<i>Journal of Diabetes</i> News

It is no secret that Type 2 diabetes and obesity go hand-in-hand: although not always concomitant, the relationship between the two disorders is clear. Thus, as obesity rates continue to grow in the Asia Pacific, so does the prevalence of Type 2 diabetes. Along these lines, this quarter we present to you the latest developments in both these areas, including coverage from the world-renowned Cleveland Clinic’s 4th Annual Obesity Summit and updates on the various Type 2 diabetes and obesity drugs in development for use in the Asia Pacific. In the face of rapid industrialization, obesity rates throughout the Asia Pacific have grown precipitously. Particularly in urban areas, eating habits and nutritional intake have started to mimic Western practice, driving the increasing prevalence. Although overall rates have remained low, the World Health Organization estimates that approximately 20% of individuals are obese in some cities in China (http://www.who.int/mediacentre/factsheets/fs311/en/index.html, accessed 21 September 2009); similar growth rates in Japan have prompted lawmakers to require all employers to join the fight against obesity, inflicting punitive measures for those who are unable to reduce the number of obese employees by 10% by 2012 and by 25% by 2015.1 Toward that end, we were lucky to attend The Cleveland Clinic’s 4th Annual Obesity Summit, held 9–11 September 2009, in Cleveland, Ohio. A world-renowned leader in the treatment of and research into obesity and metabolic disorders, the Cleveland Clinic promotes the use of bariatric surgery as a modern treatment for both obesity and Type 2 diabetes. The Clinic’s 4th annual meeting brought together leading physicians from around the world to discuss all aspects of obesity treatment, from the biological basis to the cost-effectiveness of treatment. Below, we present some highlights from the meeting. Bruce Wolfe, MD (Oregon Health and Science University, Portland, OR, USA), compared the adverse outcomes of gastric banding and gastric bypass procedures. Despite what he termed the documented benefits of improved surgical methods, only 1–2% of qualified patients decide to undergo bariatric surgery every year. In order to assess patient outcomes, Dr Wolfe and colleagues conducted the Longitudinal Assessment of Bariatric Surgery (LABS), a 30-day observational study2 that analyzed the following primary endpoints: death, deep vein thrombosis/pulmonary embolism, failure to discharge, and the requirement of re-intervention. They followed 4776 patients who were undergoing their first bariatric surgery. Of these, 25% received an adustable gastric band laparoscopically (LAP-BAND), 62% underwent laparoscopic Roux-en-Y gastric bypass surgery, 9% underwent open Roux-en-Y gastric bypass surgery, and 3% underwent another procedure. The comorbidities distribution was fairly typical for this population: 55% had hypertension, 49% experienced obstructive sleep apnea, 33% had diabetes, and 23%Kelly L. Close, Eric M. Chang, and Melissa Y. Tjota are of Close Concerns (http://www.closeconcerns.com), 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 will include this News feature, in which Close, Chang, and Tjota review the latest developments relevant to researchers and clinicians. Readers of Journal of Diabetes involved in the clincal care of patients with diabetes (including students and educators) may request a 1-year subscription to Close Concerns’ monthly newsletter, Diabetes Close Up. Please write to[email protected]if interested. were asthmatic. Rates of adverse outcomes were encouragingly low. After 30 days, only 0.3% of patients who either received LAP-BAND or underwent laparoscopic gastric bypass died, and 4.3% of these patients had at least one major adverse outcome (Dr Wolfe noted that this is very low for a procedure performed on such a high-risk patient population). Extreme body mass index (BMI) levels and an inability to walk more than 61 m were the strongest predictors of adverse outcome. Interestingly, the complication rate was increased by a factor of 4.8 for patients subjected to laparoscopic gastric bypass compared with those receiving a LAP-BAND. During his talk at The Cleveland Clinic’s 4th Annual Obesity Summit, Dr Wolfe also dispelled the myth that bands are only performed in lower-risk individuals, stating that was “certainly not true of this population”. Finally, a significant relationship was identified between the number of operations a surgeon performs every year and the proportion of adverse events experienced by the surgeon’s patients. After adjusting for the particular procedure (open versus laparoscopic) and patient risk factors, it was found that for every 10 cases per year in increased patient volume for a surgeon, the risk of adverse outcomes decreased by 10%.3 This association is especially pronounced in higher-risk individuals with obstructive sleep apnea (OSA), vein thromboembolism (VTE), and/or an inability to walk 61 m. In the session “Obesity in the Workplace”, Pierre-Yves Cremieux, PhD (University of Quebec, Quebec, Montreal, Canada), discussed the results of his research on the return on investment (ROI) of bariatric surgery, specifically identifying if and when patients financially “broke even” with respect to the cost of the surgery.4 The