Journal of Diabetes NEWS

Currently, obesity is the leading preventable cause of death worldwide and it is viewed as one of if not the most pressing public health epidemics of the 21st century. Individuals who are obese are at a greater risk of developing various diseases, including Type 2 diabetes, cardiovascular disease, sleep apnea, certain types of cancer, osteoarthritis, asthma, erectile dysfunction, and others.1 Moreover, the risk of early death is increased by 30% with every 3.1 kg (6.8 lbs) gained and severely obese individuals tend to die 8–10 years sooner than normal weight individuals.2 One of the major concerns about obesity is the increasing health care expenditures required to treat these individuals. In mid 2010, the Organization for Economic Cooperation and Development (OECD) and the World Health Organization (WHO) released a report that used an economic approach to highlight trends in obesity, causal factors affecting obesity, and effective prevention strategies.2 The first part of the OECD report discusses the alarming increase in the worldwide rate of obesity over the past 30 years, especially as the physical, social, and economic environment continues to present an obesogenic milieu. Before 1980, obesity rates were generally below 10% worldwide, but these rates have doubled or tripled in most countries. In almost half of the OECD countries (Australia, Austria, Belgium, Canada, Chile, Czech Republic, Denmark, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Israel, Italy, Japan, Korea, Luxembourg, Mexico, Netherlands, New Zealand, Norway, Poland, Portugal, Slovak Republic, Slovenia, Spain, Sweden, Switzerland, Turkey, UK, and US), 50% or more of the population is now overweight. Overall, the increasing obesity epidemic has developed as a result of multiple factors that have made lasting changes in people’s lifestyles. One commonly discussed factor is the increasing supply and availability of food and the shift from traditional meals prepared with raw ingredients to fast food. Compounding this change in diet are general decreases in levels of physical activity. Although the obesity trends do provide a great deal of data to describe the current situation, the more interesting part of the OECD report looks at what can be done to stem this epidemic. The authors first discuss the role that governments can take to improve health-related behaviors. It will be important for governments to either increase the availability of new healthy dietary and lifestyle options or to make existing healthy options more affordable and accessible. At least in the OECD countries, several governments have tried to promote a culture of living a healthy life through school programs or changes in health systems. For example, programs targeting school-age children are designed to educate them about healthy lifestyles through healthier school lunches and increased physical activity. With health systems, there have been steps to widely disseminate information about nutrition guidelines and active lifestyles. What will be particularly important as we move forward are policy changes in the food and beverage industry that affect food product formulations and provide information about food contents. The report moves on to discuss which interventions have been shown to be successful and effective. Interventions tackling obesity tend to fall into three areas: (i) health education and promotion; (ii) regulation and fiscal measures; and (iii) counseling in primary care. If these measures are combined into a comprehensive prevention strategy, it is estimated that the price of countering obesity would be as low as US$12 per capita in Mexico, US$19 per capita in Japan and England, US$22 per capita in Italy, and US$32 per capita in Canada. Furthermore, these programs are estimated to prevent 55 000 deaths from chronic disease in Mexico, 155 000 deaths in Japan, 70 000 deaths in England, 75 000 deaths in Italy, and 40 000 deaths in Canada. Interestingly, the report highlighted that individual counseling by primary care physicians was the most effective preventative measure, but it was also the most expensive. One thing to keep in mind with these preventative strategies is that it may not necessarily reduce healthcare expenditures because people will be living longer. Yet, there should be improved population health, longevity, and quality of life. Although the OECD report focused almost exclusively on obesity rates in Western countries, the obesity epidemic is also concerning in Asia, where globalization, population