mySugr accounts via the LibreLink Android app. This is outstanding news for Abbott to begin leveraging data from Libre in the widely loved mySugr app, which also has a partnership with Roche’s Accu-Chek Connect BGM. The Abbott team also told us about a new partnership with Social Diabetes, a popular Android app in the EU that enables users to log their food and insulin and get dosing recommendations from the app. We have not ever heard of this app, but it has a notable 50,000+ downloads on Android and very positive reviews. Abbott has lagged behind Medtronic and Dexcom on the data front and we’re glad to see it now making moves to maximize the value of its glucose sensing technology. Abbott’s actual symposium did not share new data or pipeline updates, but the session – “FLASH GLUCOSE MONITORING: Redefining Diabetes Management with Metrics beyond HbA1c” – featured an established, very esteemed slate of experts (Drs. Irl Hirsch, Thomas Danne) who spoke about recent clinical trials of the Libre and reasons why A1c is a flawed, or at least, incomplete outcome metric – this recalls our recent meeting at the FDA on “Outcomes Beyond A1c” and we love all the attention this area is getting. See the detailed discussion and commentary below for more on the IMPACT paper, mySugr announcement, and selected Q&A from the panel.

Diabetes Drug Highlights

4. Dr. Juris Meier (Ruhr University of Bochum, Germany) advocated for a number of changes to CVOT study design in order to optimize the impact of these trials on diabetes care. He suggested (i) eliminating the glycemic equipoise design; (ii) investigating the CV effects of both established and newer therapies; and (iii) expanding the focus to include primary prevention. We found Dr. Meier’s proposed change to the glycemic equipoise design of CVOTs to be his most controversial suggestion. He argued that this trial design, in which participants in the placebo arm receive higher insulin doses or other treatment intensification to narrow the A1c gap between agent and placebo groups, makes it difficult to discern the true CV effects of the agent in question, as its glycemic effect likely contributes to its CV benefit somewhat. This opinion stands somewhat in contrast to the more common support we’ve heard for the glycemic equipoise design although we believe there are so many issues around CVOT trials in general that it would be great to have an expert session hosted by FDA (as raised in the August 2014 meeting “FDA Public Hearing on the Confidentiality of Interim Results in Cardiovascular Outcome Safety Trials”). Dr. Bernard Zinman (Mount Sinai Hospital and the University of Toronto, Canada) remarked at a Novo Nordisk-sponsored symposium that narrowing the A1c gap between groups is strategic, as it allows us to isolate the association between therapy and cardioprotection, rather than between A1c and cardioprotection. Dr. Meier also advocated for multi-agent CVOTs, pointing out that most CVOTs published thus far compare a relatively new diabetes drug vs. placebo and suggested that head-to-head comparisons of the potential CV benefits of new drugs and relatively older agents would be helpful. Data showing the relative CV benefits of different drugs could be tremendously valuable for high-risk patients – this is certainly something we’d like to see in the coming years as CVOTs gain even more traction, though of course the costs of such a trial would be enormous and it’s unclear which stakeholders might have the incentives and means to fund the endeavor. Dr. Meier also emphasized that participants in published CVOTs have largely been investigating secondary prevention in patients with type 2 diabetes and a history of CV disease (relying on a very high-risk participant pool to reach the necessary number of CV events for a sufficiently small confidence interval in a shorter amount of time). That said, he noted that AZ’s DECLARE (for SGLT-2 inhibitor dapagliflozin) and EXSCEL (for GLP-1 agonist exenatide) will each include a cohort of participants without prior CV history. In his view (and ours), these results on primary CV prevention will be very interesting, and positive results could be a major win in two ways: (i) by promoting greater utilization of these agents across a much wider spectrum of the diabetes patient population; and (ii) by providing even more compelling evidence for cardioprotection in a broader population. We’d be thrilled to see cardioprotective medications that address primary and secondary prevention alike, though we acknowledge the massive time and monetary investment behind CVOTs which presents an obstacle to research in lower-risk populations. Ultimately, we were intrigued by Dr. Meier’s perspective on how to make CVOTs more influential in clinical practice – definitely a worthwhile goal and an important topic for discourse. And this was only one piece of the fascinating commentary we heard on CVOTs during EASD’s pre-conference sessions!

• “Excuses at the Jardiance Advisory Committee were ‘we’re not quite sure about the mechanism’ – who cares?! – and “maybe it’s by chance” – very unlikely.” Dr. Neil Poulter (Hammersmith Hospital and Imperial College, London, UK) candidly voiced his opinion on the extremely close 12-11 FDA Advisory Committee vote favoring a label update for Lilly/BI’s Jardiance (empagliflozin) to reflect CV benefits in line with EMPA-REG OUTCOME. As a reminder, the FDA recently delayed a decision on the Jardiance label change by 90 days. “While I applaud conservatism,” Dr. Poulter continued, “it’s time to take action.” Dr. Meier agreed resoundingly: “At a certain point it’s okay to be pragmatic and say even if we don’t know exactly how we’re saving lives, let’s save lives.” We’re absolutely in agreement as well, especially since getting CV data on the label for Jardiance could be a key step in encouraging greater payer coverage of the product and in spreading information on cardioprotection to busy HCPs and patients in-need. Dr. Zinman offered some plus side, sharing that Health Canada has approved a new label for Jardiance as an add-on diabetes therapy to reduce the incidence of CV death – what he described as a “very progressive label change.”  The Canadian Diabetes Association was also the first to incorporate the EMPA-REG OUTCOME results into their diabetes treatment guidelines earlier this year – clearly our friendly neighbors to the north are ahead of the curve on translating CVOTs into action!
• Several speakers claimed that positive results from EMPA-REG OUTCOME and LEADER are establishing higher standards for what diabetes drugs should accomplish. With the emergence of the SGLT-2 inhibitor and GLP-1 agonist classes, and with a trial showing cardioprotection for a product in each, a new agent that only lowers glucose probably wouldn’t fare well today. And as Dr. Zinman put it, “non-inferiority for CV outcomes may not be suitable any longer,” not with drugs that show cardioprotection on the table. He echoed Dr. Meier’s view that more studies on the relative CV effects of existing therapies would be valuable for the diabetes field. We’ve heard similar sentiments from several industry executives since the EMPA-REG OUTCOME results were revealed a year ago – it’s clear that the bar for new diabetes drugs is rising ever higher and we’re optimistic that future drugs with multiple non-glycemic benefits (cardioprotection, renal-protection, weight loss, etc.) will be able to meaningfully improve real-world patient outcomes. On the other hand, we imagine the high bar for new drugs makes it increasingly challenging for smaller, younger pharmaceutical or biotech companies to succeed in diabetes without a larger partner.
• Drs. Zinman and Meier speculated on mechanism of cardioprotection for SGLT-2 inhibitor Jardiance (empagliflozin) and GLP-1 agonist Victoza (liraglutide). In response to an audience question posed at an AZ-sponsored symposium, Dr. Zinman reminded us that differences on CV metrics for Jardiance vs. placebo groups emerged very early on in EMPA-REG OUTCOME, while Victoza took longer to show an advantage in LEADER. As such, Drs. Zinman and Meier agreed that Jardiance possibly confers CV benefit by impacting a number of risk factors – glucose lowering, weight loss, a small drop in lipid levels, a small drop in blood pressure – and/or through its impact on volume depletion while Victoza is more likely to have an atherosclerotic effect. Dr. Juris commented that he “wouldn’t be surprised by an independent, direct cardioprotective effect” of liraglutide. Dr. Zinman highlighted differences between individual products in the GLP-1 agonist class, noting the heterogeneity in CVOT results. Many look forward to seeing whether cardioprotection is a class effect for SGLT-2 inhibitors, GLP-1 agonists, or both. Results from DECLARE (for AZ's SGLT-2 inhibitor Farxiga/Forxiga [dapagliflozin]) and EXSCEL (for AZ's GLP-1 agonist Bydureon [exenatide once-weekly]), among other CVOTs, will hopefully reveal this soon. DECLARE is expected to report an interim analysis in 2017, while EXSCEL is expected to complete in 2018.