objective of this study, funded by Ethicon Endo-Surgery, was to determine whether bariatric surgery was economical for a patient’s employer. The study followed bariatric surgery patients (receiving the procedure for US$15 000–20 000) retroactively and matched these patients to people of similar medical profiles who did not undergo bariatric surgery. Large numbers of morbidly obese patients (n = 41 904) and non-morbidly obese patients (n = 82 033) were analyzed from claims databases. Dr Cremieux emphasized that although claims databases are suboptimal sources of data and are not official clinical data, they do represent claims made by the physician to the insurance company. To assess whether patients undergoing surgery saved money, overall medical costs were analyzed, including drug costs, physician costs, office visits, outpatient hospital visits, emergency room visits, and inpatient visits. Assuming a laproscopic procedure costs US$15 000 and an open surgery costs US$20 000, Cremieux et al.4 found that it will take 3 years for the laproscopic procedure and 4 years for the open surgery to compensate for the initial costs of surgery through drug costs, physician visits, emergency room visits etc. Not surprisingly, there was a significant correlation between morbid obesity and an increased incidence of comorbidities. Dr Cremieux noted that these results have particular applicability to unions, who have long-term employees and would save money by encouraging obese people to undergo bariatric surgery. For obese patients with Type 2 diabetes, the break-even point is reached even earlier than for the general obese population, which suggests that an employer may be more inclined to provide coverage for patients who are morbidly obese and have diabetes. Only two catastrophic events occurred (costs exceeded US$1 million) and both these patients were in the control group. Within 12 months, two-thirds of bariatric surgery patients who were previously on insulin stopped insulin usage. In contast, among non-insulin users, patients in the control group increasingly initiated insulin therapy, whereas almost no patients in the surgery group progressed to insulin therapy. Compared with the US, bariatric surgery is rarely performed in the Asia Pacific region (in 2004, only approximately 11 countries in the Asia Pacific region had started performing the operation, with approximately 636 operations performed overall5). However, the Asia-Pacific Bariatric Surgery Society (APBSS) continues to promote the operation throughout the region and recent research suggests positive results for Asian patients, with a mean total weight loss of 28.6% in the first year after surgery and remission of Type 2 diabetes in 78.5% of patients with the disease.6 In addition, the A1c level returned to < 7.0% in 81.5% of patients with Type 2 diabetes.6 We will wait to see whether the operation becomes more prevalent as the obesity and Type 2 diabetes epidemics continue to spread. 28–30 January 2010, Hong Kong, China: 1st International Congress on Abdominal Obesity (http://www2.kenes.com/abob/Pages/home.aspx, accessed 14 September 2009) Research continues to show that abdominal obesity or central obesity is a risk factor for developing Type 2 diabetes, hypertension, and cardiovascular disease. Results from such studies have helped fuel a greater awareness about the importance of abdominal obesity and the International Chair on Cardiometabolic Risk will host the 1st International Congress on Abdominal Obesity. This congress is one of the few international obesity conferences we know of, particularly for the Asia-Oceania region. Although specific details about each talk have not yet been published, the schedule overview shows that there will be a broad range of presentations, discussing issues from the pathophysiology of abdominal obesity, to nutritional management of abdominal obesity, and to the global cardiometabolic risk. It is also exciting to see that the confirmed list of speakers is quite the powerhouse list and includes Drs Takashi Kadowaki, Ronald Krauss, Peter Libby, Gerald Reaven, Marja-Ritta Taskinen, Luc Van Gaal, and Peter Wilson, among others. 26–28 March 2010, Kyoto, Japan: 14th International Congress of Endo_crinology (http://www.congre.co.jp/ice2010/, accessed 14 September 2009) Although this congress will include plenary lectures and sessions on a vast range of endocrinological diseases (e.g. parathyroid gland disorders, adrenal disorders, sex hormone disorders etc.), the list of symposia shows a strong emphasis on diabetes and obesity. We are most excited about the different pharmacotherapies and technologies that will be discussed at the conference. On the pharmacotherapy side, there will be talks about the recent progress with ghrelin, G-protein-coupled receptors, sirtuins, protein kinases, protein phosphatases, and peptidomics. There will also be a few talks on new technology being used in endocrine research, as well as updates on research converting stem cells or progenitor cells to β-cells. In recent years, there has been considerably more movement in the diabetes drug development programs in the Asia Pacific region, especially since the region has proved to be an attractive emerging market for pharmaceutical companies. As was mentioned in our last column,7 it was estimated