N Finer

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0.001). 20 (3%) patients were withdrawn because of increases in blood pressure; in the sibutramine group, systolic blood pressure rose from baseline to 2 years by 0.1 mm Hg (SD 12.9), diastolic blood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.

Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide

Objective:Having demonstrated short-term weight loss with liraglutide in this group of obese adults, we now evaluate safety/tolerability (primary outcome) and long-term efficacy for sustaining weight loss (secondary outcome) over 2 years.Design:A randomized, double-blind, placebo-controlled 20-week study with 2-year extension (sponsor unblinded at 20 weeks, participants/investigators at 1 year) in 19 European clinical research centers.Subjects:A total of 564 adults (n=90–98 per group; body mass index 30–40 kg m−2) enrolled, 398 entered the extension and 268 completed the 2-year trial. Participants received diet (500 kcal deficit per day) and exercise counseling during 2-week run-in, before being randomly assigned (with a telephone or web-based system) to once-daily subcutaneous liraglutide (1.2, 1.8, 2.4 or 3.0 mg, n=90–95), placebo (n=98) or open-label orlistat (120 mg × 3, n=95). After 1 year, liraglutide/placebo recipients switched to liraglutide 2.4 mg, then 3.0 mg (based on 20-week and 1-year results, respectively). The trial ran from January 2007–April 2009 and is registered with Clinicaltrials.gov, number NCT00480909.Results:From randomization to year 1, liraglutide 3.0 mg recipients lost 5.8 kg (95% confidence interval 3.7–8.0) more weight than those on placebo and 3.8 kg (1.6–6.0) more than those on orlistat (P⩽0.0001; intention-to-treat, last-observation-carried-forward). At year 2, participants on liraglutide 2.4/3.0 mg for the full 2 years (pooled group, n=184) lost 3.0 kg (1.3–4.7) more weight than those on orlistat (n=95; P<0.001). Completers on liraglutide 2.4/3.0 mg (n=92) maintained a 2-year weight loss of 7.8 kg from screening. With liraglutide 3.0 mg, 20-week body fat decreased by 15.4% and lean tissue by 2.0%. The most frequent drug-related side effects were mild to moderate, transient nausea and vomiting. With liraglutide 2.4/3.0 mg, the 2-year prevalence of prediabetes and metabolic syndrome decreased by 52 and 59%, with improvements in blood pressure and lipids.Conclusion:Liraglutide is well tolerated, sustains weight loss over 2 years and improves cardiovascular risk factors.

One-year treatment of obesity: a randomized, double-blind, placebo-controlled, multicentre study of orlistat, a gastrointestinal lipase inhibitor.

OBJECTIVE: To assess the efficacy and tolerability of orlistat (Xenical®) in producing and maintaining weight loss over a 12-month period.DESIGN: Patients were randomized to double-blind treatment with either orlistat 120 mg or placebo three times daily, in conjunction with a low-energy diet, for 12 months.SETTING: Five centres in the UK.SUBJECTS: 228 obese adult patients with body mass index between 30 and 43 kg/m2 and mean weight 97 kg (range 74–144 kg).INTERVENTIONS: All patients were prescribed a low-energy diet, providing 30% of energy from fat, designed to produce an individually tailored energy deficit of approximately 600 kcal/day, for a run-in period of 4 weeks and then 12 months, plus orlistat 120 mg or placebo three times daily.MAIN OUTCOME MEASURES: Change in body weight (the primary efficacy parameter), waist circumference and adverse events were reviewed regularly, together with serum lipids, insulin, glucose and plasma levels of fat-soluble vitamins and β carotene.RESULTS: Based on an intent-to-treat analysis, after 1 y of treatment patients receiving orlistat had lost an average of 8.5% of their initial body weight compared with 5.4% for placebo-treated patients; 35% of the orlistat group lost at least 5% of body weight compared with 21% of the placebo group (P<0.05), and 28% and 17%, respectively (P=0.04) lost at least 10% of body weight. Orlistat-treated patients showed significant decreases (P<0.05) in serum levels of total cholesterol, low density lipoprotein cholesterol, and in the low density lipoprotein:high density lipoprotein ratio in comparison with placebo. Both groups had similar adverse-event profiles, except for gastrointestinal events, which were 26% more frequent in the orlistat group but were mostly mild and transient. To maintain normal plasma levels of fat-soluble vitamins, supplements of vitamins A, D and E were given to 1.8%, 8.0% and 3.6%, respectively, of orlistat-treated patients, compared with 0.9% of placebo-treated patients for each vitamin type. After 1 y, the decrease in vitamin E and β carotene was significantly greater in orlistat-treated patients compared with those receiving placebo (P<0.001). No significant change was found in the mean vitamin E:total cholesterol ratio in either group after 52 weeks.Conclusions: Orlistat, in conjunction with a low-energy diet, produced greater and more frequent significant weight loss than placebo during 1 y of treatment. One-third of orlistat-treated patients achieved clinically relevant weight loss (≥5% initial body weight). There was also an improvement in relevant serum lipid parameters. Fat-soluble vitamin supplements may be required during chronic therapy. Orlistat was well tolerated and offers a promising new approach to the long-term management of obesity.

Predictors of weight loss and maintenance during 2 years of treatment by sibutramine in obesity. Results from the European multi-centre STORM trial. Sibutramine Trial of Obesity Reduction and Maintenance.

