Barca! Barca! Barca! Between the soccer team F.C. Barcelona’s win over Rayo, the jubilant La Mercè Festival’s fireworks, and the excitement of EASD Day #3 we have been swept up by the city. Walking through the exhibit hall on Tuesday, we saw a few major device highlights. J&J was showing off the new OneTouch Verio meter, which gives patients color coded indicators and automatic “progress” messages. We stumbled across the YOFi Meter: a single handheld contains a 20-strip cassette (Infopia strips), a lancing cassette, a color touchscreen, a cellular chip that automatically sends data to the cloud (in partnership with Qualcomm), and a built-in pedometer. Launch is slated for “next September;” although the representative would not say where. We cannot wait to try it. The mHealth focus was also present in Medtronic’s booth, where we saw the new Connected Care remote monitoring device up close for the first time – we’re glad to see multiple companies on board with seamlessly sending device data to the cloud.
On the drug side, Novo Nordisk’s neon-green exhibit was dedicated entirely to Tresiba and was swarming with visitors when we visited. That was quite an interesting approach, being therapy-specific by medicine – we have never seen this before. Janssen’s booth was exciting to see, given CHMP’s recent positive opinion for J&J’s SGLT-2 inhibitor Invokana, although of course they do not have a full approval yet. Sanofi sported a much fuller booth than usual, a reflection of exciting new additions to its portfolio. It prominently featured the new GLP-1 agonist Lyxumia, and highlighted the ways it can complement treatment with Sanofi’s bestselling basal insulin Lantus. We also got to see the MyStarExtra meter, and the JuniorStar pen designed for younger patients. We noticed an increased focus on Januvia’s CV profile at the MSD (Merck) booth than we have seen in the past, with several prominent displays dedicated to the topic and MSD’s CVOT of the agent, TECOS.
We saw exciting new data on the use of Novo Nordisk’s Victoza (liraglutide) in type 1 diabetes patients, namely from a hypoglycemia clamp study suggesting that liraglutide does not blunt the counter-regulatory glucagon response to hypoglycemia. Excitingly, liraglutide significantly decreased enrollees’ daily insulin dose by approximately 25%. Another poster suggested that sitagliptin also did not compromise counter-regulatory responses. During a morning session on GLP-1 agonists, the final three-year results of the DURATION-3 trial (originally presented at ADA) were reiterated, demonstrating that Bydureon’s A1c and weight-lowering superiority over insulin glargine were maintained out to year three. An additional sub-analysis was provided examining patients who were able to achieve and maintain A1c ≤7.0% throughout all three years vs. patients whose glycemic control deteriorated. Results of Lilly’s AWARD-3 trial for dulaglutide in people with newly diagnosed diabetes were also reiterated from ADA. In addition, we saw a re-presentation of data from the HARMONY 3 study comparing GSK’s Eperzan (albiglutide) to glimepiride and sitagliptin: albiglutide demonstrated a significantly greater effect on A1c than the two comparator therapies (a 0.9% decrease), and led to a surprisingly low incidence of nausea and vomiting for a GLP-1 agonist — a potentially potent differentiating factor.
We heard two award lectures on basic science topics today. The Minkowski lecture detailed how epigenetics, endoplasmic reticulum stress, and other factors can cause beta cell dysfunction. In the afternoon, Dr. Patrik Rorsman (University of Oxford, Oxford, UK) detailed how pancreatic beta, alpha, and delta cells electrophysiologically respond to glucose. Both lectures gave us a deeper understanding of type 2 diabetes pathophysiology and suggested potential new approaches for treatment.
- Executive Highlights
- Detailed Discussion and Commentary
- Opening Ceremony: Presidential Address
- Oral Presentations: Individualizing the Choice Among GLP-1 Receptor Agonists
- Positive Effects of Liraglutide as Adjunct to Insulin in Type 1 Diabetes: Glycemic Control and Safety in a Randomized, Double Blind, Placebo Controlled Crossover Trial
- Glycemic Control and Hypoglycemia in Metformin-Treated T2DM Patients with Exenatide BID vs. Insulin Lispro TID Added to Titrated Insulin Glargine QD: The 4B Trial
- Sustaining HbA1c Control Over Three Years During Treatment With Exenatide Once Weekly Compared With Insulin Glargine
- Efficacy and Safety of Dulaglutide vs Metformin in Type 2 Diabetes (AWARD-3)
- HARMONY 3: 104 Week Efficacy of Albiglutide Compared to Sitagliptin and Glimepiride in Patients with Type 2 Diabetes Mellitus on Metformin
- Oral Presentation: FGF-21 Cures It All?
- Glucagon Like Peptide 1 (GLP-1) in Combination With Fibroblast Growth Factor 21 (FGF-21) Enhances Browning of White Adipose Tissue
- Brown Adipose Tissue, A Sink of Glucose Disposal? Effects of FGF-21 on Glucose Metabolism in Brown Adipose Cells
- Oral Presentations: In-Patient Diabetes: Rights and Wrongs
- The Safety and Efficacy of A Subcutaneous Continuous Glucose Monitoring System Compared to Point of Care Measurement in Critically ILL Patients: A Randomised Controlled Trial
- Continuous Glucose Monitoring at The Intensive Care Unit: Nursing Workload Reduction and Cost-Benefit Analysis
- Award Lecture: 7th Albert Renold Lecture
- Award Lecture: 48th Minkowski Lecture
- Treatment with Liraglutide as Adjunct to Insulin in Type 1 Diabets: Effects on Counterregulatory Response to Hypoglycemia: A Randomized, Double Blind, Crossover Trial (Poster #1007)
- Effects of Six Weeks Treatment with Sitagliptin On Counterregulatory and Incretin Hormones during Acute Hypoglycemia in Patients with Type 1 Diabetes (Poster #599)
- Exhibit Hall
Detailed Discussion and Commentary
Opening Ceremony: Presidential Address
Welcome to Barcelona
Andrew Boulton, MD (President, European Association for the Study of Diabetes, Düsseldorf, Germany)
In a completely packed session (a projector was set up outside the auditorium!), the great Dr. Andrew Boulton gave his presidential address, focusing on the EASD’s role in research, education, and lobbying. Dr. Boulton noted the success of this year’s annual meeting, highlighting that there were 2,300 abstracts submitted this year, the second highest number ever received (fewer than 50% were accepted). Dr. Boulton also announced four new study groups within the EASD, including diabetes and cancer and non-alcoholic fatty liver disease. Turning to EASD’s mission, Dr. Bolton added the unofficial role of championing better research in Europe, specifically pointing to the controversies surrounding incretins and cancer – the former has certainly been one of the biggest topics in the drug world in the last few months. It was stirring to hear Dr. Boulton commend the ADA, EASD, and IDF’s quick response to the incretins and pancreatitis issue. He further cited the EMA CHMP’s conclusion and the results of the SAVOR and EXAMINE trials, which demonstrated little evidence for the link between incretins and pancreatic cancer (for more information, please see http://www.closeconcerns.com/knowledgebase/r/72400858 and http://close.cx/RazSAVORInterview). On a very exciting note, Dr. Boulton then highlighted the September Diabetes Technology Society’s (DTS) meeting on surveillance of blood glucose meters following FDA clearance that took place in Washington DC – he characterized it as another way that agencies such as the EASD should play a role. In line with his comments during the final panel, he also expressed support for a post-market surveillance program in Europe, too (for more detail see our report at http://close.cx/BGMSurveillence). Finally, programs such as the Alliance for Biomedical Research in Europe (BioMed Alliance) and the European Foundation for the Study of Diabetes (EFSD) allow EASD to support research through collaboration with other organizations and industries. He mentioned the one million euros for the new EFSD/Sanofi collaboration for clinical diabetes research, as well as the great success of researchers who have participated in a similar EFSD/Eli Lilly collaboration.
Oral Presentations: Individualizing the Choice Among GLP-1 Receptor Agonists
Simon Heller, MD (University of Sheffield, Sheffield, UK)
After noting that GLP-1 agonists have promising potential for use in type 1 diabetes because of their ability to suppress glucagon release, inhibit gastric emptying, and lower weight (relative to insulin), Dr. Simon Heller discussed secondary results from a randomized, single-center, placebo-controlled crossover trial investigating the effects of liraglutide (Novo Nordisk’s Victoza) on the counterregulatory response to hypoglycemia, when used as an adjunct to insulin. The study enrolled 45 participants with type 1 diabetes, and allocated them to either a 0.6, 1.2, or 1.8 mg daily dose of liraglutide, and placebo for four weeks of treatment (with a two-to-three week washout period in between). At baseline, participants had an average age of 35 years, weight of 74 kg (163 lbs), BMI of 24 kg/m2, and duration of diabetes of 17 years. Given the short duration of the trial, there were no significant differences in A1c between liraglutide and placebo. Other findings, however, were promising: the 1.2 and 1.8 mg doses of liraglutide significantly reduced daily insulin dose by 27% and 24%, respectively, versus placebo. The two top doses also reduced patients’ glucagon secretion. Even though treatment only lasted four weeks, liraglutide led to weight loss of up to 3.3 kg (7.2 lbs) (whether the investigators considered this a safety issue arose – they did not). There was no significant difference in hypoglycemia seen between the groups – this was a bit surprising. GI side effects were more common with liraglutide; none of these adverse events were severe. Dr. Heller mentioned that some patients in the study tested positive for C-peptide; during Q&A, a number of attendees suggested analyzing the data to see if these patients responded more positively to liraglutide. We are glad to see that Novo Nordisk is investigating this use of GLP-1 agonists — as a reminder, the phase 3a ADJUNCT ONE trial of liraglutide in type 1 diabetes is expected to begin this coming December.
