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 http://www.idf.org/worlddiabetescongress/programme, 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.
|Placebo||PHEN/TPM CR (7.5 mg/46 mg)||PHEN/TPM CR (15 mg/92 mg)|
|Least-squares mean % weight loss||2.8||6.6*||12.1**|
|Least-squares mean % excess weight loss||7.4||17.8*||32.6**|
|Mean ± SD baseline A1c (%)||6.7 ± 1.0||6.8 ± 1.0||6.6 ± 0.9|
|Least-squares mean % change in A1c at 56 weeks||0.05||−0.19||−0.50†|
|Mean ± SD baseline fasting glucose (mg/dL)||126 ± 29||136 ± 36||125 ± 29|
|Least-squares mean change fasting glucose at 56 weeks (mg/dL)||0.72||3.24||−11.7*|
|Resolution of diabetes (%)||1.7||8.3||15.4|
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 P < 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″; P < 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 P < 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.