International Diabetes Federation: World Diabetes Congress 2015

November 30–December 4, 2015; Vancouver, Canada Day #2 Highlights – Draft

Executive Highlights

Hello from Vancouver, where the Canadian rain and clouds didn’t dampen our spirits for day #2 of IDF (the conference’s official first day!), where we heard new data from Abbott, presentations on IDF’s latest diabetes atlas, and an array of KOL insights on the future of type 2 therapies, CVOTs, and more. The day was packed with wide-ranging symposia exploring basic and clinical science to public health, while the evening wrapped up with a slew of corporate symposia. Please see below for our top ten highlights and a handful of honorable mentions from the day and again, check out our preview if you haven’t yet done so. Also here’s our picture of the globe we mentioned from day #1 ;> it remains at the top of our minds as this meeting especially gets us thinking about the global population-level questions surrounding diabetes!

1. Abbott’s p-a-c-k-e-d corporate symposium was headlined by a slew of updates: (i) new accuracy data from a 40-patient, 14-day Chinese pivotal trial of FreeStyle Libre; (ii) news that the two six-month FreeStyle Libre reimbursement studies will report at ATTD and ADA 2016 – get your tickets for Milan and New Orleans!; (iii) FreeStyle Libre (the consumer version) has been submitted to Canadian regulatory authorities; and (iv) fresh perspective on the rousing reception FreeStyle Libre Pro has received in India.

2. Dr. Philip Home (Newcastle University, Newcastle upon Tyne, UK) argued that future type 2 diabetes therapies will need to (i) alter calorie balance to achieve greater glycemic efficacy or (ii) offer significant non-glycemic benefits.

3. Oral combination therapy was the consensus favorite approach among panelists asked how they would treat their own type 2 diabetes.

4. Dr. Irl Hirsch (University of Washington, Seattle, WA) discussed the many ways in which alternative measures of glycemic control can complement and account of insufficiencies in A1c.

5. Dr. John Buse (University of North Carolina, Chapel Hill, NC) expressed characteristic excitement about GLP-1 agonist/basal insulin combinations and raised several unresolved questions about their optimal use.

6. The latest iteration of the CVOT debate pitted concerns about scientific integrity against practical limitations of RCTs and the need for more focus on prevention.

7. An 8:30 am session in a small, second-floor room discussed the new IDF Diabetes Atlas, now posted online in full at www.diabetesatlas.org. The high-level session itself did not contribute major new insight or data beyond our initial coverage two weeks ago, though we did glean valuable perspective on the Atlas’ conservatism, uncertainty, and how much the US contributes to global costs.

8. Dr. Fran Kaufman (Chief Medical Officer, Medtronic Diabetes, Northridge, CA) stressed the value of CGM, online programs, mobile phones, and other health information technologies (IT) as effective solutions for managing diabetes prevention and treatment in large populations.

9. Integrity Applications introduced GlucoTrack, its CE-Marked non-invasive ear clip device for spot monitoring glucose in type 2 diabetes and prediabetes. The sparcely attended symposium shared an unconvincing overview of the device, including an MARD of 23%, an upfront cost of $2,000, and a one-minute measurement time for each spot reading (it’s not continuous).

10. Dr. Ambady Ramachandran (India Diabetes Research Foundation, Chennai, India) contextualized his lab’s ongoing study (NCT01570946) evaluating the efficacy of text messaging interventions in type 2 diabetes prevention, providing an in-depth review of several diabetes prevention studies conducted in India.

Table of Contents 

Top Ten Highlights

1. Abbott’s p-a-c-k-e-d corporate symposium was headlined by a slew of updates: (i) new accuracy data from a 40-patient, 14-day Chinese pivotal trial of FreeStyle Libre; (ii) news that the two six-month FreeStyle Libre reimbursement studies will report at ATTD and ADA 2016; (iii) FreeStyle Libre (the consumer version) has been submitted to Canadian regulatory authorities; and (iv) fresh perspective on the rousing reception FreeStyle Libre Pro has received in India (Dr. Viswanathan Mohan has used it in ~1,000 patients!). On the data front, Dr. Linong Ji (Peking University People’s Hospital, Beijing, China) shared new data that Abbott’s factory calibrated FreeStyle Libre system demonstrated a MARD of just 10.7% vs. YSI (n=6,969 paired sensor-YSI points) and 10.0% vs. capillary fingersticks (n=6,696 paired sensor-YSI points) in its 14-day Chinese pivotal trial (n=40). These accuracy data were actually slightly better than results from the EU pivotal trial (MARD: 11.4%), a testament to this technology’s impressive accuracy with factory calibration. Dr. Ji did not share a timeline on Chinese approval of Libre (or whether the device has yet been submitted). Our detailed write-up below shares more on the behavioral analyses and interesting Q&A with lots of audience and clinician enthusiasm. There was no commentary on the European capacity constraints or a US submission.

  • Dr. Stefano Genovese (IRCCS MultiMedica, Sesto San Giovanni, Italy) shared an update on Abbott’s two six-month FreeStyle Libre reimbursement studies – REPLACE (n=210 type 2s on MDI, A1c>7.5%) will be presented at ATTD 2016 and IMPACT (n=225 type 1s on MDI or pumps, A1c <7.5%) will be presented at ADA 2016. These studies were a very big investment and are critical for obtaining broad reimbursement, especially in Europe where patients are less accustomed to paying out of pocket for healthcare. [Libre currently has partial reimbursement only in Sweden.] Of course, these studies could also blow the doors wide open on demand for FreeStyle Libre, so Abbott will need to fix the capacity constraints very quickly.
  • Management separately shared with us that FreeStyle Libre (the consumer version) has been submitted to Canadian regulatory authorities. This is the first we had heard of this news. An approval timeline was not provided and we are still not sure when this was submitted. Still, it is big positive to see Abbott pushing its geographic footprint forward, and we hope to see the consumer version make its way to the FDA in the near future too. As a reminder, the blinded Pro version is currently under FDA review (submitted in 2Q15), with a potential launch in 2016. More below from this session!

2. Dr. Philip Home (Newcastle University, Newcastle upon Tyne, UK) argued that future type 2 diabetes therapies will need to (i) alter calorie balance to achieve greater glycemic efficacy or (ii) offer significant non-glycemic benefits. He argued that most current therapies have been able to achieve only modest A1c reductions (“could I call them pathetic?”) because they either flood the system with insulin or otherwise push glucose into the liver. The liver then “fights back” by reducing postprandial glucose uptake and increasing glucose production, limiting the effect of the therapy. Dr. Home argued that only approaches that affect calorie balance will be able to achieve greater glycemic efficacy. This could include GLP-1/glucagon dual agonists (which he sees as particularly promising), SGLT-1/2 inhibitors, fat/carbohydrate absorption inhibitors (if side effects can be reduced), and potentially metabolism enhancers that target the mitochondria. Therapies Dr. Home believes are “unlikely to get anywhere” are G-protein receptor drugs, insulin receptor agonists, 11-beta HSD1 inhibitors, glucokinase activators, glucagon antagonists, and biguanide mimetics. He also suggested that a drug could still be considered successful if it matched the efficacy of current therapies and offered additional benefits like weight reduction (GLP-1 agonists), heart failure benefits (at least one SGLT-2 inhibitor), blood pressure or LDL reductions, or possibly anti-inflammatory or anti-thrombotic effects. We loved hearing this much granularity on what it will take to meet the increasingly high bar for new type 2 diabetes therapies. The role of next-generation versions (such as oral or longer-acting formulations) of existing drug classes was one aspect of innovation not addressed in this talk. While it is unlikely that such products can offer the same sort of dramatic clinical improvements, they may be able to achieve meaningful quality-of-life and adherence benefits that can themselves improve outcomes.

3. Oral combination therapy was the consensus favorite approach among panelists asked how they would treat their own type 2 diabetes – this was a really fascinating approach for a symposium. This was not particularly surprising given that the question was asked at an AZ-sponsored symposium focused on early combination therapy. However, there was still some disagreement over the best specific agents, the role of lifestyle interventions, and the benefits of initial combination therapy vs. an aggressive sequential approach. Drs. Philip Home (Newcastle University, Newcastle Upon Tyne, UK) and John Buse (University of North Carolina, Chapel Hill, NC) worried that initial combination therapy would make it difficult to decipher which component is responsible for any side effects that might arise, particularly unexpected side effects that are not widely associated with either component. Dr. Julio Rosenstock (Dallas Diabetes and Endocrine Center, Dallas, TX) also suggested that cost could be a significant factor when deciding between various combinations. He favors SGLT-2 inhibitor/metformin combinations over DPP-4 inhibitor/SGLT-2 inhibitor combinations such as Glyxambi (empagliflozin/linagliptin) because the latter includes two expensive drugs vs. generic metformin. He argued that combinations with metformin make more sense except in cases of metformin intolerance. DPP-4 inhibitor/SGLT-2 inhibitor combinations are arguably more exciting clinically but cost is clearly an important consideration in many cases. See the panelists’ responses below:

  • Dr. Stefano Del Prato (University of Pisa, Italy): DPP-4 inhibitor/SGLT-2 inhibitor combination therapy. He also emphasized that he’d keep running everyday as he does currently since “there are ways to prevent this disease and drugs may work better under the right conditions.”
  • Dr. Daniel Drucker (Lunenfeld-Tanenbaum Research Institute, Toronto, Canada): Metformin, a DPP-4 inhibitor, and an SGLT-2 inhibitor immediately. “We need to be more like oncologists and less like cautious diabetes specialists. This is a serious disease and we need to hit it hard and hit it early.”
  • Dr. John Buse: Once-daily metformin with a DPP-4 inhibitor or an SGLT-2 inhibitor added soon after if needed, along with a “heroic lifestyle effort.”
  • Dr. Julio Rosenstock: Metformin and an SGLT-2 inhibitor. “There’s 50 years of safety data with metformin and the data is very strong with EMPA-REG OUTCOME.”
  • Dr. Philip Home: Stop eating (only half-serious, we assume). “Provided you have enough excess hepatic fat, you can actually put yourself into remission by adequate dietary measures.”