Questions and Answers
Q: Did you measure the C-peptide levels at follow-up?
A: We did measure C-peptide in all patients at the start, and we found that a few tested positive.
Q: Do you have more data on the number of hypoglycemia episodes across the three liraglutide doses?
A: We measured the hypoglycemia in terms of percentages. About 18% had symptomatic hypoglycemia, but we didn’t see any major difference in terms of daytime episodes or nighttime episodes.
Q: Did baseline C-peptide levels discriminate between responders and non-responders?
A: It’s a good question. I think our numbers are too small, but that should be looked into.
Q: Might you elaborate on the last item in your slide that said that larger trials are needed to establish the clinical benefit? How large should the numbers be, and what would you define as enough of a clinical benefit?
A: That’s a challenging question for me to answer in this short period of time. I’d say it would need to be far longer than one month. In terms of numbers, I’d say we would need to treat a few hundred patients, and it would be interesting to see if people with C-peptide positivity would see a greater impact.
Bruce Wolffenbuttel, MD, PhD (University of Groningen, Groningen, Netherlands)
Dr. Bruce Wolffenbuttel presented the results of a 30-week study comparing the efficacy and safety of exenatide BID versus insulin lispro TID as an add-on to insulin glargine therapy and metformin (with or without sulfonylurea). In the trial, participants were randomized to exenatide BID (per protocol n=247) or insulin lispro TID (n=263); respectively, 84% and 86% of participants completed the trial. At baseline, participants were on average 60 years old, had diabetes duration of 13 years, A1c of 8.2-8.3%, fasting glucose of 7.0-7.1 mmol/l (126-128 mg/dl), weight of 89-91 kg (196-200 lbs), and BMI of 32-33 kg/m2. After 30 weeks of treatment, there was no significant difference in A1c change (both treatments lowered A1c by an average of 1.1%); however, when looking at weight change, there was a significant difference (-2.5 kg [5.5 lbs] with exenatide, and +2.1 kg [4.6 lbs] with insulin lispro; p<0.0001). Though similar percentages of participants (~49-50%) achieved an A1c of ≤7% in both arms, a significantly higher percentage of participants on exenatide (44.6%) achieved the target with ≤1 kg (2.2 lbs) increase in body weight than those on insulin lispro (22.9%). In addition, patients on exenatide achieved a significant reduction in systolic blood pressure versus those on insulin lispro, as well as improvements in Diabetes Treatment Satisfaction Score (DTSQ) and Impact of Weight on Quality of Life (IWQoL). The incidence in minor hypoglycemia was significantly lower with exenatide versus insulin lispro (29.5% versus 40.7%; p=0.004), mainly attributed to a lower incidence of daytime hypoglycemia (15.2% versus 33.7%; p<0.001). A higher percentage of patients in the exenatide arm discontinued treatment (5.4% versus 2.6%), mainly due to nausea and vomiting at the beginning of the trial. Based on the results of the study, Dr. Wolffenbuttel concluded that the addition of a short-acting GLP-1 agonist instead of mealtime insulin is a novel and effective treatment strategy for patients for whom basal insulin does not provide optimal control.
Questions and Answers
Q: In the group of exenatide patients, did they continue with metformin, or did they stop metformin?
A: Both treatment arms continued on metformin, two grams daily. Sulfonylureas were stopped at the beginning of randomization.
Q: I think the GI symptoms that you mentioned probably were pertaining to metformin rather than exenatide. Do you think that was true, or do you think they were caused by exenatide?
A: I think that’s a good question. Most of all those patients were already on metformin. I think most of the side effects we saw were to the new treatment, exenatide; however, I don’t know how the combination may affect underlying small intolerances to metformin. We don’t have an answer to that.
Q: Do you have any data about glycemic variability?
A: We have some research on postprandial glucose. When you look at the blood glucose curve of a day, you see that during the day, postprandial glucose is similar. Only after lunch is it lower with lispro than exenatide, which has to do with the fact that those on lispro had a lunchtime injection.
Jaret Malloy, PhD (Bristol Myers Squibb, Princeton, NJ)
Dr. Jaret Malloy presented the final three-year results and an additional sub-analysis of the DURATION-3 trial, which compared once-weekly GLP-1 agonist Bydureon (exenatide once-weekly [EQW]) to insulin glargine (IG) in people with type 2 diabetes. Patients in the study were on background metformin or metformin + SFU (SFU was discontinued at the beginning of the study), had a mean baseline A1c of 8.3%, ~8 years diabetes duration, and a baseline BMI of 32 kg/m2. After three years, patients on EQW had better glycemic control (A1c reduction of 1.0% vs. 0.8% on IG) and weight loss (-2.5 kg [-5.5 lbs] vs. +2.0 kg [4.4lbs] on IG), whereas IG conferred better reductions in fasting plasma glucose (-2.7 mmol/L [-49 mg/dl] vs. -1.7 mmol/L [31 mg/dl] on EQW). For our full coverage of DURATION-3 three-year results at ADA 2013, please see our ADA 2013 Incretins report at http://www.closeconcerns.com/knowledgebase/r/6001b62d). The sub-analysis that Dr. Malloy presented today examined characteristics of people who were able to maintain glycemic control through all three years (A1c ≤7%) vs. those who did not maintain control (A1c >7% at two consecutive visits or A1c ≥9% at any one visit). A greater proportion of EQW patients achieved and maintained A1c control compared to IG patients (50% vs. 43% of the ITT population and 43% and 33% of the three-year completer population). This was despite a steady increase in mean insulin dose in the IG group throughout the three years. At baseline, for both the EQW and IG treatment groups, those who achieved and maintained glycemic control had a lower baseline A1c, lower FPG, and less SFU use than the group that lost glycemic control. Regardless of “goal achievement” status, EQW patients reported lower exposure-adjusted minor hypoglycemia events compared to IG patients.
Questions and Answers
Q: My experience with once-weekly exenatide is that the weight and A1c go down very nicely after one month. But after one year, despite the fact that weight goes up by two-to-three kg, the A1c is maintained and does not get worse. I think this suggests an improvement in beta cell function. What is your view?
A: We saw weight loss over the first 26 weeks to one year, which was maintained over the three year period such that you have a 2.5 kg decrease on exenatide after three years compared to a 2.0 kg increase with glargine, resulting in a 4.5 kg difference. Other long-term studies have shown maintenance of that weight loss out to five years, for example in the DURATION 1 trial. In relation to your question about beta cell function, at this point we don’t have any hard data in change in beta cell function with long-term treatment.
Q: Do you have any information about postprandial glucose profile after three years? Or is it all about FPG? What is the nature of the excellent glycemic control?
A: We don’t have postprandial measures out to three years. But what you see with insulin glargine is the maintenance of the FPG reduction and still you get gradual increases in A1c. So you could then speculate that it’s the deterioration in postprandial glucose control in that group, and at that those patients might be ones you would target with postprandial treatment. It’s similar to data you saw in the previous talk – looking at a short-acting GLP-1 agonist or mealtime insulin for those patients.
Efficacy and Safety of Dulaglutide vs Metformin in Type 2 Diabetes (AWARD-3)
Santiago Tofe Povedano, MD (Clinica Juaneda, Palma de Mallora, Spain)
Dr. Santiago Tofe Provedano presented results of Lilly’s phase 3 AWARD-3 trial for its once-weekly GLP-1 agonist dulaglutide. The primary objective was to show non-inferiority compared to metformin in people with newly diagnosed type 2 diabetes (3 months – 5 years), with superiority as a secondary objective. The same results were also presented at ADA 2013 – please see page 7 of our ADA 2013 Incretins report at http://www.closeconcerns.com/knowledgebase/r/6001b62d for our full coverage. In short, both 1.5 mg and 0.75 mg doses of dulaglutide conferred superior A1c reductions after 26 weeks, and this advantage was maintained out to 52 weeks. The high dose conferred similar weight loss as metformin, while weight loss on the low dose was lower. GI side effects were comparable between the dulaglutide and metformin arms.
Questions and Answers
Q: I’m surprised to see is that the glycemic control is almost comparable in both dulaglutide doses, but in the 1.5 mg dose, there are more GI side effects. Can you comment on that?