5. A heated debate featuring Dr. Julio Rosenstock (UT Southwestern, Dallas, TX) and Dr. Neil Skolnik (Temple University, Philadelphia, PA) unraveled the controversy over whether diabetes combination therapies should be implemented simultaneously or sequentially:

• Dr. Rosenstock staunchly argued that an aggressive, simultaneous approach to beginning a combination therapy regimen will produce better diabetes outcomes. He characterized the current AACE/ACE and ADA/EASD diabetes treatment guidelines – both of which follow the broad pattern of metformin as first-line therapy, followed by the gradual addition of other agents – as unhelpfully promoting a “treat-to-fail” paradigm whereby therapy is intensified only after patients begin failing to meet their treatment goals.  He envisions a future in which it is standard to treat everyone with “one pill of metformin and SGLT-2 inhibitor and one injection of insulin and GLP-1 agonist” – what a vision indeed (and one that would likely do away with complex diabetes treatment algorithms)! We think it’s a hassle for patients to be constantly switching from one therapy or other and believe that for many (but not all) patients, greater consideration of combination therapy, now that so much more is available, would be very helpful. Dr. Rosenstock drew support for the superiority of simultaneous initiation of combination therapy by comparing the results of his own GetGoal Duo 1 study, in which lixisenatide is added sequentially on top of an existing insulin glargine regimen, to the LixiLan-O and LixiLan-L trials, in which lixisenatide and insulin glargine were administered in a fixed-ratio coformulations. Though the study populations were similar, the sequential GetGo Duo 1 trial produced an average A1c of 7%, as opposed to an “unprecedented” 6.4% and 6.5% respectively in LixiLan-O and LixiLan-L.
• Taking the opposite position, Dr. Skolnik reminded the audience that no clinical trial to date has been designed to directly compare the efficacy of a simultaneous versus sequential approach to diabetes combination therapy. “The cure for clinical inertia is not throwing more medications at patients,” Dr. Skolnik argued, insisting that monotherapies can be effective so long as titration is done effectively. This, of course, is much easier said than done – clearly, today, for a broad population of patients, it is being done poorly. His comments were also murky – throwing “more” drugs is the last thing Dr. Rosenstock was arguing – the entire beauty of combo therapy is giving patients less to think about (one drug not too) and presumably switching far less often. Dr. Skolnik surmised his position with a quote from Mark Twain: “What gets us into trouble is not what we don’t know. It’s what we know for sure that just ain’t so.” In his view, though the idea of combatting the progression of diabetes with an aggressive combination of complementary drugs is intuitively appealing, there simply is no empirical data to support the superiority of simultaneous versus sequential therapy. Ironically, though the entirety of this Sanofi-sponsored symposium on GLP-1 agonist/insulin fixed-ratio combinations was overwhelmingly dominated by strong sentiments on the pro-simultaneous combination therapy side, Dr. Skolnik’s argument in favor of a sequential approach gained a fair amount of audience support – it isn’t surprising from our view that this “theory” is “theoretically” appealing but in practicality doesn’t work for so many patients. Symposium attendees took a blinded poll on simultaneous versus sequential approaches to diabetes combination therapy both before the debate began and after hearing Dr. Rosenstock’s and Dr. Skolnik’s competing arguments. Prior to the debate 80% of the audience voted in favor of initiating a combination therapy regimen simultaneously, and although this fell to 60% at the symposium’s end, we still believe there is major support for combo approaches – particularly when the “real world” outcomes are considered. Although we are skeptical of the effectiveness of delaying the initiation of a more potent and aggressive treatment regimen, especially given the existing long delays in diabetes treatment escalation, Dr. Skolnik brings up points that undoubtedly payers will – from our view, that is the biggest worry that payers won’t want to reimburse the therapies that clearly work well.  While Dr. Skolnik’s point that the field must be careful not to let our clinical decision-making extend past the available evidence is well-taken theoretically, we think additional trials and big data will continue to show better outcomes with the approaches that have greater potency and less hassle.

6. The always-eloquent Dr. Daniel Drucker (Mount Sinai Hospital, Toronto, Canada) called attention to the role of glucagon and the alpha cell (often overshadowed by the beta cell) in diabetes and expressed enthusiasm for combination and bihormonal therapies around the corner. According to Dr. Drucker, tackling the alpha cell may be just as important as preserving the beta cell in successful approaches to diabetes. He pointed out that alpha cell function is disrupted fairly early on in the progression of this disease, which leads to irregular endogenous glucagon secretion. The precise cause of these alpha cell effects is unknown, but Dr. Drucker explained that the causative factor is likely insulin-independent because research in type 1 diabetes shows that a patient’s abnormal glucagon profile is unimproved even after insulin treatment lowers A1c. Thus, skewed glucagon levels may have an impact on diabetes independent of insulin sensitivity and blood glucose. While diabetes drugs don’t receive much attention for their alpha cell/glucagon effects, Dr. Drucker outlined how GLP-1 agonists (including long-acting, once-weekly exenatide [AZ’s Bydureon]), DPP-4 inhibitors (such as vildagliptin [Novartis’ Galvus]), and amylin analogs are actually quite effective in reducing, and then sustaining low levels of glucagon and in decreasing hepatic glucose production. He described amylin analogs as a “very potent inhibitor of glucagon” which unfortunately haven’t seen much success in global or US markets, perhaps because the product requires multiple daily injections. Notably, SGLT-2 inhibitors increase glucagon levels and hepatic glucose production, but Dr. Drucker qualified that this issue can be easily managed by prescribing a DPP-4 inhibitor alongside an SGLT-2 inhibitor. Fixed-dose combinations of SGLT-2 inhibitors and DPP-4 inhibitors are certainly very mechanistically and clinically intriguing, though Lilly/BI’s Glyxambi (empagliflozin/linagliptin) has not appeared to gain significant traction in the US thus far – we believe that could well be due to payers not to appetite for combo therapy. AZ’s Qtern (saxagliptin/dapagliflozin) was recently approved in the EU and we’re curious if the combination of the two classes will prove more popular in Europe (though we expect reimbursement will be a major challenge in many countries). We felt that Dr. Drucker’s talk provided another strong argument for combination therapies – they can offer multifactorial biological effects and holistic care that matches the complicated molecular machinery underlying diabetes, not to mention greater convenience for patients. Furthermore, Dr. Drucker remarked that while pump devices have mostly relied on insulin so far, the future is bright for bihormonal pump therapy. He concluded with an optimistic statement: “We’re on the cusp of treating diabetes with bihormonal agents.”

7. AZ’s head of Cardiovascular and Metabolic Disease Development Dr. Marcus Schindler offered an exciting glimpse into AZ’s areas of focus in terms of promising early-stage diabetes therapies. Echoing executives from other pharmaceutical companies, Dr. Schindler emphasized the need for differentiation for new diabetes candidate therapies – new therapies must provide added value for patients, payers, and society or else payers are unlikely to reimburse them. With this framework in mind, Dr. Schindler highlighted five particularly promising avenues that AZ has invested in: (i) beta cell regeneration; (ii) thermogenesis; (iii) mimic bariatric surgery; (iv) heart failure; and (v) precision medicine. See below for details on AZ’s efforts in each of these areas. We appreciated this look at the future of diabetes therapy from AZ’s perspective and share the excitement over the potential of many of these strategies.