4. Dr. Irl Hirsch (University of Washington, Seattle, WA) discussed the many ways in which alternative measures of glycemic control can complement and account of insufficiencies in A1c. In his view, A1c remains our gold standard as a biomarker for glucose control though its limitations have provided more than enough reasons for assessing other markers. Indeed, he shared that ~14-25% of patients in his practice present with glycation gaps (i.e., A1c levels that do not reflect blood glucose), stressing that the phenomenon is far more common than is widely appreciated. As such, his presentation expounded on the strengths and limitations of fructosamine, glycated albumin, and 1,5 anhydroglucitol (1,5 AG), concluding that no single biomarker is sufficient for assessing glycemic control nor are any two biomarkers necessarily equivalent. Instead, he pushed for a multi-modal approach using a combination of biomarkers that will better predict long-term complications – composite outcomes are indeed something talked about more and more– though the kicker is that Dr. Hirsch believes the BEST future biomarker is none of these ... though it is something all patients have access to: glucose! Indeed, he impressed upon the audience that glucose itself – e.g., home blood glucose monitoring and continuous glucose monitoring – is the ideal metric for making clinical decisions, suggesting that there is little utility in a biomarker when you can use the real thing. This sentiment was perhaps best summarized by Dr. Hirsch’s closing remarks: “At the end of the day, it’s glucose that’s the enemy. Glucose monitoring is going to be the best biomarker yet!” For more on all the above and Dr. Hirsch’s certainty that c-peptide levels may provide a particularly useful marker in a composite endpoint, see our detailed report below.

5. Dr. John Buse (University of North Carolina, Chapel Hill, NC) expressed characteristic excitement about GLP-1 agonist/basal insulin combinations and raised several unresolved questions about their optimal use. He reviewed clinical trial data on Novo Nordisk’s Xultophy (insulin degludec/liraglutide) and Sanofi’s LixiLan (lixisenatide/insulin glargine), emphasizing their “clear dramatic effect” on glycemic control and significant hypoglycemia and weight benefits compared to basal insulin alone. He believes it remains uncertain how the two products will differ in clinical practice. We have generally assumed they will have fairly comparable clinical profiles, but Novo Nordisk indicated in its 3Q15 update that it believes Xultophy will be highly differentiated. Dr. Buse also suggested that GLP-1 agonist/basal insulin combinations (fixed-ratio or otherwise) come out on top in the arguably more relevant comparison to basal-bolus insulin. He noted that while the available evidence has suggested a modest advantage at best in terms of glycemic control, the significant weight and hypoglycemia benefits and the convenience of a single injection are very clinically meaningful. The major remaining questions for Dr. Buse are (i) where these combinations should be positioned in treatment guidelines; (ii) whether adding basal insulin when patients have failed on a GLP-1 agonist is as effective as the reverse; and (iii) whether GLP-1 agonists could be an alternative to basal insulin as an add-on to rapid-acting insulin. He believes the last two questions remain unresolved and require further study. While the answer to the first is complex, Dr. Buse believes that absent concerns about cost and the long-term safety of GLP-1 agonists, “you could make a very strong argument that the combined approach is clearly superior to basal insulin” as an add-on to oral therapy.

6. The latest iteration of the CVOT debate pitted concerns about scientific integrity against practical limitations of RCTs and the need for more focus on prevention. On the pro-outcomes trial side, Dr. David Nathan (Harvard University, Boston, MA) argued that while observational studies can raise important questions that inform future trials, only experimental studies can sufficiently control for bias and confounding, properly assess risk, and demonstrate causal relationships. This is evidenced by the list of prominent discrepancies between epidemiological and experimental studies in the past. Dr. Nathan did acknowledge the concerns about cost and generalizability with RCTs and noted the recent push for “pragmatic trials” to help bridge the gap to real-world practice. On the more specific question of whether outcomes trials are needed in diabetes, Dr. Nathan argued that while there is strong evidence in favor of A1c as a surrogate for microvascular benefit, the lack of clarity in the macrovascular arena means that outcomes trials are still required. On the other side, Dr. David Matthews (Oxford Centre for Diabetes, Oxford, UK) argued that while RCTs are the gold standard for answering explicit, limited questions, they carry many practical limitations. CVOTs for diabetes drugs enroll a tiny fraction of the relevant population, report only the mean or median outcome, and may be too short to be useful in many cases. Most importantly, Dr. Matthews believes they are not the smartest approach to tackling a huge epidemic like diabetes. He argued that it is clear from epidemiology that rising obesity rates are driving rising diabetes rates and that it would be more prudent to focus on large-scale prevention efforts.

7. An 8:30 am session in a small, second-floor room discussed the Seventh IDF Diabetes Atlas, now posted online in full at www.diabetesatlas.org. The high-level session itself did not contribute major new insight or data beyond our initial coverage two weeks ago (re-pasted below), though the full 144-page Atlas goes deeper into the regional trends, cost and mortality data, and methodology. Today, we gleaned particularly valuable perspective on a few fronts: (i) how conservative the 2040 estimates might be (they assume no change in diabetes prevalence and only reflect expected population growth – in particular, the US 2040 estimate for 35 million people with diabetes is highly, highly conservative in our view); (ii) how much uncertainty comes with all these estimates (data is often old or just doesn’t exist in many cases); and (iii) how much the US disproportionately contributes to global spending on diabetes (48% of all global dollars spent on diabetes, despite having 7% of global cases!). More on those fronts below.

  • On a broader note, this session was disappointing from an attendee perspective. The speakers communicated little sense of urgency, and the Atlas’ main data were presented with a half-empty room right at 8:30 am (it later filled up around 9 am, during the cost talk). For such a major IDF and diabetes community-wide project, the prioritization of this talk was baffling. Why wasn’t this a standalone, unopposed session? Why wasn’t it later in the day when more people would have attended? Why wasn’t there a greater sense of alarm in the presentation delivery? We heartily salute IDF for the tremendous effort in putting together each Atlas – this is a massive undertaking and so critical – and we hope future Congresses give this session more priority. It deserves it. We also hope IDF involves more of the diabetes community in building the next Atlas, as there is room for collaboration on numbers as important as these.

8. Dr. Fran Kaufman (Chief Medical Officer, Medtronic Diabetes, Northridge, CA) stressed the value of CGM, online programs, mobile phones, and other health information technologies (IT) as effective solutions for managing diabetes prevention and treatment in large populations. She emphasized the value technology brings to a constrained diabetes healthcare system – providers do not have sufficient time and effort to manage patients with diabetes through 10-minute visits every 90 days. Dr. Kaufman highlighted the value of CGM to enhance diabetes care, whether it’s used real-time, retrospective, integrated into the medical record, or driving closed-loop. We were particularly glad to hear her mention use of CGM in research studies to determine the effectiveness of interventions – we certainly hope to see much more of that in drug studies going forward. Dr. Kaufman expressed optimism for future integration of CGM into fully automated systems for insulin delivery (closed-loop), including systems with multiple data inputs (blood glucose, insulin, heart rate, activity, etc.). Of course, Medtronic is leading the field on closing the loop near-term, with the MiniMed 670G in a pivotal study slated to wrap up in May 2016. More broadly, she discussed the translation of evidence-based intervention programs into online formats, such as the chronic disease self-management programs developed by the Stanford Patient Education Research Center and the Diabetes Prevention Program. These programs were proven effective in prior studies, and online transference has improved their scalability and cost effectiveness. Dr. Kaufman concluded with an example of cell phone monitoring in which an Indian mobile diabetes program sent a series of text messages to one million people, demonstrating efficacy in improving physical activity, increasing consumption of fruits and vegetables, and decreasing consumption of high fat and fried foods. This vividly illustrates the considerable ROI potential of mobile phone technology, in which a vast number of people can participate in a simple, cost-effective intervention. Now that is where diabetes care HAS to go.

9. Integrity Applications introduced GlucoTrack, its CE-Marked and just-launched non-invasive ear lobe clip device for spot monitoring glucose in people with type 2 diabetes and prediabetes. The boldly titled corporate symposium (“Non-Invasive Glucose Monitoring (NIGM): Have we reached the Holy Grail?”) shared an unconvincing overview of the device to a small audience (n=40-50): an MARD of 23% vs. Hemocue fingersticks (53% in Zone A of Clarke Error Grid); an upfront cost of $2,000 and $120 for each six-month ear clip; a one-minute measurement time for each spot reading (it’s not continuous); no measurements <70 mg/dl; and the need to recalibrate the ear clip every six months with an ~20-30 minute calibration with a fingerstick. The device is said to have already launched in some places around the world (not specified), with expansion said to be expected soon. We think it has an uphill battle on many fronts (cost, accuracy, form factor, hassle), though CEO Avner Gal rightly noted that without early generation CGMs, the field would not be where current sensors are today. Still, the device has been in development for 12 years, and after clinical trials in >750 patients, it is hard to imagine a step function change in accuracy or form factor is coming anytime soon, particularly with just $2.1 million in cash in the bank as of 3Q15 and a market cap of $22 million on the OTC/QB exchange. The company has spoken to the FDA, and per its October announcement, plans to begin a US trial in early 2016. Integrity’s current product roadmap includes adding cloud connectivity, a type 1 indication, models for developing countries and the hospital setting, and more. We look forward to following the company and salute the team for trying to crack non-invasive glucose monitoring (NIGM) – as Dr. Lutz Heinemann summarized the field in his overview talk, “NIGM has a long history of continuous ambition and failure,” but it is still worth pursuing for patients. (That said, we feel most believe the Libre is nearly non-invasive.)  

  • The open-minded Dr. Irl Hirsch was more optimistic than us in Q&A, noting less concern with the MARD (“it will get better”) and questioning whether Integrity’s device would have value in the hospital and long-term care settings. Dr. Hirsch’s talk in this symposium did not speak about Integrity’s device specifically; he talked broadly about glucose monitoring in type 2 diabetes. His conclusions: (i) based on the totality of current evidence, SMBG results in a small reduction in A1c in non-insulin users; (ii) glucose testing for those who do take insulin seems to be underutilized – lots of hypoglycemia is missed right now; and (iii) A1c is not a good marker to make treatment decisions for many patients (blood glucose data is better).
  • Integrity’s device begs many thought provoking questions: What level of glucose monitor accuracy is good enough for type 2 diabetes and prediabetes? How should companies trade off accuracy vs. improved form factor vs. cost? When does the output from a less invasive glucose monitor cross from useful to dangerous? These questions have important implications not just for Integrity, but type 2-focused glucose monitors from Abbott, Dexcom/Google, Medtronic, Novartis/Google, and wellness CGM companies like Echo and Sano. (Abbott is arguably the leader right now on the composite profile, having achieved an outstanding form factor with FreeStyle Libre, a lower cost, and accuracy safe enough to dose insulin with factory calibration. But there is clearly a spectrum on the cost, accuracy, and form factor dimensions of any product.) Not every glucose-monitoring device needs to be accurate enough for dosing insulin, but there is presumably some threshold that must be hit. What is that threshold, and how should that be weighed against a smaller or less invasive or less costly device? For instance, if the Novartis/Google contact lens has a MARD of 20% (our speculation), is that good enough to drive therapeutic change in type 2 diabetes and prediabetes? At what point does the device’s clinical inaccuracy outweigh any potential benefit of more frequent monitoring? Tough questions indeed, and ones that will likely be solved only with prototypes tested in clinical trials.