A: It did not affect glycemic control because most of the GI symptoms were mild to moderate and transient – by week two or four, most patients were relieved of the symptoms.
Q: There is an analysis of metformin where they claim that the maximal effective dose is achieved with 3,000 mg/day, not 2,000. In your study maybe you did not use the highest level of metformin. So when you state that you have this comparison, I don’t know how valid that is.
A: This was the original design of the study. I don’t know if increasing to 3,000 mg/day could have achieved a further reduction in A1c level. I think there are studies that the optimal dose is 2,000 mg/day. So I don’t know. It could have been tested, but the original design of this study was 2,000 mg. I’m afraid I cannot answer this. There is one more thing. You might consider that a 0.5% reduction in A1c might be low for this metformin arm. You have to keep in mind that the patients had a pretty low baseline A1c of 7.6%. And the lower the A1c level is, the lower effect you can expect from any intervention. Secondly, 75% of patients were already treated with an oral antidiabetic agent, and as you can figure out, most were already treated with metformin. The washout period was fairly short (two weeks), so most of the patients randomized had been previously treated with metformin and likely had some effect of having already been treated by metformin.
Murray Stewart, MD (GlaxoSmithKline, King of Prussia, PA)
HARMONY 3, part of GSK’s eight-part phase 3 program for albiglutide (the once weekly GLP-1 agonist Eperzan), assessed the safety and efficacy of 30 mg albiglutide versus 2 mg glimepiride and 100 mg sitagliptin (Merck’s Januvia). Dr. Murray Stewart presented the final study results, which were first presented as a poster at this year’s ADA. At baseline, participants had an average age of 55 years, BMI of 32.6 kg/m2, weight of 91 kg (200 lbs), A1c of 8.1%, and diabetes duration of six years. After 104 weeks, albiglutide demonstrated a 0.91% A1c reduction, a statistically significantly greater reduction than with sitagliptin (0.35%) or glimepiride (0.27%) treatment. The albiglutide group lost 1.2 kg (2.7 lbs) on average, similar to the weight loss seen with placebo (1.0 kg [2.2 lbs]) and sitagliptin (0.9 kg [2.0 lbs]), and significantly better than the weight gain with glimepiride. Notably, the incidence of nausea and vomiting seen in HARMONY 3 with albiglutide (10% and 6%, respectively) was lower than the rate seen with other GLP-1 agonists, especially during the early weeks of therapy — if this finding holds true in head-to-head trials or in clinical practice, it could be a most valuable differentiating factor for albiglutide. Albiglutide had a 17% incidence of injection site reactions (most of which were mild to moderate), compared to 8% with glimepiride, and 6% with sitagliptin. There were also two adjudicated cases of probable pancreatitis in the albiglutide group, one of which was “at least possibly related to the study drug” — we note that this number represents a very small percentage of the treatment group. As background, albiglutide is under regulatory review in the EU and US; this summer, the FDA decided to postpone the drug’s PDUFA date, likely to allow for more time to review recent HARMONY trial data.
Questions and Answers
Q: I wonder about the very small weight loss you saw with [albiglutide]. Did you ask if they were having any trouble eating, or if they were eating as much as before?
A: Other than general diet instructions in the beginning, we did not impose any restrictions or ask any questions about what they ate.
Q: You mentioned that injection site issues happened, which were mostly mild and moderate. How many were severe, and what problems did you see?
A: There was only one case where there was some swelling; there were not systemic reactions. Less than 1% withdrew due to reactions.
Q: In this trial, albiglutide’s efficacy was better than that of glimepiride. With other GLP-1 agonists we have had mixed results — there was a liraglutide trial that showed that the drug was as effective as glimepiride. Why do you think you saw the efficacy difference you saw?
A: I think it may be partly related to the titration regimens. We could have maybe pushed the titration for both glimepiride and albiglutide a bit further.
Oral Presentation: FGF-21 Cures It All?
Tamer Coskun, MD, PhD (Eli Lilly, Indianapolis, IN)
Dr. Tamer Coskun presented results from a study investigating the molecular mechanisms underlying previously reported findings of synergistic body weight loss with GLP-1/FGF-21 combination therapy in mice. We haven’t seen too much data on FGFs so we wanted to include this despite the basic science focus (which is usually not our area of focus). Whereas GLP-1 is thought to reduce body weight through promoting satiety and suppressing appetite, FGF-21 lowers weight via increasing energy expenditure. When co-administered, GLP-1 and FGF-21 caused significantly greater body weight reduction (27% decrease beyond control) in diet-induced obese mice compared to treatment with either GLP-1 or FGF-21 alone (7% and 12% loss beyond control, respectively). Interestingly, even though only GLP-1 is implicated in lowering energy intake, combination treatment resulted in a robustly greater response in food intake suppression than with GLP-1 alone. Similarly, the increased energy expenditure induced by FGF-21 was significantly augmented with GLP-1, particularly during the light photoperiod when mice were sleeping. Following the completion of the 14-day treatment, researchers found that combination treatment upregulated mRNA expression of UCP1 and PGC-1a in epididymal white adipose tissue, suggesting that a transformation of white adipose tissue to a brown adipose tissue state is responsible for the pronounced weight loss observed. Furthermore, leptin signaling and sensitivity may have been potentiated, as GLP-1 and FGF-21 combination treatment increased leptin receptor expression in metabolically active peripheral tissues. The “browning” of white adipose tissue and resulting profound decrease in body weight indicates that future obesity treatments should explore the possibility of targeting mechanisms involved in both energy intake and energy expenditure.
Questions and Answers
Q: Have you tried this in humans in some way?
A: This year in Keystone we disclosed some human data with FGF-21 treatment. In one month, we observed about a two-kilogram weight loss in the treatment group vs. placebo group. However, we did not investigate the mechanistic approach or make any energy expenditure measurements.
Q: Data have shown that FGF-21 levels are already elevated in a prediabetic state. What do you think about this?
A: Yes, FGF-21 in obese and any kind of diabetes state is higher than normal. However, with pharmacological treatment with FGF-21, you see a weight-lowering effect, even though those animals initially had higher FGF-21 levels.
Q: You showed an increase in UCP1. Can you comment on protein levels? What kind of white adipose tissue do you work on?
A: We work on epididymal white adipose tissue. Protein levels of UCP1 increased in the white adipose tissue, but we don’t have that data for liver, so I can’t speak to that.
Q: Did you look at effects on brown adipose tissue?
A: I haven’t shown that here, but we did look at it. In this study, there was a trend of increase in UCP1 levels in brown adipose tissue, but it wasn’t significant.
Q: What about the discrepancy you observed in light vs. dark phases? It seems to me that the synergistic effect was more pronounced in the light phase. Did you make anything of this?
A: Losing weight while sleeping – that’s an ideal condition (laughs). They were like the control group since they were sleeping and their activity level didn’t change, but they were burning more calories.
Q: Can you comment on the huge increase in leptin receptors you found? Did you check the signaling of leptin in cells?
A: One explanation is that an enormous weight loss in a short period of time might be the cause because normally, if you administer leptin, you don't see any effect. However, when mice lose weight, you can restore leptin sensitivity. We didn’t track this at different time points. We looked at the end of the experiment after 30% weight loss. At day 8, weight loss was about 15%, so a certain degree of weight loss might trigger leptin sensitivity, though we haven’t looked at it in much detail.
Francesc Villarroya, PhD (University of Barcelona, Barcelona, Spain)
There is a growing body of evidence suggesting that brown adipose tissue (BAT) is a site of glucose uptake and utilization, and this study attempted to uncover the role of FGF-21 in inducing this activity. BAT has been shown to release FGF-21 following thermogenic activation (heat production), and thus cold-adapted rats had a markedly increased output of FGF-21. Assessment of the effect of FGF-21 expression in BAT (from mouse primary cultures) on markers of glucose metabolism found rapid induction of regulatory kinases such as ERK1/2 and p38, as well as machinery needed for glucose oxidation. Additionally, both in vivo and in vitro, FGF-21 was found to significantly induce expression of transcripts for genes associated with glucose uptake and oxidative/thermogenic activation. In parallel, exposure to FGF-21 in BAT resulted in a dose-dependent induction of glucose transporters, particularly GLUT4 and GLUT1. Dr. Villarroya postulated that FGF-21 operates through an autocrine signaling effect, whereby BAT is a sensitive target of the FGF-21 it produces, though other hypotheses exist. Researchers found these effects to be independent of the presence of insulin, making it an attractive strategy to heighten glucose disposal in patients with diabetes. Further research, however, is needed to evaluate the potential of BAT activation by FGF-21 to help prevent hyperglycemia. In our opinion, the most exciting part of the talk was the mention that results such as these support the emerging view that BAT may have endocrine properties and be a source of various hormones, FGF-21 only being one of many. Dr. Villarroya concluded by stating that the possibility is currently being investigated, and we will be sure to keep a watch out for any new developments on this front.