• Beta cell regeneration: Dr. Schindler underscored AZ’s interest in developing a deeper understanding of the beta cell, facilitated by its partnership with Harvard Medical School’s Dr. Doug Melton to produce an unlimited supply of human beta cells for study (and, eventually, for use therapeutically). In Q&A, Dr. Schindler asserted that understanding beta cell biology will be key to decoding type 2 diabetes pathophysiology and to the future of diabetes therapy.
• Thermogenesis: Dr. Schindler expressed optimism on the potential of transforming normal human white adipose tissue into metabolically-active “beige” tissue by inducing upregulation of UCP1. He shared that AZ has identified a small molecule compound that is able to dramatically increase UCP1 in human adipose tissue in vitro and suggested that, as a therapy, this compound could perhaps induce both potent insulin sensitization and weight loss. This is the first that we’ve heard of this candidate and, while it’s clearly very early-stage, we’re intrigued by AZ’s investment in this area and look forward to its fruits.
• Mimic bariatric surgery: Regarding the use of gut hormones to pharmacologically replicate the metabolic effects of bariatric surgery, Dr. Schindler especially highlighted AZ/MedImmune’s phase 1 GLP-1 agonist/glucagon dual agonist MEDI0382. New preclinical data for MEDI0382 will be presented at EASD on Wednesday, September 14 and promising phase 1 results were presented at ADA 2016 this past June. In Q&A, Dr. Schindler suggested that, in the near-term, the most-talked about novel diabetes drug class in the pipeline will be the GLP-1 agonist/glucagon dual agonists. The flurry of industry investment, as illustrated by our competitive landscape, would certainly support Dr. Schindler’s point. Dr. Schindler also noted that there is some interest in FGF21 to pharmacologically achieve the metabolic effects of bariatric surgery, though he felt that the data on the impact of FGF21 on glucose thus far was less compelling than the data on its impact on lipids.
• Heart failure: Dr. Schindler noted that there is significant interest in the use of SGLT-2 inhibitors in heart failure. He further emphasized that the Cardiovascular and Metabolic Disease unit at AZ is focused on multiple, interlinked co-morbidities of diabetes, including heart failure, NASH, and chronic kidney disease. We think it’s very smart of AZ to look at diabetes and its co-morbidities as a cohort – drugs like SGLT-2 inhibitors certainly hint at the potential for pharmacotherapies to address multiple conditions and indications.
• Precision medicine: Dr. Schindler discussed the potential of precision medicine to develop very targeted therapies. In particular, he highlighted the company’s phase 1 anti-microRNA AZD4076, which targets upregulated miR-103/107 in patients with NASH. Thus, it will hopefully eventually be possible to target this therapy to patients with higher levels of miR-103/107. Dr. Schindler also shared that this compound is an insulin sensitizer as well and could be a treatment for both diabetes and obesity and confirmed that this candidate will be injectable. Overall, Dr. Schindler was very optimistic on the prospects of the microRNA field, calling it the “next wave of innovation.” We’ve heard little about concrete precision medicine-based therapies for diabetes and we’re glad to see the promise of harnessing individual characteristics for target treatment coming into fruition and materializing into actual therapeutic candidates.

8. Dr. William Cefalu discussed recent developments in diabetes to answer the questiton of whether we are on the verge of a revolution in diabetes treatment. In regard to "precision medicine", he suggested “not quite yet”, but with new technology, computational power, etc., small steps are being taken each year. He also went through an exercise as to what treatment guidelines would look like today if we "wiped the slate clean” and based only on recent evidence as opposed to changing current diabetes treatment guidelines for a true paradigm shift. He reviewed a series of exciting developments in the diabetes field, including the individualization of A1c targets, a greater push to counteract clinical inertia through aggressive sequential therapy intensification or early use of simultaneous combination therapy, the increasingly mainstream acceptance of bariatric surgery as a legitimate diabetes treatment for some patients, and the use of precision medicine to both potentially identify which patients will best respond to lifestyle therapy and to create targeted pharmacogenetic therapies for specific subtypes of diabetes. Despite these exciting new developments, Dr. Cefalu acknowledged that current diabetes treatment hasn’t been “revolutionized” (defined as “changed radically or fundamentally”) yet, but emphasized that each year brings small steps toward a true paradigm shift. In fact, Dr. Cefalu suggested that in 10-15 years, diabetes treatment could be well on its way toward this goal. Turning to the current diabetes treatment algorithm paradigm, Dr. Cefalu proposed a new goal-oriented treatment paradigm (see below). Most notably, Dr. Cefalu’s algorithm called into question metformin’s long-standing position as the go-to first-line diabetes therapy for patients with type 2 diabetes and suggested that while it may remain preferred for many patients, other diabetes drug classes could also be considered as first-line options. Dr. Cefalu acknowledged that physicians such as Dr. Skyler have previously argued against the use of metformin as the first-line treatment for the majority of patients. In addition, Dr. Cefalu’s schematic strongly emphasizes therapy intensification if A1c is greater than 7% and explicitly offers initial combination therapy initiation with either insulin and oral agents, GLP-1 agonists and oral agents, or a combination of oral agents. Aggressive goal-oriented treatment intensification and the option to use combinations of diabetes drugs has a role in the current ADA/EASD and AACE/ACE guidelines as well, though Dr. Bailey’s graphic brings these two points front and center. Still, the point is well-taken – perhaps it’s time for a bottom-up redesign of treatment algorithms as opposed to periodic and fairly minor updates.

9. The always-insightful Dr. Clifford Bailey provided an overview of the positives and potential drawback of a wide range of upcoming diabetes treatments under investigation, offering a glimpse at what might be the next frontier of diabetes therapy. Dr. Bailey categorized the investigational treatments into six broad mechanisms of action: (i) support pancreatic beta cells; (ii) curb alpha cells; (iii) enhance incretin effects; (iv) counter insulin resistance; (v) induce glucosuria; and (vi) insulins.

• Support pancreatic beta cells: Dr. Bailey noted that there’s a litany of different candidate classes targeting beta cell function in some way, including glucokinase activators (GKA), imeglimin, GPR40, GPR119, GIP, and PDE inhibitors. He emphasized that it’s extremely difficult to determine at this point which of these strategies will prove successful and underscored that, ultimately, all of these therapies depend on some degree of beta cell function. Given the progressive beta cell decline associated with type 2 diabetes and the current lack of beta cell restoration options, Dr. Bailey suggested that other, non-beta cell strategies of treatment may be more promising in the long term.
• Curb alpha cells: Dr. Bailey did not express a ton of confidence in this strategy for diabetes treatment. He acknowledged that clinical data for Lilly’s discontinued glucagon receptor antagonist LY2409021 demonstrated impressive rapid A1c reductions, but cautioned that if a patient stopped taking the glucagon receptor antagonist, he would quickly experience a rebound in hyperglycemia.
• Enhance incretin effects: Dr. Bailey was very positive about several intriguing therapies in the pipeline that harness the incretin effect. In terms of innovations in delivery, he highlighted Novo Nordisk’s oral formulation of GLP-1 agonist semaglutide and Intarcia’s implantable GLP-1 agonist ITCA 650 (exenatide mini-pump). Looking beyond GLP-1 agonists, Dr. Bailey expressed optimism for GLP-1/glucagon dual agonists, GLP-1/GIP/glucagon triple agonists, and fixed-ratio combinations of GLP-1 agonists and basal insulins.
• Counter insulin resistance: Dr. Bailey particularly highlighted the potential of adiponectin receptor agonism to improve insulin sensitivity and was especially impressed by the preclinical results of small molecule adiponectin receptor agonist AdipoRon.
• Induce glucosuria: After briefly touching on the three currently-available SGLT-2 inhibitors (Lilly/BI’s Jardiance [empagliflozin], J&J’s Invokana [canagliflozin], and AZ’s Farxiga [dapagliflozin]), Dr. Bailey expressed optimism for the potential of SGLT-1 inhibition with Sanofi/Lexicon’s SGLT-1/2 dual inhibitor sotagliflozin. He suggested that the dual inhibitor will be able to offer greater A1c reduction than single SGLT-2 inhibitors through the effect of the SGLT-1 inhibition in the GI tract.
• Insulins: “We gotta get smart.” Dr. Bailey emphasized that glucose-responsive insulin is the next frontier for this class. He outlined two main methods through which to achieve this goal: (i) encasing the insulin in a microencapsulation device or in nanoparticles that break apart and release increasing doses of insulin in response to higher levels of glucose and (ii) attaching an oligosaccharide to insulin so that it will be bound by lectin and inactive until higher concentrations of glucose compete for the lectin binding sites and release the insulin. This was recently discussed at a JDRF forum on smart insulin. 