10. Dr. Ambady Ramachandran (India Diabetes Research Foundation, Chennai, India) contextualized his lab’s ongoing study (NCT01570946) evaluating the efficacy of text messaging interventions in type 2 diabetes prevention, providing an in-depth review of several diabetes prevention studies conducted in India. The ongoing study began enrolling participants (n=20,000) in India and the UK in 2011, and results are currently pending. According to Dr. Ramachandran, the study is based on findings from a series of studies demonstrating that (i) lifestyle intervention is effective at preventing the progression to diabetes; and (ii) mobile phones can allow this intervention to be scalable and reach large populations via simple short messaging service (SMS). As an example, he shared results from the first Indian Diabetes Prevention Program (IDDP-1) in the early 2000s, which followed 531 participants with impaired glucose tolerance for three years to evaluate the effectiveness of lifestyle management and metformin on preventing progression to type 2 diabetes. Study results showed that 55% of the control group developed diabetes, while the lifestyle modification intervention reduced diabetes conversion by 28.5%. There was no additional benefit of using metformin. He noted that compared to DPP studies in the US and Finland, the IDDP-1 showed diabetes onset at a younger age and lower BMI. Next, Dr. Ramachandran highlighted key results from multiple recent studies investigating the efficacy of SMS in reaching a large number of people at a low cost and influencing them to change their behavior to improve health. Most notably, a randomized clinical trial demonstrated a 36% risk reduction in the incidence of type 2 diabetes in the intervention group compared to control. The intervention involved frequent mobile phone messaging with content tailored to participant sub-groups using the trans-theoretical model (a framework for changing behavior). The intervention significantly reduced the incidence of diabetes during the 2-year period, and HDL cholesterol and diet improved as well. We are pleased to see a focus on prevention in India, where diabetes rates are climbing past 69 million, resources are limited, and simple mobile phones are ubiquitous.

Honorable Mention

  • Dr. Urd Kielgast (Hvidovre University Hospital, Copenhagen, Denmark) offered a middling take on GLP-1 agonists in type 1 diabetes: positive on safety and more pessimistic on efficacy. On safety, she concluded that there is no increased hypoglycemia risk, impairment of counterregulatory mechanisms, or other serious or unexpected side effects associated with the class in type 1 diabetes. However, she did note that gastrointestinal side effects are more common and that the long-term implications of the increase in heart rate and reduced systolic blood pressure are unknown at this point (we assume the blood pressure effect would be more positive than negative if anything but clearly need long-term trials to be sure). The question of efficacy is more complex. Dr. Kielgast pointed to promising early-stage data showing substantial reductions in postprandial glucose with GLP-1 agonists regardless of beta cell function. The drugs also led to A1c reductions, lowered insulin doses, and weight loss in uncontrolled proof-of-concept studies. As we have unfortunately learned over the past few months, the results from placebo-controlled trials – Novo Nordisk’s phase 3 ADJUNCT ONE and ADJUNCT TWO studies for Victoza (liraglutide) being the largest – were less encouraging. Novo Nordisk subsequently decided not to pursue a type 1 diabetes indication for liraglutide – a disappointing but understandable decision in our view. We imagine other GLP-1 agonist manufacturers will now be more reluctant to pursue type 1 diabetes indications as a result. However, Dr. Kielgast noted that she would like to see studies in new-onset patients and studies of short-acting GLP-1 agonists, which have a greater effect on gastric emptying. We also think benefits like weight loss and potentially reduced glycemic variability could be meaningful for at least some patients, but we are fairly pessimistic that there will be a regulatory path forward in the near future.
  • Dr. Carla Greenbaum (Benaroya Research Institute, Seattle, WA) delivered a passionate talk on the need for disease-modifying therapies for type 1 diabetes – and for endocrinologists to overcome their fear of immunotherapy. To those who argue that advances in current treatment will make disease-modifying therapies unnecessary, Dr. Greenbaum responded that “we’re not as good as we think we are.” She pointed to T1D Exchange data showing “pretty lousy” glucose control across the board, significant rates of severe hypoglycemia, and declining but still prevalent rates of complications. She argued that the best place for disease-modifying treatments is before clinical diagnosis, at stage one of the recently published JDRF/ADA staging system (multiple autoantibodies with normal blood glucose). She also emphasized that children need to be considered as an independent group, as they experience a much faster rate of disease progression than adults. Dr. Greenbaum has been a staunch advocate of this point and co-chaired a consensus conference on the topic earlier this year. In terms of specific therapies, Dr. Greenbaum highlighted teplizumab, rituximab, abatacept, and alefacept as the four candidates that have demonstrated efficacy and a reasonable safety profile in clinical trials. She made the important point that the level of efficacy seen in those trials (~20-25% benefit vs. control) is comparable to that produced by approved immune therapies for other diseases – the trick is figuring out how best to use them. The issue of expectations is perhaps one of the biggest challenges facing this field: there has been so much hope and hype around a “cure” for type 1 diabetes that an immunotherapy or cell replacement approach could be perceived as a disappointment even if it produces real clinical benefits.
  • Novo Nordisk presented a series of posters addressing its own products and broader considerations in clinical practice.
    • In a meta-analysis, Victoza (liraglutide 1.8 mg) demonstrated greater A1c reductions than SGLT-2 inhibitors in patients with type 2 diabetes on metformin. The analysis (n=17 RCTs) found that both doses of Victoza demonstrated greater mean reductions in A1c than any dose of any of the three approved SGLT-2 inhibitors. Victoza was also associated with a greater percentage of patients reaching an A1c goal of ≤7%. However, weight loss was similar between Victoza and the SGLT-2 inhibitors, with the higher 300 mg doses of J&J’s Invokana (canagliflozin) and 25 mg doses of Lilly/BI’s Jardiance (empagliflozin) producing larger weight reductions that the lower 1.2 mg dose of Victoza.
    • Three posters showed that Ryzodeg (insulin degludec/insulin aspart) produced lower rates of overall and nocturnal hypoglycemia than NovoMix 30 and/or basal-bolus insulin degludec and insulin aspart. This was true regardless of baseline A1c, disease duration, or BMI. Patients treated with Ryzodeg also had lower fasting plasma glucose vs. both comparators. Ryzodeg-treated patients with a BMI ≤30 or a disease duration longer than 10 years saw significant differences in insulin dose at the end of the trials as well.
    • The Perceptions of Control study identified barriers to insulin therapy intensification in patients with poorly controlled type 2 diabetes on basal insulin from the patient and physician perspective. The most common barriers cited by patients in the web-based survey were fear of weight gain (45%), the perception that intensification would signal disease progression (44%), fear of hypoglycemia (41%), and reluctance to add more injections (41%). Overall, 57% of patients surveyed stated they were only somewhat willing or not at all willing to initiate  bolus insulin. The primary source of physician reluctance to intensify was the belief that their patients would not agree to intensification (noted by 62% of physicians). Other top reasons included hypoglycemia concerns (46%), mental illness (48%), poor cognitive skills (46%), and concerns about patient adherence (41%) as barriers to intensification. This study dovetailed nicely with Dr. Lawrence Fisher’s (UCSF, San Francisco, CA) actionable talk on barriers to insulin initiation yesterday. The two together emphasize the need for better provider education on how to talk about insulin, and perhaps better patient-provider communication in general.
    • Four posters examined the physical, emotional, and economic implications of post-meal hyperglycemia. 27% of respondents with recent post-meal hyperglycemia in one survey reported missing work time and a whopping 71% reported decreased work productivity. Another survey found that people with post-meal hyperglycemia had significantly more healthcare visits (5.5 visits in the past year vs. 4.4 visits for patients without post-meal hyperglycemia). The same study found that those with post-meal hyperglycemia also measured their blood glucose more frequently (1.9 extra measurements per day vs. 1.2, p<0.001) and were more likely to report diabetes-related complications. A third study found that contributing factors for post-meal hyperglycemia included stress (in 27% of respondents), eating out at a restaurant (25%), being busy (21%), and feeling tired (19%). Physical and emotional consequences included tiredness, dizziness, and feelings of demoralization, lack of sociability, and irritability.
  • Lilly presented a new poster from its phase 3 AWARD-8 study, demonstrating that Trulicity (dulaglutide) as an add-on to sulfonylurea is more effective than a sulfonylurea alone. The randomized, double-blind, placebo-controlled trial (n=300) evaluated the efficacy and safety of treatment with dulaglutide vs. placebo in sulfonylurea-treated patients over 24 weeks. From a baseline A1c of 8.4%, participants in the dulaglutide-treated group experienced a 1.3% greater A1c reduction than those in the placebo group (p<0.001). In addition, those treated with dulaglutide were more likely to reach a target A1c <7% (55% of those in the dulaglutide-treated group vs. 19% in the placebo group; p<0.001). Dulaglutide treatment significantly improved fasting plasma glucose over placebo (p<0.001) as well. The dulaglutide group showed some weight reduction (-0.9 kg), although the between-group weight change was not statistically significant. As expected, the most common adverse events associated with dulaglutide treatment were gastrointestinal-related (10.5% nausea and 8.4% diarrhea), leading to six discontinuations in the dulaglutide group vs. none in the placebo group. Hypoglycemia rates were also higher in the dulaglutide-treated group (p=0.025), although the overall incidence remained low at 11.3%. Overall, the trial demonstrated that dulaglutide is a safe and effective treatment when added on to sulfonylureas – while this finding isn’t particularly surprising, it could lend confidence to providers who may have been previously hesitant to prescribe the two together.

Detailed Discussion and Commentary

Corporate Symposium: One Year of Flash Glucose Monitoring: The Global Clinical Experience (Sponsored by Abbott)

FreeStyle Libre Accuracy China Study

Linong Ji, MD (Peking University People’s Hospital, Beijing, China)

Dr. Linong Ji shared never-before-seen data from Abbott’s 40-patient, 14-day Chinese pivotal trial of its factory calibrated FreeStyle Libre system, which demonstrated excellent accuracy vs.  both YSI and capillary fingersticks. MARD was just 10.7% vs. YSI (the study had 6,969 paired sensor-YSI points) and 10.0% vs. capillary fingersticks (the study had 6,696 paired sensor-YSI points). The data were impressively consistent across the board as 87% of points were in Zone A of the Consensus Error Grid and 13% in Zone B in both environments, a testament to the device’s accuracy as patients would experience it (i.e., relative to fingersticks). Similar to the EU pivotal trial, accuracy did not significantly deteriorate between days 1-7 vs. days 8-14. The data actually represent a slight improvement on what has been achieved in the EU pivotal trial, where Libre demonstrated an overall MARD of 11.4% vs. FreeStyle Precision BGM (n=13,195 paired points) and 11.8% vs. YSI (n=1,238 paired sensor-YSI points). The overall accuracy in these clinical trials is highly encouraging, and once manufacturing scales up, Abbott will need to maintain those results at scale – we have little doubt on that front, but factory calibration is of course not easy. As a final note, Dr. Ji did not share a timeline on China approval of Libre (or whether the device has yet been submitted to regulatory authorities).

