Stephan Rössner

Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study

BACKGROUND In animal models, cannabinoid-1 receptor (CB1) blockade produces a lean phenotype, with resistance to diet-induced obesity and associated dyslipidaemia. We assessed the effect of rimonabant, a selective CB1 blocker, on bodyweight and cardiovascular risk factors in overweight or obese patients. METHODS patients with body-mass index 30 kg/m2 or greater, or body-mass index greater than 27 kg/m2 with treated or untreated dyslipidaemia, hypertension, or both, were randomised to receive double-blind treatment with placebo, 5 mg rimonabant, or 20 mg rimonabant once daily in addition to a mild hypocaloric diet (600 kcal/day deficit). The primary efficacy endpoint was weight change from baseline after 1 year of treatment in the intention-to-treat population. FINDINGS Weight loss at 1 year was significantly greater in patients treated with rimonabant 5 mg (mean -3.4 kg [SD 5.7]; p=0.002 vs placebo) and 20 mg (-6.6 kg [7.2]; p<0.001 vs placebo) compared with placebo (-1.8 kg [6.4]). Significantly more patients treated with rimonabant 20 mg than placebo achieved weight loss of 5% or greater (p<0.001) and 10% or greater (p<0.001). Rimonabant 20 mg produced significantly greater improvements than placebo in waist circumference, HDL-cholesterol, triglycerides, and insulin resistance, and prevalence of the metabolic syndrome. The effects of rimonabant 5 mg were of less clinical significance. Rimonabant was generally well tolerated with mild and transient side effects. INTERPRETATION CB1 blockade with rimonabant 20 mg, combined with a hypocaloric diet over 1 year, promoted significant decrease of bodyweight and waist circumference, and improvement in cardiovascular risk factors.

Who succeeds in maintaining weight loss? A conceptual review of factors associated with weight loss maintenance and weight regain

Weight loss is difficult to achieve and maintaining the weight loss is an even greater challenge. The identification of factors associated with weight loss maintenance can enhance our understanding for the behaviours and prerequisites that are crucial in sustaining a lowered body weight. In this paper we have reviewed the literature on factors associated with weight loss maintenance and weight regain. We have used a definition of weight maintenance implying intentional weight loss that has subsequently been maintained for at least 6 months. According to our review, successful weight maintenance is associated with more initial weight loss, reaching a self‐determined goal weight, having a physically active lifestyle, a regular meal rhythm including breakfast and healthier eating, control of over‐eating and self‐monitoring of behaviours. Weight maintenance is further associated with an internal motivation to lose weight, social support, better coping strategies and ability to handle life stress, self‐efficacy, autonomy, assuming responsibility in life, and overall more psychological strength and stability. Factors that may pose a risk for weight regain include a history of weight cycling, disinhibited eating, binge eating, more hunger, eating in response to negative emotions and stress, and more passive reactions to problems.

Effect of sibutramine on weight maintenance after weight loss: a randomised trial*

BACKGROUND Sibutramine is a tertiary amine that has been shown to induce dose-dependent weight loss and to enhance the effects of a low-calorie diet for up to a year. We did a randomised, double-blind trial to assess the usefulness of sibutramine in maintaining substantial weight loss over 2 years. METHODS Eight European centres recruited 605 obese patients (body-mass index 30-45 kg/m2) for a 6-month period of weight loss with sibutramine (10 mg/day) and an individualised 600 kcal/day deficit programme based on measured resting metabolic rates. 467 (77%) patients with more than 5% weight loss were then randomly assigned 10 mg/day sibutramine (n=352) or placebo (n=115) for a further 18 months. Sibutramine was increased up to 20 mg/day if weight regain occurred. The primary outcome measure was the number of patients at year 2 maintaining at least 80% of the weight lost between baseline and month 6. Secondary outcomes included changes in uric acid concentrations and glycaemic and lipid variables. Analysis was by intention to treat. FINDINGS 148 (42%) individuals in the sibutramine group and 58 (50%) in the placebo group dropped out. Of the 204 sibutramine-treated individuals who completed the trial, 89 (43%) maintained 80% or more of their original weight loss, compared with nine (16%) of the 57 individuals in the placebo group (odds ratio 4.64, p<0.001). Patients had substantial decreases over the first 6 months with respect to triglycerides, VLDL cholesterol, insulin, C peptide, and uric acid; these changes were sustained in the sibutramine group but not the placebo group. HDL cholesterol concentrations rose substantially in the second year: overall increases were 20.7% (sibutramine) and 11.7% (placebo, p<0.001). 20 (3%) patients were withdrawn because of increases in blood pressure; in the sibutramine group, systolic blood pressure rose from baseline to 2 years by 0.1 mm Hg (SD 12.9), diastolic blood pressure by 2.3 mm Hg (9.4), and pulse rate by 4.1 beats/min (11.9). INTERPRETATION This individualised management programme achieved weight loss in 77% of obese patients and sustained weight loss in most patients continuing therapy for 2 years. Changes in concentrations of HDL cholesterol, VLDL cholesterol, and triglyceride, but not LDL cholesterol, exceed those expected either from weight loss alone or when induced by other selective therapies for low concentrations of HDL cholesterol relating to coronary heart disease.