movements, technology transfers, economic growth, and East–West exchanges have promoted the adoption of a more Western diet and lifestyle.3 Although the percentage of the population that is overweight or obese in Asian countries is generally lower than that in Western countries, the prevalence of diabetes in most Asian countries (including China, Korea, Singapore, Taiwan, and Thailand) is similar to or higher than the prevalence rates in Western countries.2,4,5 Such trends indicate that the risks for Type 2 diabetes begin at a lower body mass index (BMI) cut-off for Asians. In fact, a recent study by Palaniappan et al. found a significantly higher prevalence rate of metabolic syndrome among Asian Indian, Chinese, Filipino, Japanese, Korean and Vietnamese individuals than non-Hispanic White individuals in every BMI category.6 With these apparent differences in the pathophysiological manifestation of Type 2 diabetes between those of Asian and European descent, the prospects of soaring obesity rates in Asia, which will likely accompany the rapid economic development in this region in the coming decades, is alarming, at best. It is clear that tremendous efforts will need to be made in Asia to stem both the obesity and diabetes epidemics in the near future, not only through the implementation of effective and comprehensive prevention strategies, such as those outlined above, but also through increased investment and research into improved diagnostic tools, therapies, and treatment strategies aimed specifically at Asian populations. Shortly after the publication of the OECD’s report on obesity, we attended The Obesity Society’s 28th Annual Scientific Meeting, held 8–12 October 2010 in San Diego, California (http://www.obesity.org/obesity2010/abstracts.asp, accessed September 2010). Every year, The Obesity Society’s meeting is one of the more important and well-attended obesity conferences worldwide, and this year was no different. At the meeting we had the opportunity to learn from a number of leading experts on a variety of topics, including obesity prevention, weight loss drug development, bariatric surgery, nutrition, and public policy. Below we present some of our top highlights. Aila Rissanen, MD, PhD (Helsinki University Central Hospital, Helsinki, Finland), presented new data on the effects of Novo Nordisk’s glucagonlike peptide-1 (GLP-1) agonist liraglutide (Victoza) on the prevalence of prediabetes and metabolic syndrome in obese adults without Type 2 diabetes over 104 weeks. Study participants (n = 564) were randomized to one of six arms: orlistat 120 mg t.i.d.; placebo; liraglutide 1.2 mg; liraglutide 1.8 mg; liraglutide 2.4 mg; or liraglutide 3.0 mg. The inclusion criteria required participants to have a BMI between 30 and 40 kg/m2, a stable body weight, and fasting plasma glucose (FPG) <126 mg/dL (i.e. non-diabetic). At 52 weeks, patients on all doses of liraglutide and placebo were switched to the 2.4 mg dose, the most efficacious dose of the drug with regard to weight loss (those on orlistat continued treatment with orlistat for the duration of the trial). However, after analysis of the initial 52-week data, the 3.0 mg dose of liraglutide was determined to provide the greatest reductions in weight. Consequently, patients on the 2.4 mg dose were subsequently switched to the 3.0 mg dose for the remainder of the trial. After 104 weeks, there was a considerable decline in the prevalence of metabolic syndrome across all treatment groups: orlistat (38% prevalence of metabolic syndrome at baseline vs. 20% at week 104), placebo (51% vs. 21%), liraglutide 1.2 mg (42% vs. 22%), liraglutide 1.8 mg (36% vs. 15%), liraglutide 2.4 mg (37% vs. 16%), and liraglutide 3.0 mg (42% vs. 16%). The prevalence of prediabetes also fell significantly with liraglutide treatment: orlistat (29% prevalence of prediabetes at baseline vs. 32% at week 104), placebo (33% vs. 24%), liraglutide 1.2 mg (31% vs. 22%), liraglutide 1.8 mg (30% vs. 14%), liraglutide 2.4 mg (34% vs. 16%), and liraglutide 3.0 mg (29% vs. 16%). Notably, those in the orlistat group experienced a 14% increase in the prevalence of diabetes; we assume this is due to the fact that diabetes is a progressive disease, although it makes us wonder about the impact of orlistat on β-cells. Of the patients with prediabetes at baseline (approximately one-third of the population), a sizable 63% of the liraglutide 2.4 mg and 3.0 mg patients (n = 51) had normalized their glycemic control after 104 weeks. Of the remaining 37% of these