  • In a follow-up conversation with management, we learned that FreeStyle Libre (the consumer version) has been submitted to Canadian regulatory authorities. This is the first we had heard of this news publically. A timeline was not provided and we are still not sure when this was submitted. It is positive to see Abbott pushing its pipeline forward, and we hope to see the consumer version make its way to the FDA in the near future. As a reminder, the blinded Pro version is currently under FDA review, with a potential launch in 2016.
  • The Chinese pivotal study was conducted similarly to the US studies with three centers across China in type 1 and type 2 patients on insulin therapy. Patients wore two sensors on the back of their arm for 14 days and were asked to: (i) perform eight capillary blood glucose tests daily; (ii) scan the sensor following each test; and (iii) attend three in-clinic eight-hour YSI sessions. Notably, Dr. Ji shared that patients had a mean baseline A1c = 8.6%, ranging from a low of 5.6% to a high of 13.4% for a nice mix of well-controlled and out-of-control patients.
  • There was one rather significant difference between the China and US data – the mean lag time was 3.1 minutes in China vs. 4.5 minutes stateside. Dr. Ji could not explain the discrepancy though he hypothesized that it may reflect ethnic differences. Indeed, it’s tough to say what’s causing the difference. Sample size? A different batch of devices?
  • MARD was not broken down by glucose range, so accuracy in hypoglycemia is an unanswered question for the Chinese study. Just like the EU, we assume the product label will recommend a confirmatory fingerstick when patients are hypoglycemic.  Still, patients in the real world clearly trust the device enough to never test, so we have little concern about the hypoglycemia data in this study.
  • Dr. Ji shared positive data from user experience studies of FreeStyle Libre in the pivotal study. There was no background on how these questions were asked – we assume Yes/No. Said Dr. Ji jokingly, “This is probably due to the fact that I treat them too well.” Jesting aside, the data do point to why European patient uptake has been so strong in these early days, especially in those that have avoided current CGM due to comfort/wearability:
    • 100% agreed that the sensor was easy to apply.
    • 100% agreed that applying the sensor was less painful than a routine fingerstick.
    • 100% agreed that the system was packaged with sufficient information to use the system.
    • 100% agreed that the amount of pain felt when applying the sensor to the arm was acceptable.
    • 100% agreed that the amount of bleeding experienced when applying the sensor to the arm was acceptable.
    • 100% agreed that the sensor was comfortable to wear.
    • 97.5% agreed that the sensor was easy to wear due to its small size.
    • 100% agreed that the sensor did not get in the way of daily activities.
    • 100% agreed that scanning the sensor is less painful than pricking a finger.
    • 100% agreed that scanning the sensor is easier than pricking a finger.
    • 100% agreed that the amount of erythema on the arm when the sensor was removed was acceptable.
    • 100% agreed that the amount of edema on the arm when the sensor was removed was acceptable.
  • Very few adverse events were reported among patients in the study. Only 9 subjects reported any sort of discomfort related to the sensor insertion and all reports were consistent with what would be expected following insertion of a sensor into the skin. There were no severe adverse events reported and all patients were able to see the trial to conclusion:
    • Moderate erythema – 6 patients
    • Bruising – 2 patients
    • Mild pain – 1 patient
  • Though not indicated for long-term or deep underwater wear, commentary during Q&A suggested that Libre has been used accurately by divers for up to an hour and to a depth of 30 meters. Dr. Genovese summed up his personal experience with such off-label wear quite succinctly: “It works perfectly!”
  • The Chinese Clinical Trial Registry (ChiCTR-OPC-15006147) for the study was last updated in June: A Multicenter Clinical Accuracy Evaluation of the Abbott Sensor Based Interstitial Glucose Monitoring System in Chinese Diabetes Subjects.

Professional Use of FreeStyle Libre Pro: The Clinical Experience in India

Viswanathan Mohan, MD, PhD (Dr. Mohan’s Diabetes Specialties Center, Chennai, India)

A series of case studies presented by Dr. Mohan provided insight into the incredible reception FreeStyle Libre Pro has seen in India. We were floored by his estimate that he has already used the blinded 14-day sensor in ~1,000 patients (whoa!) in just nine months. He spoke in glowing terms about the pattern recognition in Abbott’s Ambulatory Glucose Profile, the value in optimizing patients’ therapy by helping providers feel more successful, and – most importantly – making the invisibility of diabetes more tangible to patients. It sounds like the device has been used far more often in type 2 patients, though Dr. Mohan suggested that the device holds value for anyone on insulin. Especially for patients in India who cannot afford the technology themselves, he impressed upon the audience that two weeks of wear provides a valuable retrospective look to identify trends and can even inform smarter allocation of limited fingersticks. Indeed, we thought that one of Dr. Mohan’s most fascinating comments during Q&A was that Libre Pro makes patients “trust SMBG more” (because now they see single values in the context of broader patterns!). Ultimately, the spectacular reception bodes very well for the Libre Pro sensor that is expected to launch in the US next year (submitted in 2Q15). Abbott did not comment on this timeline (though they were asked) and we assume this is still on track.

  • Although Libre Pro has only approved in adults, commentary during Q&A suggested that providers in India are even taking liberties with the sensor in children. The off-label use does not appear to be affecting accuracy in the slightest. Said Dr. Mohan, “We’ve learned a lot of things. I know it’s not approved, but talk about clinical value … We do it!”
  • As a reminder, Medtronic announced the launch of CareLink iPro Pattern Snapshot yesterday, a new one-page download report for the blinded iPro2 professional CGM. The report prominently shows a patient’s top three glucose patterns and lists up to six possible causes for each one. We do think FreeStyle Libre Pro’s 14-day wear, factory calibration, and slim form factor is a big step up over iPro2’s three-day wear, the need to retrofit the raw sensor data to fingerstick readings, and the larger transmitter.

Flash Glucose Monitoring: Use of AGP in Clinical Practice in the EU

Stefano Genovese, MD (IRCCS MultiMedica, Sesto San Giovanni, Italy)

Dr. Stefano Genovese saved the best for last as the major highlight of his presentation came in his closing sentence with an update on Abbott’s two six-month FreeStyle Libre reimbursement studies – REPLACE (n=210 type 2s on MDI, A1c>7.5%) will be presented at ATTD 2016 and IMPACT (n=225 type 1s on MDI or pumps, A1c <7.5%) will be presented at ADA 2016. Both studies are listed as “ongoing and not currently recruiting” participants on ClinicalTrials.gov with completion slated for December 2015 and September 2015, respectively. As a reminder, the goal of the type 2 study is to show a change in A1c at six months, while the type 1 study seeks to reduce time spent in hypoglycemia at six months. We can hardly express how much we are looking forward this data as reimbursement is critical around the globe, especially in Europe where patients are less accustomed to paying out of pocket for healthcare. [Libre currently has partial reimbursement only in Sweden.] If these studies report positive results and Abbott obtains widespread reimbursement, the company will have its hands full meeting demand.

  • The bulk of Dr. Genovese talk presented the FreeStyle Libre and its accompanying Ambulatory Glucose Profile as clinical tools that can facilitate patient education, improve pattern management, and reduce glycemic variability. Drawing from multiple studies, Dr. Genovese cited glycemic excursions as a driver of microvascular complications and mortality due to the associated oxidative stress. In order to reverse this trend, Dr. Genovese espoused more frequent glucose monitoring – he shared that less than 40% of patients on SMBG in Italy check their glucose more than four times per day whereas ~90% on Libre scan their glucose>four times per day.

FreeStyle Libre Accuracy Study

Timothy Bailey, MD (UCSD, San Diego, CA)

Dr. Timothy Bailey reprised the topline results from Abbott’s 72-patient, 14-day CE Mark pivotal trial – first shared at EASD 2014 – which demonstrated an overall MARD of 11.4% vs. FreeStyle Precision capillary fingersticks (87% of points were in Zone A of the Consensus Error Grid, 13% in Zone B). He opened with a short and sweet introduction to FreeStyle Libre, leading awe-struck attendees through the nuances of flash glucose monitoring: 14-day wear, factory calibrated, approved for wear on the upper arm, etc. Indeed, audiences continue to flock to Libre symposia and this was no exception – the room was packed till the very end! In terms of material itself, the vast majority of Dr. Bailey’s presentation echoed his previous talks on the same topic (ATTD 2015).

Panel Discussion

Q: This is a major paradigm shift to have Libre available. I think the presenters were highly complementary. Can you talk quickly about the various error grids that are used to assess the results?

Dr. Timothy Bailey (UCSD, San Diego, CA): I hate error grids. But they’ve proved to be very useful from a regulatory point of view. They were invented because most glucose monitors were not accurate and it was decided that meters that made less egregious errors were better. However, now in the US, almost 99% of readings are in Zone A and B, so it’s not very useful for comparing technologies.

Q: Bananas and other fruits can cause errors in BGM readings? Do you think that was why there was a higher MARD for Libre vs. capillary?

Dr. Linong Ji (Peking University People’s Hospital, Beijing, China): Yes. Ultimately, we should not interpret just one point though. I like the term “context.” We should use the collective data set to make a clinical judgment.

Dr. Bailey: It’s a good point about bananas and other foods that can interfere with readings. We instructed participants in our trials to do accurate readings. That’s why in reality SMBG may underperform and that’s why the SMBG is different.

Q: Can you talk about the availability and timeline for Libre in Canada and the US?

Mr. Steve Scott (Abbott Diabetes Care, Alameda, CA): The answer to that we’re in the process of trying to get approval for the device in the US, and we’ve submitted the device to Health Canada and can’t really talk about more than that.

Q: Is Libre really CGM in disguise?

Dr. Stefano Genovese (IRCCS MultiMedica, Sesto San Giovanni, Italy): I think it was a good idea of Abbott to design Libre this way. It is a CGM because the sensor continues to measure glucose. However, it is also called “Flash” because the measurement and the possibility to see the measurement is on request. But the actual fact is that the sensor continues to measure everything. It’s the way you use it. The device doesn’t have alarms and this is a problem with CGM, because patients complain about CGM alarms during the night. In the end, Libre gives you all the information a CGM gives you.