Effects of liraglutide in the treatment of obesity: a randomised, double-blind, placebo-controlled study

BACKGROUND The frequency of obesity has risen dramatically in recent years but only few safe and effective drugs are currently available. We assessed the effect of liraglutide on bodyweight and tolerability in obese individuals without type 2 diabetes. METHODS We did a double-blind, placebo-controlled 20-week trial, with open-label orlistat comparator in 19 sites in Europe. 564 individuals (18-65 years of age, body-mass index 30-40 kg/m2) were randomly assigned, with a telephone or web-based system, to one of four liraglutide doses (1.2 mg, 1.8 mg, 2.4 mg, or 3.0 mg, n=90-95) or to placebo (n=98) administered once a day subcutaneously, or orlistat (120 mg, n=95) three times a day orally. All individuals had a 500 kcal per day energy-deficit diet and increased their physical activity throughout the trial, including the 2-week run-in. Weight change analysed by intention to treat was the primary endpoint. An 84-week open-label extension followed. This study is registered with ClinicalTrials.gov, number NCT00422058. FINDINGS Participants on liraglutide lost significantly more weight than did those on placebo (p=0.003 for liraglutide 1.2 mg and p<0.0001 for liraglutide 1.8-3.0 mg) and orlistat (p=0.003 for liraglutide 2.4 mg and p<0.0001 for liraglutide 3.0 mg). Mean weight loss with liraglutide 1.2-3.0 mg was 4.8 kg, 5.5 kg, 6.3 kg, and 7.2 kg compared with 2.8 kg with placebo and 4.1 kg with orlistat, and was 2.1 kg (95% CI 0.6-3.6) to 4.4 kg (2.9-6.0) greater than that with placebo. More individuals (76%, n=70) lost more than 5% weight with liraglutide 3.0 mg that with placebo (30%, n=29) or orlistat (44%, n=42). Liraglutide reduced blood pressure at all doses, and reduced the prevalence of prediabetes (84-96% reduction) with 1.8-3.0 mg per day. Nausea and vomiting occurred more often in individuals on liraglutide than in those on placebo, but adverse events were mainly transient and rarely led to discontinuation of treatment. INTERPRETATION Liraglutide treatment over 20 weeks is well tolerated, induces weight loss, improves certain obesity-related risk factors, and reduces prediabetes. FUNDING Novo Nordisk A/S, Bagsvaerd, Denmark.

Energy intake and appetite are suppressed by glucagon-like peptide-1 (GLP-1) in obese men

BACKGROUND: Peripheral administration of glucagon-like peptide-1 (GLP-1) for four hours, to normal weight and obese humans, decreases food intake and suppresses appetite.OBJECTIVE: The aim of this study was to assess the effect of an eight hour infusion of GLP-1 on appetite and energy intake at lunch and dinner in obese subjects.DESIGN: Randomised, blinded cross-over design with intravenous infusion of GLP-1 (0.75 pmol·kg−1·min−1) or saline.SUBJECTS: Eight obese (body mass index, BMI, 45.5±2.3 kg/m2) male subjects.MEASUREMENTS: Ad libitum energy intake at lunch (12.00 h) and dinner (16.00 h) after an energy fixed breakfast (2.4 MJ) at 08.00 h. Appetite sensations using visual analogue scales, (VAS) immediately before and after meals and hourly in-between. Blood samples for the analysis of glucose, insulin, C-peptide, GLP-1 and peptide YY. Gastric emptying after breakfast and lunch using a paracetamol absorption technique.RESULTS: Hunger ratings were significantly lower with GLP-1 infusion. The summed ad libitum energy intake at lunch and dinner was reduced by 1.7±0.5 MJ (21±6%) by GLP-1 infusion (P=0.01). Gastric emptying was delayed by GLP-1 infusion, and plasma glucose concentrations decreased (baseline: 6.6±0.35 mmol/L; nadir: 5.3±0.15 mmol/L). No nausea was recorded during GLP-1 infusion.CONCLUSIONS: Our results demonstrate that GLP-1 decreases feelings of hunger and reduces energy intake in obese humans. One possible mechanism for this finding might be an increased satiety primarily mediated by gastric vagal afferent signals.

