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Q What is the effectiveness of anti-obesity medications in trials with ⩾1 year follow up?
Clinical impact ratings GP/FP/Primary care ★★★★★★☆ IM/Ambulatory care ★★★★★☆☆ Endocrine ★★★★★★☆
Medline (1966 to December 2002), EMBASE/Excerpta Medica (1980 to December 2002), Cochrane Controlled Trials Register (Issue 3, 2002), Current Controlled Trials metaRegister of Controlled trials (December 2002), bibliographies of relevant studies, and experts and manufacturers.
Study selection and assessment:
randomised controlled trials (RCTs) of approved anti-obesity agents for weight loss or weight maintenance in adults with body mass index (BMI) ⩾30 kg/m2 or ⩾27 kg/m2 plus ⩾1 obesity related comorbid condition (eg, coronary artery disease, stroke, type 2 diabetes, heart failure, dyslipidaemia, hypertension, reproductive or gastrointestinal cancer, gallstones, fatty liver disease, osteoarthritis, and sleep apnoea), had blinding of patients and healthcare providers, included a placebo group or another anti-obesity drug group, used an intention to treat analysis, and had ⩾1 year of follow up. Studies of off-label therapy; drugs with high addiction potential that preclude long term use; or investigational, herbal, or alternative compounds were excluded. Study quality was assessed.
weight loss at 1 year.
Only trials of orlistat and sibutramine met the selection criteria. 16 RCTs (11 of orlistat and 5 of sibutramine) were included. 14 RCTs (11 of orlistat and 3 of sibutramine) were weight loss trials in which drug therapy was used in conjunction with a weight loss diet for 1 year. 2 RCTs of sibutramine were weight maintenance trials with 12 to 18 month follow up.
11 weight loss trials (n = 6021, mean age 49 y, 71% women, mean BMI 35.7 kg/m2) used standard doses of orlistat (120 mg, 3 times/d). 3 weight loss trials (n = 929, mean age 47 y, 80% women, mean BMI 33.4 kg/m2) used sibutramine, 10 to 20 mg/day. Patients who received orlistat had a 2.7 kg (95% CI 2.3 to 3.1 kg; 11 RCTs) greater weight loss (2.9%, CI 2.3 to 3.4; 10 RCTs) than patients who received placebo, and sibutramine group patients had a 4.3 kg (CI 3.6 to 4.9 kg; 3 RCTs) greater weight loss (4.6%, CI 3.8 to 5.4; 3 RCTs) than placebo group patients. More orlistat and sibutramine group patients achieved 5% and 10% weight losses than placebo group patients (table).
2 sibutramine weight maintenance trials (n = 627, mean age 49 y, 83% women, mean BMI 37 kg/m2) used a 10 mg/day dose of sibutramine. Results from these 2 trials were not pooled, but both showed greater weight loss in participants who received sibutramine than did those who received placebo.
Orlistat and sibutramine are modestly effective for weight loss at 1 year.
Abstract and commentary also appear in ACP Journal Club.
Padwal et al have systematically reviewed the effectiveness and safety of approved anti-obesity medications in clinical trials that lasted for ⩾1 year for which the results were available by the end of 2002. Norris et al have done a meta-analysis of studies reported before September 2002 that examined the efficacy of pharmacotherapy for weight loss over 8–57 weeks in adults with type 2 diabetes. Norris et al also report the limited data describing the effects of fluoxetine. More research is needed before the clinical usefulness of this agent can be established. The authors of both reviews conclude that available licensed therapies (eg, sibutramine and orlistat) help induce weight loss. Although of shorter duration, trials of sibutramine suggest that the magnitude of weight reduction is similar to that seen with orlistat.
A number of important questions need to be addressed before advocating widespread use of pharmacological treatments for weight reduction. Norris et al attempted to obtain results of unpublished studies of weight loss treatments but were unable to identify whether publication bias had occurred. It is difficult to infer whether some patients might respond better to certain weight loss therapies because sampling frames, the method of recruitment, and selection of participants were rarely described. Attrition is an important issue in weight loss studies because patients who do not achieve their goal weight often do not return for follow up.
The safety of pharmacological interventions also needs to be considered. Orlistat treatment has been associated with lower concentrations of fat soluble vitamins in plasma. Sibutramine is a similar compound to dexfenfluramine, which has been associated with pulmonary hypertension and valvular heart disease. In the studies reviewed, these serious side effects were not identified. Common side effects were dry mouth, constipation, and insomnia and more rarely palpitations and increased blood pressure. However, sibutramine is contraindicated in people with coronary artery disease, congestive heart failure, arrhythmias, stroke, or inadequately controlled hypertension or those receiving psychiatric medications. These restrictions limit its usefulness in clinical practice.
Both orlistat and sibutramine are associated with improved cardiovascular risk factors. However, it is not known whether treatment with these agents reduces risk of cardiovascular events. Since the work of Padwal et al and Norris et al, 1 other important study in this field has been published. A 4 year, double blind, randomised, prospective trial of 3305 people with BMI ⩾30 kg/m2 who were randomised to lifestyle intervention plus either orlistat, 120 mg 3 times daily, or placebo showed that orlistat treatment combined with lifestyle changes reduced incident diabetes by 37%.1 It is uncertain if treatment with drugs, such as orlistat or sibutramine, is associated with weight cycling, which appears to adversely affect cardiovascular risk factors.
Commentary continued on next page.
Although orlistat and sibutramine undoubtedly produce weight loss, the effect is modest and is less than can be achieved with intensive lifestyle interventions. Combining increased physical activity and calorie restriction has been shown to reduce the risk of incident diabetes by as much as 58% in 2 similar studies.2,3 Lifestyle interventions have been poorly studied but are the preferred treatment option for most individuals, although many persons who are overweight or obese are unable to undertake or adhere to intensive lifestyle interventions, especially over the longer term. Until effective methods of obesity prevention are introduced, a role for pharmacological treatment of obesity remains. Further research is required to establish cost effectiveness and to identify subgroups of patients who are most likely to benefit from different approaches to weight loss.
For correspondence: Dr R Padwal, University of Alberta and Walter C. Mackenzie Health Sciences Centre, Edmonton, Alberta, Canada.
Source of funding: no external funding.
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