Journal of Diabetes NEWS


  • Benjamin M. KOZAK,

  • Adam S. BROWN,

  • Kelly L. CLOSE

  • Benjamin M. Kozak, Adam S. Brown, and Kelly L. Close are of Close Concerns (, a healthcare information company focused exclusively on diabetes and obesity care. Close Concerns publishes Diabetes Close Up and Closer Look, periodicals that bring together news and insights in these areas. Each quarter, the Journal of Diabetes includes this News feature, in which Kozak, Brown, and Close review the latest developments relevant to researchers and clinicians. Readers of the Journal of Diabetes involved in the clinical care of patients with diabetes (including students and educators) may request a complimentary 1-year subscription to Close Concerns’ quarterly newsletter, Diabetes Close Up (

The International Diabetes Federation’s (IDF) 21st World Congress

Between 4 and 8 December, 2011, the International Diabetes Federation (IDF) held its 21st World Congress in Dubai, United Arab Emirates. A record 15 100 attendees from 172 countries packed the Dubai International Exhibition and Convention Centre for the 5-day conference, up 21% from 12 500 attendees in Montreal, Canada, in 2009. The 2011 World Congress marks the first time the conference was held in the IDF Middle East and North Africa Region, which has six of the world’s top 10 countries for diabetes prevalence: these are nations in which one of five adults has diabetes. The Middle East and North Africa region of the world will also be one of the hardest hit by diabetes in coming years, with the number of cases expected to rise from 32.8 million to 60 million (83% growth) between 2011 and 2030 according to the IDF’s recently released Fifth Edition of the Diabetes Atlas.1 The IDF 2011 meeting showcased six tracks, 1500 speakers, and was primarily focused on drugs and type 2 diabetes. Some of our favorite talks from the meeting are highlighted below (see, accessed 9 January 2012).

During the President’s Oration, Jean Claude Mbanya, MD, PhD (President of IDF, Cameroon), delivered an inspiring speech in which he expressed pride in the strides already taken and awe in the challenges that lie ahead with respect to the diabetes epidemic. He noted that the number of people with diabetes is roughly equivalent to the entire population of the Middle East and North African region: ‘the combined population of 20 nations’. No country is immune, Dr Mbanya said, and no country has the epidemic under control. Rising health costs are crippling governments. Diabetes is related to other non-communicable disease, infectious disease, economic and environmental sustainability, and human development; failure to address diabetes means failure to address all of these. And yet: ‘Where is the outrage?’, he asked. ‘Where is the outrage for lack of insulin?’ Dr Mbanya decried that ‘it is impossible to understand why these diseases are not the top priority.’ For some reason, deaths from pneumonia or malaria cause outrage but not deaths from diabetes. Four diseases that represent over 60% of burden, namely diabetes, cardiovascular disease, chronic respiratory disease, and cancer, receive only 3% of official development assistance for health. ‘It just doesn’t make sense. We can’t [give] policy makers the excuse of the global financial crisis to compromise the health of millions.’ To this, there was applause. Dr Mbanya argued that society already has the tools to turn the global diabetes epidemic around. He stressed that a solution-oriented approach was needed, such as the IDF’s Global Diabetes Plan 2011–2021, the goals of which are: (i) to improve health outcomes for people with diabetes; (ii) to prevent the development of type 2 diabetes; and (iii) to stop discrimination against people with diabetes. In closing, Dr Mbanya stated, ‘I’m filled with optimism for the future. I didn’t think we’d come so far in these few short years. But it’s all just words until we see a difference.’

Nick Wareham (Institute of Metabolic Science, Cambridge, UK) gave a valuable overview of IDF’s Global Diabetes Plan 2011–2021, sharing insights as to how we can better integrate diabetes care and prevention. The IDF’s Global Diabetes Plan 2011–2021 features an overarching model based on answering the question, ‘What are the key attributes of diabetes care systems?’ According to Dr Wareham, the framework was designed to avoid the complicated ‘medical textbook discussions’ and drill down to the key pillars of diabetes care systems. Encouragingly, it is designed to be simple and enable implementation by community health workers and non-diabetologists. The framework is described by seven Rs:

  • 1 Recognize/Reconsider. This is the first essential step in a diabetes care system: you must recognize whether someone has diabetes and, if so, what type. Dr Wareham talked about the difficulty of drawing a line between abnormality and normality. For example, when a group of experts convened at an National Institutes of Health (NIH) meeting a few years ago, they were unable to create an operational definition of type 1 and type 2 diabetes. In his view, the purpose of a diagnostic label is to bring about action by the health system or practitioners. Unfortunately, he believes we’ve lost that way of thinking, perhaps because diagnostic labels sometimes get in the way and lead us down the wrong path.
  • 2 Registration. Registration is an essential pillar of a diabetes care system. It enables tracking, recording, and subsequent patient follow-up. Dr Wareham noted that the registration system can be as simple as a piece of paper and a pen, or as complicated as an electronic medical records system.
  • 3 Risk assessment. Dr Wareham devoted the majority of his attention to risk assessment. He began by reiterating the central idea in his publication in Diabetologia 2011:2 the tools you use depend on what you’re trying to accomplish. Next, Dr Wareham provided a clinical case study to demonstrate the value of risk assessment. For example, quantifying an individual’s risk (e.g. Framingham Risk Score) would facilitate risk ranking and targeting those with the highest risk; this is especially useful because resources are limited and not everyone with prediabetes progresses to diabetes. Risk assessment also provides an estimate of the likely benefit from an intervention. Finally, risk assessment can motivate patients to change their behavior.
  • 4 Respond. Of course, it’s not enough to simply carry out risk assessment. The clinician and/or the patient must take action.
  • 5 Recall and Review. Dr Wareham described the importance of recall and review, summarizing some of the scientific literature supporting their use.2,3

Jianzhong Xiao, MD (China–Japan Friendship Hospital, Beijing, China), presented informative data from IDF’s Diabetes Impact study in China. The initiative interviewed 3035 people from 10 provinces in China and gathered particularly interesting data on costs and medication use. Overall, people with diabetes in China spend two to four times more on medical expenses than their non-diabetic counterparts (matched for age, sex, and location) and use about twice the number of hospital services. Furthermore, less than half the patients in the study were on oral medications, <1 in 10 was on insulin, and only one of 50 was on a statin. Metformin was the most commonly prescribed medication (22% of individuals), followed by sulfonylureas (16%), insulin (9%), and α-glucosidase inhibitors (8%). Dr Xiao closed by highlighting China’s heavily aging population, which will only exacerbate the burden diabetes will place on society.