Does Excess Pregnancy Weight Gain Constitute a Major Risk for Increasing Long-term BMI?

Objective: The objective was to assess the relevance of the recommendations of the Institute of Medicine (IOM), regarding gestational weight gain (GWG) for long‐term BMI development.

Effect of a very low energy diet on moderate and severe obstructive sleep apnoea in obese men: a randomised controlled trial.

Objective To assess the effect of weight loss induced by a very low energy diet on moderate and severe obstructive sleep apnoea in obese men. Design Single centre, two arm, parallel, randomised, controlled, open label trial. Blocked randomisation procedure used for treatment allocation. Setting Outpatient obesity clinic in a university hospital in Stockholm, Sweden. Participants 63 obese men (body mass index 30-40, age 30-65 years) with moderate to severe obstructive sleep apnoea (apnoea-hypopnoea index (AHI) ≥15), treated with continuous positive airway pressure. Interventions The intervention group received a liquid very low energy diet (2.3 MJ/day) for seven weeks to promote weight loss, followed by two weeks of gradual introduction of normal food, reaching 6.3 MJ/day at week 9. The control group adhered to their usual diet during the nine weeks of follow-up. Main outcome measure AHI, the major disease severity index for obstructive sleep apnoea. Data from all randomised patients were included in an intention to treat analysis (baseline carried forward for missing data). Results Of the 63 eligible patients, 30 were randomised to intervention and 33 to control. Two patients in the control group were dissatisfied with allocation and immediately discontinued. All other patients completed the trial. Both groups had a mean AHI of 37 events/h (SD 15) at baseline. At week 9, the intervention group’s mean body weight was 20 kg (95% confidence interval 18 to 21) lower than that of the control group, while its mean AHI was 23 events/h (15 to 30) lower. In the intervention group, five of 30 (17%) were disease free after the energy restricted diet (AHI <5), with 15 of 30 (50%) having mild disease (AHI 5-14.9), whereas the AHI of all patients in the control group except one remained at 15 or higher. In a subgroup analysis of the intervention group, baseline AHI significantly modified the effectiveness of treatment, with a greater improvement in AHI in patients with severe obstructive sleep apnoea (AHI >30) at baseline compared with those with moderate (AHI 15-30) sleep apnoea (AHI −38 v −12, P<0.001), despite similar weight loss (−19.2 v −18.2 kg, P=0.55). Conclusion Treatment with a low energy diet improved obstructive sleep apnoea in obese men, with the greatest effect in patients with severe disease. Long term treatment studies are needed to validate weight loss as a primary treatment strategy for obstructive sleep apnoea. Trial registration Current Controlled Trials ISRCTN70090382.

Prevalence of Obesity in Sweden

Although the prevalence of obesity in Sweden still is low in an international perspective, the development during the last decades is alarming in adults, adolescents and children alike. The prevalence of obesity [body mass index (BMI) > 30 kg m−2] in adults has doubled during the last two decades and is now approximately 10% in both men and women, according to estimates based on self‐reported BMI from repeated random samples of the population. However, prevalence estimates based on measured BMI from the WHO MONICA study indicate that the self‐reported data result in underestimates. In military conscripts, the prevalence of obesity (BMI > 30 kg m−2) almost quadrupled to 3.2% from 1971 to 1995, while the overweight fraction (BMI > 25 kg m−2) more than doubled to 16.3%. The development in younger age groups seems to be similar; the prevalence of overweight [International Obesity Task Force (IOTF)/Cole] in children aged 10 years in Gothenburg has doubled to 18% (2.9% obese) during the last decade, and similar figures have been reported in other studies. However, most reports on childhood overweight stem from the larger metropolitan areas, and hence may be underestimates because of the urban–rural influence on obesity‐status. Recent data from non‐urban areas in the northern part of Sweden estimate the prevalence of overweight (BMI > 20 kg m−2) in 10‐year‐olds to above 30%. In the most comprehensive study in children, including both rural and urban areas, BMI was measured among all children aged 10 years (n = 5517; 92.7% of the population) in the county of Ostergotland, and the prevalence of overweight (IOTF/Cole) was 22% in both boys and girls, of which 4% and 5% were obese respectively.