10. Excitement over the emerging class of GLP-1 agonist/basal insulin fixed-ratio combinations permeated the discussion in several sessions. This was perhaps most evident at a Sanofi-sponsored symposium titled ‘Facing New Horizons: Optimism and Opportunities in Diabetes Management,’ a provocative insinuation about the potential of these fixed-ratio combinations to usher in a new era of diabetes treatment. The ever eloquent Dr. Alice Cheng (St. Michael’s Hospital, Toronto, Canada) made a convincing case for this, arguing that “hitting hard and hitting early” with combination therapy soon in the treatment algorithm is a promising way to improve the number of patients achieving their glycemic targets, and that new GLP-1 agonist/insulin fixed-ratio combinations present an optimal avenue for this. Two such drugs are Sanofi’s iGlarLixi (lixisenatide/insulin glargine), pending approval in the US and EU, and Novo Nordisk’s Xultophy (liraglutide/insulin degludec), available in the EU and pending approval in the US. In addition to reducing treatment complexity and the number of injections patients must administer, Dr. Cheng praised the potential of GLP-1 agonists and insulin to both complement one another’s efficacy and mitigate one another’s potential side effects when formulated in a single injection. This is well-demonstrated by the phase 3 LixiLan-O and LixiLan-L trials, in which iGlarLixi demonstrated greater A1c reductions vs. either component alone. Furthermore, iGlarLixi showed a neutral to positive effect on body weight (mitigating the weight gain concerns that come with insulin) and was associated with fewer GI side effects (a common adverse event for GLP-1 agonists). Dr. Cheng likened these synergistic effects to those seen in oral tablets containing two or more antihyperglycemic therapies, forecasting that the GLP-1 agonist/insulin fixed-ratio combination class will be as revolutionary as fixed-dose combination pills were decades ago. Dr. Julio Rosenstock (UT Southwestern, Dallas, TX) expressed a similar sentiment, confidently predicting that GLP-1 agonist/insulin fixed-ratio combinations, in particular Sanofi’s iGlarLixi, will soon become a preferred option to advance type 2 diabetes therapy early in the treatment algorithm.

11. Drs. Kamlesh Khunti (University of Leicester, UK), and Joao Raposo (Diabetes Education Study Group, Portugal) attributed less-than-ideal rates of adherence to a lack of high-quality diabetes education programs and suggested partnerships with pharma as an intriguing solution. Dr. Khunti drew an astute parallel between drugs and education – you wouldn’t buy a drug that hasn’t been rigorously tested for quality, so we shouldn’t sell diabetes education unless it’s of the highest quality. He argued that expanding access to high-quality education programs should be a top priority, and that we must value diabetes education to the same extent that we value drug therapy in order to increase patient uptake of these resources, which remains low at ~50% even in regions with an accessible program. Dr. Khunti recognized that this area of behavior change research is tricky, and that pharmaceutical companies are reluctant to invest in studies focused on education when they could be investing in next-generation diabetes drugs. Dr. Raposo contested this point, however, suggesting that pharma might present the ideal opportunity for enhanced diabetes education. For a new diabetes drug to be successful today, he explained, companies have to sell not only the medicine but a slew of support services to make the product attractive and user-friendly. “Now is the moment for people interested in education to approach pharma and make sure they’re selling quality-assured education programs.” We were very intrigued by Dr. Raposo’s idea – how fantastic would it be for companies with the resources for quality assurance to provide the diabetes education necessary to help patients understand their condition and to motivate them to remain engaged in their diabetes care over the long term? Without question, we’re excited by the prospect. We so appreciated the actionable suggestions to improve treatment adherence that we heard during pre-conference sessions. Speakers thwarted patient-blaming and instead considered innovative, feasible solutions with an open mind.

• “A clinician wants a patient to adhere to treatment, but a person with diabetes wants diabetes to adhere to her life.” Ms. Klara Pickova (Ambit Media, Prague, Czech Republic), a patient with type 1 diabetes, captured wonderfully the major miscommunication that occurs when providers use almost-accusatory words like “non-adherence” or “compliance,” putting undue burden on people who have other stressors beyond diabetes in their lives. The conception of “adherence” as a patient’s responsibility to stick to a treatment regimen is narrow and reductive. We loved Ms. Pickova’s expansion of the “adherence” definition to make it more productive in helping patients achieve the best possible health outcomes – in her view, solutions to improve patient engagement rest on healthcare professionals identifying what’s important to a real-world patient and aligning diabetes care with those goals. Like us, many other conference attendees found this quote powerful. In fact, Dr. Bastian Hauck (Abenteur Diabetes, Denmark) shared that he felt compelled to tweet the quote immediately, and that the online diabetes community was reacting to it almost instantaneously.

12. A Novo Nordisk-sponsored symposium provided an enthusiastic and comprehensive overview of the company’s next-generation basal insulin profile, highlighting the benefits of Tresiba (insulin degludec) beyond glycemic control, as evidenced by the recent SWITCH 1 trial. In this double-blind trial, first presented in poster form at ADA 2016, 501 patients with type 1 diabetes were randomized to receive once-daily doses of either Novo Nordisk’s Tresiba (insulin degludec) or Sanofi’s Lantus (insulin glargine) for 32 weeks, followed by a crossover to the other drug for another 32 weeks. Tresiba produced impressive reductions in hypoglycemia over Lantus: an 11% reduction in blood glucose-confirmed symptomatic hypoglycemia, a 36% reduction in nocturnal hypoglycemia, and a 35% reduction in severe hypoglycemia. Furthermore, Tresiba achieved this in the context of non-inferiority to Lantus in terms of A1c reduction. Hypoglycemia is one of the principal concerns surrounding insulin therapy, and an unending source of worry for patients, families, and physicians alike. We applaud the arrival of an insulin with reduced hypoglycemia risk, and hope Tresiba sets the stage for an era of insulins with benefits beyond glycemic control.

• Indeed, in a joint session the previous day, Drs. Nebojsa Lalic (University of Belgrade, Serbia) and Asimina Mitrakou (National and Kapodistrian University of Athens, Greece) emphasized the many non-glycemic benefits offered by Tresiba and Sanofi’s fellow next-generation basal insulin Toujeo (U300 insulin glargine). In particular, Dr. Lalic highlighted the improvements in hypoglycemia with both products while Dr. Mitrakou emphasized their benefits on body weight and overall patient quality of life (as measured by patient-reported questionnaires). In the ensuing Q&A discussion, both speakers readily agreed that there was “no doubt” that analog insulins – both “old” and “new” – are vast improvements over human insulin. We certainly appreciated the focus on the substantial benefits of these new insulins beyond A1c reduction and the illustration of the added value of these products, despite their non-inferior status with “old” basal insulin Lantus (insulin glargine) in terms of A1c. Unfortunately, despite this consensus, the discussion also revealed the challenges to insulin access in developing countries: Dr. Lalic shared that, in Serbia, patients must first initiate human insulin and generally only switch to insulin analogs if the patient is experiencing poor outcomes with the human insulin. As an audience member from the UK put it, this sort of strategy could be considered unethical to the extent that patients with good glucose management are in a sense “punished” by denying them access to the latest treatments. We certainly hope that governments and other payers will begin considering patient-centric outcomes beyond A1c in their reimbursement decisions.

