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This study was undertaken to investigate the association among BMI and lipid hydroperoxide (LH), total antioxidant status (TAS), superoxide dismutase (SOD), and reduced glutathione (GSH). Ninety (n = 90) healthy males and females (n = 23/67) (29 normal weight (BMI: 22.74 +/- 0.25 kg/m(2)), 36 overweight (BMI: 27.18 +/- 0.23 kg/m(2)), and 25 obese (33.78 +/- 0.48 kg/m(2))) participated in the study. Data collected included anthropometric measures, fasting blood glucose, lipid profile, LH, TAS, and enzymatic antioxidants (SOD, and reduced GSH). The results of the study showed that obese individuals had significantly increased LH levels compared to normal-weight individuals (obese vs. normal weight (0.88 +/- 0.05 vs. 0.67 +/- 0.03 micromol/l, P < 0.01)) but the increased levels were not significantly different when compared to the overweight group (obese vs. overweight (0.88 +/- 0.05 vs. 0.79 +/- 0.05 micromol/l)). No other consistent significant differences in TAS, SOD, and GSH were identified between groups. This study concluded that only obesity and not moderate overweight elevates LH levels. Furthermore, the levels of TAS, SOD, and GSH in obesity do not explain the increased LH levels observed in obesity.

Uncertainties about the cardiovascular safety of sibutramine led to the SCOUT trial that is investigating sibutramine plus weight management in high-risk, overweight/obese patients. A 6-week lead-in period during which all patients received sibutramine permitted an initial assessment of tolerability. A total of 10,742 patients received sibutramine and 3.1% of these discontinued due to an adverse event; issues affecting more than 10 patients were drug intolerance, headache, insomnia, nausea, dry mouth, and constipation-, tachycardia-, and hypertension-related events. Serious adverse events, most commonly associated with the System Organ Class, Cardiac disorders, were reported by 2.7% of patients; however, the majority was not considered sibutramine-related. Adverse events relating to high blood pressure and/or pulse rate, whether reported as adverse events leading to discontinuation, or serious adverse events were reported by less than 0.2% of patients. No serious or individual events leading to discontinuation occurred in more than 25 patients. There were 15 (0.1%) deaths; 10 were attributed to a cardiovascular cause. Discontinuations for adverse events were lower than anticipated. Serious adverse events generally reflected sibutramine's known pharmacology or were related to cardiac disorders already present in this high-risk population. When compared with epidemiological data, overall mortality rate was low and sibutramine was well tolerated in this mainly off-label population. No new safety issues were detected.

Obesity is a global issue with increasing evidence that overweight and obesity are associated with a higher chronic disease risk. Despite over 10 years of government recognition of a need to develop and implement effective prevention strategies, all age groups are getting fatter with overweight becoming the `norm'. Modest weight loss reduces many of the risk factors that accompany obesity, notably type 2 diabetes, hypertension and dyslipidaemia. Adherence to lifestyle changes required to achieve these improvements is poor and progressively more weight-loss medications are used as adjunctive therapy, while bariatric surgery is performed for the severely obese. Currently available pharmacotherapy shows encouraging benefits in clinical trials but remains unproven as an effective strategy to support long-term weight loss and weight maintenance and for translation of improved surrogate risk markers into fewer cardiovascular events and a longer life. Three large clinical trials are ongoing in an attempt to answer this question. Br J Diabetes Vasc Dis 2008; 8: 170—176

AIM: To study the associations between weight loss with sibutramine and orlistat with psychological aspects that may interact with patients' response to these drugs. METHODS: A total of 478 obese patients with a mean body mass index of 42 +/- 12 kg/m(2) gave self-reported, retrospective data on different types of previous weight loss treatments (sibutramine and orlistat, and Weight Watchers used as a control condition) including the amount of weight lost with these treatments, eating behaviour (Dutch Eating Behaviour Questionnaire) and personality (NEO Personality Inventory - Revised). RESULTS: Greater weight loss with sibutramine was associated with lower levels of restrained eating and higher levels of 'neuroticism', in particular 'anxiety' and 'depression'. Greater weight loss with orlistat was associated with aspects of the personality dimension 'conscientiousness' (e.g. 'order' and 'deliberation'). CONCLUSION: Sibutramine may exert its greatest effect in patients whose eating is a 'natural' response to hunger rather than regulated by cognitions and conscious controls. Patients with low levels of restraint could be more sensitive to the satiety-enhancing effect of sibutramine. They may be able to reduce their food intake without cognitive interference and/or start to control their eating most radically in response to enhanced satiety. Enhanced satiety may also help patients withstand a wish to eat triggered by psychological distress. Possible central nervous system effects on mood could also have reduced eating, which was related to distress. The administration regimen of orlistat is more demanding, requiring greater adherence. This can account for the finding that personality attributes such as conscientiousness are important for success.

Huntington's disease (HD) is a debilitating autosomal dominant, neurodegenerative disease with a fatal prognosis. Classical symptoms include motor disturbances, subcortical dementia and psychiatric symptoms but are not restricted to this triad. Patients often experience other problems such as weight loss, although why and when this occurs in the disease course is not known. We studied metabolism using whole body indirect calorimetry in both early stage HD patients and in the R6/2 transgenic mouse model of HD, at times before and after they displayed signs of disease. Using this combined approach we found that patients with early HD tended to be in negative energy balance for reasons not related to their movement disorder, which was paralleled in the transgenic R6/2 mice. These mice had significantly elevated total energy expenditure as they developed overt disease with weight loss due primarily to a loss of muscle bulk. This study has shown for the first time that in HD there is the development of early negative energy balance, which in turn may cause weight loss with loss of muscle bulk in particular. The reason for this is not known but may reflect a catabolic state secondary to hypothalamic pathology, as abnormalities have been reported in the hypothalamus early in the disease course.