As mentioned previously, the pharmacological management of type 2 diabetes was a major focus of this year’s meeting. Michael Trautmann, MD (Eli Lilly, Indianapolis, IN, USA), presented results from a clinical study examining the delivery of exenatide once-weekly (EQW) in native Chinese subjects with type 2 diabetes treated with metformin. Patients (n = 26) received weekly injections of 2 mg EQW for 10 weeks, followed by a 10-week washout period. The results suggested that a steady state of 300–400 pg/L EQW was achieved by 8 weeks of dosing, which was maintained for 3 weeks following treatment cessation; similarly, mean fasting plasma glucose decreased from 9.1 mmol/L (163.8 mg/dL) to a steady state of 6.3 mmol/L (113.4 mg/dL) at 6–8 weeks of dosing. Body weight began to decline after 2 weeks of dosing, leading to a 4.5 kg (9.9 lbs) loss at 10 weeks of treatment with slight regain to an overall 4.0 kg loss (8.8 lbs) after washout (baseline 69.8 kg [153.8 lbs]). As expected, gastrointestinal side effects were most frequent, occurring at somewhat higher rates than reported in prior clinical trials (40% diarrhea, 40% vomiting, 16% nausea). Overall, Dr Trautmann concluded that the results were similar to those seen in Western patients, supporting further clinical research in Chinese patients with EQW.

John Buse, MD, PhD (University of North Carolina, Chapel Hill, NC, USA), gave a thorough presentation on the relevant considerations when using glucagon-like peptide-1 (GLP-1) analogs in clinical practice. He opened with a review of topline results from head-to-head clinical trials of the short-acting (exenatide twice daily; Byetta; Amylin, San Diego, CA, USA) and long-acting (liraglutide; Victoza; Novo Nordisk, Bagsvaerd, Denmark) agonists, noting superior effects on A1c, fasting plasma glucose, and gastrointestinal side effects with liraglutide, although a lesser reduction in postprandial glucose levels. He also examined studies comparing liraglutide with longer-acting options (exenatide once weekly [Bydureon; manufacturered by Amylin and Alkermes, Dublin, Ireland] and albiglutide) and pointed out that liraglutide was associated with greater reductions in A1c and weight, but also increased rates of gastrointestinal adverse events. In the Q&A session, although Dr Buse stressed that he saw strong potential for once-weekly and once-monthly dosing, he suggested the doses for these agents may not have been optimized in development. Compared with basal insulin, Dr Buse summarized evidence indicating that the GLP-1 agonists were associated with similar or greater A1c reductions, weight loss instead of weight gain, similar rates of hypoglycemia (lower when not given with sulfonylureas), and increased rates of gastrointestinal side effects. However, he voiced a stronger interest in the combination use of GLP-1 agonists with basal insulin,, highlighting the results from a 30-week Phase III study,4 which showed a strong reduction in A1c when exenatide twice daily was added to background insulin glargine, which was subsequently optimized (8.3–6.7% with exenatide vs 8.5–7.4% with placebo). This result was particularly impressive given the average diabetes duration of 12 years and the relatively poor prior response to insulin therapy among the trial’s participants. Dr Buse suggested combination GLP-1/basal insulin therapy could offer a niche for short-acting GLP-1 agonists (given their greater effects on postprandial glucose versus long-acting GLP-1 agonists), although further research is necessary.

Regarding earlier stage development, Vivian Fonseca, MD, FRCP (Tulane University Medical Center, New Orleans, LA, USA), presented 12-week results from a dose-finding study of ipragliflozin (Astellas Pharmaceuticals, Tokyo, Japan), a sodium-dependent glucose transporter 2 (SGLT-2) inhibitor. The study enrolled patients with type 2 diabetes (n = 412), whether drug naïve or treated with oral antihyperglycemic agents (the former went through a 6-week washout period). Patients were randomized to placebo, metformin, or one of four ipragliflozin doses (12.5, 50, 150, or 300 mg once daily). Ipragliflozin caused dose-dependent glycemic benefits that were significantly better than those of placebo and, for doses ≥50 mg, comparable to those of metformin (i.e. approximately 0.5% from a baseline of approximately 8.0%). Ipragliflozin also caused a trend towards dose-dependent weight loss, with a notable magnitude given the study’s short duration (2.3 kg [5.1 lbs] for the 300 mg dose vs 0.68 kg [1.5 lbs] for placebo). All groups were comparable in terms of rates of treatment-emergent adverse events (TEAEs), as well as urinary tract infections (UTIs), but genital tract infections (GTIs) were more common with ipragliflozin than placebo (4.1% vs 1.4%). Safety and tolerability will be critical for the success of any SLGT-2 inhibitor; thus far, it is not clear how particular candidates compare with one another in this regard.

John Wilding, DM (University Hospital Aintree, Liverpool, UK), presented the results of a Phase IIb dose-ranging study of AstraZeneca’s now discontinued glucokinase activator AZD1656. In the study, patients on background metformin (n = 458) were treated with fixed daily doses of 20 or 40 mg AZD1656, titrated doses of 10–140 or 20–200 mg AZD1656, glipizide, or placebo for 4 months. There was a 0.8% decline in A1c from 8.3 with titrated doses of 10–140 and 20–200 mg AZD1656, adjusted for the 0.2% increase with placebo, a decline similar to the 0.85% seen with glipizide. Fixed doses of 20 mg (0.16%) and 40 mg (0.22%) AZD1656 had similar effects to placebo. Patients treated with titrated doses of 10–140 and 20–200 mg AZD1656 exhibited 12%–13% hypoglycemia rates compared with placebo (1.1%), and triglyceride levels increased by approximately 20%, without an effect on high-density lipoprotein (HDL), low-density lipoprotein (LDL), total cholesterol, body weight, or blood pressure. Although these rates of hypoglycemia appear less than those observed with some of the other discontinued glucokinase activators, AstraZeneca’s management has suggested AZD1656 was discontinued due to inability to meet ‘predefined internal criteria for the product’. Forest/TransTech and Advinus Therapeutics, which continue to develop glucokinase activators, have stressed that their programs are liver selective, minimizing the risk of hypoglycemia; however, unless the side effect profile allows for relatively innocuous administration or the drugs show additional metabolic benefit, we remain uncertain on the future of the class relative to other options.