Detailed Discussion and Commentary

Corporate Symposium: Dexcom Continuous Glucose Monitoring: Leading the Way as the Standard of Care, Clinical Outcomes and Market Access

Impact On Hypoglycemia Awareness Of Real-Time CGM And Intermittent Continuous Glucose Data (I HART CGM)

Nick Oliver, MD (Imperial College, London, UK)

Dr. Nick Oliver presented preliminary data from a fascinating investigator-initiated head-to-head study comparing the hypoglycemia impact of Dexcom’s G5 (n=15) vs. Abbott’s FreeStyle Libre (n=17) in type 1s with very impaired hypoglycemia awareness (one severe event in the past 12 months or a Gold Score >4). Following a two-week baseline run-in with blinded Dexcom G4, CGM-naïve patients on MDI (baseline A1c: 7.5%) were randomized to use either G5 or FreeStyle Libre for eight weeks. Dexcom’s G5 won handily on the primary hypoglycemia endpoint, showing a significant reduction in time spent <60 mg/dl (3.3 mmol): from 6.1% at baseline to 3.3% in the last four weeks of the study (p=0.02). By contrast, the FreeStyle Libre group saw no significant change in hypoglycemia (from 7.4% to 8.2%; p=0.5), for a between-group difference of 3.6% (p=0.03). This translated to a clinically significant 52 minutes per day less time in hypoglycemia (<60 mg/dl) with G5 in a very high-risk group. All other hypoglycemia thresholds were also in favor of G5 (<70, <63, <50 mg/dl) and statistically significant. Notably, there were no significant between-group differences in time-in-range or time in hyperglycemia – both groups saw strong and nearly equal improvements. Dr. Oliver emphasized that the alarms really drove the greater hypoglycemia improvement in the G5 group, a key device feature for patients with a high degree of impaired hypoglycemia awareness. He called FreeStyle Libre “reflective” and G5 “reactive,” and noted that hypoglycemia measurement (frequency, severity) and awareness should be considered before commencing CGM – presumably to stratify patients to see if they need alarms. The study is not yet complete and will report more data in early 2017. Dr. Oliver emphasized that these are preliminary results and will hopefully be published at some point in the future.

• Though these were preliminary results from a small trial, we were glad to see a very strong study design (randomized, parallel group, strong parity, latest devices), an investigator initiated study, a test of these two great technologies head-to-head, and an important study in a high-risk patient group. These comparative effectiveness studies must happen to give providers, payers, and patients better data – who is most likely to benefit from a particular technology?
• The temptation is to say “G5 > Libre,” but this misses the more interesting point: when should one glucose sensing technology be used vs. another? High-risk patients with significant hypoglycemia unawareness SHOULD have the benefit of CGM alarms – this small study provides clear data on that front, assuming equal access and patient preferences. Of course, access and patient preferences are rarely equal between two options, which is why both of these technologies exist in the first place – offering a broader spectrum of device form factors, cost, and features to target different patient populations. This is not an “either-or” but a “both-and” – how can we bring glucose sensing to the masses in the most cost-effective way? CGM has not been accessible to nearly enough people to date, which is what motivated Abbott to rethink the design with FreeStyle Libre. We’re glad to see Dexcom/Verily doing the same and we hope both companies can expand the market significantly beyond those studied in this trial (who will most certainly benefit from traditional CGM, and for whom reimbursement should be a no-brainer).
• As might be expected, the sensor failure rate was higher in the FreeStyle Libre arm (7/60 sensors, 11.7%) vs. the G5 arm (1/120 sensors, 0.8%) – each group had only one sensor with unacceptable accuracy, though the Libre group had six out of the 60 sensors fall out before the 14-day life. We have heard some complaints about this aspect of FreeStyle Libre – particularly for very active patients – and we wonder if Abbott will work on improving the adhesive or providing patients with over-tape.

 HYPOGLYCEMIA RESULTS

• Dexcom’s G5 won handily on the primary hypoglycemia endpoint, showing a significant reduction in time spent <60 mg/dl (3.3 mmol): from 6.1% at baseline to 3.3% in the last four weeks of the study (p=0.02). By contrast, the FreeStyle Libre group saw no significant change in hypoglycemia (from 7.4% to 8.2%; p=0.5), for a between-group difference of 3.6% (p=0.03). This translated to a clinically significant 52 minutes per day less time in hypoglycemia (<60 mg/dl) with G5 in a very high-risk group.
• The results were highly consistent for time <50 mg/dl and <70 mg/dl, suggesting across-the-board reduction in hypoglycemia with G5.
  
  • Time <50 mg/dl was 3.7% with G5 at baseline, which was more than halved in the last four weeks of the study to 1.4% (p=0.02). Libre users saw no significant change in time <50 mg/dl (4.6% to 5.2%; p=0.49), translating to a between group difference of 2.9% in favor of G5 (p=0.02), or 42 minutes fewer per day under 50 mg/dl.
  • Time <70 mg/dl was 10.1% in the G5 group at baseline, which improved to 7.1% in the last four weeks of the study (p=0.04). By contrast, the FreeStyle Libre group saw no significant change in time <70 mg/dl (from 11.1% to 12.9%; p=0.33), for a between-group difference of 4.9% in favor of G5 (p=0.04), or 71 minutes per day fewer under 70 mg/dl with G5.

TIME-IN-RANGE RESULTS

• Both G5 and FreeStyle Libre improved time-in-range from baseline, but there were no significant differences between the groups.
  
  • Time in 70-180 mg/dl improved a whopping +9.6%-point with G5 (57.2% to 66.8%; p=0.03) and +6.6%-points with Libre (52.2% to 58.8%; p=0.004) from baseline to the last four weeks of the study. This equated to over two more hours per day in range with G5 and 90 minutes more per day in range with Libre. There was no statistical difference between the groups (p=0.5).
  • Time in 70-140 mg/dl was 39.8% with G5 at baseline and improved to 45.4% in the final four weeks of the study (+5.6%; p=0.23). Libre users saw a similar +4.6%-point boost in time in range (35.1% to 39.8%; p=0.06). Put simply, both groups saw roughly one more hour per day in range by the end of the study, and no statistically significant difference between the groups (p=0.86).

HYPERGLYCEMIA RESULTS

• Both G5 and FreeStyle Libre improved hyperglycemia from baseline, but there were no significant differences between the groups.
  
  • Time >180 mg/dl improved a solid -6.5%-point with G5 (32.6% to 26.1%; p=0.11) and -8.4%-points with Libre (36.7% to 28.3%; p=0.01) from baseline to the last four weeks of the study. This equated to 90 minutes less per day in hyperglycemia with G5 and two hours less per day in hyperglycemia with Libre. There was no statistical difference between the groups (p=0.69).
  • Time >270 mg/dl was cut in both study groups: from 10.8% to 5.5% in the G5 group (-5.3%; p=0.007) and 10.7% to 6.1% in the Libre group (-4.6%; p=0.018). This translates to an hour less per day in each group spent at dangerously high blood glucose levels over 270 mg/dl. There was no statistical difference between the groups (p=0.77).