Objective: To evaluate a novel quantitative magnetic resonance (QMR) methodology (EchoMRI-AH, Echo Medical Systems) for measurement of whole-body fat and lean mass in humans. Methods and Procedures: We have studied (i) the in vitro accuracy and precision by measuring 18 kg Canola oil with and without 9 kg water (ii) the accuracy and precision of measures of simulated fat mass changes in human subjects (n = 10) and (iii) QMR fat and lean mass measurements compared to those obtained using the established 4-compartment (4-C) model method (n = 30). Results: (i) QMR represented 18 kg of oil at 40°C as 17.1 kg fat and 1 kg lean while at 30°C 15.8 kg fat and 4.7 kg lean were reported. The s.d. of repeated estimates was 0.13 kg for fat and 0.23 kg for lean mass. Adding 9 kg of water reduced the fat estimates, increased misrepresentation of fat as lean, and degraded the precision. (ii) the simulated change in the fat mass of human volunteers was accurately represented, independently of added water. (iii) compared to the 4-C model, QMR underestimated fat and over-estimated lean mass. The extent of difference increased with body mass. The s.d. of repeated measurements increased with adiposity, from 0.25 kg (fat) and 0.51 kg (lean) with BMI 30 kg/m2. Discussion: EchoMRI-AH prototype showed shortcomings in absolute accuracy and specificity of fat mass measures, but detected simulated body composition change accurately and with precision roughly three times better than current best measures. This methodology should reduce the study duration and cohort number needed to evaluate anti-obesity interventions.

In 2005, for the first time in European history, an extraordinary expert panel named BSCG (Bariatric Scientific Collaborative Group), was appointed through joint effort of the major European scientific societies which are active in the field of obesity management. Societies that constituted this panel were: IFSO – International Federation for the Surgery of Obesity, IFSO-EC – International Federation for the Surgery of Obesity – European Chapter, EASO – European Association for Study of Obesity, ECOG – European Childhood Obesity Group, together with the IOTF (International Obesity Task Force) which was represented during the completion process by its representative. The BSCG was composed not only of the top officers representing the respective scientific societies (four acting presidents, two past presidents, one honorary president, two executive directors), but was balanced with the presence of many other key opinion leaders in the field of obesity. The BSCG composition allowed the coverage of key disciplines in comprehensive obesity management, as well as reflecting European geographical and ethnic diversity. This joint BSCG expert panel convened several meetings which were entirely focused on guidelines creation, during the past 2 years. There was a specific effort to develop clinical guidelines, which will reflect current knowledge, expertise and evidence based data on morbid obesity treatment.

Despite increasing prevalence of obesity, no country has successfully implemented comprehensive pathways to provide advice to all the severely obese patients that seek treatment. We aimed to formulate pathways for referral into and out of weight assessment and management clinics (WAMCs) that include internal medicine/primary care physicians as part of a multidisciplinary team that could provide specialist advice and interventions, including referral for bariatric surgery. Using a National Institute of Health and Care Excellence (NICE)-accredited process, a Guidance Development Group conducted a literature search identifying existing WAMCs. As very few examples of effective structures and clinical pathways existed, the current evidence base for optimal assessment and management of bariatric surgery patients was used to reach a consensus. The model we describe could be adopted internationally by health services to manage severely obese patients.

Objective: This study aims at assessing the status of obesity management in the European region and identifying future goals and objectives of professionals working in the field of obesity. Methods: Presidents of all 31 EASO-affiliated (EASO = European Association for the Study of Obesity) national associations for the study of obesity were asked to invite 5 obesity experts from their country to participate in a survey. A total of 74 obesity professionals out of 23 countries participated. Questions addressed the development of guidelines, the status of obesity management, and goals and objectives for the future in obesity management. Further, EASO's three vice-presidents participated in in-depth, semi-structured interviews, in which they were asked to provide their reflection on the survey data. Results: Most countries define obesity as a clinical and chronic disease, but various differences in obesity management standards exist across Europe. Existing guidelines mainly focus on the acute treatment of obesity rather than on long-term approaches. Conclusion: Multidisciplinary approaches for obesity management and the collaboration between general practitioners and hospitals as well as between professionals at the local level and networks of obesity management centers need to be improved across Europe. Good practices and evidence are available.

Summary At a time when obesity is reaching epidemic proportions across the western world and increasing rapidly in developing countries, clinicians clearly are becoming more aware of the need to offer weight management advice and effective treatment to patients, especially those with a high risk of developing type 2 diabetes. For those patients with a BMI ≥ 30.0 kg/m 2 or for those with a BMI of 27.0 kg/m 2 with an obesity-related disease such as dyslipidaemia or type 2 diabetes mellitus, modest weight loss in the order of 5% achieved by modification of dietary intake and activity behaviour can significantly improve risk factors for obesity-related diseases and delay progression to type 2 diabetes. Unfortunately, rates of adherence with dietary-based weight management programmes are generally low and for most patients weight regain with time is common. The use of weight loss medications is recognised as a positive strategy for helping patients adhere to lifestyle advice, and has been shown to result in clinically significant and meaningful improvement of symptoms, risk factors and quality of life. Appropriate selection and use of weight management drugs requires an understanding of the benefits and risks associated with each of the available drugs. Clinical trials are ongoing to determine whether weight management interventions (including anti-obesity pharmacotherapy) will impact upon clinical outcome and life expectancy. © 2006 Asian Oceanian Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.

In 2005, for the first time, an expert panel named “The Bariatric Scientific Collaborative Group” (BSCG), was appointed through a joint effort of the major European Scientific Societies which are active in the field of obesity management. Societies that constituted this panel were: International Federation for the Surgery of Obesity – European Chapter (IFSO-EC), European Association for the Study of Obesity (EASO), European Childhood Obesity Group (ECOG) and the International Obesity Task Force (IOTF) which was represented during the completion process by its representatives. The BSCG was composed of officers representing the respective Scientific Societies (including four acting Presidents, two past Presidents, one Honorary President, and three Executive Directors). The panel was also balanced by the presence of many other opinion leaders in the field of obesity. The BSCG composition allowed coverage of the key disciplines in comprehensive obesity management, as well as being reflective of European geographic and ethnic diversity. This joint BSCG Expert Panel has convened several meetings which were entirely focused on guideline creation during the past 2 years. There was a specific effort to develop and concur on clinical guidelines which reflect current knowledge, expertise and evidence- based data on treatment of morbid obesity.