Dr. Viswanathan Mohan (Dr. Mohan’s Diabetes Specialties Center, Chennai, India): As far as India is concerned, it is a CGM because we don’t give patients the real-time monitoring capability with the Pro version. We do have Medtronic’s consumer CGM available to patient, but a big difference is the cost. Libre is also less painful and more convenient. No calibrations are VERY convenient. So ultimately, getting Libre for 14 days at lower cost with much less pain is wonderful for us. That’ s why this system has taken off in this country.

Dr. Bailey: I can’t prescribe Libre, but my savvy patients ask about it. SMBG is universally strongly disliked. The big difference is the factory calibration and no fingersticks. I would summarize by saying that CGM and Libre are different technologies, and I have patients that like CGM because it saves them from hypoglycemia at night. But I would say that that’s the minority of patients.

Dr. Mohan: We’ve been saying that Libre replaces SMBG. I have a slightly different take. For us, it doesn’t replace SMBG because we don’t give patients the Pro week after week. That would be too expensive. Instead, we tell them what the problems are and then we tell the when to do SMBG. Most of our patients are type 2s and we tell them that these are the points when you should check – 3 AM, after dinner, their trouble spots, etc. Now patients trust the SMBG a little more and I think Libre and SMBG can be kind of complementary.

Q: Can you talk about the patient experience with and feedback that you’ve received in practice? Are patients seeing a change in lifestyle and outcomes as measured by A1c?

Dr. Genovese: To be honest, I wanted to present some data but I cannot talk about that in a scientific symposium. I can tell you my opinion: the quality of life has DEFINITELY increased. Libre has been used and QoL has improved a lot. In particular, the number of patients measuring and evaluating their blood glucose more than four times a day has increased to 90% in Italy vs. less than 40% who measure four times a day on SMBG. Libre is increasing the quality of life and changing how patients think about diabetes. I used to say that with SMBG we have a measure of glucose at one point in time. With this approach, you have the trend and the movement of many variables. Patients have much better knowledge about their condition.

Q: Can you talk about the cost in the EU?

Dr. Genovese: The starter kit is something like 150 euros, and it contains the reader plus two sensors. Each sensor is 50 euros, individually. Overall, this comes out to about 4 euros per day. So the cost is higher than SMBG but not so high.

Q: Can a person with an American credit card buy it?

Dr. Genoese: If you go to the website from a particular country, it goes to the country’s website. Another way is if you have a friend in EU.

Mr. Scott: The product is only for sale in those countries and only for use by residents in those countries.

Q: Can you clarify how many times the sensor actually measures glucose?

Mr. Scott: The system measures glucose every minute. Because of limited storage on board, what is put into memory on the body is one data point every 15 minutes. However, the ability to scan and get a reading is available every minute.

Q: Dr. Genovese, have your type 1 patients finding a decrease in the incidence of hypoglycemia?

Dr. Genovese: We are collecting the data. The primary endpoint of the IMPACT study is the time in hypoglycemia. Our expectation is that patients using Libre have fewer hypoglycemic events than those using SMBG because they check their blood glucose far more often. I cannot give you the data in a formal way because we are collecting the data still.

Q: What patients are best for Libre Pro vs. the consumer version?

Dr. Mohan: We have only Libre Pro in India. Certainly, I think it is better in type 2s. In type 1s, I think you need the consumer version because retrospective data itself isn’t as helpful. With a type 1 patient, getting a two-week pattern can be useful but it can also be useless since sometimes there is so much fluctuation that it is quite maddening. For type 2s though, it is fantastic. The majority of our patients have type 2, so it’s fantastic in India.

Q: It’s always really nice to have another tool in the toolbox. Has anyone had any experience with this device in children or women in pregnancy?

Dr. Mohan: Abbott asked me not to talk about this because it’s not approved. But yes, we have used Libre in kids. We did it in a newly diagnosed child recently who travelled to see me from 200 miles away. I was able to identify a lot of hypoglycemia because of Libre and we reduced the night dose. We did a second AGP a few months later. We’ve learned a lot of things. I know it’s not approved but in terms of clinical value … We do it!

Dr. Genovese: Abbott is doing studies, rest assured. On the use of these instruments, I just want to give an example. Libre is indicated in water for no more than one hour at a depth of no more than one meter. I have a good friend who is type 1 in Italy who loves to diving and he uses Libre diving for one hour at depth of 30 meters. It works perfectly.

Q: Is Libre covered by insurance companies where it is available?

Mr. Scott: Libre has limited reimbursement in in Sweden. It is our intention to make device available to a larger population.

Q: What happens at 14 days?

Mr. Scott: The device ceases to function at 14 days.

Symposium: Hemoglobin A1c – The Good, The Bad, and The Ugly

Alternative Markers of Glycemic Control

Irl Hirsch, MD (University of Washington, Seattle, WA)

In front of a far far FAR-beyond capacity audience (we mean this quite literally as organizers had to turn away about ~100 attendees at the door who wanted to get in!), Dr. Irl Hirsch discussed the ways in which alternative measures of glycemic control can complement and account of insufficiencies in A1c. His thoughts spanned from the reasons that A1c deviates from reality (particularly true for patients with other comorbidities such as anemia) to the strengths and limitations of fructosamine, glycated albumin, and 1,5 anhydroglucitol (1,5 AG). In his view, A1c remains our gold standard as a biomarker for glucose control though its limitations have provided more than enough reasons for assessing other markers. He stressed that a multi-modal approach using a combination of biomarkers may ultimately better predict long-term complications – composite outcomes are something we continue to hear more and more about – though the kicker is that Dr. Hirsch believes the BEST future biomarker is none of these ... though it is something all patients have access to: glucose! Indeed, he impressed upon the audience that glucose itself – e.g., home blood glucose monitoring and continuous glucose monitoring – is the ideal metric for making clinical decisions, suggesting that there is little utility in a biomarker when you can use the real thing. This sentiment was perhaps best summarized by Dr. Hirsch’s closing remarks: “At the end of the day, it’s glucose that’s the enemy. Glucose monitoring is going to be the best biomarker yet!” Below, we summarize a number of other major takeaways from Dr. Hirsch’s presentation along with his thoughts on beta-cell function as a novel and underappreciated marker of diabetes progression.

  • Dr. Hirsch shared that ~14-25% of patients in his practice present with glycation gaps (i.e., A1c levels that do not reflect blood glucose), stressing that the phenomenon is far more common than is widely appreciated. There are a number of reasons for the divergence – hemoglobin variants, decreased red blood cell survival, drug interference, etc. – though ultimately Dr. Hirsch stressed that A1c measurements cannot be relied on for clinical decision-making in all patients (and, we would add, certainly should not be compared between individuals!).
  • Dr. Hirsch opened his lecture by introducing the potential of fructosamine (a ketoamine that includes all glycated proteins) as an alternative biomarker to A1c. He noted that it is a cheaper and easier test to perform and, in certain situations, can resolve situations where A1c does not reflect mean glucose. Dr. Hirsch shared a personal anecdote of confronting and identifying a glycation gap, describing a 52-year-old woman who repeatedly presented with an A1c between 7.4-7.8% but whose fingerstick tests consistently ranged between 220-240 mg/dl. [For context, there is a clear discordance here as BG values of 220-240 mg/dl typically correlate with an A1c between 9.0-10%.] Dr. Hirsch’s solution? A fructosamine analysis. Dr. Hirsch stressed that clinicians have a responsibility to understand A1c and, in certain situations, depend more heavily on fructosamine and SMBG data to make treatment decisions.
    • Despite these benefits, Dr. Hirsch was quick to point out that fructosamine also has its share of problems: (i) it provides only a 21-day history of glycemia; (ii) the relationship between glycemia and fructosamine is not a straight line; (iii) fructosamine is influenced by bilirubin, uric acid, and high protein turnover (as seen in dialysis); (iv) lower levels in children and obese patients due to lower protein levels; and (v) it needs to be corrected by serum albumin, which can rarely be performed by clinical labs.
    • Of even more concern, Dr. Hirsch put forth the question that was on many clinicians’ minds: How do you translate a fructosamine reading into an A1c? As Dr. Hirsch said jokingly, “I’m not a clergy; I’m not used to converting people!” He noted that there is very little evidence for making sense of this metric, though drew from the literature to provider clinicians with “the best evidence we have.” See below.

Table: Approximate Comparison of Blood Glucose, A1c, and Fructosamine Levels

Glucose (mg/dl)               

Fructosamine (mmol)

A1c (%)

90

212.5

5.0

120

250

6.0

150

287.5

7.0

180

325

8.0

210

362.5

9.0

240

400

10.0

270

437.5

11.0

300

475

12.0

330

512.5

13.0

360

550

14.0

390

587.5

15.0

  • Dr. Hirsch also discussed the striking potential of glycated albumin (GA) as an alternative to A1c. In his view, GA has many advantages relative to fructosamine considering that there is no impact from anemia (from renal disease, pregnancy, or cirrhosis) and that there is no impact from serum albumin levels. It also better correlates to postprandial hyperglycemia than A1c, though on the other hand, he noted that albumin metabolism can impact GA levels and that the metric tends to read low with obesity (“Why is that? I’m not sure!”).
    • “That’s a surprise!” exclaimed Dr. Hirsch upon polling the audience and finding that almost no one had access to GA in their practice. He noted that the metric is gaining popularity in pockets of the US as it has been reported to be a consistent marker of glycemic variability.
  • Ultimately, Dr. Hirsch stressed that no single biomarker is sufficient for assessing glycemic control nor are any two biomarkers necessarily equivalent. He did share that both frustosamine and GA have shown a strong associated with microvascular complications (similar to the association observed between complications and A1c), though only A1c has shown a correlation with cardiovascular complications. He concluded that composite biomarkers may very well better predict long-term complications than any single biomarker alone, making a few suggestions himself: A1c+ GA for diabetic retinopathy? A1c+1,5 AG for cardiovascular disease?
    • Notably, Dr. Hirsch did suggest that c-peptide levels may provide a particularly useful marker in a composite endpoint. He cited T1D Exchange data, noting that results actually elucidated a sub-population of ~25% patients who did not develop complications even after 40 years of living with diabetes and that this endogenous insulin protected patients from severe hypoglycemia. We certainly believe that there is value in investigating beta cell preservation as a marker diabetes progression though more research is certainly needed on this front.
  • We would be remiss not to mention that Dr. Hirsch also turned to 1,5 anhydroglucitol (1,5 AG) as a potential marker of short-term glycemic control … though was not so hot on its utility. For context, he noted that 1,5 AG is a metabolically inert polyol that competes with glucose for reabsorption in the kidneys. Otherwise stable levels of 1,5-AG are rapidly depleted as blood glucose levels exceed the renal threshold for glucosuria, providing a metric of how long patients are in hyperglycemia. As a result, the metric can be used in people with diabetes to identify glycemic variability or a history of high blood glucose even if current glycemic measurements (A1c or BG) have near normal values. Broadly, we hear VERY little about 1,5 AG tests (yes, they are approved by the FDA) though found it notable to hear Dr. Hirsch suggest that the metric may be useful filling the gap and offering complementary information to A1c and fructosamine tests.
    • The interesting obstacle with 1,5 AG is that the metric can only be used in patients with an A1c<8.0%. Why? Because when A1c’s rise above 8.0%, patients are in consistent glycosuria. In simple terms, there is no change from baseline, which is what informs the reading.
    • On an interesting note, Dr. Hirsch noted that 1,5 AG is actually removed from the kidneys by SGLT-4 transporters, a clinically relevant fact given the growing prominence of SGLT-2 inhibitor therapy. As a result of this mechanism, there is actually interference with the measurement of 1,5 AG in patients using SGLT-2 inhibitors that blocks the transport of 1,5 AG. As such, he encouraged the handful of those in the audience using 1,5 AG analyses to be mindful of this fact (something that we certainly weren’t aware of!).