Questions and Answers
Q: What’s happening to fatty acid oxidation?
A: Fatty acid oxidation has some particular complexities because it is hard to mimic the uptake of triglycerides into BAT, which happens in vivo, when studying the system in vitro.
Q: Have you done any postprandial studies to look at FGF-21 expression in BAT?
A: We have not managed this yet.
Oral Presentations: In-Patient Diabetes: Rights and Wrongs
Daphne Bloom (Medical Student, Onze Lieve Vrouwe Gasthuis, Amsterdam, Netherlands)
This trial compared the efficacy and safety of CGM (FreeStyle Navigator; n=87) vs. point-of-care testing (Accu-Chek Inform II; n=90) to guide insulin dosing in ICU patients. Data from the FreeStyle Navigator CGM or Accu-Chek BGM was inputted into a computerized insulin titration program, which nurses then used to obtain an insulin dose. The study was somewhat biased against CGM, as the program was only designed to use single glucose values (i.e., not continuous data or trends). Overall, there was no significant difference between the two groups in terms of hypoglycemia or time spent in target range – this was not that surprising given the algorithm’s limitations. However, the big difference came in the average number of blood samples that were required per patient per 24 hours: just two in the CGM group vs. 12 in the point-of-care testing group (p<0.01). We thought this was fairly compelling – both technologies offered similar glucose control, though CGM did so with significantly less effort. Given the subsequent presentation on nursing burden and cost-effectiveness (see below), we viewed this as a net positive study for in-hospital CGM.
Questions and Answers
Dr. Silvio Inzucchi (Yale University, New Haven, CT): I’m confused about the way the CGM data was plugged into the computer algorithm. You got continuous CGM data every 10 minutes. Point-of-care testing was less often. It sounds like you had much more information with CGM. Was each CGM data point entered into the computerized algorithm?
A: The glucose values were only entered whenever the protocol asked for it. The FreeStyle Navigator was also entered into the algorithm when it had alarms. But there was a disadvantage. If the FreeStyle Navigator alarmed, the blood glucose was entered into the system, and the system then gave advice. If after 15 minutes the blood glucose level was still not in the target range, the CGM alarmed again, and the value was entered into the protocol. But the more frequently you enter values, the advice is not adjusted from these frequent values. So you see higher doses of insulin and faster drops in glucose.
Q: So you may have found a better result with a different protocol?
A: We think if the protocol was adjusted it would have been more in favor of CGM.
Q: What is your experience with the reliability of CGM in this specific subgroup of patients? How good does this match patients in the ICU? For these patients, is subcutaneous measurement equally reliable?
A: Yes, it is. In a previous study, we compared different types of CGM. We compared values with arterial blood glucose using a blood gas analyzer. The study showed that this device was reliable and had accurate glucose values.
Marjolein Sechterberger, MD (Academic Medical Center, Amsterdam, Netherlands)
This study was an economic sub-analysis of that discussed above, which compared use of CGM (FreeStyle Navigator) to point-of-care testing (Accu-Chek Inform II) in the ICU setting. Overall, the researchers found that use of CGM reduced nursing workload by 63%, saving nurses 22 minutes per patient per day over point-of-care testing (“This is clinically meaningful in a busy ICU setting”). Additionally, CGM also reduced costs by 12 euros per patient per day (41 vs. 53 euros) – see below for the specifics of what costs were included. We were quite glad to see this positive data, as the need for better inpatient glycemic control is profound, and CGM has the power to help. We note that this cost-benefit data did not look at clinical outcomes, since the study duration was quite short – we continue to hope that someone conducts a large, long-term hospital study comparing CGM vs. point-of-care testing. If done properly, we are optimistic that CGM would not only improve outcomes, but would demonstrate striking cost-effectiveness.
The researchers documented the average time it took to complete CGM and point-of-care testing tasks – on average, point-of-care measurements took three minutes, sensor placement took 3.5 minutes (presumably done only ones), sensor calibration took 2.5 minutes, and obtaining a CGM value and entering it into the glucose algorithm took 0.3 minutes.
The cost-benefit analysis demonstrated a 12 euro per day advantage for CGM – this analysis included a broad array of estimates. Personnel costs were estimated at 38 euros per hour. Device costs included: the FreeStyle Navigator receiver 1,009 euros (1.38 euros per day), 61 euros per sensor (24.40 euros per day), and 892 euros for the Accu-Chek Inform II meter (1.22 euros per day). Ongoing material costs were estimated at: 0.7 euros for point-of-care measurement and 1.19 euros for the FreeStyle Navigator calibration strip (we’re not sure why the latter was more than double the price of the former). Finally, laboratory costs for point-of-care glucose measurement were estimated at 1.66 euros (it was not specified what this included and whether it was per day, per patient, or per test).
Questions and Answers
Q: Say I want to convince the person who manages the budget of my hospital, “I need CGM in my unit.” What comes first – time burden? Euros? Both?
A: Yes, of course. Nursing time in the ICU setting is very diverse and glucose control is only a part of the daily tasks of nurses. However, it’s important to keep in mind that it takes substantial time for glycemic control. You could maybe diminish the costs by use of a CGM system.
Q: Did the protocol require confirmation of any of the CGM data with point-of-care testing prior to action being taken. If the CGM alarmed, were the nurses able to act directly on the CGM data, or did they have to perform a fingerstick test to confirm?
A: It depends. Normally during the study, the values of the CGM system were used for the glucose control algorithm.
Q: I’m a physician from Denmark. I want to ask about the priority of this data. I’m concerned about the workload for nurses. I’d imagine better quality, less hypoglycemia, better outcomes, and shorter patient stays. I’m just curious why you prefer to focus on workload for nurses.
A: We were limited by the amount of data generated by the randomized controlled trial. This was only powered to detect a difference in hypoglycemia or hyperglycemia events. There was no long term data that we could use for the economic analysis. It was a sub analysis, and we were limited by the data. Maybe just focusing on nursing workload can be extended when you have more available data.
Dr. Silvio Inzucchi (Yale University, New Haven, CT): Nice study, and I understand the importance. But the value added of 22 minutes per day is only cost savings if the nurse can do something else productive during that time. It’s unlikely they could take another patient on. In that small savings of time, unless the minutes can be apportioned to something else of value, it’s not really cost savings.
A: Nursing personnel costs was only part of the economic analysis. There were diminished laboratory costs as well – that was substantial.
Award Lecture: 7th Albert Renold Lecture
The Pancreatic Islet: More than the Sum of its Parts?
Patrik Rorsman, MD, PhD (University of Oxford, Oxford, UK)
Dr. Patrick Rorsman delivered a thought provoking lecture on the pathophysiology of pancreatic beta, alpha, and delta cells in type 2 diabetes from the perspective of electrophysiology. His fast paced lecture had three main takeaway messages on islet cell biology: 1) rodent and human islets are not the same, 2) type 2 diabetes involves impaired beta cell function, not just mass, and 3) glucagon and somatostatin secretion are implicated in diabetes, in addition to insulin. We were particularly fascinated by Dr. Rorsman’s explanation for how molecular/cellular defects resulting in too much KATP channel activity in islet cells at high glucose levels (e.g., via reduced metabolism) can result in 1) impaired glucose-stimulated insulin secretion, 2) reduced glucagon secretion during hypoglycemia, and 3) paradoxical stimulation of glucagon during hyperglycemia. He noted that type 2 diabetes islets and fetal islets are similar in their electrophysiological response, suggesting that diabetic islets do not die as much as they revert to their fetal state. Dr. Rorsman also asserted that insulin secretion predominately inhibits glucagon secretion by stimulating the secretion of somatostatin. Thus, he proposed that somatostatin receptor antagonists could be an effective therapy for people with diabetes. Unfortunately, he sighed, “pharma has fallen out of love with somatostatin receptor antagonists.”
Dr. Rorsman noted that one theory for why insulin secretion is biphasic is the presence of different insulin granule pools within beta cells: readily releasable granules on the cell’s edge and reserve granules found closer to the cell’s interior. The first phase of insulin secretion would result from the exocytosis of a pool of readily releasable granules and the second phase would result from the later exocytosis of reserve granules.
Under this model, people with type 2 diabetes lack the first phase of insulin secretion and have a reduction in second phase insulin response due to their loss of beta cells and, therefore, insulin granules.
Dr. Rorsman believes these functional pools exist, but that the model of beta cell loss does not explain the distortion of insulin secretion’s biphasic nature. His evidence is that sulfonylureas are able to restore the first phase of insulin secretion – a phenomena difficult to explain if the granule pools from which the insulin originates do not exist anymore after beta cells are lost. Additionally, he estimates that a person’s total daily requirement of insulin could be supplied by only 5% of beta cells’ granule content. Thus, he thinks it is unlikely that the 30-40% reduction in beta cell mass reported with type 2 diabetes is severe enough to cause a shortage of insulin granules.