In 2005, for the first time in European history, an extraordinary Expert panel named 'The BSCG' (Bariatric Scientific Collaborative Group), was appointed through joint effort of the major European Scientific Societies which are active in the field of obesity management. Societies that constituted this panel were: IFSO - International Federation for the Surgery of Obesity, IFSO-EC - International Federation for the Surgery of Obesity - European Chapter, EASO - European Association for Study of Obesity, ECOG - European Childhood Obesity Group, together with the IOTF (International Obesity Task Force) which was represented during the completion process by its representative. The BSCG was composed not only of the top officers representing the respective Scientific Societies (four acting presidents, two past presidents, one honorary president, two executive directors), but was balanced with the presence of many other key opinion leaders in the field of obesity. The BSCG composition allowed the coverage of key disciplines in comprehensive obesity management, as well as reflecting European geographical and ethnic diversity. This joint BSCG expert panel convened several meetings which were entirely focused on guidelines creation, during the past two years. There was a specific effort to develop clinical guidelines, which will reflect current knowledge, expertise and evidence based data on morbid obesity treatment.

Introduction: Roux-en-Y gastric bypass (RYGB) reduces cardiometabolic risk through different potential mechanisms. High density lipoprotein cholesterol (HDL-C) changes might explain part of this benefit. Hypothesis: We assessed the effect of RYGB on HDL vasoprotective properties in comparison with a hypocaloric diet-induced weight loss. Methods: HDL was isolated from serum of obese patients (BMI > 35 kg/m2) before and 6 months after RYGB (n=32) or diet (n=32). In endothelial cells stimulated with HDL, we quantified nitric oxide (NO) production by DAF-2 fluorescence and paraoxonase-1 antioxidant activity (PON-1). Total cholesterol, low density lipoprotein (LDL-C), HDL-C, and triglycerides (TG) as well as glucose plasma fasting levels were measured. Results: At baseline there was no significant difference in mean body weight (BW) and BMI between RYGB and diet patients (119.9 Kg; 42kg/m2 vs. 110.9 kg; 37.4 kg/m2, respectively, p=0.06). At 6 months, BW and BMI were not different (RYGB: 94kg; 33 kg/m2; diet: 99kg; 33.4 kg/m2, p=ns). In both groups, mean total cholesterol and TG were reduced; LDL-C decreased only after RYGB. Total HDL-C increased 6 months after both interventions (RYGB: 1.2±0.5 baseline vs 1.3±0.4 after 6months; diet 1.1±0.25 baseline vs 1.3±0.3 after 6months, p Conclusions: Our study shows that although HDL concentration increased after RYGB and diet-induced BW loss, only RYGB restored endothelial protective HDL properties even though patients were still obese. This suggests that BW loss is not sufficient or critical to improve the protective properties of HDL, unless accompanied by yet unknown surgery-specific effects.

Despite the availability of evaluated and approved obesity drugs—and even though some patients will have failed to lose weight after non-drug treatment—doctors have been reluctant to prescribe drugs. The reasons for this may include memories of the adverse events with amphetamine, and amphetamine-like drugs, and the serious complications from combining phentermine and fenfluramine. Current drugs recommended for treating obesity have all been evaluated and approved by regulatory standards that apply to all drug treatments. The use of obesity drugs should follow the principles of any other therapeutic area—that is, they may be prescribed after assessment of the potential benefits and risks (both clinical and economic), with appropriately informed patients, and with medical monitoring of the results of treatment. Many people, including doctors, still believe that a short course of drug treatment might “cure” obesity or that efficacy is measured only by ever-continuing weight loss. These misconceptions are at odds with biology: people who become obese have a lifelong tendency both to defend their excess weight and to continue to gain extra body fat. Effective management, including drugs when needed, must be life long and focused on weight loss maintenance in a similar fashion to the effective treatment for hypertension or diabetes. Drug efficacy can be considered in terms of the impact on measures such as body mass index or fat distribution, risk factors, disease improvement, or reduction in clinical end points. Starting drug treatment should always be regarded as a therapeutic trial and stopped if weight loss is not apparent after one …

Background: Early weight loss is generally considered to predict long-term weight outcome in obese patients, and this is reflected in prescribing guidelines for antiobesity drugs. For example, the current prescribing guidelines for the antiobesity drug, sibutramine, indicate that if patients have not lost 2 kg (or 4 lb) in the first 4 weeks of treatment with sibutramine 10 mg, the physician should re-evaluate the therapy, which may result in increasing the dose to 15 mg or discontinuation. This regimen may deny treatment to a large group of patients who might otherwise benefit, particularly patients with type 2 diabetes who often find it more difficult to lose weight than non-diabetic obese individuals. Materials: We have re-analysed pooled data from seven randomized, controlled studies of sibutramine-induced weight loss and maintenance in which patients (n = 928; 75% female) had taken sibutramine 10 or 15 mg continuously for 12 months, in order to determine the predictors of success in weight loss (defined as loss of at least 5% of initial body weight at Month 12) in both diabetic and non-diabetic patients. Sensitivity and specificity analyses were used to calculate optimal predictive values. Results: In both diabetic and non-diabetic patients, weight loss of 4 kg at 3 months was identified as the optimal predictor for achieving at least 5% weight loss at 12 months. This target was associated with the best average values for sensitivity, specificity and accuracy, as well as high positive (78% vs. 84% for non-diabetics and 76% vs. 85% for diabetics, compared to existing guidelines target of 2 kg after 1 month treatment) and negative predictive values (63% vs. 71% for non-diabetics; 52% vs. 70% for diabetics). Conclusion: Sibutramine, in conjunction with diet and exercise, should be continued for at least 3 months (providing there are no adverse effects) to determine whether or not patients are likely to achieve a clinically valid outcome at 1 year. This highlights the need to ensure that regulatory restrictions reflect the needs of clinical practice.

Summary Background: The prevalence of obesity is rising, but little is known about its psychosocial correlates. Aim: To assess psychological co-morbidities and impairment of quality of life in obese individuals seeking treatment at two specialist centres in the UK. Design: Retrospective analysis of anthropometric and questionnaire data collected at initial clinic visit. Methods: Patients attending for a first visit between April 2004 and March 2005 completed questionnaires that included scales for measurement of anxiety and depression (Hospital Anxiety and Depression Scale), eating disorder-behaviour (Eating Disorder Inventory 2), assessment of body image (Body Image Assessment for Obesity) and quality of life (Impact of Weight on Quality of Life—Lite). We examined the relationships between variables measured on these scales and anthropometric data. Results: Of 253 questionnaires evaluated, there were elevated scores for depression in 48%, and elevated scores for anxiety in 56%. Twenty-two percent demonstrated scores suggestive of a personality trait that overlaps with an eating disorder; an additional 11.5% had an elevated score for bulimia. About a third of individuals had significant impaired quality of life in the areas of examined. Discussion: Psychological co-morbidities are common in obese individuals attending specialist weight-management clinics, and may merit consideration at (or before) commencement of a weight loss programme.