Catecholamine resistance in fat cells of women with upper-body obesity due to decreased expression of beta2-adrenoceptors

SummaryUpper-body obesity is an important risk factor for developing non-insulin dependent diabetes. To investigate the possibility that a lipolysis defect is present in this form of obesity, we examined the adrenergic regulation of lipolysis in abdominal subcutaneous fat cells from 25 women with upper-body obesity and 24 non-obese women. Lipolytic noradrenaline sensitivity (but not the maximum rate of lipolysis) was reduced by 10-fold in obese women (p<0.01). The noradrenaline resistance could be ascribed to a 10-fold decrease in lipolytic beta2-adrenoceptor sensitivity (p<0.01). The lipolytic sensitivity of beta1- and alpha2-adrenergic receptors was normal in the obese women. A 70 % reduction in the cell surface density of beta2-adrenoceptors was observed compared to the control subjects (p<0.01). However, beta1-receptor density as well as steady-state mRNA levels for beta1- and beta2-receptors were normal in obese women. Lipolytic noradrenaline sensitivity correlated inversely with BMI (adjusted r2=0.76 together with fat cell volume in stepwise regression analysis). The fasting plasma level of free cortisol was 30 % lower in obese compared to non-obese women (p<0.05) but obesity did not influence resting plasma catecholamine levels. Thus, lipolytic catecholamine resistance is present in abdominal obesity, due to low density of beta2-adrenoceptors, which in its turn may be caused by a post-transcriptional defect in beta2-receptor expression. Whether abnormalities in circulating free cortisol levels have caused the impaired lipolytic function of these receptors in upper-body obesity remains to be established.

Weight development over time in parous women—The SPAWN study—15 years follow-up

BACKGROUND: Weight gain is common after pregnancy. Most studies suggest that weight gain associated with a pregnancy is between 0.5 and 3.8 kg up to 2.5 y of follow-up. However, 73% of the female patients at our obesity clinic identified pregnancy as an important trigger for marked weight retention. The majority retained more than 10 kg after each pregnancy. The aim of this study was to examine long-term weight development after pregnancy in a 15 y follow-up of women who took part in the Stockholm Pregnancy And Womens Nutrition (SPAWN) study.METHOD AND SUBJECTS: The SPAWN study is a long-term follow-up study of women who delivered children in 1984–85 in Stockholm (n=2342). A total of 1423 participants (response rate=61%) completed questionnaires, which covered eating behaviour and exercise, demographic information including social situation and status and details of the pregnancy before, during and up to 1 y after pregnancy. After 15 y, these women were invited to take part in the follow-up study. Anthropometric measurements and the same questionnaire data were collected from the 563 women who participated (response rate=40%). The sample was divided into two main groups: those who were normal weight before pregnancy and remained normal weight, and those who were normal weight before pregnancy and had become overweight at 15 y follow-up.RESULTS: Those women who became overweight had a higher pre-pregnant body mass index (BMI) (22.3±1.5 vs 20.5±1.6 kg/m2, P<0.001), gained more weight during pregnancy (16.3±4.3 vs 13.6±3.7 kg, P<0.001) and had retained more at 1 y follow-up. The women who became overweight had a steeper weight trajectory gaining more from 1 y follow-up to 15 y follow-up (11.1±6.5 vs 4.5±6.5 kg, P<0.001), with a higher BMI at 15 y follow-up of 27.5±2.6 vs 22.5±2.3 5 kg/m2 (P<0.001). However, differences between those who became overweight and those who did not could not be explained by age, number of children and various socioeconomic factors. Features of pregnancy that did differ between the two groups were breastfeeding and smoking cessation. However, women who became overweight had lower lactation scores than women who remained normal weight. Relatively more subjects of the group that became overweight stopped smoking during pregnancy.DISCUSSION: Pregnancy is a vulnerability factor for some women to become overweight. This study attempted to identify those factors that place initially normal weight women on a steeper weight trajectory as a result of pregnancy. Demographic, behavioural, physical and psychological characteristics only partly explain the weight gain observed at 15 y follow-up. Further research is required to investigate the relative role of these characteristics in predicting postpregnancy weight development.