Questions and Answers

Q: Unlike A1c, GA and frustosamine haven’t really been standardized in the same way. We don’t have a standard methodology. There are huge fluctuations between labs at different times. There’s no standardization yet.

A: I couldn’t agree with you more. I couldn’t agree with you more. The way that I look at this is that I can’t predict what’s going to happen over the next 10-15 years, but these biomarkers are still in an early stage of study like A1c was 10 years ago. I don’t think we’re going to see the same research into these metrics because we already have A1c. I’d like to think we would. But I’m not optimistic.

Debate: Do We Still Need More Outcome Trials In Diabetes?

Yes, Nothing Else Truly Suffices

David Nathan, MD (Harvard University, Boston, MA)

Arguing in favor of outcomes trials, Dr. David Nathan asserted that while observational studies can raise important questions that inform future trials, only controlled experimental studies can sufficiently control for bias and confounding, properly assess risk, and demonstrate causal relationships. This is evidenced by the list of prominent discrepancies between epidemiological and experimental studies in the past. Dr. Nathan did acknowledge the concerns about cost and generalizability with RCTs and noted the recent push for “pragmatic trials” to help bridge the gap to real-world practice. He did not explicitly endorse this approach, but we believe it could be a very promising way to strike the right balance between scientific rigor and clinical relevance. Dr. Robert Califf, President Obama’s nominee for FDA Commissioner, has been an advocate of pragmatic trials in the past, suggesting that this could become a priority for the FDA if he is confirmed. On the more specific question of whether outcomes trials are needed for diabetes drugs, Dr. Nathan argued that while there is strong evidence in favor of A1c as a surrogate for microvascular benefit, the lack of clarity in the macrovascular arena means that outcomes trials are still required. Even if that is the case, we believe there is still plenty of room for revision of the current guidelines for these trials, potentially including more flexible endpoints, longer durations, or use of active comparators. We look forward to watching results emerge for GRADE, a trial that Dr. Nathan is helping lead.

No, There Are Other Good Alternatives

David Matthews (Oxford Centre for Diabetes, Oxford, UK)

On the opposing side, Dr. David Matthews argued that while RCTs are the gold standard for answering explicit, limited questions, “the truth from an RCT can be very thin.” He showed a pie chart illustrating the tiny fraction of the total type 2 diabetes population enrolled in most CVOTs and argued that this is often not sufficiently acknowledged when interpreting results. He also noted that trial results only refer to the mean or median outcome of an intervention, and the wide distribution of individual responses is often forgotten when interpreting the data. As many others have noted, he argued that most current CVOTs may be too short to provide useful information: UKPDS would also have been neutral if it lasted 18 months to three years.  Most importantly, Dr. Matthews believes that conducting RCTs of specific drugs in patients with advanced diabetes is not the smartest approach to tackling the epidemic. He argued that it is very clear from epidemiology that rising obesity prevalence is driving rising diabetes prevalence and that it would be more prudent to focus on large-scale prevention efforts comparable to those in the infectious disease field. Dr. Matthews also made the oft-cited point that these trials are very expensive, estimating their cost at $8-$16 billion by 2020.

  • “Could we do something more useful with $16 billion?” We thought this was an excellent thought-provoking question – while the information gained from CVOTs has clearly been valuable, it is less clear whether it has been worth the cost. Dr. Matthews’ proposed alternative topics for investigation:
    • Scaling up community prevention interventions
    • Primary pathology of the beta cell
    • Effects of calorie labeling and soda taxation
    • Optimizing retinopathy screening and prevention of blindness
    • Biological solutions like stem cells and transplantation

IDF Diabetes Atlas Seventh Edition

The IDF Diabetes Atlas Seventh Edition

An 8:30 am session in a small, second-floor room discussed the new IDF Diabetes Atlas, now posted online in full at www.diabetesatlas.org. The high-level session itself did not contribute major new insight or data beyond our initial coverage two weeks ago (re-pasted below), though the full 144-page Atlas goes deeper into the regional trends, cost and mortality data, and methodology. Today, we gleaned particularly valuable perspective on a few fronts: (i) how conservative the 2040 estimates might be (they assume no change in diabetes prevalence and only reflect expected population growth – in particular, the US 2040 estimate for 35 million people with diabetes is highly, highly conservative in our view); (ii) how much uncertainty comes with all these estimates (data is often old or just doesn’t exist in many cases); and (iii) how much the US disproportionately contributes to global spending on diabetes (48% of all global dollars spent on diabetes, despite having 7% of global cases!).

  • In the Atlas’ follow-up press conference, the report’s main statistician explained to us why the 2040 projections may be very, very conservative: they assume constant 2015 levels of diabetes prevalence multiplied by expected population growth. There is no other modeling involved, including for trends in obesity or people with diabetes living longer. This is concerning for the US estimate of 35 million people with diabetes by 2040, up from 29 million in 2015 – that translates to a highly conservative 240,000 newly diagnosed Americans with diabetes per year over the next 25 years, a dramatic and unrealistic slowdown from 1.4 million new annual diabetes cases in 2014 (per new CDC data posted today). While new annual diabetes cases have fallen for five straight years, the 2014 number of 1.4 million new cases is down only marginally from 1.7 million per year in 2009 – moving to 240,000 new cases per year seems hard to believe any time in the next decade.
    • The same conservatism applies to the projected 642 million people with diabetes globally by 2040. From the current level of 415 million, the 2040 projection implies 9 million new diabetes cases per year annually for the next 25 years. For comparison, from 1995 to 2015, IDF’s estimates translated to 14 million new diabetes cases per year (135 million -> 415 million). Is a 36% reduction in annual diabetes diagnoses likely over the next 25 years?
  • We were also reminded of the challenges and uncertainty in putting the Atlas together, given the available data sources. Half of all countries and territories worldwide have no recent nationwide studies on diabetes prevalence, and their estimates are based on extrapolations from other similar countries. An example of uncertainty comes from the Atlas’ mortality data (5 million deaths attributable to diabetes per year), which relies on studies that are 10+ years old to estimate relative risks. More recent data indicates improved survival with diabetes (Harding et al., Diabetes Care 2014; Green et al., Clin Epidemiology 2015). On the other hand, the 5 million deaths could be an underestimate, as it excludes those <20 years and over years, and those with prediabetes (IFG and IGT).
    • We’re glad that IDF has added confidence intervals around many of the estimates this year, though the mortality estimate does not include one. In today’s discussion of the mortality data, WHO’s Dr. Gojka Roglic said the Atlas estimates of mortality are “more realistic” than routine health stats, but there is a “high level of uncertainty” since “many assumptions” are involved and there is lack of recent large cohort studies with long-term follow-up. We have little doubt in her ultimate conclusion, however: “Diabetes causes a similar or higher number of deaths as do major priority infectious diseases.”
    • In another example, the type 1 diabetes data in the Atlas only includes children from 0-14 years, as studies typically lack data on type 1 in other age groups. The actual prevalence of type 1 diabetes – both in the US and globally – continues to remain a big mystery!
  • There was no mention of the IDF’s call to action during the 2015 G7 Summit, which asked for nations to develop and implement cost-effective policies to improve diabetes outcomes and prevent new cases. A centerpiece of this call is support for a tax on sugar-sweetened beverages as part of IDF’s 12-point Framework for Action on Sugar. This was surprising.
  • Dr. Jonathan Shaw (Baker IDI Heart and Diabetes Institute, Melbourne, Australia) reviewed the latest atlas data on the cost of diabetes, emphasizing the vast inequities in health expenditures throughout the world. Using the assumption that healthcare expenditures for people with diabetes are on average two times higher than those without diabetes, Dr. Shaw shared that 12% of the world’s healthcare budgets are spent on diabetes (age 20-79 years) with over 80% of countries spending 5%-20% of their healthcare budgets on diabetes. He reported the total global expenditure for diabetes to be $673 billion, estimated to increase 19% by 2040 with cases of diabetes expected to increase 35% in this time period; according to Dr. Shaw, this disparity in growth is suggested to be due to the expectation that many of the countries with the largest growth in prevalence have low per capita spending.
    • Most notably, Dr. Shaw stressed the incredible imbalance of how the healthcare dollar is spent worldwide as the top countries with highest diabetes-related health expenditure do not match with the top countries with highest diabetes prevalence. Specifically, he showed that the US comfortably outspends anywhere else in the world while regions such as India and Mexico rank high on prevalence but much lower with regards to expenditure. According to Dr. Shaw, one in four people with diabetes lives in North America and Europe, although the combined region spends every two of three healthcare dollars on diabetes. In addition, the per capita health spend is 260 times greater in the US compared to the Central African Republic, significantly greater than the two regions’ differences in GDP and thus suggesting a drastic difference in prioritization of healthcare expenditures. As he pointed to differences in wealth and prevalence as contributors to this variation, Dr. Shaw concluded by emphasizing the reality that a person with diabetes has more or less money attributed to him depending on where in the world he is. Ironing out these disparities will certainly require a multidisciplinary approach and we hope that industry’s worldwide presence can direct attention to such issues and help local governments recognize the urgency of diabetes. For examples of such work, please see Novo Nordisk’s global efforts through Cities Changing Diabetes as well as the Novartis Access portfolio.