Aim: The aim of this study was to evaluate the effect on body weight and safety of subcutaneously administered recombinant leptin in obese adults and to evaluate whether the timing of recombinant leptin administration influences efficacy. Methods: A randomized, double-blind, placebo-controlled, multicentre study was designed, comprising of a 3-week dietary lead-in followed by a 12-week leptin or placebo treatment period. A total of 284 overweight and obese (body mass index 27–37.0 kg/m2) predominantly white (98%) women (66%) and men (34%) with a mean (±s.d.) 46.8 ± 10.4 years of age were randomized into three treatment groups with three matching placebo groups. Recombinant leptin was administered by subcutaneous injection [10 mg/morning, 10 mg/evening or 20 mg/day (10 mg twice daily)]. Patients were counselled at baseline to reduce dietary intake by 2100 kJ/day (500 kcal/day), and dietary advice was reinforced every 2–4 weeks. Results: No statistically significant change in body weight occurred with recombinant leptin treatment compared with placebo treatment in any treatment group. No clinically significant adverse effects were observed with the exception of an increase in injection-site reactions in patients treated with recombinant leptin (83%) vs. placebo (36%). Conclusions: Administration of recombinant leptin to an overweight and obese population, in addition to a mildly energy-restricted diet, was not efficacious in terms of weight loss at the doses and schedules studied. The hypothesis that nocturnal administration of recombinant leptin might have a specific effect on weight loss was not supported.

Currently available anti-obesity drugs sibutramine and orlistat, and the soon to be available rimonabant, all produce similar degrees of clinically meaningful weight loss and weight loss maintenance, even though they differ considerably in their mode of action. Pharmacologically induced weight loss has a beneficial impact on a number of metabolic and cardiovascular risk factors, such as glucose homeostasis, blood pressure, central adiposity, and dyslipidaemia. In some cases, these effects appear to be over and above that explained by weight loss. These effects are important if obese patients are to be treated not just for their weight but also to reduce coexisting metabolic and cardiovascular risk factors.

Objective: To explore predictors of programme adherence and weight loss in patients participating in a weight management programme using meal replacements (MR). Design: One hundred and fifty healthy obese women, age 48.5 years (s.d. = 8.3); weight, 97.6 kg (13.4); body mass index (BMI) 36.5 (3.7), participated in a longitudinal study with a 16-week acute weight loss phase (Phase 1) followed by 1 year of a trial of weight-loss maintenance (Phase 2). Energy intake during Phase 1 totaled 900 kcal (3.7 MJ) a day from a diet including two MR. Energy intake during Phase 2 consisted of either MR or a low-fat diet with a calculated energy deficit of 600 kcal/day (2.5 MJ). Methods: Weight, height and waist circumference were measured and body composition assessed by air plethysmography (Bodpod). Glucose and insulin were measured by standard immunoassays and insulin sensitivity assessed by homeostatic model assessment. Results: At the end of 16 weeks, 114 subjects (76%) completed Phase 1 and achieved a mean weight loss of 8.95 kg (3.38). Adherence to Phase 1 was predicted by weight loss over the first 2 weeks (p

uropean guidelines on cardiovascular disease prevention in clinical practice have identified obesity and smoking as primary risk factors for cardiovascular disease, the increased prevalence of which underlines the need for new therapeutic targets. The endocannabinoid (EC) system is a physiological system, comprising the cannabinoid receptors, cannabinoid type 1 (CB1) and type 2 (CB2), and their natural ligands, such as anandamide and 2-arachidonyl-glycerol (2-AG). The system plays a key role in energy balance regulation, both centrally and peripherally impacting on food intake, lipid and glucose metabolism, and fat accumulation. The EC system is also involved in nicotine dependence. Over activity of the EC system, associated with obesity or chronic tobacco use, leads to increased levels of endogenous ligands (endocannabinoids) and disrupts the feedback mechanism related to steady state homeostasis. Rimonabant, the first selective CB1 receptor blocker, normalises the EC system, reduces food intake and body weight, improves lipid and glucose metabolism and insulin sensitivity and reduces nicotine self-administration. Clinical trials are ongoing to support the therapeutic potential of rimonabant in reducing these multiple cardiovascular risk factors.

Background/Aims Obesity has become a global epidemic, and a major preventable cause of morbidity and mortality. Management strategies and treatment protocols are however poorly developed and evaluated. The aim of the Counterweight Programme is to develop an evidence-based model for the management of obesity in primary care. Methods The Counterweight Programme is based on the theoretical model of Evidence-Based Quality Assessment aimed at improving the management of obese adults (18-75 years) in primary care. The model consists of four phases: (1) practice audit and needs assessment, (2) practice support and training, (3) practice nurse-led patient intervention, and (4) evaluation. Patient intervention consisted of screening and treatment pathways incorporating evidence-based approaches, including patient-centred goal setting, prescribed eating plans, a group programme, physical activity and behavioural approaches, anti-obesity medication and weight maintenance strategies. Weight Management Advisers who are specialist obesity dietitians facilitated programme implementation. Eighty practices were recruited of which 18 practices were randomized to act as controls and receive deferred intervention 2 years after the initial audit. Results By February 2004, 58 of the 62 (93.5%) intervention practices had been trained to run the intervention programme, 47 (75.8%) practices were active in implementing the model and 1256 patients had been recruited (74% female, 26% male, mean age 50.6 years, SD 14). At baseline, 75% of patients had at one or more co-morbidity, and the mean body mass index (BMI) was 36.9 kg/m(2) (SD 5.4). Of the 1256 patients recruited, 91% received one of the core lifestyle interventions in the first 12 months. For all patients followed up at 12 months, 34% achieved a clinical meaningful weight loss of 5% or more. A total of 51% of patients were classed as compliant in that they attended the required level of appointments in 3, 6, and 12 months. For fully compliant patients, weight loss improved with 43% achieving a weight loss of 5% or more at 12 months. Conclusion The Counterweight Programme is an evidence-based weight management model which is feasible to implement in primary care.

