Background Liraglutide 3·0 mg was shown to reduce bodyweight and improve glucose metabolism after the 56-week period of this trial, one of four trials in the SCALE programme. In the 3-year assessment of the SCALE Obesity and Prediabetes trial we aimed to evaluate the proportion of individuals with prediabetes who were diagnosed with type 2 diabetes. Methods In this randomised, double-blind, placebo-controlled trial, adults with prediabetes and a body-mass index of at least 30 kg/m2, or at least 27 kg/m2 with comorbidities, were randomised 2:1, using a telephone or web-based system, to once-daily subcutaneous liraglutide 3·0 mg or matched placebo, as an adjunct to a reduced-calorie diet and increased physical activity. Time to diabetes onset by 160 weeks was the primary outcome, evaluated in all randomised treated individuals with at least one post-baseline assessment. The trial was conducted at 191 clinical research sites in 27 countries and is registered with ClinicalTrials.gov, number NCT01272219. Findings The study ran between June 1, 2011, and March 2, 2015. We randomly assigned 2254 patients to receive liraglutide (n=1505) or placebo (n=749). 1128 (50%) participants completed the study up to week 160, after withdrawal of 714 (47%) participants in the liraglutide group and 412 (55%) participants in the placebo group. By week 160, 26 (2%) of 1472 individuals in the liraglutide group versus 46 (6%) of 738 in the placebo group were diagnosed with diabetes while on treatment. The mean time from randomisation to diagnosis was 99 (SD 47) weeks for the 26 individuals in the liraglutide group versus 87 (47) weeks for the 46 individuals in the placebo group. Taking the different diagnosis frequencies between the treatment groups into account, the time to onset of diabetes over 160 weeks among all randomised individuals was 2·7 times longer with liraglutide than with placebo (95% CI 1·9 to 3·9, p<0·0001), corresponding with a hazard ratio of 0·21 (95% CI 0·13–0·34). Liraglutide induced greater weight loss than placebo at week 160 (–6·1 [SD 7·3] vs −1·9% [6·3]; estimated treatment difference −4·3%, 95% CI −4·9 to −3·7, p<0·0001). Serious adverse events were reported by 227 (15%) of 1501 randomised treated individuals in the liraglutide group versus 96 (13%) of 747 individuals in the placebo group. Interpretation In this trial, we provide results for 3 years of treatment, with the limitation that withdrawn individuals were not followed up after discontinuation. Liraglutide 3·0 mg might provide health benefits in terms of reduced risk of diabetes in individuals with obesity and prediabetes. Funding Novo Nordisk, Denmark

The development of consensus guidelines for obesity is complex. It involves recommending both treatment interventions and interventions related to screening and prevention. With so many publications and claims, and with the awareness that success for the individual is short-lived, many find it difficult to know what action is appropriate in the management of obesity. Furthermore, the significant variation in existing service provision both within countries as well as across the regions of Europe makes a standardised approach, even if evidence-based, difficult to implement. In formulating these guidelines, we have attempted to use an evidence-based approach while allowing flexibility for the practicing clinician in domains where evidence is currently lacking and ensuring that in treatment there is recognition of clinical judgment and of regional diversity as well as the necessity of an agreed approach by the individual and family. We conclude that i) physicians have a responsibility to recognise obesity as a disease and help obese patients with appropriate prevention and treatment, ii) treatment should be based on good clinical care and evidence-based interventions and iii) obesity treatment should focus on realistic goals and lifelong management.

A series of four trials was carried out to investigate the effects of caffeine and coffee on the metabolic rate and substrate utilization in normal weight and obese individuals. In the first trial 8 mg/kg caffeine was compared with a placebo in normal weight subjects. Metabolic rate increased significantly during the 3 hr after caffeine ingestion. While plasma glucose, insulin, and carbohydrate oxidation did not change significantly, plasma free fatty acid levels rose from 432 +/- 31 to 848 +/- 135 muEq/liter and were accompanied by significant increases in fat oxidation during the last hour of the test. In the second and third trials the effects of coffee providing 4 mg/kg caffeine were studied in control and obese subjects. Metabolic rate increased significantly in both groups; however, significant increases in fat oxidation were only observed in the control group. Plasma free fatty acids did not change in the obese. In the fourth trial, coffee was taken with a 3080 kJ meal. The thermic effect of the meal was significantly greater after coffee than after decaffeinated coffee and again fat oxidation was significantly greater after coffee. In conclusion caffeine/coffee stimulates the metabolic rate in both control and obese individuals; however, this is accompanied by greater oxidation of fat in normal weight subjects.

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OBJECTIVE: To study whether weight reducing treatment modulates serum concentration of TNF-a a and two soluble TNF-a a receptors in obese subjects. SUBJECTS AND MEASUREMENTS: Serum concentrations of TNF-a a and two soluble receptors (sTNF-R1, sTNF-R2), plasma glucose, insulin, total cholesterol, HDL-cholesterol and triglicerides were measured in 27 obese subjects (age 48 AE 12 y, body mass index (BMI): 36 AE 6 kgam 2 ) before and after 3 months weight reducing treatment consisted of a diet & 1000 kcaladay and physical exercises. RESULTS: The mean loss of weight during 3 months' treatment was 9.3 AE 3.3 kg. The serum concentration of TNF-a a decreased after weight loss and at the same time both of the receptors (sTNF-R1,sTNF-R2) increased signi®cantly. CONCLUSION: The observed decrease of the serum concentration of TNF-a a and the increase in both TNF soluble receptors after weight reducing treatment in obese subjects, may be a counter-regulation preventing further weight loss.

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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.