Instead, Dr. Rorsman thinks beta cells’ electrophysiology can explain biphasic insulin secretion. According to Dr. Rorsman, biphasic insulin secretion is due to differences in beta cells’ action potential upon detecting elevated glucose levels. At first the beta cell emits high amplitude action potentials. Action potential amplitude appears to be correlated with the extent of insulin secretion. Thus, these initial high amplitude action potentials drive the first phase of insulin secretion. After a short period of time, however, the beta cell begins firing action potentials with a lower amplitude, though it continues to do so for a longer period of time. This pattern of action potentials results in the second phase of insulin secretion.
Additionally, his model explains type 2 diabetes’ loss of the first phase and impairment of the second phase of insulin secretion. Dr. Rorsman hypothesized that impaired glucose metabolism causes the beta cell’s potassium ion channels (ATP-sensitive potassium channel) to incompletely close. This causes the beta cells to be partially depolarized and less electrophysiologically responsive to glucose. Beta cells’ sluggish electrical response to rises in glucose would then cause the loss of the first phase of insulin secretion. Beta calls would also have a reduced rate of action potential firing, explaining the diminished second phase of secretion. Additionally, since the cells are partially depolarized, they would sometimes fire spontaneous action potentials at low glucose levels. This, Dr. Rorsman noted, might explain people with type 2 diabetes’ elevated basal insulin secretion.
Dr. Rorsman voiced support for the use of glucose kinase activators. He explained that in one study (Doliba et al., Am J Physiol 2011) Roche’s piragliatin (now discontinued) a glucokinase insulin activator normalized insulin secretion by accelerating glucose metabolism.
Dr. Rorsman hypothesized that glucose-induced inhibition of glucagon secretion is mediated by insulin but by somatostatin. For background, insulin secretion is known to stimulate the secretion of somatostatin and some people believe it drives the inhibition of glucagon secretion. Dr. Rorsman, however, presented data showing that if you inhibit the secretion of somatostatin, insulin’s impact on glucagon secretion is significantly reduced.
Thus, Dr. Rorsman proposed that somatostatin receptor antagonists could be an effective therapy for people with type 2 diabetes. He noted that somatostatin receptor antagonists greatly improve diabetic rodents’ glucose counter-regulation. Unfortunately, he sighed, “Pharma has fallen out of love with somatostatin receptor antagonists.”
According to Dr. Rorsman, alpha cells intrinsically regulate the secretion of glucagon at low glucose levels (which do not produce an insulin response) in an electrophysiological manner. In contrast to beta cells, normal alpha cells have large action potentials in the presence of low glucose levels, stimulating the secretion of glucagon. When glucose levels increase, the amplitude of the alpha cells’ action potentials declines, reducing the amount of glucagon secreted. Thus, normal alpha cells secrete some glucagon when glucose levels are low and top when glucose levels are high.
In type 2 diabetes, however, alpha cells’ electrophysical regulation of glucagon secretion becomes impaired. Similar to beta cells in type 2 diabetes, alpha cells become less electrophysically active. The resultant infrequent action potentials coming from alpha cells results in reduced glucagon secretion in the presence of glucagon. When glucose levels rise, the type 2 diabetes alpha cell begins firing its low-amplitude action potentials at would a normal alpha cell. This means a person with type 2 diabetes paradoxically secretes more glucagon in these presence of hyperglycemia than hypoglycemia.
Turning to the other pancreatic cells, Dr. Rorsman questioned if diabetologist’s focus on the beta cell over the alpha and delta cell is warranted. He explained that type 2 diabetes’ impact on glucagon and somatostatin secretion is actually more dramatic than its impact on insulin secretion.
Dr. Rorsman catalogued the many differences between rodent and human islets. Given these differences, he questioned if the detailing of the rodent islet’s biology was a waste of time, since “rodent diabetes is not a major clinical problem.”
Award Lecture: 48th Minkowski Lecture
The Heart of The Matter: Beta Cells in Diabetes
Miriam Cnop, MD, PhD (Universite Libre de Bruxelles, Brussels, Belgium)
In front of a packed lecture hall and crowded overflow lobby (which was far larger than the typical overflow room), Dr. Miriam Cnop walked us through her and others’ research on the biology of beta cell dysfunction and death. Dr. Cnop framed the topic by noting that though the beta cell’s demise is central to the pathogenesis of type 2 diabetes, the underlying mechanisms of this phenomena is poorly understood. Dr. Cnop believes that a key regulator of this process is epigenetics. Since human beta cells have long lifespans (a person’s beta cell population is largely established by the time a person is 20 years), they are exposed to environmental stresses over a long period of time and can acquire epigenetic alterations. Indeed, islets from people with type 2 diabetes have been shown to have epigenetic dysregulation, as indicated by differential DNA methylation. Dr. Cnop identified endoplasmic reticulum (ER) stress as a key mechanism of palmitate-induced beta cell dysfunction (palmitate is a saturated fatty acid). Thus, she hypothesized that ER stress induced by saturated free fatty acids is a potential contributory mechanism for beta cell failure, as well as insulin resistance, in type 2 diabetes.
Dr. Cnop’s first assertion was that beta cell dysfunction and apoptosis – not defective beta cell regeneration – are key components of type 2 diabetes. She pressed that little to no evidence exists for beta cell neogenesis or replication in adult obesity of type 2 diabetes. Instead, Dr. Cnop underscored that research exists suggesting that a person’s beta cell population is probably established by the time they are 20 years old.
Due to a beta cell’s long existence, they have nearly a lifespan over which to acquire epigenetic alterations, according to Dr. Cnop. These epigenetic modifications can establish stable alterations in gene expression. Dr. Cnop explained that these modifications play a key role in beta cell biology and potentially in the pathogenesis of diabetes. Indeed, islets from people with type 2 diabetes have differential DNA methylation in more than 250 genes affecting beta cell function and survival, pointing to epigenetic dysregulation.
Dr. Cnop hypothesized that ER stress might represent a common molecular mechanism for the development of insulin resistance and beta cell failure. Dr. Cnop identified ER stress as a key mechanism of palmitate-induce beta cell dysfunction. Additionally, ER stress is believed to be present in liver, fat, and muscle in obesity and diabetes, potentially resulting in insulin resistance. Dr. Cnop suggested that future research should determine if the ER stress response can be modulated to prevent or treat type 2 diabetes.
Additionally, Dr. Cnop suggested that tRNA modifications could be a novel mechanism of beta cell failure. This hypothesis is grounded on the association between TRMT10A deficiency, a defective tRNA modification, and early onset diabetes (as well as microcephaly).
Thomas Pieber, Sigrid Deller, Martina Brunner, Lene Jensen, Erik Christiansen, Fumiaki Kiyomi, Simon Heller
Incretin therapies have been shown to reduce glucagon levels in type 1 and type 2 diabetes — a desirable effect in most cases, as glucagon contributes to higher blood sugar levels. However, a potential concern for use in type 1 diabetes is whether impaired glucagon secretion could hinder recovery from hypoglycemia, a process that is already partially compromised in type 1 diabetes patients. Dr. Simon Heller’s research group designed a hypoglycemic clamp study to test whether Novo Nordisk’s GLP-1 agonist Victoza (liraglutide) would affect the glucagon counter-regulatory response to hypoglycemia in 45 type 1 diabetes patients. In a plot of glucagon levels compared to plasma glucose level during the induced hypoglycemia sessions, liraglutide treatment downshifted the glucagon level curve compared to placebo (as would be expected), but patients in each liraglutide group responded to hypoglycemia with an increase in glucagon secretion. The poster also noted that baseline levels of glucagon were lower in the liraglutide treatment groups compared to the control. The secretion of adrenaline and cortisol in response to hypoglycemia (other counter-regulatory hormones for hypoglycemia) were also not impaired by any liraglutide dose. Significantly less insulin was needed in the three liraglutide groups during the hypoglycemic clamp than in the corresponding placebo groups, likely due to the overall repression of glucagon levels conferred by liraglutide. The investigators note that the potential benefit of this phenomenon merits further study. Overall, the results of this study were encouraging that liraglutide does not completely eliminate the glucagon counterregulatory response to hypoglycemia.
JE Schopman, JBL Hoekstra, BM Frier, MT Ackermans, JJ de Sonnaville, AM Stades, R Zwertbroek, JJ Holst, FK Knop, F Holleman
Because the glucagon response to type 1 diabetes is diminished in people with type 1 diabetes, and because incretin-based therapies are known to repress glucagon secretion, this study investigated whether use of the DPP-4 inhibitor sitagliptin (Merck’s Januvia) would diminish the counter-regulatory glucagon response to hypoglycemia in people with type 1 diabetes. In this single-center, randomized double-blind, placebo-controlled, three-period cross-over study, 16 male patients with type 1 diabetes and intact hypoglycemia awareness received 100 mg/day sitagliptin or placebo for six weeks and were monitored during three acute hypoglycemic events (at baseline, after sitagliptin, and after placebo). Glucagon and adrenergic counterregulatory responses were not changed by sitagliptin treatment.