Current cardiovascular risk scores do not include obesity or fat distribution as independent factors, and may underestimate risk in obese individuals. Assessment of early vascular ageing (EVA) biomarkers including arterial stiffness, central blood pressure, carotid intima-media thickness and flow-mediated vasodilation may help to refine risk assessment in obese individuals in whom traditional cardiovascular risk scores and factors suggest no need for specific medical attention. A number of issues need to be addressed before this approach is ready for translation into routine clinical practice. Methodologies for measurements of vascular markers need to be further standardized and less operator-dependent. The utility of these nontraditional risk factors will also need to be proven in sufficiently large and properly designed interventional studies. Indeed, published studies on vascular markers in obesity and weight loss vary in quality and study design, are sometimes conducted in small populations, use a variety of differing methodologies and study differing vascular beds. Finally, current vascular measurements are still crude and may not be sufficient to cover the different aspects of EVA in obesity.

BACKGROUND/OBJECTIVES: The Sibutramine Cardiovascular OUTcomes (SCOUT) trial showed a significantly increased relative risk of nonfatal cardiovascular events, but not mortality, in overweight and obese subjects receiving long-term sibutramine treatment with diet and exercise. We examined the relationship between early changes (both increases and decreases) in pulse rate, and the impact of these changes on subsequent cardiovascular outcome events in both the placebo and sibutramine groups. SUBJECTS/METHODS: 9804 males and females, aged >= 55 years, with a body mass index of 27-45 kg m(-2) were included in this current subanalysis of the SCOUT trial. Subjects were required to have a history of cardiovascular disease and/or type 2 diabetes mellitus with at least one cardiovascular risk factor, to assess cardiovascular outcomes. The primary outcome event (POE) was a composite of nonfatal myocardial infarction, nonfatal stroke, resuscitated cardiac arrest or cardiovascular death. Time-to-event analyses of the POE were performed using Cox regression models. RESULTS: During the initial 6-week sibutramine treatment period, the induced pulse rate increase was related to weight change (1.9 +/- 7.7 beats per minute (bpm) with weight increase; 1.4 +/- 7.3 bpm, 0-5 kg weight loss; 0.6 +/- 7.4 bpm, >= 5 kg weight loss). Throughout the subsequent treatment period, those continuing on sibutramine showed a consistently higher mean pulse rate than the placebo group. There was no difference in POE rates with either an increase or decrease in pulse rate over the lead-in period, or during lead-in baseline to 12 months post randomization. There was also no relationship between pulse rate at lead-in baseline and subsequent cardiovascular events in subjects with or without a cardiac arrhythmia. CONCLUSION: Baseline pulse rate and changes in pulse rate may not be an important modifier nor a clinically useful predictor of outcome in an individual elderly cardiovascular obese subject exposed to weight management.

Sibutramine has a dual mode of action. It reduces food intake and attenuates the fall in metabolic rate associated with weight loss. The drug's neurochemical actions can also be distinguished from those of previous centrally acting anti-obesity agents. Clinical trials show that two out of three patients taking sibutramine lose >/= 5% weight and that the drug can enhance the maintenance of weight loss. Early weight loss predicts long-term success and can be used to guide clinical practice. To maximize the benefits of sibutramine, it is important that patients receive adjunctive diet and lifestyle therapy.

Objective: Using the Eating Disorder Inventory (EDI-2) to identify a normative range in a UK obese population referred to a specialist hospital obesity clinic and to assess the response of the scale to the nonsurgical treatment of obesity. Methods: A total of 100 obese (BMI>30) patients attending an obesity clinic completed the EDI-2. In a separate sample, 45 obese patients participated in a dietary weight loss program consisting of an acute (10 weeks) and a long-term (2 year) weight maintenance phase. The EDI-2 was administered at baseline and at the end of the acute weight loss phase. Results: Most obese subjects showed elevated scores for body dissatisfaction (BD), which improved with weight loss. Eight percent had EDI scores suggesting psychological traits central to eating disorders. Conclusion: Most obese subjects do not have a trait central to an eating disorder as defined by the EDI-2, but do have high scores for BD that respond to weight loss. A few patients show scores suggesting an eating disorder that may benefit from psychological evaluation.

Editor – Cruz-Jentoft and Landi's fine review of the growing importance of sarcopenia ( Clin Med April 2014 pp 183–6) omitted to discuss the increasingly recognised condition of sarcopenic obesity. At an individual level the classification of overweight and obesity by body mass index (BMI) as a

SummaryBackgroundExcess body fat is associated with an increase in risk of type 2 diabetes and hypertension in adulthood and these risks can adversely affect progression of arterial disease. We aimed to assess the impact of lifelong patterns of adiposity on cardiovascular risk factors and carotid intima media thickness (cIMT) in later life in participants in the 1946 British birth cohort study.MethodsThe National Survey of Health and Development Study was a nationally representative sample of 5362 singleton births to married parents in England, Scotland, and Wales, stratified by social class, during 1 week in March 1946. Our present study is based on the 60% of participants still alive and with a known present address in England, Scotland, or Wales who attended a clinic assessment after invitation aged 60–64 years. We included participants with lifetime adiposity measures, cardiovascular risk factors, and cIMT measured at 60–64 years. Participants were classified as normal weight or overweight or obese at each age (36, 43, 53, and 60–64 years) in adulthood, and childhood overweight was defined. Patterns of BMI change were identified and we used BMI to define adiposity status. We used multivariable linear regression to establish the cross-sectional association of BMI category at age 60–64 years with cIMT, adjusted for various confounders.FindingsWe included 1273 (45%) of 2856 participants eligible in 2006–10 (at age 60–64 years) in this study. Compared with normal weight, overweight and obesity were associated with higher cIMT (0·029 mm, 95% CI 0·014–0·043) and systolic blood pressure (7·95 mm Hg, 5·86–10·0). Increased cIMT, systolic blood pressure, leptin, prevalence of diabetes, and reduced adiponectin were all associated with duration of exposure to adult adiposity (p