liraglutide-treated patients with prediabetes at baseline, 35% continued to have prediabetes at week 104 and 2% progressed to diabetes. Liraglutide demonstrated a marked improvement over orlistat (n = 22), with 32% of patients normalizing their glucose and 68% remaining prediabetic (the percentage going to diabetes was zero). Of those with normoglycemia at baseline, 7% of liraglutide 2.4 mg/3.0 mg-treated patients progressed to prediabetes, compared with 17% of orlistat-treated patients. (All numbers are based on the intent-to-treat (ITT) population with last observation carried forward (LOCF) analysis.) Dr Raissanen briefly presented data on adverse events. Approximately 6% of patients in both the orlistat and placebo groups experienced serious adverse events, compared with 10%, 11%, 8% and 11% in the 1.2, 1.8, 2.4, and 3.0 mg liraglutide-treated groups, respectively. The percentage of patients withdrawing from the study due to adverse events tended to increase with dose (3% with orlistat, 6% for placebo, 8% for liraglutide 1.2 mg, 13% for liraglutide 1.8 mg, 14% for liraglutide 2.4 mg, and 10% for liraglutide 3.0 mg). Not surprisingly, gastrointestinal (GI)-related adverse events were the most commonly reported with liraglutide, with significantly higher rates of nausea and vomiting for all doses of the GLP-1 agonist than with placebo or orlistat. There were no major hypoglycemic episodes requiring third-party intervention and no confirmed cases of FPG <56 mg/dL for any treatment. In a separate poster presentation, Michael Lean, MD (University of Glasgow, Glasgow, UK), presented the weight loss results from the above study on liraglutide. Weight loss was significantly greater for patients receiving liraglutide 2.4/3.0 mg than for patients receiving orlistat. Using ANCOVA analysis on the ITT population with LOCF from randomization, patients receiving liraglutide 2.4/3.0 mg reached an estimated average of 5.3 kg (11.7 lbs) weight loss compared with an estimated average of 2.3 kg (5.1 lbs) weight loss with orlistat (P < 0.001). Using similar analyses on the completer population from screening, including 2 weeks run in period with lifestyle changes, patients on liraglutide 2.4/3.0 mg lost an estimated average of 7.8 kg (17.2 lbs), whereas those on orlistat lost 5.4 kg (11.9 lbs) on average (P = 0.09). Using observed values (ITT but not LOCF), at the end of 104 weeks those on orlistat lost an average of 6.7 kg (14.8 lbs), whereas those originally assigned to placebo lost an average of 9.4 kg (20.7 lbs) and those originally assigned to liraglutide 1.2, 1.8, 2.4, and 3.0 mg experienced average weight losses of 8.8 kg (19.4 lbs), 9.9 kg (21.8 lbs), 9.4 kg (20.7 lbs), and 10.3 kg (22.7 lbs) from baseline, respectively (baseline weights were not provided). Although the placebo weight loss looks high at first glance, as a reminder these patients were switched to liraglutide at 52 weeks. This enabled the gathering of additional safety data on the high doses of liraglutide (for those originally in the placebo group) and also showed that weight loss seen in active treatment groups from randomization could be repeated when liraglutide was used to “replace” placebo starting at week 52. The percentage of patients achieving 5% and 10% reductions in weight at the two-year mark was also significantly higher for patients receiving liraglutide 2.4/3.0 mg compared with patients receiving orlistat. Using logistic regression analyses on the ITT population with LOCF from randomization, 52% of patients on liraglutide 2.4/3.0 mg lost at least 5% of body weight, whereas only 29% of those on orlistat lost over 5% in body weight (P < 0.001); 26% of patients on liraglutide 2.4/3.0 mg experienced at least 10% weight loss, compared with 16% of patients on orlistat (P = 0.04). We certainly see the results from this trial as a major positive for liraglutide (and likely the GLP-1 class as a whole); the drug now appears to hold promise not only as a treatment for Type 2 diabetes, positioning liraglutide as a powerful tool with which to address both the diabetes and obesity epidemics. We hope future studies will confirm these findings and encourage companies to work with regulatory agencies to create official prediabetes and weight loss indications for currently available and future GLP-1 agonists. Also in the poster session, Corby Martin, PhD (Pennington Biomedical Research Center, Baton Rouge, Louisiana), discussed results from a double-blind randomized trial that sought to elucidate whether lorcaserin (Arena Pharmaceutical’s 