In one of our favorite debates of the meeting, Ralph DeFronzo, MD (University of Health Science Center, San Antonio, TX, USA), and Jaako Tuomilehto, MD, PhD (University of Helsinki, Helsinki, Finland), discussed whether pharmacologic therapy should be used to prevent diabetes. Arguing the pro position, Dr DeFronzo stated that non-pharmacologic therapy is neither effective nor cost-effective in the long-term. Citing the Diabetes Prevention Program,5 he noted that after 6 years of follow-up, the metformin and lifestyle groups converged at around 2 kg (4 lbs) weight loss. Moreover, 10-year Diabetes Prevention Program data indicated a US$1500 cost per patient compared with placebo plus lifestyle intervention and US$30 cost savings with metformin. For pharmacological therapy, he presented a detailed summary slide indicating a relative risk reduction with pharmacotherapy across all prevention trials; in particular, he was excited about the potential for reducing side effects using combination low-dose pioglitazone/metformin, especially as generic pioglitazone becomes available (expected to reach the US market by August 2012). Notably, he concluded with strong support for the incretin therapies in diabetes prevention, citing what he deemed ‘one of the most dramatic studies ever carried out’,6 in which a single dose of liraglutide was able to normalize insulin sensitivity in type 2 diabetes patients. In the Q&A session, he also addressed dipeptidyl peptidase (DPP)-4 inhibitors (‘I’ve suggested to every pharmaceutical company with a DPP-4 that this is where the future is going’); although benefits to diabetes risk factors have not proven as strong with DPP-4 inhibitors as with GLP-1 agonists, ease of administration is certainly striking with this oral class.

In methodical fashion, Dr Tuomilehto argued against the use of pharmacotherapy for diabetes prevention. Although he conceded that pharmacotherapy does reduce the incidence of diabetes, he suggested its effectiveness comes with excessive stipulations; citing the Diabetes Reduction Assessment with ramipril and rosiglitazone Medication (DREAM) trial,7 he noted that although rosiglitazone produced a 60% reduction in diabetes over a 5-year period, the observed relative risk (0.39) was similar to that expected (0.44; calculated assuming a 0.6 change in risk for each 1 mmol/L [18 mg/dL] decrease in 2-h glucose) solely accounting for the drug’s effects on blood glucose. Thus, once treatment is stopped, patients revert in risk, requiring lifelong treatment to maintain preventative effects. With many treatments showing side effects and extensive costs, he suggested this widely limits the applicability of pharmacotherapy. Again citing the DREAM trial,8 Dr Tuomilehto highlighted the increase in congestive heart failure observed with rosiglitazone as well as the €750 price per patient, with no obvious end to therapy.

There were also a number of notable talks on the prevention and clinical management of obesity. Nancy Bohannon, MD, FACP, FACE (St. Luke’s Hospital, San Francisco, CA, USA), reported on results in patients with type 2 diabetes and body mass index (BMI) >35 kg/m2 who were randomized to placebo or low- or standard-dose phentermine/topiramate controlled release (PHEN/TPM CR; Qnexa; Vivus, Mountain View, CA, USA) as part of Vivus’ 56-week CONQUER (effects of low-dose, controlled release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults) study. Patients in the full-dose treatment arm (n = 65) experienced least-squares mean weight loss of 12.1%, significantly better than the 2.8% least-squares mean weight loss in the placebo group (n = 58). Benefits were also seen in A1c, fasting glucose, and resolution of diabetes (Table 1). The nature and prevalence of adverse events were similar to those seen in previous PHEN/TPM studies. Rates of constipation, upper respiratory tract infarction, paresthesia, insomnia, dry mouth, headache, and dysgeusia seemed to increase in response to treatment. We understand that this analysis was performed in light of the IDF’s controversial position statement9 that encourages the use of bariatric surgery in patients with diabetes and BMI >35 kg/m2. In a sort of response to this position statement, Dr Bohannon noted the similarities in excess weight loss (approximately 32%) between full-dose PHEN/TPM and two separate observational studies of laparoscopic adjustable gastric banding surgery in obese people with diabetes.10,11 She noted that the comparison is only directional owing to the differences in study designs and patient populations. Nonetheless, it is highly encouraging to see new therapies starting to fill the gap between current medications and surgery, especially therapies that are effective in this high-risk group of obese patients.

Table 1.   Effects of low- or standard-dose phentermine/topiramate controlled release (PHEN/TPM CR; Qnexa; Vivus, Mountain View, CA, USA) versus placebo on weight and glycemic control
 PlaceboPHEN/TPM CR (7.5 mg/46 mg)PHEN/TPM CR (15 mg/92 mg)
  1. *< 0.05, **< 0.0001 compared with placebo; = 0.0002 compared with placebo.

No. patients582465
Least-squares mean % weight loss2.86.6*12.1**
Least-squares mean % excess weight loss7.417.8*32.6**
Mean ± SD baseline A1c (%)6.7 ± 1.06.8 ± 1.06.6 ± 0.9
Least-squares mean % change in A1c at 56 weeks0.05−0.19−0.50
Mean ± SD baseline fasting glucose (mg/dL)126 ± 29136 ± 36125 ± 29
Least-squares mean change fasting glucose at 56 weeks (mg/dL)0.723.24−11.7*
Resolution of diabetes (%)1.78.315.4