Public health initiatives focused on obesity prevention and lifestyle intervention programmes for patients with obesity have struggled to contain the obesity epidemic to date. In recent years, antiobesity drug therapies have had a limited role in clinical treatment algorithms for patients with obesity. Indeed, a number of high-profile antiobesity drug suspensions have markedly impacted upon the landscape of obesity pharmacotherapy. In this review, we discuss the advent of an increasing array of pharmacotherapeutic agents, which are effective both in inducing weight loss and in maintaining weight loss achieved by lifestyle measures. The development of these drugs as antiobesity agents has followed varying paths, ranging from lorcaserin, a selective serotonin agent, exploiting the beneficial central actions of fenfluramine but without the associated systemic side effects, to liraglutide, a gut hormone already used as a glucose-lowering drug but with appetite-suppressant properties, or the novel drug combination of phentermine/topiramate, two ‘old’ drugs used in lower doses than with previous therapeutic uses, resulting in an additive effect on weight loss and fewer side effects. We summarize the key findings from recent randomized controlled trials of these three drugs. Although these agents lead to clinically important weight loss when used as monotherapy, the use of antiobesity drugs as adjunctive therapy post intensive lifestyle intervention could prove to be the most successful strategy. Moreover, a progressive approach to obesity pharmacotherapy perhaps offers the best opportunity to finally address the obesity crisis on a mass scale.

Background: Liraglutide 3.0 mg, with diet and exercise, produced substantial weight loss over 1 year that was sustained over 2 years in obese non-diabetic adults. Nausea was the most frequent side effect.\ud Objective: To evaluate routinely collected data on nausea and vomiting among individuals on liraglutide and their influence on tolerability and body weight.\ud Design: A randomized, placebo-controlled, double-blind 20-week study with an 84-week extension (sponsor unblinded at 20 weeks, open-label after 1 year) in eight European countries (Clinicaltrials.gov: NCT00422058).\ud Subjects: After commencing a 500-kcal/day deficit diet plus exercise, 564 participants (18–65 years, body mass index (BMI) 30–40 kg m−2) were randomly assigned (after a 2-week run-in period) to once-daily subcutaneous liraglutide (1.2, 1.8, 2.4 or 3.0 mg), placebo or open-label orlistat (120 mg × 3 per day). After 1 year, participants on liraglutide/placebo switched to liraglutide 2.4 mg, and subsequently, to liraglutide 3.0 mg (based on 20-week and 1-year results, respectively).\ud Results: The intention-to-treat population comprised 561 participants (n=90–98 per arm, age 45.9±10.3 years, BMI 34.8±2.7 kg m−2 (mean±s.d.)). In year 1, more participants reported greater than or equal to1 episode of nausea/vomiting on treatment with liraglutide 1.2–3.0 mg (17–38%) than with placebo or orlistat (both 4%, Pless than or equal to0.001). Most episodes occurred during dose escalation (weeks 1–6), with ‘mild’ or ‘moderate’ symptoms. Among participants on liraglutide 3.0 mg, 48% reported some nausea and 13% some vomiting, with considerable variation between countries, but only 4 out of 93 (4%) reported withdrawals. The mean 1-year weight loss on treatment with liraglutide 3.0 mg from randomization was 9.2 kg for participants reporting nausea/vomiting episodes, versus 6.3 kg for those with none (a treatment difference of 2.9 kg (95% confidence interval 0.5–5.3); P=0.02). Both weight losses were significantly greater than the respective weight losses for participants on placebo (P\ud Conclusion: Transient nausea and vomiting on treatment with liraglutide 3.0 mg was associated with greater weight loss, although symptoms appeared tolerable and did not attenuate quality-of-life improvements. Improved data collection methods on nausea are warranted.

Sibutramine offers a new opportunity to provide a comprehensive weight reduction programme for many overweight and obese patients. A methodical and team approach to managing patients on sibutramine plus diet and exercise should hold the key to the best use of this adjunctive therapy in real clinical practice. This paper provides an overview of how to care for patients who are in need of weight management, and shows that simple measures and well organised, good clinical practice are all that is required to achieve clinically important weight reduction and longer term care.

Summary Aims: To assess the efficacy and tolerability of sibutramine 15 mg once daily as a weight reduction agent in overweight and obese patients (body mass index (b.m.i.) > 26 kg/m2) with type 2 diabetes when given with a customised, reduced-calorie diet, and to evaluate the influence of weight loss on diabetic control. Methods: Randomised, placebo-controlled, double-blind, parallel-group, 12-week study conducted at two hospital-based obesity/diabetes clinics. Patients were men and women aged 30–65 years, with b.m.i. > 26 kg/m2 and ≤ 35 kg/m2 and treated or untreated type 2 diabetes diagnosed ≥ 6 months previously. Each patient was given sibutramine 15 mg or placebo once daily and advised to follow a customised diet of 500 kcal/day less than the individual's energy needs. The principal measure of efficacy was change in body weight (b.w.). Additional efficacy measurements were changes in b.m.i., body composition as measured by dual-energy X-ray absorptiometry, and change in waist and hip measurements. Changes in diabetic control were assessed by blood glucose levels fasting and after a standard test meal, fasting insulin level, and glycosylated haemoglobin level. Adverse events (AEs) were monitored at each visit, and routine laboratory safety tests were done at 4-week intervals. Results: Ninety-one patients were randomised into the study, 44 to placebo and 47 to sibutramine 15 mg once daily. Eighty-three patients (91%) completed the study, 40 (91%) on placebo and 43 (91%) on sibutramine. Mean weight reduction from baseline was statistically significantly greater with sibutramine than with placebo at every measurement and at the end of the study (2.4 vs. 0.1 kg at week 12; p 5% of their baseline b.w. was 19% in the sibutramine group and 0% in the placebo group (p 26 kg/m2) with type 2 diabetes. Sibutramine was well tolerated, and significant improvement in diabetic control was seen in conjunction with weight reduction on sibutramine treatment.

SummaryThis study provides economic information on the costs of obesity in the UK using a modified method of attributable risk to establish the full resource implications of treating obesity and associated diseases. Prevalence estimates of obesity, defined as a Body Mass Index (BMI) greater than 30 kg/m2, together with estimates of the risk of obesity-related diseases relative to a BMI range close to ideal, are used as the basis of the costing. The total costs of treating obesity and its related diseases are estimated at £355 million (in 1995 prices). The total costs of treating obesity directly, estimated at £3.8 million, are dominated by the costs arising from the treatment of attributable diseases, estimated at £351 million.