November Coverage of IDF’s Seventh Diabetes Atlas

  • IDF just published the seventh edition of its Diabetes Atlas: an estimated 415 million adults have diabetes (1 in 11 people on the planet), projected to reach 642 million by 2040 (+55% from 2015). The 2015 number is a 9% increase from 382 million in the previous Atlas (2013). The new 2040 projection revises the previous 2035 projection of 592 million, a 50 million projected increase in global patients in five years.
  • Nearly half (47%) of adults with diabetes are undiagnosed worldwide. A striking two-thirds of adults with diabetes in Africa are estimated to be undiagnosed. The three countries with the highest number of people with diabetes are still China (110 million), India (69 million), and the United States (29 million). The highest future growth rate of the three is in India.
  • One in eight global healthcare dollars ($673 billion) is spent on diabetes, a striking 23% increase from $548 billion in 2013. This number is projected to exceed $800 billion in 2040. We’re sure this estimate is low – see below for more.

IDF just published the seventh edition of its Diabetes Atlas on the state of the global diabetes pandemic: an estimated 415 million adults have diabetes in 2015, a 9% increase from 382 million in 2013 (the Sixth Atlas), and an unbelievable trajectory from 30 million people with diabetes in 1985. IDF now estimates 642 million people could have diabetes by 2040, a 55% increase from 2015. The new 2040 projection of 642 million implies a change from the Sixth Atlas’ 2035 projection of 592 million.

In 2015, an estimated one in eight global healthcare dollars ($673 billion) was spent on diabetes, rising a remarkable 23% from $548 billion in 2013. This is projected to exceed $802 billion in 2040 – this implies 19% growth, which seems like a considerable underestimate given the projected 55% growth in diabetes. One person now dies from diabetes every six seconds (5 million deaths per year), up from every seven seconds and 4.9 million annual deaths in the 2013 Atlas. That makes diabetes a bigger killer than HIV, tuberculosis and malaria combined.

The three countries with the highest number of people with diabetes are still China (110 million, +11% from 2013), India (69 million, +6% from 2013), and the US (29 million, +20% from 2013). By 2040, IDF projects 151 million diabetes cases in China (+38% from 2015), 124 million in India (up a startling +78% from 2013), and 35 million in the US (+20% from 2013). We wonder if the China projection might even be an underestimate – JAMA reported last year that 493 million Chinese adults (50%!) have prediabetes. As well, the US projection for 2040 is extremely low in our view; an increase of 6 million patients over 25 years doesn’t make sense in the context of at least a million people a year added to the total in the past decade. If this changes, the global spending estimate would increase substantially too, since the US accounts for a disproportionate share of spending.

India and China are unquestionably the biggest countries of concern in terms of population burden. But in the Middle East and North Africa, 10.7% of adults have diabetes. Over two-thirds of people with diabetes in Africa are estimated by IDF to be undiagnosed, compared to one-half in the US. The proportion of people who die from diabetes before the age of 60 is >60% in almost every African country – the greatest proportion in the world. Of all reported regions, Africa has the lowest annual diabetes-related healthcare expenditures (<$100 million in most countries). Three out of four people with diabetes live in low- and middle-income countries, down slightly from 77% in the Sixth Atlas.

IDF estimates 318 million adults have prediabetes as defined by the strict WHO definition of Impaired Glucose Tolerance. We trend past Atlas estimates below, which tend to vary and probably underreport the prevalence of prediabetes (as measured by fasting glucose and A1c).

  • For the first time, IDF has added confidence intervals to quantify the uncertainty around estimates of diabetes prevalence. These are fairly wide in most cases – for instance, the number of people with diabetes globally could be as low as 340 million or up to 536 million rather than 415 million. Similarly, the 2040 number could be as low as 521 million or as high as 829 million rather than 642 million. This is obviously a tremendously difficult task and we salute IDF for taking it on and admitting the intervals around its estimates. It certainly does not change the overall message.
  • The 2013 Atlas estimate grew 4% from 2011, while the 2015 estimate grew 9% from 2013. That could suggest growth in diabetes has accelerated in the last two years or it may be that estimates are better this year than in 2013.
  • Even so, IDF’s 2040 projections could be very conservative indeed. The projection calculations only use changes in the predicted population and urbanization changes available from the United Nations Population Division – they do not include any predictions for changes in obesity or other risk factors, and if current trends continue, these projections might be conservative.
  • In 30 years, we’ve gone from 30 million people with diabetes to 415 million (see below). The actual number of people with diabetes has surpassed the future projection ~12-15 years early, and:
    • The 1995 and 2000 projections for 2025 were passed in 2010, 15 years early
    • The 2003 estimate for 2025 was passed in 2011, 14 years early
    • The 2006 estimate for 2025 was passed in 2013, 12 years early
    • The last three future projections (2011, 2013, 2015) have given up on 2025, instead projecting out to 2030, 2035, and 2040The growth in future projections has ranged from 0-26%, while actual diabetes growth has ranged from 12-28%.

Figure 1: Actual (1985-2015) and Projected (2025-2040) Number of People with Diabetes Worldwide

Table 1: Growth of Actual (1985-2015) and Projected (2025-2040) Number of People with Diabetes Worldwide

Year of Estimate Future Projection

1985

1995 2025

2000 2025

2003 2025

2006 2025

2009 2030

2011 2030

2013 2035

2015 2040

People with Diabetes (millions)

30

135

151

194

246

285

366

382

415

Growth from Previous Estimate

 --

350%

12%

28%

27%

16%

28%

4%

9%

Projected People with Diabetes (millions)

 --

299

300

333

380

438

552

592

642

Growth from Previous Projection

 --

 --

0%

11%

14%

15%

26%

7%

8%

  • Gestational diabetes affects one in seven births worldwide (16%), and a shocking one in four births in Southeast Asia. These numbers are new in this edition of the Atlas – they were not made available in the Sixth edition – and are higher than we would have guessed. We definitely see more focus on gestational diabetes as a public health effort of late and are hoping to see even more going forward.
  • IDF reports that 542,000 children (0-14 years) have type 1 diabetes worldwide, with 86,000 new cases each year. Both increased 9% from 497,100 and 79,100 in the Sixth Atlas. The Atlas materials don’t report type 1 diabetes in adults, so total worldwide prevalence is hard to gauge. JDRF has previously reported that 85% of people with type 1 diabetes are adults, which could imply 3.6 million adults globally with type 1 diabetes. That would total ~4.1 million people with type 1 worldwide, or 1% of people with diabetes on the planet. The 1% may well be correct – the ADA has long said “5-10% of all those with diabetes” have type 1, and we know that globally, type 2 diabetes is even more widespread. This is a massive effort by IDF – we do not think there is huge focus on type 1, and we think this estimate may be a mistake or just an underestimate.

Diabetes Prevelance by Country

  • India and China are clearly the areas of biggest concern for current and upcoming global diabetes burden. A combined 270 million people with diabetes are expected in China and India by 2040, up from 179 million today. The top 10 countries are expected to remain largely the same by 2040, though Japan falls off the list, Mexico rises from #6 to #5, and Pakistan comes into the top 10. Once again we see the US 2040 estimate as incredibly low and note that only a 21% increase in the US is low compared to the next lowest growth rate of 60%!

Table 2: Top 10 Countries by number of people with diabetes

2015

2040
(Growth from 2015)

1. China: 110 million

1. China: 151 million (+37%)

2. India: 69 million

2. India: 124 million (+80%)

3. USA: 29 million

3. USA: 35 million (+21%)

4. Brazil: 14 million

4. Brazil: 23 million (+64%)

5. Russian Federation: 12 million

5. Mexico: 21 million (+75%)

6. Mexico: 12 million

6. Indonesia: 16 million (+%60)

7. Indonesia: 10 million

7. Egypt: 15 million (+60%)

8. Egypt: 8 million

8. Pakistan: 14 million*

9. Japan: 7 million

9. Bangladesh: 14 million (+100%)

10. Bangladesh: 7 million

10. Russian Federation: 12 million (+2%)

*2015 number not reported in embargoed materials, but we will update once they full Atlas is posted online.

  • China has the highest number of adults with diabetes (110 million), the second highest diabetes health expenditure ($51 billion), and the fourth highest number of children with type 1 diabetes (30,500). By 2040, the number of adults is predicted to increase to 150.7 million people, and the health expenditure to USD 72 billion.
  • We are also concerned for countries in South and Central America, where diabetes will increase an estimated 65% by 2040. In Mexico, the diabetes epidemic is mostly affecting the working-age population, but the government there is actively involved in helping to reduce type 2 diabetes risk factors, which is excellent news. It will be interesting to see what longer-term results from Mexico’s sugar tax. 

Prevalence of Prediabetes

  • IDF estimates 318 million adults (20-79) have prediabetes as defined by the strict WHO definition of Impaired Glucose Tolerance: plasma glucose 7.8-11.1 mmol/l [140-200 mg/dl] two hours after a 75 g oral glucose load. This is a higher threshold than broader definitions of ‘prediabetes’ (e.g., A1c, fasting plasma glucose). We further analyze IGT below.
  • IDF has estimated the number of people with Impaired Glucose Tolerance (IGT) and made future IGT projections since the second edition of the Diabetes Atlas (see below). Interestingly, while the number of people with diabetes worldwide has grown rapidly each year, the number of people with IGT decreased in several Atlas editions. This may be due to changes in screening for IGT across the world, changes in the rate of progression from prediabetes to type 2 diabetes, or changes in IDF estimation methods. IGT trends are difficult to interpret, as an increase in the number of people with IGT could mean that a smaller proportion of people are progressing to type 2 diabetes, or that a greater number of people are at risk for developing type 2 diabetes.
    • A reported 86 million Americans (CDC) and 493 million Chinese adults (JAMA 2013) have prediabetes, which makes IDF’s global number (318 million) seem incredibly low. This boils down to the definition of prediabetes! The CDC’s prediabetes estimates are based on A1c and/or fasting glucose (FG), while the IDF’s IGT estimates are calculated using the more stringent oral glucose tolerance test (GTT). Therefore, while 86 million people in the United States have prediabetes (as reported by the CDC), only 52 million people in all of North America and the Caribbean have IGT (as reported by IDF). This discrepancy is further illustrated by the Xu et al. 2013 JAMA paper, which assigned a prediabetes diagnosis to Chinese adults who fell into at least one of the following three categories: FG of 100-125 mg/dl, 2-hour GTT of 140-199 mg/dl, and an A1c of 5.7%-6.5%. Based on these results, an estimated 50% of Chinese adults had prediabetes = 493 million people! Notably, 35% of the population had prediabetes based on their A1c, 27% had prediabetes based on their FG, and only 8% had prediabetes based on their GTT results. This underscores why the IDF estimate is so low – GTT is a very strict definition.