Arya Sharma, MD, PhD (University of Alberta, Alberta, Canada), delivered a rich set of insights on clinical obesity management. A firm believer that obesity should be managed like other diseases, Dr Sharma described a staging system (the Edmonton Obesity Staging System12) for classifying high body weight based on its health effects, and emphasized that obesity is a lifetime diagnosis (even if a successful treatment can bring it ‘into remission’ for a long time); in both cases, language reminiscent of cancer and other seriously regarded medical conditions is used. He emphasized that differential diagnosis for obesity should include a full consideration of factors that can contribute to weight gain (e.g. mental health, sociocultural influences, side effects of medications, lack of education etc.) so that referrals and treatment plans are more effective (e.g. he noted that a nutritionist is not trained to help patients who are overweight because they are depressed). Along this line, Dr Sharma argued that obesity should be thought of as ‘obesities’, because energy imbalance can reflect a variety of etiologies and require a variety of treatments. Dr Sharma was generally positive on drugs and surgery as options for some patients, and he commended the IDF for recommending that bariatric surgery be considered as a treatment for type 2 diabetes. However, he stressed that no drug or surgery is a miracle cure and that good obesity management involves setting realistic expectations and educating patients about the benefits of modest weight loss (or even a slowed pace of weight gain, if that is all that can be achieved). A rather gritty truth, but one that is good for the clinical community (and the world as a whole) to hear.

Claude Marcus, MD (Karolinska Institute, Stockholm, Sweden), presented on the Adolescent Morbid Obesity Surgery (AMOS) study, discussing the 2-year follow-up results of 81 adolescents (mean age 16.5 years) undergoing laparoscopic gastric bypass surgery. Mean weight decreased from a baseline of 133 kg (292 lbs; BMI 45.5 kg/m2) to 89 kg (195 lbs; BMI 30 kg/m2) at the 2-year mark, with the vast majority of this weight loss occurring during the first year after surgery. Interestingly, 43% of subjects exhibited weight gain during the second year; the only significant difference between this group and those who did not gain weight was higher insulin levels in the former group. In addition to weight loss, other cardiometabolic parameters improved following surgery. For example, A1c went from 4.37% at baseline to 4.17% at 2 years, fasting insulin decreased from 31.7 to 7.4 mU/L, and fasting glucose went from 5.1 mmol/L (91.8 mg/dL) to 4.9 mmol/L (88.2 mg/dL). Blood pressure went from 124/78 to 117/71 mmHg. There were also significant declines in LDL–cholesterol, triglycerides, apolipoprotein (Apo) A and ApoB, C-reactive protein, and white blood cell count, whereas HDL increased significantly (all changes < 0.001). Notably, a staggering 67% of individuals recorded low vitamin levels, despite prescribed supplementation (adherence to supplementation was not specified), a reminder that the effectiveness of bariatric surgery has to be weighed against lifelong nutritional deficiencies and other side effects, especially when individuals as young as 13 years of age are undergoing the operation. Five reoperations (1%) occurred during the study period. According to the speaker, the treatment was generally well tolerated and quality of life was improved in all parameters of the SF-36 (i.e. physical and psychological). We will be interested to see long-term follow-up of these and other young patients undergoing bariatric surgery to better understand the durability of weight loss and the prevalence of side effects and complications.

Finally, Paul Sacher, RD, MBDA (UCL Institute of Child Health, MRC Childhood Nutrition Research Centre, London, UK), presented on the work of the Mind, Exercise, Nutrition, Do it! (MEND) program, a 10-week, family-based childhood obesity intervention followed by an online-based maintenance and support program until 24 months. The initial phase consists of twice-weekly 2-h group sessions that include behavior modification, nutrition education, and physical activity. In 10 173 children (mean age approximately 10 years) who went through the 24-month program between 2007 and 2010, mean BMI and waist circumference decreased by 0.8 kg/m2 (from 27.2 to 26.4 kg/m2) and 2.6 cm (1″; < 0.0001). The study also found that parent-reported levels of their child’s physical activity increased 3.6 h/week and sedentary activities decreased 5.8 h/week (all < 0.0001). Other improvements were noted in heart rate (a decrease of 8.7 b.p.m. on a step-test recovery), self-reported body image measures, and even a slight decline (1.2%) in parental BMI. Although the time commitment (4 h/week for the 10-week intensive phase) is obviously not insignificant, Mr Sacher noted that mean attendance of the MEND sessions was quite high (78.5%) and the dropout rate was only 11.4%. Notably, an independent UK cost-effectiveness study found that the incremental cost-efectiveness ration (ICER) of MEND is £1671, well below the National Institute for Health and Clinical Excellence’s (NICE) cost-effective threshold of £20 000–30 000; this translates to a 10–13-fold return on investment and this is certainly valuable to bring to policymakers. We were glad to hear that the group is also rolling out the program in a number of other countries, including the US, Canada, and Australia, and will be adding other age groups as well as primary prevention.

Advance Technologies and Treatments for Diabetes 5th Annual Conference

This year, the Advanced Technologies and Treatments for Diabetes (ATTD) annual meeting was held in Barcelona, Spain, between 8 and 11 February 2012. There, we had the opportunity to learn about the latest in diabetes technology: everything from the artificial pancreas (AP) to continuous glucose monitoring (CGM) and the newest in software to insulin delivery. This year, a record 1656 participants were in attendance, up from 1400 in London (in 2011) and 915 in Basel (in 2010). As expected, the major focus was the AP, with six sessions and an all-day AP@home conference devoted specifically to the hot topic. In addition, ATTD 2012 offered a glimpse into the powerful data being gathered by the T1D Exchange, a registry of nearly 25 000 type 1 diabetes patients in the US (see, accessed 15 January 2012).

The noteworthy duo of Boris Kovatchev, PhD, and Patrick Keith-Hynes, PhD (both from the University of Virginia, Charlottesville, VA, USA), provided an update on the Diabetes Assistant, a mobile phone-based AP system. First presented at the Diabetes Technology Meeting in October 2011, the Diabetes Assistant runs on an Android-capable cellular phone and is compatible with a variety of insulin pumps, sensors, and control algorithms.