STUDY DESIGN DETAILS

• At baseline, patients had a mean A1c of 7.5%, a mean age of ~50 years, a mean duration of diabetes of ~29 years, and a mean Gold Score of ~4.8. There were no significant differences between the groups. The study enrolled patients that experienced severe hypoglycemia in the last 12 months requiring third party assistance, or those with a gold score of >4. Patients had to have been on MDI for >6 months and type 1 diabetes for greater than three years.
• Notably, the study hypothesized that FreeStyle Libre Libre would have an equivalent impact on hypoglycemia as the Dexcom G5 CGM. The primary outcome was the difference in % time spent <60 mg/dl from baseline to the end of the eight-week study. Glucose data from baseline came from a two-week run-in period measured via blinded Dexcom G4. Patients were then randomized to use FreeStyle Libre or Dexcom G5 for eight weeks. Glucose outcomes were calculated from the last 30 days of each treatment period. Analysis was intention to treat. A telephone visit occurred at week 2 and a clinic visit occurred at week 4.
• The data today reported results from 32 out of a planned 45 CGM naïve, MDI-using adults (18+ years) with type 1 diabetes. Patients also had the opportunity to continue on Dexcom G5 for 8 weeks following the main study period, though that data was not presented today. A total of 34 patients have been randomized to date, and two are currently ongoing (one in each group), leaving 32 presented today.

Questions and Answers

Dr. Pratik, Choudhary (London, UK): This is a really important debate. In the Dexcom group, did you have predictive alarms set up to avoid hypos? And the algorithms in Dexcom and Libre are very different. Is there a problem in interpreting the hypoglycemia data?

A: We call this hypoglycemia, but it’s not. It’s interstitial fluid measurement, either calibrated in the factory or fingersticks to the blood value. It’s not true hypoglycemia. These are different algorithms. It may be if we had YSI, we would see different results. But these are the devices we have, these are how they work in real time, and these are the outcomes we measure and things we are empowering and asking patients to respond and react to. For the technical aspects, there may be differences we are not pulling out, but this is the real life hypoglycemia point of view, and it’s important.

For predictive alarms, apart from setting it at 3.9 mmol/l (70 mg/dl), we let participants do what they wanted with receiver.

Q: I assume you don’t have A1c for an eight-week study, but do you have mean sugar?

A: I’m not sure it adds a great deal. This is a high risk group of people with severe hypoglycemia. In my clinical practice, if they had an A1c that went up, I wouldn’t be too bothered – that’s an acceptable outcome to reduce the risk of severe hypoglycemia. In both groups A1c fell, and fell significantly, but there were no between group differences.

Q: What about nighttime?

A: I’ll tell you in January. We will look at nocturnal and 24-hour data.

Q: Did you have any questionnaires on fear of hypoglycemia and fear of hypoglycemia at night?

A: No, we don’t have a night-specific one.

Q: Which system is more closely to real blood glucose?

A: Within this study, I don’t know. This is not an accuracy study. Both technologies in the UK are licensed for non-adjunctive use. FreeStyle Libre has no fingersticks. We are unable to make any accuracy comparison. There are other data, not in a hypoglycemia impaired population, that compare accuracy. With G5, it’s about 9%-10% absolute difference from blood glucose.

CGM Reimbursement Update and Cost Effectiveness in 2016

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

Dr. Claudia Graham gave a persuasive and highly encouraging update on CGM reimbursement, arguing that CGMs are highly cost effective (evidence: Germany’s positive reimbursement decision), should absolutely come before pumps (“If you have only $5,000 to spend per year, where would you spend that money?”), and now have some reimbursement (albeit limited) in 11 EU countries (see slide below). She shared a fascinating cost-effectiveness analysis used as an example in Germany, which gave Dexcom CGM a compelling incremental cost-effectiveness ratio (ICER) of 12,533 euros/QALY, far below NICE’s threshold of 20,000-30,000 euros/QALY, and even better than atorvastatin’s 40,069 euros/QALY. This assumed 2.3 fingersticks per day (calibration plus some extra), no receiver cost, and a 50% reduction in severe hypoglycemia events – the latter is of course not a proven fact with CGM, but is “very doable” in Dr. Graham’s view. She highlighted the DiaMonD study results from ADA 2016 and noted the study has been submitted for publication and will hopefully be out soon. In her slide on US reimbursement, Dr. Graham encouragingly said that 25% of US payers have CGM coverage policies for type 2s on insulin, more than we would have guessed. Overall, her talk echoed the one she gave at EASD 2015, strongly urging CGM first, given the high cost of pumps. In the UK, Dexcom CGM costs 3,465 pounds per year (direct pricing from Dexcom), less than half of the 7,196 pounds per year for sensor-augmented pump therapy as listed in the NICE sensor augmented pump assessment in 2015 (slide below). “Let’s give CGM that first start,” she said. Dexcom is focused on driving cost-effectiveness in three areas: (i) appropriate patient selection (e.g., hypoglycemia prone, high A1c patients, pediatrics); (ii) lower-cost technology (e.g., remove cost of receiver, reduce transmitter costs, reduce/eliminate fingersticks); and (iii) simplifying healthcare instructions (e.g., online training).

• “Why has it taken so long for CGM to gain access in Europe?” Dr. Graham highlighted the lengthy assessment processes (70 months on average in Germany, five years in the UK) and individual country-by-country systems. “It takes a long time in Europe to convince the authorities, to have the right data, and to have support of the experts and position statements. But it’s still taken too long for CGM. I’m disappointed about that.” She noted three particular challenges:
  
  • Misperceptions that CGM had to be used with a pump, or follow a pump, or be a last resort. Pumps came to market first, and have been linked to the artificial pancreas quest for a long time. There has also been a belief that MDIs are not “tech savvy” (“it’s too much for my patients”) – DIaMonD and COMISAIR (see below) disprove that. “We lost sight that CGM and pumps can be used alone. Most of Dexcom patients are trained online in how to use the device in under an hour, and they get it. It’s surprisingly intuitive on how to use this.”
  • Rapid product iterations make it difficult to assess effectiveness. Outdated publications are used in meta-analyses for health technology assessment, and these include much older technologies that are less effective.
  • Outcome publications and models have primarily been done on sensor-augmented pumps. These are “confusing and costly,” she noted.

CGM and Multiple Daily Injection Patients: A1c Outcomes and Clinical Benefit Demonstrated by the COMISAIR Study

Martin Prazny, MD (Charles University, Prague, Czech Republic)

Dr. Prazny covered the newly published 52-week (!) COMISAIR trial (n=65; Soupal et al., DT&T 2016), offering a highly positive takeaway for Dexcom: adding CGM to MDI drove a similar A1c reduction as adding CGM and a pump (-1.2%; baseline: 8.3%). Further, adding a pump alone (no CGM) only drove a 0.5% reduction in A1c (baseline: 8.4%). Though the study was very small (n=18 on MDI + SMBG, n=12 on MDI+CGM, n=20 on pump + SMBG, and n=15 on pump + CGM), it was great to see the long length and four-group design. We first heard about this study in the AADE 2016 exhibit hall, and the results confirm the preliminary findings from the DIaMonD study (presented at ADA) – CGM offers significant benefits to MDIs.

Improving Diabetes Management with Advances in Health Technology (Sponsored by Roche)

Characteristics of the new Accu-Chek Insight CGM system

Günther Schmelzeisen-Redeker (Roche, Mannheim, Germany)

Roche’s Günther Schmelzeisen-Redeker presented the most details ever on its Accu-Chek Insight CGM, which is currently in CE Mark approval trials and on track to launch by the end of the year – we learned today that the initial launch will be limited to “specialized diabetes centers” in the Netherlands, Norway, Denmark, and Sweden. Preliminary pivotal data in 36 patients wearing two sensors each (abdomen) suggests an overall mean ARD of 10.5% over seven days with two fingerstick calibrations per day (n=6,403 paired fingerstick BGM-CGM points). The accuracy was similar across the different glucose ranges (see below), though we’d note very few (3.7%) points in the <70 mg/dl range. Consistent with other CGMs, accuracy was slightly worse on day one (13%) and improved by day seven (9%). The Insight’s accuracy was similar during induced glycemic excursions (10.9%), and a section of the talk highlighted the short five-minute CGM-blood glucose time delay – we assume that is equal to or within a few minutes of other systems and are not sure if it is a clinically meaningful advantage. The sensor has a two-hour warm-up time and seven-day wear.