Figure 2: Actual (2003-2015) and Projected (2025-2040) Number of People with Impaired Glucose Tolerance Worldwide

Table 3: Growth of Actual (2003-2015) and Projected (2025-2040) Number of People with Impaired Glucose Tolerance Worldwide

Year of Estimate

Future Projection

2003

2025

2007

2025

2010

2030

2011

2030

2013

2035

2015

2040

People with IGT (millions)

314

308

344

280

316

318

Growth from Previous Estimate

--

-2.00%

12%

-23%

13%

0.60%

Projected People with IGT (millions)

472

418

472

398

471

481

Growth from Previous Projection

--

-11%

11%

-16%

18%

2%

Basic and Clinical Science: New Views on Incretins

GLP-1 and Type 1 Diabetes: Sufficient Efficacy and Safety?

Urd Kielgast, MD, PhD (Hvidovre University Hospital, Copenhagen, Denmark)

Dr. Urd Kielgast offered a middling take on GLP-1 agonists in type 1 diabetes: positive on safety and more pessimistic on efficacy. On safety, she concluded that there is no increased hypoglycemia risk, impairment of counterregulatory mechanisms, or other serious or unexpected side effects associated with the class in type 1 diabetes. However, she did note that gastrointestinal side effects are more common and that the long-term implications of the increase in heart rate and reduced systolic blood pressure are unknown at this point (we assume the blood pressure effect would be positive if anything but clearly need long-term trials to be sure). The question of efficacy is more complex. Dr. Kielgast pointed to promising early-stage data showing substantial reductions in postprandial glucose with GLP-1 agonists regardless of beta cell function. The drugs also led to A1c reductions, lowered insulin doses, and weight loss in uncontrolled proof-of-concept studies. As we have unfortunately learned over the past few months, the results from placebo-controlled trials – Novo Nordisk’s phase 3 ADJUNCT ONE and ADJUNCT TWO studies for Victoza (liraglutide) being the largest – were less encouraging. Novo Nordisk subsequently decided not to pursue a type 1 diabetes indication for liraglutide – a disappointing but understandable decision in our view although we do question what sub-group analysis in a very large trials . We imagine other GLP-1 agonist manufacturers will now be more reluctant to pursue type 1 diabetes indications as a result. However, Dr. Kielgast noted that she would like to see studies in new-onset patients and studies of short-acting GLP-1 agonists, which have a greater effect on gastric emptying. We also think benefits like weight loss and potentially reduced glycemic variability could be meaningful for at least some patients, but we are fairly pessimistic that there will be a regulatory path forward in the near future.

  • Dr. Kielgast shared results from an unpublished study (n=12) of liraglutide vs. placebo to support the safety of GLP-1 agonists in type 1 diabetes. The 12-week trial found no difference in gastric emptying rate or glucagon response during hypoglycemia between the liraglutide-treated and placebo-treated groups. There was also no difference in cortisol, growth hormone, adrenaline, or noradrenaline levels.
  • Dr. Kielgast presented results from two placebo-controlled trials suggesting modest efficacy with liraglutide in type 1 diabetes. A randomized, double-blind, placebo-controlled trial in normal-weight patients with type 1 diabetes (n=40) found no significant difference in A1c reduction, glycemic variability, 24-hour glucose profiles, hypoglycemia event rate, or diastolic blood pressure with liraglutide vs. placebo after 12 weeks. However, the liraglutide-treated group did experience a significant 3.1 kg mean weight loss (compared to a 1.1 kg weight gain in the insulin monotherapy group; p<0.0001), a significant reduction in bolus insulin dose (p=0.02), and a reduction in systolic blood pressure (p=0.04). Similarly, the Lira-1 study in patients with type 1 diabetes and obesity observed no improvement in 24-hour glucose profiles or glycemic variability among patients treated with liraglutide. While there was a significant difference in A1c reduction after three months, the effect was lost at six months due to the A1c plateauing in the liraglutide group and continuing to decrease in the insulin-only group. There was a significant difference in body weight reduction (p=0.015) and bolus insulin dose (p=0.02), however.

Debate: Bariatric Surgery vs. Medications in the Treatment of Type 2 Diabetes

It Is Time To Move Bariatric Surgery Into The Guidelines For Care

Philip Schauer, MD (Cleveland Clinic, Cleveland, OH)

Dr. Philip Schauer opened this lively debate by providing an overview of the breadth of scientific evidence supporting surgery as a treatment for type 2 diabetes. He drew from a variety of studies, focusing on 11 RCTs that have compared bariatric surgery to medical treatment since 2011. Ten of those studies have shown superiority of surgery over medical management at achieving remission of diabetes and glycemic improvement. He also cited additional data from the Swedish Obesity Study showing reductions in all-cause mortality, CV morbidity/mortality, and microvascular complications associated with surgery vs. medical management. Despite this degree of evidence, Dr. Schauer noted that many prominent diabetes organizations still exclude metabolic surgery from their guidelines (e.g., ADA) and he pushed for reconsideration of these guidelines …  especially in adequately controlled individuals with BMI <35 kg/m2. Indeed, we have heard growing calls for earlier intervention with surgery, as speakers including Drs. Lena Carlsson (University of Gothenburg, Sweden), Robert Eckel (University of Colorado, Aurora, CO), and Harold Lebovitz (State University of New York, Brooklyn, NY) have argued for intervention as early as in prediabetes. While surgery may not be the scalable solution we are looking for in prediabetes or patients with BMI <35 kg/m2, it is certainly encouraging to hear the support for an additional treatment option for a patient population that has very little guidance on treatment and prevention of type 2 diabetes.

Medical Therapy Is Still The Mainstay of Treatment For The Majority of Patients with Type 2 Diabetes

Ildiko Lingvay, MD (University of Texas Southwestern Medical Center, Dallas, TX)

Dr. Ildiko Lingvay positioned bariatric surgery as “a very effective option for few” vs. medications as “the only option for many.” She did not discount the efficacy of surgical interventions (“The benefits of bariatric surgery are not to be argued”) but instead suggested that the required commitment for sustained lifestyle change is the biggest limitation for patients who are eligible for surgery. She did also acknowledge that the immediate surgical and long-term metabolic complications are important considerations that limit the pool of eligible candidates though – to our surprise – called cost a minuscule deterrent in the big scheme of things. Why? Because even in regions where bariatric surgery is well-covered by insurance (e.g., Canada), she noted that the prevalence of surgery is in <0.5% of the eligible population. Said Dr. Lingvay: “The most common response I get when I propose bariatric surgery is that, ‘I don’t want to part with my food.’” Ultimately, she noted that bariatric surgery is worth it if clinicians can identify patients who: (i) are determined and commitment to long-term lifestyle change; (ii) adherent to long-term follow up; (iii) willing to have surgery; (iv) newly diagnosed; and (v) lack preexisting psychological issues. Ultimately, we felt both speakers were closer together than they were apart and continue to feel that this discussion is moving toward a question of WHERE bariatric surgery fits within the diabetes care model than IF it fits at all. We were also especially impressed by Dr. Lingvay’s presentation – watch out for this rising star!

Response and Rebuttal

Dr. Philip Schauer: This was a very interesting talk. I wish I could have heard you discuss some of the limitations of medical therapy. I could have gone on for half an hour talking about blindness, stroke, ten-year reduction in mortality with poorly controlled diabetes. Certainly, there are significant and important long-term complications of bariatric surgery and selection is very important, but I do think we have to balance those risks with the fact that patients who have poorly controlled diabetes know exactly what kind of lifestyle they are heading toward. I think it is about getting to the best patient. I don’t think the majority of patients need surgery, but I do think that many need it. I disagree that the difference is in patients’ willingness. In my study, I showed that patients were very satisfied with surgery. I think the difference is that there are very few guidelines for bariatric surgery and that in the US, very few insurance plans cover bariatric surgery. I think we’re closer together than we are apart.

Dr. Ildiko Lingvay: I fully agree on many of the things you have said: (i) the complications of diabetes are bad; (ii) insurance companies should cover bariatric surgery; and (iii) surgery should be part of the options for patients with diabetes. This is where we stop agreeing. I think that the fact that patients are not willing to get bariatric surgery is important. The data you are citing are in patients who are willing to have the surgery. That’s a self-selected population. In my practice, I am aggressive in offering surgery and I offer it to a third or half of my patient. I probably have less than 5% who set up appointment with a bariatric surgeon and way less than 1% actually go through with surgery. So I do think that the patients are part of the problem and that by just pushing for more surgery, we are going to do more surgery but we’re not going to be selective enough.

Symposium: Viruses and Type 1 Diabetes

Emerging Findings Regarding Viruses in Type 1 Diabetes – Lessons from nPOD

Mark Atkinson, PhD (University of Florida, Gainesville, FL)

Dr. Mark Atkinson shared some data from nPOD (the JDRF Network for the Pancreatic Organ dDonors with Diabetes) on the association of viruses, in particular enteroviruses, with type 1 diabetes and discussed the network’s future directions. S He specifically, he discussed the work of the nPOD-Virus group, which has shown through various a variety of methods that a  viral infection of the pancreas and/or s in pancreatic beta cells are appears far more frequently in peopleersons donors with type 1 diabetes. In addition, Dr. Atkinson highlighted findings demonstratingFor decades, studies have suggested a potential association between viral infections and the development of type 1 diabetes but those efforts, near exclusively, involved investigation of blood samples in living subjects. While such efforts are important, nPOD represents the first large-scale study of viruses at the site of the disorder’s origin, the pancreas.  that viral infection is detected in both recent onset and long-standing cases of type 1 diabetes. The group is also working on applying more novel techniques such as electron microscopy, imaging mass-spectrometry, and RNA sequencing to further improve techniques currently used. Overall, Dr. Atkinson noted that data up to this point from the nPOD-Virus group, while  have ssupporteding the presence of viruses, but the evidence remains mostly indirect as hande pointed to the need for continuedmore work to identify a specific virus or group of viruses. L Specifically looking forward, he shared that the nPOD group aims to coordinate studies toward this goal though virus identification involving studies by involving laser capture dissection of islets, proteomics, virus amplification in vitro, and more. electron microscopy, imaging mass-spectrometry, and RNA sequencing; all to further improve on techniques currently used. We are impressed with the magnitude of research nPOD has been able to drive forward and applaud the network’s constant innovation to do bigger and better things with its samples – to learn more about nPOD and how to help contribute, please see our diaTribe article.

 

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