Dr Keith-Hynes also provided an overview of additional elements newly available or in development for the Diabetes Assistant, including a remote monitoring package, an Android-capable wristwatch that communicates with the Assistant via Bluetooth (dubbed the ‘AP Companion’), a system completely running on Bluetooth, and the incorporation of Insulet/Dexcom’s integrated pump/CGM iDex and Dexcom’s new G5 sensor platform. Early data from the Juvenile Diabetes Research Foundation (JDRF) outpatient closed-loop trial, which uses the Assistant, suggest positive results: summary figures from the first six patients indicate no significant difference between the percentage of time spent within range (70–180 mg/dL) across the outpatient open-loop (approximately 80%), inpatient closed-loop (approximately 70%), and outpatient closed-loop (approximately 60%) periods of the trial, with no episodes of hypoglycemia (<70 mg/dL) observed during the outpatient closed-loop period. Fresh data from the first patient in the AP@home outpatient closed-loop trial, which also uses the Assistant, showed no episodes of hypoglycemia/hyperglycemia, and 76.2% of readings within the 70–180 mg/dL target range. We look forward to seeing whether such results can be replicated further and are eager to see how the Assistant will be incorporated into future AP research.

Tadej Battelino, MD, PhD (University Children’s Hospital and University of Ljubljana, Ljubljana, Slovenia), presented brand new results from DREAM 3, which is studying the MD-Logic AP in overnight ‘transitional’ studies at three diabetes camps in Europe. He first discussed the pilot study that took place last October; the overnight system significantly increased time in range and decreased hypoglycemia. Dr Battelino followed with a preliminary analysis of the DREAM 3 main studies; although the data were not significant, they certainly trended in the right direction of reduced hypo- and hyperglycemia. As more data is collected, we expect the benefits of the overnight closed-loop system will be more convincingly demonstrated. We are very glad to see successful outpatient studies: ATTD gave us a tangible sense of just how far research has come and how quickly it is moving. Dr Battelino ended the presentation with a dramatic YouTube video filmed on the night of the DREAM-3 pilot closed-loop study. As an aside, Dr Moshe Phillip has been characterizing the DREAM 3 pilot study as the first outpatient trial of the closed-loop, although there is some debate as to whether it was truly as ‘outpatient’ as Dr Claudio Cobelli’s more ambitious study a few weeks later. Dr Cobelli’s study featured a hotel room stay, meals out in restaurants, a mobile phone-based portable system, and even a bicycle ride around the city! The fact that we can have such a debate is pretty amazing: just a couple of years ago many thought the possibility of an outpatient AP study was an event for the distant future.

Also on the AP front, Steven Russell, MD, PhD (Massachusetts General Hospital, Boston, MA, USA), gave an overview of his team’s work on bihormonal closed-loop control (including Drs Ed Damiano and Firas El-Khatib among others),13 emphasizing the system’s effective prevention of hypoglycemia, robustness to sensor and pump failure, the use of only weight for algorithm initialization, and the wide variability observed in insulin pharmacokinetics (a mean lispro Tmax of 70 min and a range of 24–166 min). He called the latter a ‘critical determinant of success’. Most notable was Dr Russell’s discussion of the team’s upcoming portable AP experiments (starting mid-2012). We last heard about this trial at the ADA last June, so this was a welcome update. The newest version of the team’s portable bihormonal AP will use an iPhone 4S communicating with two Tandem insulin pumps. The team is still evaluating which sensor to use (Dexcom G4, Medtronic Enlite, or Abbott Navigator), although it has settled on the Abbott Navigator for the time being. Regarding the supply problems with the Navigator, Dr Russell stated, ‘We think we found a solution to get around it.’ We thought this was quite interesting and wish he had provided details; as a reminder, Abbott has an ongoing clinical trial of the next-generation Navigator II continuous glucose monitor.

Regarding the future of CGM, Tom Peyser, PhD (VP Science and Technology, Dexcom, San Diego, CA, USA), gave an excellent overview of the ongoing sensor innovation at Dexcom, beginning with Dexcom’s evolution from the early 2000s to today. We were happy to hear new data on the Gen 4 CGM sensor, which will offer significant accuracy and reliability improvements over the Seven Plus. In clinical studies, the average mean absolute relative difference (MARD) for the Seven Plus was 15.9%, ranging from a low of 6.6% (a very accurate sensor) to a high of 62.3% (SD 8.5%). With the Gen 4 CGM, the lower 12.3% MARD was complemented by reduced range and sensor variability: a low of 6% to a high of 29.1% (SD 5.2%). When thinking about the percentage of sensors that ‘worked really well’ (i.e. MARD < 12.5%), the Seven Plus recorded 58%, compared with 77% recorded by the Gen 4 CGM. Dr Peyser also showed a mockup of the Gen 4 CGM’s receiver, which will feature a color screen and a receiver that looks more like a consumer electronic device. In an effort to provide the best possible sensor for AP studies, Dexcom is also developing a special version of the Gen 4 CGM for AP researchers (an investigational device exemption [IDE] is expected by the middle of 2012). Looking further down the line, data on Gen 5, Gen 6, and the GlucoClear 2 may be presented at ATTD 2013 in Paris. To conclude, Dr Peyser gave the audience a sneak peek at preliminary data from the first clinical study of the GlucoClear 2 in-hospital CGM. The device recorded a MARD of 5.2%, good enough to meet both the current and proposed International Organization for Standardization (ISO) blood glucose standards.

On the more clinical side, Richard M. Bergenstal, MD (International Diabetes Center, Minneapolis, MN, USA), described the characteristics and demographics of the participants in the T1D Exchange Clinic Registry. To date, the Registry includes 22 300 type 1 diabetes patients from 67 clinical centers across the US, many smaller and not associated with an academic institution to better reflect (as many asserted in the Q&A) ‘real life’. Data collected from patient questionnaires and medical records indicated a broad representation of ages, ages of diagnoses, and disease duration in the dataset; however, perhaps reflecting the nature of the disease, Caucasian patients (83%) were in the vast majority. To be explored in later sessions, Dr Bergenstal suggested that the data collected would help answer whether various treatments and practices (particularly insulin delivery method and frequency of blood glucose monitoring) actually improved patient outcomes in real-life settings. He indicated that the data could challenge or confirm many of the assumptions held about diabetes care as well, noting in particular low rates of weekly downloading (at most 2% in patients over 13 years of age) and CGM use (at most 3% in patients under 25 years of age, although 14% in patients over 26 years of age; we believe actual use nationally is even lower). In addition, the percentage of patients experiencing severe hypoglycemia (11–14% in patients over 26 years of age) or diabetic ketoacidosis (DKA; 4–10% across all ages) in the past year were surprisingly high.