BACKGROUND: In this report we assess pre-treatment determinants of weight loss and maintenance outcome in The Sibutramine Trial of Obesity Reduction and Maintenance (STORM), a 2 y randomized, double-blind, placebo-controlled, European multicenter study examining the effect of sibutramine (Sib) on inducing and maintaining weight loss in obese subjects.MATERIAL: A total of 605 obese patients (BMI: 30–45 kg/m2) of both gender were included from eight European centers and treated for 24 months. The patients were treated for the initial 6 months by Sib (10 mg/day) and a low-fat low-energy, individualized diet (600 kcal/day deficit). The 467 patients who achieved >5% weight loss after 6 months were randomized 3:1 to Sib (10 mg/day) (Sib/Sib) and placebo (Sib/Pla) for weight maintenance over a further 18 months.MAIN OUTCOME AND ANALYSES: Pre-treatment individual characteristics were assessed as predictors of 6 months weight loss (kg) and 24 months weight maintenance using simple and multivariate correlation and regression analyses.RESULTS: In univariate analyses, the 6 month weight loss (n=505) was positively associated with pre-treatment body weight (r=0.27), height (r=0.18), fat-free mass (r=0.21) (all P<0.001), fat mass (r=0.13, P0.03), and resting metabolic rate (r=0.13, P<0.003). However, no relation was found with age, gender, smoking status, age at onset of obesity, or number of previous slimming attempts. The same predictors were found for weight change to endpoint in the Sib/Sib group (n=350), while no predictors were identified in the Sib/Pla (n=114). In the multivariate regression analysis only pre-treatment body weight predicted weight loss at 6 months (P<0.001). Weight change (kg) to 24 month was predicted by: 4.34+0.07*body weight (kg)−4*treatment (Sib=1, Pla=0)−0.06*age (y), (r 2=8%, P<0.001).CONCLUSION: Only pre-treatment body weight seems to be an important independent predictor of 6 months weight loss and 24 month weight maintenance in this study on diet and Sib. As only 8% of the variation in 24 months weight change could be explained by the predictors, the clinical value of this information is limited.International Journal of Obesity (2001) 25, 496–501

Tolerability of nausea and vomiting and associations with weight loss in a randomized trial of liraglutide in obese, non-diabetic adults.

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.Objective:To evaluate routinely collected data on nausea and vomiting among individuals on liraglutide and their influence on tolerability and body weight.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).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).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 ⩾1 episode of nausea/vomiting on treatment with liraglutide 1.2–3.0 mg (17–38%) than with placebo or orlistat (both 4%, P⩽0.001). 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<0.001) or orlistat (P<0.05). Quality-of-life scores at 20 weeks improved similarly with or without nausea/vomiting on treatment with liraglutide 3.0 mg.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.

Reply: Is obesity a disease?

We are grateful for the opportunity to respond to Drs Heshka’s and Allison’s paper. In contrast, we consider obesity to be a disease that results from the processes of undesirable positive energy balance and weight gain. To suggest obesity is not a disease suggests expediency that perpetuates the myth that obesity is simply an affliction of modern society without medical consequence. We agree the need for conceptual clarity in science and philosophy and suggest that there are strong reasons for identifying obesity as a disease:

The implementation of the Counterweight Programme in Scotland, UK

BACKGROUND The Counterweight Programme is a proven model for the management of obesity in the UK, evaluated over 5 years (2000-05) and demonstrating clinical and cost effectiveness. The Scottish Government commissioned three phases of Counterweight implementation during the period 2006-08. The first two phases linked the Counterweight Programme to a primary care cardiovascular disease prevention programme; the third phase was commissioned independent of other interventions. Aim. To assess the implementation of the Counterweight Programme in 13 Health Boards in Scotland and compare 12-month outcomes with published Counterweight data. METHODS Patients with a body mass index (BMI) ≥ 30 kg/m(2) or BMI ≥ 28 kg/m(2) with at least one co-morbidity were screened for the Counterweight Programme. Patients were asked to attend nine structured appointments with a trained Counterweight Programme practitioner over 12 months. RESULTS Six thousand seven hundred and fifteen patients from 184 general practices, 16 pharmacies and one centralized community-based service in 13 Health Boards, with a mean BMI of 37 kg/m(2) were enrolled in the Counterweight Programme. Twenty-six per cent had a BMI ≥ 40 kg/m(2). Attendance for patients at 3, 6 and 12 months follow-up was 55%, 37% and 28%. Of those who attended at 12 months, 35.2% had maintained a weight loss of ≥5% compared to 30.7% in the original evaluation. CONCLUSIONS Evaluation of the Counterweight Programme in Scotland demonstrated consistency in characteristics of patients enrolled into the programme. There was evidence of higher loss to follow-up in a population not routinely engaging with primary care but evidence of greater weight losses among those who attended.

The Eating Disorder Inventory in a UK National Health Service Obesity Clinic and its response to modest weight loss.

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.

Obesity remains under diagnosed in English hospital in-patients.

SUMMARY There is a high prevalence of obesity in hospital populations. BMI and waist circumference are both simple and inexpensive screening tools for detection of obesity and if used would allow clinical guidelines for weight management to be implemented. Health care professionals should routinely screen all in-patients for overweight and obesity in UK hospitals, but compliance with this performance measure is poor. We found that weight was recorded only in 50-70% hospital in-patients. BMI was recorded in less than 50% of patients and waist circumference was never even mentioned in hospital notes.:

Changes in body weight and pulse: outcome events in overweight and obese subjects with cardiovascular disease in the SCOUT trial.

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.