Bayer: Bayer’s booth focused entirely on its alpha-glucosidase inhibitor Glucobay (acarbose), with no information on their blood glucose meters. Although we also saw a focus on Glucobay at last year’s EASD booth, it was notable not to see a single meter or mention of a meter in the booth. Bayer’s booth was positioned along an outside edge of the exhibition hall, directly in front of the Animas/LifeScan and to the left of BD’s booth. “Glucobay” was looped gently across the tops of most stations in mint green writing that complemented the similarly colored carpet. One Glucobay station sported the same game as last year, giving attendees 40 seconds to identify five differences between two pictures of a hamburger and french fries shaped like a tarantula; each missing item in the second picture represented something that would have raised a patient’s post-prandial glucose level (for example, one french fry was missing). We thought it was a clever way to incorporate learning into the booth. Additionally, each picture described benefits of taking Glucobay, including phrases we saw last year like: “Protect them from the danger of glucotoxicity.” Other phrases revolved around Glucobay’s ability to lower the risk of CV events. After participants successfully completed the game, they exchanged their win for a USB with publications on the efficacy of the drug. There were large monitors with the results of two trials, one indicating that acarbose is a better add-on to metformin than glibenclamide, and the second highlighting the success of acarbose as an add-on to DPP-4 inhibitors (it decreases levels of GIP and increases levels of GLP-1). Bayer also had an espresso station and sitting area to relax during a busy exhibit hall.
BD: The BD booth resembled the focus of ADA and AADE and was divided into three sections: its 4 mm needle, lipohypertrophy, and needle safety. On the far side, there was a live demonstration of lipohypertrophy with a real diabetes patient. A representative from BD Medicine described the dangers of lipohypertrophy and how to avoid it, which included using a 4 mm needle. The rep explained that the needle is short enough to avoid reaching muscle and is also small enough to provide extra area for insulin infusion – both aspects decrease the risk of lipohypertrophy. At the end of his presentation, the representative even demonstrated how to detect lipohypertrophy on the patient; after the official presentation had ended, the patient even offered to have members of the audience try to find lipohypertrophy on his abdomen (we saw at least two people take advantage!). For those not yet ready to palpate in an Exhibit Hall, attendees could also enter a raffle to win a lipohypertrophy educational briefcase. Attendees seemed excited after the live presentation, and we expect that even more visitors will be drawn to the demonstration in the next few days – the screen with a countdown to the next demonstration was smart marketing! Also near this side of the booth was a mannequin with a rubber abdomen, which one representative used to demonstrate how easy it is to hit muscle when using a needle longer than 4 mm; the floor immediately turned red, indicating that the needle had gone through the “subcutaneous tissue” of the mannequin. We’ve got to hand it to BD – they are one of the best at interactive booth demos! The other end of the exhibit was dedicated to needle safety, with descriptions and demonstrations of the company’s dual protected needles. A rep noted that these are especially useful for patients with needle-phobia. In the middle of the booth, there was a large screen describing what BD does (since it is a US company), and also what they do and plan to do internationally. When we questioned reps on when there would be EasyFlow technology needle in Europe, they responded that they are “looking to keep moving forward” on that front.
BMS/AZ: We were eager to see BMS/AZ's booth to see how the EU launch of their SGLT-2 inhibitor Forxiga (dapagliflozin) is progressing. A giant representation of a sugar dispenser with a spigot first caught our attention as we approached the booth. We then noticed Forxiga's logo (a picture of which can be seen at http://close.cx/ForxigaLogo), which has a prominent downward arrow down the center, reflecting the agent's mechanism of action. Three brightly colored squares surround the arrow, which meandering through the booth we learned reflect Forxiga's lowering effect on A1c, weight, and blood pressure. Indeed, a survey of HCPs BMS/AZ were conducting on touch screens showed (at the time of our visit) that the two aspects HCPs who have tried Forxiga value most are 1) its delivery of effective A1c and 2) impact on weight loss and blood pressure. The other characteristics prescribers value (in order of decreasing ranks) are 3) its insulin independent mechanism, 4) that is it easy to understand and explain, and 5) its convenience for patients. We were slightly surprised that substantially fewer HCPs listed these latter two aspects as the item they value most when compared to the top three characteristics. HCPs who have not tried Forxiga yet indicated that they are also interested in the same characteristics of Forxiga, in approximately the same order. Overall, the booth was largely dedicated to Forxiga, however, BMS/AZ tied Forxiga into the rest of their portfolio (Bydureon, Byetta, Onglyza, and Kombiglyze) at screens throughout the booth, explaining to HCPs how they can individualize patient care using the Alliance's agents. Additionally, HCPs could "connect, shake, and inject" Bydureon under the tutelage of a representative at a stand in one corner of the booth.
Boehringer Ingelheim: BI’s booth was adjacent to the massive booth of its alliance partner Lilly. The space was brightly lit and was very open, giving it a cheery feel. The sound of chirping birds emanated from a Kinect motion-controlled video game, in which players flew around a simulated landscape as a bird (the mascot for BI/Lilly’s Tradjenta and Jentadueto). Next to the game was a life-sized artificial purple tree, with bright yellow plastic birds constructing their own nests. Two modestly-sized banners stated that Tradjenta (spelled Trajenta in Europe) demonstrated sustained A1c reductions over two years of clinical study, and that some patients experienced reductions of up to 1.2%. The other half of BI’s booth featured an educational campaign on SGLT-2 inhibitors, which did not mention any specific drug names (understandably so, as empagliflozin is still under regulatory review in the US and EU and thus cannot be marketed).
Cellnovo: Cellnovo did not have a booth at EASD 2013, but met with us to provide an update on the progress of their insulin pump system. The company has been conducting patient studies in the UK, leading up to multi-center usability trials over the next few weeks. The company is still aiming for a UK commercial launch before the end of 2013, a roll out to other European countries following the UK launch, and a plan to file in the US in 2014. The company received a CE mark in Europe roughly a year ago. In recent weeks, the company has obtained third party data on pump accuracy and precision for basal and bolus delivery and for occlusion performance, and it compares well to other commercially available pumps. A strong differentiating feature of the system is remote monitoring and data management – it’s possible to see all historic data from the handset and pump via an online web portal in near real-time. The touchscreen handheld has a cellular data connection, and notably, the system can also trigger text message alerts. We were also interested to hear about a new ‘Before and After’ analysis for meals – this should really help patients and HCPs optimize meal-specific bolusing. As a reminder, the Cellnovo system consists of four components – a pump/rechargeable battery unit, a disposable insulin cartridge, a color touchscreen handset with an integrated meter, and a cloud-based data management system. Cellnovo’s system is more of a patch pump than a traditional pump, though it still requires a very short 0.4 inch (1 cm) infusion set.
Dexcom: The Dexcom booth represented the company’s smallest of the major 2013 conferences, to be expected given the more challenging reimbursement environment for CGM in Europe – that said, the placement of the booth was terrific and traffic was quite good. The exhibit’s back wall reiterated the main news from Dexcom’s ATTD 2013 booth: a CE Mark for use of the G4 Platinum CGM in patients as young as two years old. Dexcom has now begun marketing in this population, something it had not yet started at ATTD in February. At the booth’s central table, attendees could talk to reps and see a demo of the G4 Platinum receiver. Along the left side, Dexcom’s Studio software and pattern recognition were available for demo. Unlike ADA and AADE, the Dexcom Share remote monitoring product was not on display. Those looking for brochures could peruse them in five different languages, reflecting just a smidgeon of the 22 countries where Dexcom CGM is now available. This was very impressive. We asked the rep specifically about China, as it has been mentioned in recent earnings calls. His comments confirmed the comments by Dexcom management in the 2Q13 call – the key is deciding what product to go to China with, since the regulatory review takes more than two years and first requires an FDA approval. In line with one of Dexcom’s marketing messages of the year, a sign declared, “CGM first – the first step for success.” That marketing really targets a more traditional belief (by some) that pumps should come before CGM, a more simplistic view. In our view, the decision to adopt a pump, a CGM, or perhaps both should be left up to sound clinical judgment and patient needs and preferences – reimbursement, of course, will always weigh in.