Satish Garg, MD (University of Colorado, Denver, CO, USA), followed by presenting a wealth of rich data on the use of self-monitoring of blood glucose (SMBG) and CGM in the Registry. In the cohort of SMBG users, demographics of frequent testers were as to be expected, with patients on insulin pumps and of higher incomes testing more frequently. In what Dr Garg dubbed ‘the most important slide of the presentation’, results indicated a near 2.0% improvement in A1c in patients testing ≥10 compared with 0–2 times per day; this relationship was maintained when results were broken down by age group and into patients on pumps versus multiple daily injections (MDI), provoking Dr Garg to ask, ‘How many more randomized trials does one need?’ A similar trend was seen among CGM users, with an approximate 0.5% benefit in A1c compared with non-CGM users across all age groups, with mean A1c values declining with increasing frequency of use. Approximately 65% of patients reported discontinuing previous CGM use, with the most frequently cited reasons including not wanting to wear the device anymore, too many alarms, accuracy concerns, and cost. We believe this is similar to SMBG and pump use in earlier days, when the development of the technology was in earlier stages and there was room for improvement. Overall, these results are a positive for CGM and monitoring companies, with a clear demonstrated benefit for their products (results we hope will be presented to payors and policymakers), although the data certainly make the current obstacles to wider adoption and use more apparent as well. It is clear that companies must be nimble in improving their products and we believe this is probably quite challenging in the current regulatory environment.

Irl B. Hirsch, MD (University of Washington, Seattle, WA, USA), augmented the T1D data by presenting some stunning data from the largest group of insulin pumpers ever studied. He remarked that understanding what the data are telling us is a unique opportunity. Fifty-five percent of the T1D Exchange sample used an insulin pump, a group of over 10 000 people. In this sample, a large majority reported using Medtronic pumps, followed by Animas and Insulet. Insulin aspart (Novo Nordisk’s Novolog) was the most commonly reported insulin used, particularly in children for reasons unknown. Interestingly, patients aged 26–64 years tended to leave in the infusion set for longer than recommended. Most notably, the use of insulin pumps was associated with a lower A1c than MDI for all ages (e.g. compared with MDI users, A1c was 0.6% lower in pumpers 18–25 years of age). Dr Hirsch also noted that younger people bolus more and use the bolus calculator more; although this did not confer an A1c advantage, we wonder about glucose variability broadly. Pump use was also greater for higher socioeconomic status. We believe the T1D Exchange presents a hugely exciting opportunity to further gather clinical insights, especially for use in reimbursement and public policy setting.

Steven M. Willi, MD (The Children’s Hospital of Philadelphia, Philadelphia, PA, USA), assessed the incidence of diabetic ketoacidosis (DKA) and severe hypoglycemia (SH), identified the clinical and demographic factors that are associated with acute complications, and examined how they relate to insulin delivery method. Approximately 7% of respondents in the T1D Registry have had one or more episodes of DKA, with the majority (5%) having had only one episode in the past year. ‘Tricky’ teens and young adults had the most DKA, whereas patients with a lower A1c or use of an insulin pump or CGM had much lower rates of DKA. At the other end of the glucose scale, SH, defined as a seizure or coma, was scarily common: 7.5% of patients had had at least one episode in the past 12 months, 4% had had two or more, and 0.75% had had nine or more. In contrast with DKA, children and young adults had lower rates of SH, which could be because of more physiological resilience. Rates of hypoglycemia also tended to rise with age to levels higher than in the Diabetes Contorl and Complications Trial (DCCT). Surprisingly, there is no clear relationship at all between A1c and the incidence of SH, except possibly for younger people (where higher A1c corresponds with more SH). Again, both the pump and CGM (to a small extent) are associated with fewer episodes. Although conventional wisdom has been that tighter control leads to more frequent SH, clearly educated pump and CGM use are beneficial. Finally, it was very clear that both DKA and SH disproportionately affect minorities and those of lower socioeconomic status.

Jay Skyler, MD (University of Miami Miller School of Medicine, Miami, FL, USA), closed the conference by addressing a fascinating area of research in type 1 diabetes, namely that of multihormonal control. He began by noting that an insulin/glucagon-only view of type 1 diabetes is overly simplified; given the complex biology, we also need to consider the effects of other hormones, such as amylin, GLP-1, leptin, and C-peptide. We enjoyed his comprehensive research review of each hormone, ranging from work in the 1970s on glucagon to GLP-1 and leptin studies in the past couple of years. The theme that ran throughout his presentation was the importance of suppressing glucagon, one of the many effects these hormones have on the body. Overall, Dr Skyler believes insulin-only control of type 1 diabetes is insufficient and attention to other hormones may improve both glycemic control and patients’ quality of life. We were glad to hear his enthusiasm and hope that the paucity of research into other hormones for type 1 diabetes is addressed in coming years.