Weight loss can reduce the increased cardiovascular risk associated with obesity. Pharmacotherapy is a recognized weight loss treatment option; however, cardiovascular safety issues with some previous weight loss drugs raise concerns for newly approved pharmacotherapies. Phentermine is approved for short-term obesity treatment in conjunction with lifestyle modifications, but is commonly used chronically. Topiramate, approved for treating epilepsy and preventing migraines, also induces weight loss. A single-dose combination of low-dose phentermine and topiramate extended-release was recently approved by the United States Food and Drug Administration as an adjunct to lifestyle intervention for the chronic treatment of overweight/obese adults. This review summarizes and evaluates the cardiovascular risk/benefit profile associated with phentermine and topiramate, individually and in combination. Cardiovascular data associated with long-term use of phentermine and topiramate extended-release indicate that this combination may be a safe and effective option for reducing weight in overweight/obese patients at low-to-intermediate cardiovascular risk.

There is evidence that drugs altering food intake such as dexfenfluramine, sibutramine and orlistat have useful therapeutic effects, with an acceptable side effect profile. 'Thermogenic' drugs, such as ephedrine and caffeine, are also effective, but less well tolerated and may, in any case, work by producing anorexia. The state of drug treatment for obesity now is similar to the early days of antihypertensive treatment in the 1960s when reserpine, ganglion blockers and nonselective adrenergic blocker were all that was available. There is considerable reason for optimism that the next 10 years will bring better treatments for the obese.

Objectives To examine the effect that health professional (HP) advice to lose weight has on overweight and obese adults’ motivation to lose weight and attempts to lose weight. Design Cross-sectional survey. Setting Great Britain. Participants 810 overweight or obese (body mass index ≥25 kg/m2) adults. Main outcome measures Participants were asked if they had ever received HP advice to lose weight and reported their desire to weigh less (ideal weight ≤95% of current weight) and whether they were attempting to lose weight. Results Only 17% of overweight and 42% of obese respondents recalled ever having received HP advice to lose weight. HP advice was associated with wanting to weigh less (89% vs 61% among those not receiving advice) and attempting to lose weight (68% vs 37%). In multivariable analyses, HP advice to lose weight was associated with increased odds of wanting to weigh less (OR=3.71, 95% CI 2.10 to 6.55) and attempting to lose weight (OR=3.53, 95% CI 2.44 to 5.10) independent of demographic characteristics and weight status. Conclusions HP advice to lose weight appears to increase motivation to lose weight and weight loss behaviour, but only a minority of overweight or obese adults receive such advice. Better training for HPs in delivering brief weight counselling could offer an opportunity to improve obese patients’ motivation to lose weight.

OBJECTIVE To assess the association of hypoglycemic treatment regimens with cardiovascular adverse events and mortality in a large population of type 2 diabetic patients at increased cardiovascular risk. RESEARCH DESIGN AND METHODS This analysis included 8,192 overweight patients with type 2 diabetes from the Sibutramine Cardiovascular Outcomes (SCOUT) trial randomized to lifestyle intervention with or without sibutramine for up to 6 years. Patients were grouped according to hypoglycemic treatment at baseline. The primary end point was the time from randomization to the first occurrence of a primary outcome event (POE), nonfatal myocardial infarction, nonfatal stroke, resuscitation after cardiac arrest, or cardiovascular death. Multivariable Cox proportional hazards regression models were used to assess the impact of antiglycemic treatment on POE and all-cause mortality. RESULTS Treatments for type 2 diabetes were as follows: diet alone (n = 1,394 subjects), metformin monotherapy (n = 1,631), insulin monotherapy (n = 1,116), sulfonylurea monotherapy (n = 1,083), metformin plus sulfonylurea (n = 1,565), and metformin plus insulin (n = 1,000); 905 subjects experienced a POE and 708 died. Metformin monotherapy was associated with lower risk of POE than insulin (hazard ratio [HR], 0.74; 95% CI, 0.57–0.95; P = 0.02). Diet alone also was associated with lower risk of POE (HR, 0.65; 95% CI, 0.48–0.87; P = 0.004). Metformin monotherapy also was associated with lower mortality (HR, 0.73; 95% CI, 0.54–0.99; P < 0.05), whereas no other monotherapies or combination therapies were significantly associated with POE or all-cause mortality compared with insulin as monotherapy. CONCLUSIONS In obese patients with type 2 diabetes and high risk of cardiovascular disease, monotherapy with metformin or diet-only treatment was associated with lower risk of cardiovascular events than treatment with insulin.

The incidence of obesity and its associated comorbidities have significantly increased over the years with adverse health and financial consequences for society. Lifestyle changes are essential for the prevention and treatment of obesity but their benefit appears limited as inadequate and nonsustained weight loss results have been reported. Pharmacotherapy is frequently advocated as part of a weight loss strategy. In this review, we will discuss the antiobesity drugs with Food and Drug Administration approval and their cardiovascular implications.Orlistat (Xenical) remains the single monotherapy that has approval in Europe. Topiramate (Topamax) and phentermine have long been approved in the United States, whereas lorcaserin and the extended release combination of phentermine with topiramate have recently gained approval. The development of single peptides targeting gut hormones or other host signals related to obesity may represent promising therapeutic options.Despite the recent failures of a number of antiobesity drugs, the pharmacotherapy of obesity is progressing rapidly. Treating the obese cardiovascular patient has proven challenging. Efficacy, safety and the sustainability of weight loss are key areas of focus in drug development strategies.