that there were 240 million individuals with diabetes in 2007, of which 110 million were in Asia. Moreover, of the estimated 380 million individuals expected to have diabetes in 2025, 60% will be in Asia. Not only do these individuals provide a large target population to market diabetes drugs and devices to, but they can also help in the drug-development process by participating in clinical trials. A significant rise has been seen in the number of clinical trials conducted in the Asia Pacific region because the costs are lower in these regions and the areas have large populations to work with. Thus, we bring you a review of what is happening on the drug development front in the Asia Pacific region. Alizyme and Takeda have been working on the development of cetilistat (ATL-962), which is currently in Phase 3 trials in Japan. Cetilistat is a lipase inhibitor (similar to orlistat, Roche’s Xenical/GlaxoSmithKline’s Alli) that blocks fat digestion and absorption, consequently reducing caloric intake. The initial partnership agreement was reached in September 2004 and included a milestone US$3 million payment from Takeda in September 2008 upon the decision to move the drug into Phase 3 trials. However, on 24 July 2009, Alizyme suspended trading of its shares, entering administration; the company is still currently searching for a partner to fund the development of cetilistat in the West. In December 2008, AstraZeneca and Bristol-Myers Squibb announced the expansion of the scope of their collaboration on dapagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, to include development and commercialization of the drug candidate in Japan. Dapagliflozin is in Phase 2 trials in Japan. On 31 July 2009, the US Food and Drug Administration (FDA) also announced the approval of Onglyza (saxaglitpin; Bristol-Meyers Squibb, Ney York, NY, USA) within the US. The companies have voiced interest in driving Onglyza sales in emerging markets, with a particular focus on India and China. In partnership with Abbott, Daiichi Sankyo has been developing a peroxisome proliferator-activated receptor (PPAR)-γ agonist, namely CS-011 (rivoglitazone), which is currently in Phase 3 trials. There are plans to file the drug in the US, Europe, Japan, and Asia in 2011. PAM-1616 is a PPAR-γ modulator that is in preclinical development. In late June 2009, Glenmark announced that its dipeptidyl peptidase (DPP)-4 inhibitor melogliptin would likely begin Phase 3 trials in the US by the end of 2009, with an estimated launch in 2013. The Phase 3 trials are being designed to examine the compound as both a monotherapy and as a combination therapy with other Type 2 diabetes drugs. Hanmi Pharmaceuticals has a long-acting exendin-4 analog (LAPS-Exendin/HMC11260C) that is currently in preclinical development. The long-acting protein/peptide discovery (LAPSCOVERY) platform links proteins/peptides to a recombinant carrier, enabling extended duration of action and reduced doses. There are currently two products in Kissei’s pipeline being developed for Type 2 diabetes: KMV-0207 (Phase 1) and KGA-3235/DSP-3235 (Phase 1). Both are being developed with Dainippon Sumitomo (Japan). The mechanism of action for KMV-0207 is currently unknown, whereas KGA-3235/DSP-3235 is an SGLT2 inhibitor. Little information is available about non-PPARγ targets being developed by this company, all of which are still in the lead development stage. Novo Nordisk has been seeking approval of liraglutide, its once-daily glucagon-like peptide (GLP)-1 analogue, in Japan and China. The Pharmaceuticals and Medical Devices Agency decision in Japan is expected in the first half of 2010 and plans to file liraglutide in China are still pending. In addition, the company recently received approval in the second quarter of 2009 to market its long-acting insulin analogue Levemir (insulin detemir) in China; Novo Nordisk plans to launch the product in 2010. According to company management, this development will distinguish Novo Nordisk as the only company to market all three types of modern insulin in China. Otsuka has had an exclusive licensing agreement with Bristol-Myers Squibb for Onglyza (saxagliptin) in Japan since December 2006. Sanwa Kagaku Kenkyusho is developing a DPP-4 inhibitor (SK-0403) that is in Phase 2 trials. At the end of September 2008, Takeda filed an application with the Japanese Ministry of Health, Labour and Welfare for Actos (pioglitazone) orally disintegrating tablets in 15- and 30-mg doses. In addition, in October 2008, the company filed an application for the fixed-dose combination of Actos and metformin with the Japanese Ministry of Health, Labour and Welfare. The Japanese Ministry of Health, Labour and Welfare also approved Actos for concomitant therapy with biguanides in December 2008. Finally, Takeda has also expanded its pipeline of combination therapy pursuits with a Blopress (candesartan cilexetil; angiotensin receptor blocker)/Actos combination in Phase 3 trials and an alogliptin/metformin combination in Phase 1 trials. The company continues to pursue its strategy of combining Actos with other therapies and is looking to do the same with its DPP-4 inhibitor candidate alogliptin. Takeda has several drug candidates in its pipeline, as summarized in Table 1.

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