Company Updates

Company Updates

November 30:Advinus Therapeutics reported positive results from a 14-day multiple ascending-dose study for its once-daily glucokinase activator GKM-001 in 60 people with type 2 diabetes. The results demonstrated effective glucose lowering across all doses tested without incidence of hypoglycemia or other clinically relevant adverse events
December 6:WellDoc announced positive results from a real-world demonstration project for its mobile-based diabetes management system, the WellDoc DiabetesManager. Over an average follow-up period of 12 months, those using the WellDoc Diabetes Manager reduced their emergency room visits and hospital stays by 58% compared with the 12 months prior to the initiation of the project. All 32 participants reported that the instant coaching feedback was helpful and agreed that the system increased the frequency of their blood glucose testing
December 6:The European Commission approved Novartis’ DPP-4 inhibitor Galvus (vildagliptin 50 mg q.d.) for use in patients with type 2 diabetes who have moderate or severe renal impairment
December 8:The US Food and Drug Administration (FDA) approved Sanofi’s iBGStar, a compact blood glucose meter that can connect to iPhone and iPod Touch devices, allowing for the transfer of blood glucose readings to an iPhone application. The application allows for visualization of glucose results over time, the ability to email information to family and healthcare professionals quickly, and the ability to add contextual tags to individual blood glucose readings
December 21:Vivus reported topline results from the Fetal Outcome Retrospective TopiRamate ExpoSure Study (FORTRESS), a study to assess the rate of congenital deformities following topiramate use. In the study, in mother–infant dyads that were exposed to topiramate during the first trimester of pregnancy (the total topiramate cohort), the prevalence of oral cleft was 0.36% (7/1945), compared with rates of 0.16% (21/13 512) in infants whose mothers had previously taken antiepileptic drugs but not during the pregnancy of interest (the formerly exposed cohort) and 0.07% (9/13 614) in infants of women with similar medical profiles to those in the total topiramate cohort (the similar medical profile cohort). The relative risk (95% confidence interval) of an oral cleft was 2.36 (0.99–5.59) for the total topiramate cohort versus the formerly exposed cohort and 5.44 (2.03–14.61) for the total topiramate cohort versus the similar medical profile cohort. Full, validated results from FORTRESS are expected in the second half of 2012
December 22:Novo Nordisk filed its next generation once-daily basal insulin (insulin degludec) for approval in Japan. The company previously submitted both insulin degludec and degludecPlus (an insulin degludec and insulin aspart coformulation) in the US on 29 September 2011 and in the European Union (EU) on 26 September 2011. The US FDA has subsequently set a Prescription Drug User Fee Act (PDUFA) date of 29 July 2012 for these products. Phase III trials have suggested reduced incidence of hypoglycemia and greater dosing flexibility with insulin degludec versus Lantus (insulin glargine; Sanofi, Paris, France)
January 4:Medtronic announced US FDA approval of mySentry, a remote monitoring system that enables a parent or caregiver to see real-time insulin pump and CGM information from another room. The device is indicated for remote home monitoring of a single Minimed Paradigm Real-Time Revel insulin pump and has two principal components: (i) a monitor that displays CGM and insulin pump information (e.g. at a parent’s or caregiver’s bedside); and (ii) the ‘outpost’, which sends and receives information from the insulin pump to the monitor (e.g. in a child’s bedroom)
January 4:Arena announced that it had submitted its response to the Complete Response Letter for lorcaserin to the US FDA. The company’s response included results from BLOOM-DM (the trial in which lorcaserin was evaluated in patients with type 2 diabetes), as well as data and analyses further characterizing the tumor findings from a 2-year rat carcinogenicity study. These studies investigated the mechanism of action of lorcaserin-associated rat mammary tumors and used rats to study lorcaserin’s abuse potential; in vitro studies were also set up to characterize lorcaserin’s serotonin 5-HT2 receptor activity. Management expressed confidence that the mammary tumor mechanism-of-action studies demonstrate a link between lorcaserin, prolactin, and the development of mammary tumors. The US FDA has subsequently classified Arena’s response as a Class 2 resubmission, placing potential approval of lorcaserin on 27 June 2012
January 4:Osiris Therapeutics reported interim results from a Phase II trial of Prochymal, a formulation of adult mesenchymal stem cells (MSCs), in people with newly diagnosed type 1 diabetes (n = 63). The study examined the ability of Prochymal to preserve β-cells and slow the progression of type 1 diabetes over a 2-year period. At 1 year, intravenous infusions of Prochymal were reportedly well tolerated, with no differences in adverse event rates between the Prochymal and placebo groups. With regard to efficacy, no significant differences in stimulated C-peptide levels were observed between the two arms (the primary efficacy endpoint), although a trend towards fewer hypoglycemic events in the Prochymal arm was observed. A full analysis will be performed following an additional year of follow-up (for a total of 24 months)
January 9:D. Medical received European Conformity (CE) mark approval for its Spring Zone durable insulin pump in the EU. The product is differentiated by its small size and light weight (85 g, including 300 units of insulin and a battery), quiet delivery, environmental (pressure and temperature) adaptability, and strong safety system, which enables real-time checking for occlusion, detachment, or pump malfunction, any of which triggers insulin delivery to stop. D. Medical is currently seeking a worldwide partner for commercialization of its pump technology
January 11:Lexicon reported topline results from a Phase I study evaluating the synergistic effects of combined LX4211 (Lexicon’s dual SGLT-2 and SGLT-1 inhibitor) and sitagliptin (Januvia; Merck, Whitehouse Station, NJ, USA) therapy. In the study, 18 participants with type 2 diabetes were administered 400 mg LX4211, 100 mg sitagliptin, or both at separate times following a 14-day washout of metformin. The combination therapy was found to: (i) significantly increase total GLP-1 compared with sitagliptin alone (< 0.001); (ii) significantly increase active GLP-1 compared with both individual therapies alone (< 0.001); (iii) significantly increase total petptide YY compared with sitagliptin alone (< 0.05), although much less so than LX4211 alone; (iv) significantly lower postprandial glucose compared with either drug alone (< 0.05); and (v) significantly lower blood insulin levels compared with sitagliptin alone (< 0.05). Each of the three treatment regimens was reported to be well tolerated
January 12:The US FDA approved Roche’s Accu-Chek Nano SmartView blood glucose meter. The meter is reportedly smaller than a credit card and will be the first meter to use Accu-Chek SmartView strips, Roche’s first strips not to require coding. The SmartView strips will be the second strips in the US to use Roche’s maltose-independent strip chemistry, which debuted in late 2011 with the Aviva Plus strips. The Nano SmartView’s other features include a large, backlit LCD display (white text on black background), customizable test reminders, pre-/post-meal tagging, and calculation of glucose averages