Many words have been written about the epidemic of type 2 diabetes (T2D) in developed and developing countries, and there are few clinicians at the coal face who do not feel overwhelmed by the tsunami of diabetes cases being experienced, particularly in multi-ethnic urban areas. It is clear that preventing diabetes is certainly more cost effective than treating the condition and its attendant complications. We now have strong randomised trial evidence that intervention, either by pharmacological or lifestyle methods, in patients with pre-diabetes can reduce risk of incident diabetes. 1,2,3 The seeds of diabetes are, however, sown in childhood and nurtured by environmental factors which require concerted action to break. It is clear, therefore, that prevention of diabetes should start earlier than the phase of pre-diabetes. Increasingly concerning is the fact that the onset of T2D is occurring at an ever-younger age and is now common among children and young adults. In high-risk ethnic groups, it seems likely that T2D is set to take over from type 1 as the predominant cause of diabetes in children. 4,5 The younger the age of onset of the disease, the greater the potential for complications to occur. While obesity and sedentary physical lifestyles are the main enabling factors for T2D in youth, there is growing evidence that in-utero exposure to hyperglycaemia may increase the risk of diabetes in offspring. 6 This may suggest that vigorous control of hyperglycaemia in women with gestational diabetes may be of importance in the prevention of diabetes in their children. In the UK, the National Institute of Health and Clinical Excellence (NICE) has recently published guidelines on the prevention of diabetes. 7 They exhort local and national action to tackle obesity and physical inactivity. Local action suggested includes provision of community-based weight management programmes for people who are overweight or obese, which is sensible given the outcomes of lifestyle interventions in trials of pre-diabetes and in people with early diabetes. The guidelines appropriately state that communities at high risk of diabetes should be targeted with culturally appropriate interventions. Implementation, however, has been limited and timid at best – perhaps from an unwarranted sense of nihilism by those responsible for commissioning and a lack of financial incentives (for example from Quality Outcomes Framework payments) by those who might support or deliver these interventions. When patients are referred for intervention it is often too little and too late. The guidelines also exhort national governmental action to prevent diabetes. They suggest that the UK government works with food manufacturers to improve composition of foods and develop clear nutritional labelling information, and also with food retailers to reduce the costs of healthier foods. The UK government’s response has been muted and restricted to policies around ‘nudging’ people into healthy behaviours. Information programmes such as ‘Change 4 Life’ have been pushed as a national response to this public health crisis. 8 The effects of such policies appear to be limited and at best offer a minor short term benefit. Such programmes have also received criticism for their sponsorship by commercial companies producing sugar-sweet

Background: The predictive value of serum uric acid (SUA) for adverse cardiovascular events among obese and overweight patients is not known, but potentially important because of the relation between hyperuricaemia and obesity. Methods: The relationship between SUA and risk of cardiovascular adverse outcomes (nonfatal myocardial infarction, nonfatal stroke, resuscitated cardiac arrest or cardiovascular death) and all-cause mortality, respectively, was evaluated in a post-hoc analysis of the Sibutramine Cardiovascular OUTcomes (SCOUT) trial. Participants enrolled in SCOUT were obese or overweight with pre-existing diabetes and/or cardiovascular disease (CVD). Cox models were used to assess the role of SUA as an independent risk factor. Results: 9742 subjects were included in the study; 83.6% had diabetes, and 75.1% had CVD. During an average follow-up time of 4.2 years, 1043 subjects had a primary outcome (myocardial infarction, resuscitated cardiac arrest, stroke, or cardiovascular death), and 816 died. In a univariate Cox model, the highest SUA quartile was associated with an increased risk of cardiovascular adverse outcomes compared with the lowest SUA quartile in women (hazard ratio [HR]: 1.59; 95% confidence interval [CI]: 1.20-2.10). In multivariate analyses, adjusting for known cardiovascular risk factors the increased risk for the highest SUA quartile was no longer statistically significant among women (HR: 0.99; 95% CI: 0.72-1.36) nor was it among men. Analyses of all-cause mortality found an interaction between sex and SUA. In a multivariate Cox model including women only, the highest SUA quartile was associated with an increased risk in all-cause mortality compared to the lowest SUA quartile (HR: 1.51; 95% CI: 1.08-2.12). No relationship was observed in men (HR: 1.06; 95% CI: 0.82-1.36). Conclusion: SUA was not an independent predictor of cardiovascular disease and death in these high-risk overweight/obese people. However, our results suggested that SUA was an independent predictor of all-cause mortality in women.

Aims: Weight loss is expected to improve glycaemic control in patients with diabetes or at high risk hereof. Sibutramine causes weight loss and is associated with an increased risk of myocardial infarction and stroke in high-risk patients. We examined the impact of sibutramine-induced weight loss on glycaemic control. Methods and results: In total, 8192 obese patients with diabetes were randomized to sibutramine or placebo plus diet and exercise after a preliminary 6 weeks in which all patients received sibutramine. Patients were classified into four groups of weight change. A total of 1582 patients had a weight loss >5.7 kg; 2047 patients lost 3.7-5.7 kg; 2432 patients lost

Obese patients are prone to arterial hypertension, require more antihypertensive medications, and have an increased risk of treatment-resistant arterial hypertension. Obesity-induced neurohumoral activation appears to be involved. The association between obesity and hypertension shows large inter-individual variability, likely through genetic mechanisms. Obesity affects overall cardiovascular and metabolic risk; yet, the relationship between obesity and cardiovascular risk is complex and not sufficiently addressed in clinical guidelines. The epidemiological observation that obesity may be protective in patients with established cardiovascular disease is difficult to translate into clinical experience and practice. Weight loss is often recommended as a means to lower blood pressure. However, current hypertension guidelines do not provide evidence-based guidance on how to institute weight loss. In fact, weight loss influences on blood pressure may be overestimated. Nevertheless, weight loss through bariatric surgery appears to decrease cardiovascular risk in severely obese patients. Eventually, most obese hypertensive patients will require antihypertensive medications. Data from large-scale studies with hard clinical endpoints on antihypertensive medications specifically addressing obese patients are lacking and the morbidity from the growing population of severely obese patients is poorly recognized or addressed. Because of their broad spectrum of beneficial effects, renin-angiotensin system inhibitors are considered to be the most appropriate drugs for antihypertensive treatment of obese patients. Most obese hypertensive patients require two or more antihypertensive drugs. Finally, how to combine weight loss strategies and antihypertensive treatment to achieve an optimal clinical outcome is unresolved.

Obesity is a significant health problem worldwide and is associated with a number of co-morbidities including type 2 diabetes mellitus, hypertension, dyslipidemia, obstructive sleep apnea, and cardiovascular disease. A number of different pathophysiologic mechanisms including increased inflammation, oxidative stress, and insulin resistance have been associated with initiation and progression of atherosclerotic disease in obese individuals. Lifestyle modifications have provided modest results in weight reduction and the focus of interest has now shifted towards drug development to treat severely obese individuals with a body mass index (BMI)