We also saw the first pictures of the commercial system today (see below), which has a round adhesive, a fairly large on-body transmitter (roughly two thumb drives in size; see second picture for a sense of thickness), and a slightly intimidating syringe-like insertion device. The Bluetooth-enabled transmitter sends data directly to an Android smartphone app, and it appeared that no receiver will be included – this is great to see at launch and key for competition. The app has the standard Roche utilitarian design – nothing flashy and roughly similar-looking to the Accu-Chek Connect BGM app.

• How does the Insight CGM stack up against the competition? This accuracy – if observed in real life –puts Roche right in the ballpark of competitor systems: Abbott’s FreeStyle Libre (11.8% factory cal), Dexcom’s G5 (9.0%, two cals per day), Medtronic’s Enlite 3 (10.5%, two cals per day), and Senseonics’ Eversense (8.8%-11.6%, two cals per day). Of course, it is always difficult to understand how systems compare based on individual trials. Competitively speaking, just as important for the Insight CGM are the cost, insertion process, calibration hassle, and on-body form factor, which appear to lag behind competitors based on what we saw today. It’s excellent to see Bluetooth compatibility and Android at launch.
  
  • Still, we’re glad to see a major player like Roche investing significantly CGM, which should help build the highly underpenetrated EU market. Given the number of patients in need, we believe many companies can be successful and help make CGM standard of care. Of course, Roche also has diversified its portfolio with the Senseonics distribution partnership, giving it two different CGM products to market.

*SMBG >80 mg/dl – relative differences; SMBG <80 mg/dl – absolute differences

• Study design details: CGM accuracy was compared to BGM (presumably Roche’s own). The study is ongoing, but data presented today was from 36 patients (n=27 type 1s, n=9 type 2s) wearing two CGM systems simultaneously for seven days. On two of the days patients had induced glucose variations, which were not further detailed (e.g., were they on days 4 and 7?). The frequency of SMBG measurement was one per hour during the daytime, and increased to one every 15 minutes during the induced excursions
  
  • Study Design Limitations: The study (i) is smaller compared to competitor studies (e.g., Enlite 3’s pivotal had a remarkable 23,709 total paired CGM-YSI points); (ii) had very few points (3.7%) in hypoglycemia (e.g., Dexcom’s G4 and Software 505 pivotal had 14%-15% of points <80 mg/dl); (iii) included 9 of the 36 patients as type 2s (we’re not sure if they were all on insulin); and (iv) only include two in-clinic days (relative to the typical three in competitor studies of seven-day CGMs). We note the trial did not use YSI, which is a limitation in one sense (doesn’t show the true accuracy of the system), but a strength in another (accuracy vs. BGM is more real-world from a patient perspective).

Questions and Answers

Dr. Boris Kovatchev (UVA, Charlottesville, VA): Do you have data on the frequency of large sensor deviations beyond 20%?

A: I don’t have it with me. We’re in the middle of data evaluation.

Dr. Kovatchev: That would be good to add.

Q: What about newer sensors with no need for calibration?

A: We need calibration – two per day over seven days. We need this for our performance data.

Corporate Symposium: Redefining Diabetes Management with Metrics Beyond HbA1c (Sponsored by Abbott)

Data from Abbott’s IMPACT study (presented in poster form at ADA) was published in the prominent UK medical journal The Lancet today, alongside a very balanced (but mostly positive) accompanying Comment from Cambridge’s Dr. Roman Hovorka and colleagues. This publication was mentioned only briefly in today’s symposium, and represents a major victory for the company and hopefully a positive for eventual reimbursement. There were not major new details in the paper vs. the ADA poster, but getting the dramatic 38% hypoglycemia reduction (~74 minutes fewer per day) published in such a prestigious journal helps build the evidence base and reduces the noise factor around “no alarms.” We also learned today that a new integration agreement between Abbott and mySugr will allow Libre users to automatically and passively upload data to their mySugr accounts via the LibreLink Android app. This is outstanding news for Abbott to begin leveraging data from Libre in the widely loved mySugr app, which also has a partnership with Roche’s Accu-Chek Connect BGM. The Abbott team also told us about a new partnership with Social Diabetes, a popular Android app in the EU that enables users to log their food and insulin and get dosing recommendations from the app. We have not ever heard of this app, but it has a notable 50,000+ downloads on Android and very positive reviews. Abbott’s actual symposium did not share new data or pipeline updates, but the session – “FLASH GLUCOSE MONITORING: Redefining Diabetes Management with Metrics beyond HbA1c” – featured an established slate of experts (Drs. Irl Hirsch, Thomas Danne) who spoke about recent clinical trials of the Libre and reasons why A1c is a flawed, or at least, incomplete outcome metric.

• The Lancet publication is largely comprised of the information we covered at ADA (Poster 868-P). The accompanying commentary from Dr. Hovorka et al. is balanced but mostly positive, noting that the Libre’s lack of alarms “has surprisingly little effect on user acceptability” and that the device could alleviate many of the barriers to wider adoption of CGM, such as the need for calibrations, alarm fatigue, frequent sensor changes, and cost. However, they do caution that “studies in a more generalizable clinical population, in which aspects of behavior modification induced by use of this technology can be ascertained, are needed to provide further guidance to healthcare providers and funders, as well as comparisons with emerging automated insulin-delivery systems.” 
  
  • The Commentary notes that the convenience of FGM trumps that of SMBG (after 90 days, Libre users scanned an average of 15 times/day, compared with the 6 fingersticks/day of the SMBG group), which fosters rapid behavioral adaptation. The downside is that this requires “unrelenting round-the-clock attention to diabetes self-care,” which many patients may not commit to. The study did not include details on how the patients altered their management in response to the additional data (and Dr. Bolinder indicated during Q&A that it is unknown at this point). As a reminder, the study population was intentionally composed of well-controlled patients with lots of hypoglycemia at baseline (mean A1c=6.7%), though the commentary wonders how well the improvements would translate to other groups who may have different interactions with the technology. This is the classic commentary about any study, and overall, we think Abbott should be highly commended for running IMPACT in type 1s and REPLACE in poorly controlled type 2s.
• Abbott’s integration with mySugr is a win for both companies and particularly for Libre users, who can now view glucose levels alongside the rest of their food and medication data in the motivating mySugr app. In June, Abbott struck a similar data integration agreement with Diasend’s mobile app. It is excellent to see Abbott making it easier for patients to view and extract insights from their data, especially in a mobile app. Abbott has lagged behind Medtronic and Dexcom on the data front and we’re glad to see it now making moves to maximize the value of its sensor.
• Highlights from the symposium included: Dr. Thomas Danne (Auf der Bult Hospital for Children and Adolescents, Hannover, Germany) on FGM in the pediatric population, Dr. Jan Bolinder (Karolinsak University Hospital Huddinge, Stockholm, Sweden) on IMPACT results, and Dr. Irl Hirsch (University of Washington Medical School, Seattle, WA) on the limitations of A1c.
  