January 18:Bristol-Myers Squibb and AstraZeneca announced the receipt of a complete response letter from the US FDA for their SGLT-2 inhibitor dapagliflozin in which the agency requested ‘additional clinical data to allow a better assessment of the benefit-risk profile’, including data from ongoing studies and potentially data from additional trials. Although little additional information regarding these requests was provided by the companies, it is suspected that the agency’s concerns largely center around the drug’s potential bladder and breast cancer risk and, to some extent, its potential hepatotoxicity, the paucity of data for specific subgroups, the potential use of dapagliflozin in renally impaired individuals, and the lack of pharmacokinetic and pharmacodynamic data, concerns voiced by members of the Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) during their discussion of the benefit–risk profile of dapagliflozin in July 2011
January 18:Novartis launched its DPP-4 inhibitor Galvus (vildagliptin) in China. Galvus is approved for use as an add-on therapy to metformin in the country.
January 27:Amylin announced that the US FDA had approved exenatide once weekly (Bydureon) as an adjunct therapy to diet and exercise in adults with type 2 diabetes. Bydureon is approved for use as both a second-line monotherapy (i.e. after discontinuing metformin) and in combination oral diabetes medications (i.e. metformin, sulfonylureas, thiazolidinediones). A pen for Bydureon is expected to be available by late 2012/early 2013, which should help simplify administration of the drug (Bydureon currently requires manual reconstitution before injection). Amylin also revealed plans to initiate Phase III trials for a suspension formulation of exenatide once weekly in 2012 (eliminating the need for reconstitution) as well as Phase III trials for a once monthly version of exenatide in 2013
January 30:The US FDA approved Jentadueto, Eli Lilly and Boehringer Ingelheim’s fixed-dose combination tablet for the treatment of type 2 diabetes comprised of the DPP-4 inhibitor Tradjenta (linagliptin) and metformin. The drug requires twice daily dosing and is contradicted in patients with renal impairment
February 3:Merck announced that the US FDA had approved Janumet-XR, a fixed-dose combination of the DPP-4 inhibitor Januvia (sitagliptin) and extended-release metformin. Janumet-XR is now the second DPP-4 inhibitor/extended-release metformin combination to be approved in the US, following Bristol-Myers Squibb’s and AstraZeneca’s Kombiglyze-XR. Janumet-XR can be administered once-daily and is contradicted in patients with renal impairment
February 8:Sanofi revealed expectations to file its once-daily GLP-1 agonist lixisenatide (Lyxumia) for approval in the US in November 2012. The compound was filed in the EU in October 2011 and a decision is expected from the European Medicines Agency (EMA) by the end of 2012. Sanofi management particularly stressed the potential use of lixisenatide on top of basal insulin therapy because of the drug’s demonstrated postprandial effects. In the Phase III trial GETGOAL Duo 1 (n = 446), the addition of lixisenatide to Lantus (insulin glargine) significantly decreased A1c compared with the addition of placebo to Lantus over 24 weeks (< 0.0001). Mean A1c decreased from 7.60% to 6.96% in the lixisenatide-treated group (placebo value not given). Lixisenatide significantly improved 2-h postprandial glucose compared with placebo (mean difference −3.16 mmol/L; < 0.0001). Mean weight loss was also significantly greater with lixisenatide treatment (mean difference in body weight change between the lixisenatide and placebo-treated groups −0.89 kg; = 0.0012)
February 8:Sanofi announced that two Phase III trials (EDITION I and EDITION II) for the company’s next-generation insulin glargine product were now underway. The product is expected to have a flatter pharmacodynamic and pharmacokinetic profile than Lantus, as well as a lower injection volume. Both trials will enroll approximately 800 patients with diabetes requiring high-dose insulin, and both are expected to be completed by March 2013
February 9:Cellnovo announced the launch of the company’s mobile-connected diabetes management system in the UK. The Cellnovo system is comprised of an insulin patch pump that communicates wirelessly with a hand-held touch-screen controller. The controller integrates a blood glucose meter as well as an activity monitor and displays and stores blood glucose and insulin delivery data. The controller also features a mobile data connection to a web-based clinical management system. When the controller enters sleep mode (usually after 3 min non-activity), it automatically transmits information (blood glucose, activity, pump, food) to the online portal, where the patient and healthcare providers can view it
February 15:Topline data were presented from a Phase I/II trial for Bayhill’s proinsulin DNA vaccine (BHT-3021) for the treatment of type 1 diabetes. In the trial, 80 adults with type 1 diabetes were randomized to receive once weekly intramuscular injections of BHT-3021 (0.3, 1, 3, or 6 mg) or placebo for 12 weeks. Participants were followed-up for to a total of 36 weeks. Overall, the therapy was found to be safe and well tolerated. Promisingly, although not powered to detect differences in clinical efficacy, the 1.0 mg dose was found to significantly preserve C-peptide over placebo at 15 weeks (= 0.026). Bayhill is currently planning a Phase II trial that will examine the 1.0 mg dose in a recent-onset type 1 diabetes population
February 21:Recruitment was initiated for the pivotal trial that will support the filing of Medtronic’s low glucose suspend (LGS) insulin pump (the Veo) in the US. The 260-patient study, called ASPIRE, has an estimated completion date of June 2013. It will randomize patients to one of two groups: (i) an experimental group using the Medtronic Veo with LGS; or (ii) a control group wearing the Revel 2.0 with no LGS feature. The primary objective of the 5-month study is to ensure that LGS does not result in an unacceptable worsening of glycemic control as measured by A1c. The study’s secondary objective is to demonstrate that the use of LGS is associated with a reduction in nocturnal hypoglycemia (as measured by CGM)
February 22:During the second FDA Advisory Committee meeting for Vivus’ Qnexa, the EMDAC voted 20–2 in favor of recommending approval of Qnexa to treat overweight and obesity despite lingering concerns and uncertainties regarding potential teratogenicity and cardiovascular side effects. Overall, the final outcome of the panel was determined by a number of key factors, including: (i) the advisory committee’s recognition of the significant unmet medical need for the treatment of obesity; (ii) Vivus’ comprehensive risk mitigation strategy; (iii) the ability for better oversight of the use of phentermine and topiramate in combination; (iv) the compelling efficacy of Qnexa; and (v) comfort in the fact that the FDA has the authority to hold Vivus accountable for a post-approval cardiovascular outcomes trial to be conducted in a timely manner. The FDA is expected to make a final decision by Qnexa’s PDUFA date of 17 April 2012
February 23:Dexcom announced that it had completed the pivotal trial for its fourth-generation continuous glucose monitor sensor and expects to file a premarket approval (PMA) application with the US FDA by the beginning of the second quarter of 2012. Topline results from the study demonstrated an impressive MARD of 12.3%. Assuming a standard 6-month FDA review, the sensor is on track for approval in late 2012 at the earliest. The filing of the PMA supplement for the Animas Vibe (Animas/Dexcom’s CGM-enabled insulin pump) is expected 100 days after the PMA filing for the fourth-generation sensor