5-HT2c receptor agonist under development as a weight loss therapy) mediates weight loss by reducing energy intake and appetite. Overweight and obese adults were randomized to receive placebo (n = 28) or 10 mg lorcaserin twice daily (n = 29) for 56 days. In the first 7 days of the study, weight maintenance was imposed on all study participants. Beginning on day 8, all participants began targeting a 600 kcal/day energy deficit through a standardized diet and exercise plan. Food intake was measured in the laboratory at lunch and dinner after an overnight fast. Furthermore, ratings of appetite were measured using the Eating Inventory. At baseline, the average age was approximately 49 years, body weight was 101.3 kg (23.4 lbs) in the placebo arm and 96.7 kg (213.2 lbs) in the lorcaserin arm, and average BMI was approximately 35 kg/m2. Participants in the lorcaserin arm achieved significantly greater weight loss than those in the control arm at the end of the study. Patients treated with lorcaserin averaged 3.7 kg (8.1 lbs) weight loss, whereas individuals treated with placebo averaged 2.2 kg (4.8 lbs) weight loss (P < 0.01). We note that much of the difference in weight loss between the groups was attributable to differences in fat-free mass. Lorcaserin was also found to significantly decrease energy intake and appetite ratings compared with placebo. After 7 days, the period in which weight maintenance was enforced, while food/energy intake was observed to decrease in both groups, the reduction in food intake was significantly greater in lorcaserin-treated patients (470 kcal) than in placebo-treated subjects (205 kcal; P < 0.01). Appetite/prospective food eating was also significantly decreased over the 56-day study in the lorcaserin group, as determined by the Eating Inventory (P < 0.05). Thus, the investigators concluded that lorcaserin reduces weight primarily through its effects on energy intake and appetite. On 22 October 2010, Arena received a complete response letter from the US Food and Drug Administration (FDA) for lorcaserin (see http://invest.arenapharm.com/releasedetail.cfm?ReleaseID=521977, accessed October 2010), delaying the drug candidate’s approval in the US. The agency’s concerns included the unknown implications of mammary masses in female rats, the exposure–response relationship for mammary adenocarcinomas, and the unclear mechanism of action and safety margin for lorcaserin-related brain astrocytomas. Arena is preparing to file lorcaserin in the European Union in 2011. Robert Kushner, MD (Northwestern University Feinberg School of Medicine, Chicago, Illinois), presented on the use of bariatric surgery as a weight loss tool. He first provided an overview of the four bariatric procedures currently performed in the US: (i) lap adjustable gastric band surgery (LAGB); (ii) gastric sleeve surgery (GS); (iii) Roux-en-Y gastric bypass (RYGB); and (iv) bilial pancreatic diversion (BPD). Historically, RYGB has been the gold standard, although LAGB is gaining traction. RYGB has considerable impact on the GI tract, requiring two anastomoses and resulting in stomach division and decreased micronutrient uptake. In contrast, LAGB has minimal impact on the GI tract, with minimal trauma and no effect on micronutrient absorption, as well as being reversible surgery. However, LAGB surgery introduces the possibility of slippage leaks and infections. Meanwhile, RYGB remains the preferred method of bariatric surgery for patients with diabetes because of its effects on neuromodulation and gut hormone levels. Dr Kusher next detailed the efficacy of bariatric surgery for weight loss, as well as for its related comorbidities. In a meta-analysis performed by O’Brien et al. in 2006, RYGB, LAGB, and BPD all led to 50% or greater reductions in excess weight, sustained at 10 years after the operation.7 Patients who undergo RYGB tend to experience more rapid weight loss, whereas patients who undergo LAGB tend to experience more gradual weight loss (both result in an average long-term reduction in excess weight of 50%–60%). Furthermore, bariatric surgery also leads to improvements and resolution in Type 2 diabetes, hypertension, hyperlipidemia, and sleep apnea.8 In a study by Schauer et al. in 2003, patients with Type 2 diabetes who underwent bariatric surgery decreased insulin and oral antidiabetic medication use by approximately 80%.9 However, Dr Kusher pointed out that some bariatric procedures result in the malabsorption of micronutrients. 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