  • Dr. Danne championed the use of FGM in pediatric populations. Children are notorious for their unpredictable lifestyles, which give rise to higher glycemic variability and risk of hypoglycemia. Due to the legacy effect (or “metabolic memory”), it is crucial that both elements of poor glucose control are minimized as soon and as much as possible. Dr. Danne asserted that FGM can lead to better control and higher quality of life of the child and family – reducing painful fingersticks, allowing parents to check a child’s glucose at night without disturbing him/her, etc. Libre is currently approved for children as young as four years in Europe; we saw the accuracy data in an oral at ATTD 2016).
  • Dr. Bolinder’s talk focused on the IMPACT trial (presented in poster form at ADA), which found that, relative to SMBG, well-controlled (baseline A1c: 6.7%) type 1 patients using FreeStyle Libre spent ~74 minutes fewer per day <70 mg/dl (a 38% reduction; p<0.001). There was not a significant difference in A1c between the groups by study end, though both saw a non-significant 0.15% increase from baseline to six months (6.7% to 6.9%). The quality of the A1c was unquestionably better in the Libre group. In addition, quality of life metrics were almost entirely in favor of Libre. See our detailed coverage here and the Lancet publication here.
  • Dr. Irl Hirsch on how we manage type 2 diabetes: “Wrong!” Dr. Hirsch walked attendees through a litany of primary literature to prove his point: A1c does not reliably correlate with an average glucose level on an individual basis, ESAs (erythropoietin stimulating agents) cause a decrease in A1c, iron causes an increase in A1c, aortic disease causes reduced red blood cell survival and subsequent decrease in A1c, the list goes on. Yet the standard of care is to escalate or deescalate a type 2 patients’ therapy based on an A1c, which may or may not accurately reflect the patient’s glycemia, measured every 3-4 months. As only Dr. Hirsch could put it, “It is ok to be glucocentric while treating glucose.” Well said! We’ll be back with our full report from this talk.

Selected Questions and Answers

Q: What do patients do on Libre to improve metabolic control and achieve benefits?

Dr. Bolinder: We don’t know exactly. My personal guess is that they make proactive decisions rather than retrospective analyses. It’s not the one and only value that you measure that’s important, it’s the trend. If you look at where your glucose is heading within the next hour or two, you can make proactive changes. I think this because of the SWITCH study, where patients used a sensor for a period and were switched over to SMBG again. All improvements from using the sensor were damaged when they switched back SMBG.

Q: Do patients/parents need education to use FGM properly because of all of the data generated?

Dr. Danne: Yes, I think that’s imperative. The first prescription should be made by a diabetes team experienced with the system, one that understands the trends and arrows. It’s not a BGM, but it measures interstitial glucose.

Q: How are reductions in nocturnal hypoglycemia explained without alarms?

Dr. Ajjan: Because we review the patterns of glucose. That way we can find hypoglycemias and adjust accordingly. You don’t necessarily need the alarm.

Dr. Bolinder: I’m not an entirely AGP fan, because I think it’s the proactive manner that you make the changes. The highest frequency of scanning [in IMPACT] occurred in the evening before going to bed, then patients can make the adjustments to minimize risk of hypoglycemia during the night. In addition, please remember that these patients also monitored on average 1-2 times every night. That is something that we perhaps had not been aware of. Night contains things that we are not quite aware of that the patients do.

Q: Why was IMPACT restricted to type 1 diabetes with a1c higher than 7.5%?

Dr. Bolinder: Please remember that the aim of the study was to evaluate effectiveness in preventing hypoglycemia. So we selected patients in which you’d expect increased risk of hypoglycemia. We clearly stated that future studies are needed to evaluate the device in other patient groups. The first that comes to mind is patients that don’t achieve targets.

Non-Corporate Symposium: New Technologies and Therapies in Diabetes Improving Patient Quality of Life (IDF Europe Symposium)

The Role of New Insulins in Diabetes Treatment

Nebojsa Lalic, MD, PhD (University of Belgrade, Serbia) and Asimina Mitrakou, MD, PhD (National and Kapodistrian University of Athens, Greece)

Questions and Answers

Professor Dario Rahelić (Dubrava University Hospital Zagreb, Croatia): You discussed new insulin analogs in comparison to older insulin analogs, but what about in comparison to human insulins? How do they compare in terms of price, cost-effectiveness, efficacy, quality of life, hypoglycemia, and weight gain?

Professor Asimina Mitrakou (National and Kapodistrian University of Athens, Greece): I think this questions has already been answered. Between human insulins and analogs, there is no doubt that analogs are better. Even in terms of cost-effectiveness, they are better. The NICE guidelines only look at cost, so they’re limited in what they tell us. The ADA/EASD guidelines are better. What we don’t have data on is the cost-effectiveness comparison between new insulin analogs versus old analogs.

Professor Rahelić: Will you comment on the NICE guidelines from your own perspective?

Professor Mitrakou: We don’t implement them. They talk about cost and not efficacy.

Professor Nebojsa Lalic (University of Belgrade, Serbia): In order to show that insulin analogs end up with better A1c, you need an enormous study with an enormous number of people and different comparators, which none of the pharmaceutical companies want to do. There is a definite clinical sense that there is an improvement in nocturnal and overall hypoglycemia with analogs. This has played into the guidelines and we ended up with almost all European countries switching to insulin analogs. It would be difficult to organize a comparison between the new analogs and human insulins these days because you couldn’t recruit enough patients. Another point is the NICE guidelines have evolved over the last decade from not recognizing the analogs at all to allowing the introduction of premixed analogs based on the psychological perception of the patient (such as the patients being more willing to commit to premixed analogs). This type of patient quality of life comparison is very difficult to do and the companies are aware of that. In our country, some of them are searching for possible studies of glucose variability with human insulins compared to with the latest generation of insulin analogs.

Professor Rahelić: In some countries, the government would like to switch again from insulin analogs back to human insulins because of the price.

Professor Mitrakou: With type 1, you have to respect their condition and not look at the cost. Type 2 is different so you can go with human insulin.

Q: Do you think we need to consider quality of life on parity with some of the clinical indicators? When we look at indicators for evaluation, it tends to be “has A1c changed?” and quality of life doesn’t really come into it, particularly at the NICE or at the EMA level.

Professor Mitrakou: Yes, I think quality of life should be considered. We measure A1c and hypoglycemia, but how does if actually affect the patient’s quality of life when there’s less hypoglycemia? Know that would count a lot.

Professor Lalic: I agree completely with this. Because this is an IDF symposium, I would also ask if these more developed countries could give us more advice on how to promote these parameters for consideration in the payer regulations. In Serbia, we don’t have this consideration. You have to start human insulin and the patient has to be unstable with fasting hypoglycemia in the morning in order to switch to a long-acting insulin analog. Considering psychological effects, quality of life… that would sound like virtual reality if we brought that up as a parameter to the funders. There are countries where quality of life is not on the agenda.

Comment: That sounds like it’s also a moral hazard issue. If you have bad glucose control, you get better treatment and technology. If you have good glucose control, we’re going to punish you for it and not give you the therapies you want. That actually sounds unethical more than anything else.

Professor Rehelić: I want to emphasize the importance of organizing in diabetes. We were able to do a lot this way in Croatia. We increased the number of test strips for pediatric patients from 2000 to 2500. Three years ago, the first step in insulin treatment was human insulin or premixed analogs – the majority of people with type 2 diabetes were initiated on insulin with premixed analogs. Now it’s completely changed. Together with patient organizations and professional organizations, we pursued our Ministry of Health. We asked the Minister of Health, “Do you consider Croatia to be part of the European community?” He replied, “Yes, I proudly consider Croatia part of the European community. We then said, “If you’re so proud Croatia is part of the European community, how can you have people with diabetes in Croatia not receiving the same treatment options as other people in the European community?” Together, we can do a lot.

--by Adam Brown, Abigail Dove, Helen Gao, Brian Levine, Payal Marathe, and Kelly Close