Diasend: The online data management company’s booth had a clearly visible slogan as we entered: “Easy diabetes communication.” Indeed, Diasend is now compatible with an 70+ devices, including several new additions: Insulet’s second-generation OmniPod, Ypsomed’s myLife Unio BGM, Dexcom’s G4 Platinum, Bayer’s Contour Next, and even pendiq’s smart insulin pen. Diasend has also launched compatibility with mobile apps like Glooko and Sanofi’s iBGStar. In addition to new devices, the platform’s newest innovation allows users to compare pump setting changes over time. Looking to the future, Diasend hopes to include more pump features – one of the biggest pieces of user feedback has been a desire to see everything on one page. We asked about the standardized Ambulatory Glucose Profile report for CGM data (a major focus of Abbott’s symposium on Day #2), and the rep told us it’s “easy” to do on a technical front. The “hope” is to have this available on Diasend next year. Last, Diasend is deciding how to incorporate all the data from activity trackers – we think this would be a huge win for patients and providers, though the rep made it clear to us that the value of additional data must be balanced against information overload. As a result, Diasend is still brainstorming on how to best present this data. We’ll stay tuned!
Janssen’s booth occupied about one third of the overall J&J exhibit. Although the CHMP gave a recent positive opinion on J&J’s SGLT-2 inhibitor, Invokana, the company still does not have actual approval. Upon entering the booth, visitors were greeted with a cross section of the renal system that surrounded an introductory video to the role of the kidney in type 2 diabetes management. The exhibit was mostly “self-serve” with regards to information: visitors could stand at one of several computer stations to sign up to receive more information on Invokana online, or visitors could walk themselves through interactive touch-screens with a few slides on SGLT-2 inhibition and the benefits of reversing glucotoxicity. We imagine J&J is excited to be bringing a product like Invokana to market – in the EU, reimbursement is always a challenge but the potential to help patients easily is great.
J&J Animas: At the end of sprawling LifeScan booth, there was a large picture of the Animas Vibe that highlighted its bolus options, bolus calculator, shortcuts, fine-tuned control, high-contrast screen, uninterrupted insulin delivery, waterproof nature, and accurate carb counter. One counter highlighted the Animas Vibe purely as a pump, and a second showed the device used in conjunction with the Dexcom G4 Platinum CGM. As a reminder, this combination was just approved in Canada at the beginning of September. As of the last update in Dexcom 2Q13, Animas had just received a round of written questions from the FDA regarding approval of the pump. We have not heard of an updated timeline but are excited for prospects in the US – we imagine Animas is as well so it can get a pump with sensing on the market, particularly since it seems like integrated pump / CGM products will get the best reimbursement.
J&J LifeScan: The J&J Animas/LifeScan booth had sleek white walls with dark blue accents, including lights radiating out from behind each display case. All of LifeScan’s OneTouch products were displayed alongside each other and the slogan, “A World Without Limits for People with Diabetes.” This has been in LifeScan’s marketing for years and is such a compelling message for patients. The products in the booth included the OneTouch Delica lancing device and several meters: OneTouch SelectSimple (a buttonless meter targeted towards emerging markets), OneTouch Verio Pro+ (a hospital meter), OneTouch Verio IQ (pattern recognition, and the new OneTouch Verio. Representatives were pleased to welcome back the Verio IQ after it was removed from the market earlier this spring (see our report at http://www.closeconcerns.com/knowledgebase/r/fe264e79). The new OneTouch Verio meter was a focus of the booth’s marketing – signage emphasized the meter’s large high-resolution color screen, which gives lots of information without needing push any buttons: 1) the blood glucose level in large font; 2) a color-coded indicator circle for low, in-range, and high blood glucose results; and 3) automatic messages (e.g., “Your average over the last 7 days is 6.2 mmol/l”). We are especially big fans of the color coded results – we think the subtle psychology and context that color gives the numbers could really help patients visualize results and remind them when it is appropriate to intervene. Certainly, patients on the Dexcom G4 Platinum CGM have widely cited the color receiver screen as a big benefit of the product (read our test drive at http://diatribe.org/issues/48/test-drive). We also like the messages feature, which LifeScan has dubbed “Progress Notes” – very motivational! There were no reps on hand when we walked through the booth, though the LifeScan UK website suggests in can only be pre-ordered right now.
Lexicon exhibited for the first time at a major diabetes meeting, which we found very exciting. The booth was simple, with a backdrop of the company’s logo and slogan, “Discovering Breakthrough Treatments for Human Disease.” Lexicon had copies available of the three posters it is presenting at EASD – two of them concerning positive phase 2b results on blood pressure, body weight, or triglycerides findings from the phase 2b study of LX4211 (the company’s SGLT-1/SGLT-2 dual-inhibitor), and the third concerned preclinical data on the blood glucose-lowering effects of an SGLT-1 inhibitor (LX2761) in mice. Visitors could also take printouts with educational information on SGLT-1 and SGLT-2 inhibition as well as a list of the company’s peer-reviewed publications on LX4211.
Lilly: Similar to previous conferences, Lilly’s exhibit was modeled after a home, with a different product or theme featured in each room of the house. Humalog was prominently featured in the “kitchen,” where Humalog pens were displayed under glass casing. The dining room contained examples of Lilly’s new Savvio Humalog pen, which is smaller than its predecessor (the Savvio is not yet available in the US). iPad displays in the “children’s playroom” featured Lilly’s innovative partnership with Disney to provide resources for children and teens with diabetes. The DPP-4 inhibitor Tradjenta (linagliptin) occupied a small corner of the booth, but when we asked about the drug, we were referred over to Boehringer Ingelheim’s nearby booth, which had more information on the drug. A separate room featured the Diabetes Conversations toolkit, which was sponsored by Lilly and developed by Healthy Interactions in collaboration with IDF. The booth displayed examples of diabetes “conversation maps” that providers could use with patients of all ages to facilitate productive discussions on diabetes management. The maps were quite bright and full of information — we were impressed and assume that while they may present somewhat of an information overload for some patients, for others who are more “information seekers”. On a positive note for attendees, Lilly also sponsored a fairly large internet terminal adjacent to its booth.
Medtronic: Walking up to the Medtronic booth, it was impossible to miss the plasma screens and signage exclaiming, “Proven stellar results – only with the MiniMed Veo system.” Prominent statistics boldly summarized the results of the ASPIRE in-home study of the Veo published in NEJM at ADA 2013: 38% less hypoglycemia exposure, 30% fewer hypoglycemia events, 0 severe events. For complete coverage of this trial, see page 90 at http://www.closeconcerns.com/knowledgebase/r/94f937d8. Walking in to the booth, we were excited to see Medtronic’s newest remote monitoring product, Connected Care, on display. This portable, hockey-puck-sized hub has a cellular chip in it that sends pump and CGM data directly to CareLink and a mobile app. As we understand it, the portable device’s battery is rechargeable and the hub would not have to be plugged into a wall (i.e., it could be carried in a backpack and pump/CGM data would be wirelessly sent to CareLink). At ATTD 2013, it was only advertised on a video screen, so it was great to see it on the demonstration table for the first time. We arrived to the booth for the 10:30 am demo, but it was not working at the time. The rep told us there is no launch date as of yet, as the product is still in the prototype phase (the goal is to make it smaller). We think parents will love it. For some, it also may have an advantage over Dexcom Share, since Share will need to be plugged into the wall (though Dexcom’s Gen 5 will send data straight from the transmitter to the smartphone). The last major update in the Medtronic booth came on the Enhanced Enlite sensor (called “Enlite 2” on Medtronic’s F4Q13 earnings call) – the product received CE Mark within the last three weeks. It has two main innovations: an 80% reduction in implanted volume size over the Enlite and improved sensor-transmitter communication. The rep could not tell us if the size reduction translates into better accuracy, as that “has not been tested yet.” Similar to the Enlite, Enlite Enhanced will still be six-day wear. Attendees seeking some competition could answer multiple choice questions about Medtronic products, diabetes, or general knowledge questions – these were pretty hard! Results were displayed prominently on a large electronic leaderboard next to the popular European coffee station.
Merck Sharp & Dohme: Located toward the center of the exhibit hall, the MSD booth had a stronger emphasis on Januvia’s (sitagliptin) cardiovascular profile than the Merck booths at ADA and AADE, or the MSD booth at EASD 2012. Two of the most prominent displays detailed TECOS, Merck’s CVOT of sitagliptin and results from a pooled analysis showing that Januvia did not increase the incidence of major adverse cardiovascular events (MACE). When we asked a MSD representative about what MSD is concluding from SAVOR-TIMI 53, BMS/AZ’s CVOT for Onglyza (saxagliptin), he highlighted that the trial showed that saxagliptin has “no benefit; no risk. It is like taking a placebo – a lollypop.” In contrast, he noted, early findings with sitagliptin “suggest it might have a benefit” and MSD is looking forward to seeing TECOS’ results in 2014. In terms of glycemia, he remarked, MSD’s competitors have conducted head-to-head trials of their agents versus sitagliptin, and have opted not to publish the data, since it is not in their favor. We believe this increased focus on CV safety is in line with a broader trend at EASD 2013, where CVOTs and CV profiles are one of the hottest topics.
Novo Nordisk’s exhibit was devoted entirely to Tresiba (insulin degludec) today – we hear that the exhibit will rotate themes each day such that, for example, that on day #4 it will be dedicated to Victoza, etc. Uncharacteristically, the long, rectangular booth was tucked away towards the back of the hall, but we could spot the neon green shirts of the sales representatives from a mile away. Apparently others could too because the exhibit was swarming with people while we visited. The sleek green and white booth’s centerpiece was a giant, forest-green parachute anchored to heavy block letters reading “7.0%,” suggesting Tresiba provided a smooth ride down to goal. Visitors could either learn about Tresiba’s benefits at individual stations staffed with sales representatives and FlexTouch demo pens, or a 27-screen panel at the front of the booth. After filling out a worksheet asking questions such as “What are the three key benefits of Tresiba?” (correct answers: A1c reduction, reduction of nocturnal hypoglycemia, and flexible dosing), visitors earned a notebook to take home. A food station at the center served coffee and lunch wraps. Finally, at the back of the booth, visitors could meet members of Team Novo Nordisk, the cycling team made entirely of members with type 1 diabetes. Text on the exhibit walls politely reminded attendees in Spanish that Tresiba was not yet approved in Spain. Novo Nordisk had a second satellite booth devoted to the results of the DAWN2 study, which confirmed that physical, financial, and emotional burdens associated with diabetes are carried by patients’ entire families. We were glad to see so much focus on the behavioral elements of diabetes.
Roche: The Roche booth, prominently located upon entering the hall from registration, had a square in the middle surrounded by three circular areas. Each circle represented a different aspect of care: therapy optimization, patient engagement, and efficiency. Within each were two computers with representatives standing nearby to demonstrate how various Roche meters fit under each category. Under the ‘therapy optimization’ heading, reps showed attendees how the Roche data downloading works. In the ‘patient engagement’ circle, we saw how easy the FastClix lancing device is to use. The rep demonstrated it along with the Accu-Chek Compact Plus, noting how the integrated system reduces the burden on the patient to carry separate supplies around. Turning toward the center of the booth, one side of the square had a television screen rotating between advertisements of meters and key meter features, such as a better bolus calculator. A second side of the square touted that all Roche meters meet the new ISO standards – and even stricter standards. Strategically, Roche prominently flashed this on the side of the booth facing the interior of the Exhibit Hall. With all of the discussion of BGM post-marketing surveillance and strip accuracy (in both the US and Europe), we think this was a smart move on Roche’s part. The third wall showed a flow circle of “personalized diabetes management,” moving from “structured education” to “treatment efficiency assessment” to “personalized treatment” to “analysis” to “data documentation and visualization” to “structured blood glucose monitoring” and back to the start. The last side of the wall housed one of the many coffee stands in the exhibit hall and a seating area, ready to give weary visitors a rest.
Sanofi: The company’s large booth enjoyed front-and-center placement, adjacent to the entrance most attendees used to enter the exhibit hall, and was abuzz with activity. As opposed to Sanofi booths we have seen at recent US conferences, which have been more low-key, its EASD booth was packed with displays — a testament to the number of new products Sanofi was showcasing. The front half of the booth was dominated by exhibits for Lyxumia (lixisenatide), the company’s new once-daily GLP-1 agonist. Rather than standing alone, the Lyxumia portion of the booth was interspersed with information on Sanofi’s bestselling basal insulin Lantus (insulin glargine). A series of displays titled “A Positive Addition” noted that Lantus primarily affects fasting glucose, Lyxumia primarily effects postprandial glucose, and therefore the two used in tandem can provide an effective and comprehensive way to lower patients’ A1cs — this text was accompanied by an image of a Lantus pen and Lyxumia pen overlaid at right angles, forming a plus-sign. Perhaps because of the space required for the new Lyxumia display, Sanofi’s rapid-acting insulin analog Apidra barely had any presence in the booth — after some searching, we managed to find one single display for the insulin off to one side. A great deal of space was dedicated to the company’s new JuniorStar insulin pen, designed for younger diabetes patients (the JuniorStar is currently not available in the US). A series of large displays highlighted the device’s design features, including the fact that it is lightweight yet robust, can administer half units of insulin, is easy to read, requires less pressure for injection, and can easily be dialed down. The pen was part of a featured campaign to “Lighten Lives” of type 1 diabetes patients. The MyStarExtra meter (made by AgaMatrix) was on display for the first time this year — the meter provides patients with a three-day fasting glucose average, a trend arrow, and even an A1c estimate! Sales representatives noted that the product is launching in Spain and Italy this year, with more countries to follow in 2014. This was one of the new products we were most excited to see. There will also be updates of meters coming for the newest iPhones, as we understand it, and there will be an Android system as well.
VPD: As we passed by this small booth, we couldn’t help but notice the glossy posters advertising the 2in1 Smart BGM that plugs into the headphone jack of an Apple iPhone/iPad/iPod and Samsung Galaxy SIII. Unlike Sanofi’s iBGStar meter, the 2-in-1 meter does not function as a standalone device – to test blood glucose, it must be plugged into the headphone jack with the app open. The product has a CE Mark and is currently available in 12 countries in Europe (the rep specifically mentioned Norway, Sweden, Denmark, Slovenia, Slovakia, and Austria). Distribution varies in each country, and the rep assured us that the device has reimbursement. A sign advertised the “special exhibition price” of 45 euros for the small thumbnail-sized meter and 100 test strips. In the US, the meter will be marketed under the brand “Gmate Smart.” We asked the rep about FDA approval, and he told us that it was submitted to the agency, though “lots of questions” came back (we presume because it doesn’t function as a standalone meter like the iBGStar). The rep lamented that very innovative products are challenging, as they fall outside the rules (“It’s like Steve Jobs,” he said). We previously wrote about this product in Closer Look on August 20, 2012. At the time, the South Korea-based company, Philosys, expected FDA approval of the Gmate Smart in 3Q12. Obviously, that has not panned out. We will certainly look for any news on the device, though are not optimistic approval is coming anytime soon. Still, we think the product is an encouraging and valuable idea – the meter is very tiny, the data upload is very easy, and patients nearly always carry their smartphones with them.
YOFiMeter: Tucked in a small booth in the middle of the exhibit hall the YOFiMeter booth drew us in with the tagline, “First cellular all-in-one BGM” next to a Qualcomm partnership logo. In short, this seems to be the ultimate all-in-one meter – a single handheld contains a 20-strip cassette (Infopia strips), a lancing cassette, a color touchscreen, a cellular chip that automatically sends data to the cloud, and a built-in pedometer. All the rep would tell us was that it would be on the market “next September.” It was unclear if this was EU, US, or both, though we’d assume EU to start. After watching a short video of various patients using the device (e.g., an elderly person, a teen skateboarding), we got a demo of the meter. It works as follows: 1) slide a plastic bar forward on the side of the meter to expose a test strip; 2) press finger against lancing port hole on the side of the device; 3) press lit up button to lance finger; 4) apply blood to strip; and 5) get result (it took about seven seconds by our count). The meter prominently displayed the result on the color touchscreen, offered extensive tagging capabilities (exercise, carbs, insulin, other medications, even leaving a voice note!), and automatically sent the blood glucose result to the cloud (we didn’t see any demonstration of the system’s backend or a web portal). Similar to Telcare’s meter, a test is followed by a feedback message (we got a green thumbs up) and a time in range chart. All of it seems customizable as well (e.g., you can choose the picture that is displayed after a test). We found the system quite easy to use, especially the highly responsive touchscreen. We look forward to learning much more about the device, especially where and when it will launch. Intuity has been developing the all-in-one POGO device for quite a while (without the cellular chip or color touchscreen), though we understand it’s been difficult to get through the FDA. YOFi’s website (http://www.yofimeter.com) is just a single page right now with a company logo, two slogans (“Diabetic living made easier” and “Dawn of a new era in BGM technology”), and a contact email address: info@Yofimeter.com.
Ypsomed: The sprawling bright green Ypsomed booth had a corner devoted to each of the company’s areas of focus: ClickFine pen needles (new 4 mm x 32 gauge), the Insulet OmniPod, infusion sets, and the Unio blood glucose meter. We immediately talked to a rep about the new second-gen OmniPod, a major focus of the booth’s marketing. Notably, we learned that ~10,000 patients in Europe are on the OmniPod (as of Insulet’s 4Q12 call in February, the company had 45,000 patients on the OmniPod, up 50% from 30,000 at the end of 2012). We asked the rep where the OmniPod is not currently available in Europe – it sounds like France, Italy, and Spain though we are working to verify this. The rep emphasized that France is particularly challenging on the reimbursement front. We appreciated another demo of the Unio blood glucose meter system, which has a compactly designed, integrated case that conveniently positions the meter, strips, and lancet device for fast testing. Attendees looking for freebies could take their turn at a Play+Win slot machine-type game, while hungry booth-goers could grab green apples, chocolates, and pretzels.
-- by Adam Brown, Poonam Daryani, Hannah Deming, Jessica Dong, Hannah Martin, Manu Venkat, Vincent Wu, and Kelly Close