Context:

Pharmacological and surgical treatments for weight loss have become both more numerous and more commonly used. This report was commissioned to review the evidence on such treatments in adults, adolescents, and children.

Objectives:

To assess the efficacy and safety of the weight loss medications sibutramine, orlistat, fluoxetine, phentermine, and diethylpropion; to assess the evidence for other medications that have been used for weight loss including bupropion, zonisamide, topiramate, and sertraline; and to assess the efficacy and safety of various types of bariatric surgery.

Data Sources:

We searched numerous electronic databases electronically, including MEDLINE® and EMBASE, for potentially relevant studies. We scanned the reference lists of recent extensive reviews on sibutramine, orlistat, and bariatric surgery. We also contacted experts in the field.

Study Selection:

We screened 1,063 articles. We quality-reviewed 78 medication studies that reported on sertraline (1 article), zonisamide (1 article), orlistat (49), buproprion (5), topirmate (9), and fluoxetine (13). Meta-analysis was performed for all medications except sertraline and zonisamide which are summarized in the text. We quality-reviewed 159 surgery studies reporting on weight loss and considered an additional 8 surgery studies reporting only on complications, for a total of 167 surgery studies. Of these 167 studies, 20 were duplicate publication of an already included study. Of the remaining 147 studies, 89 contributed to the weight loss analysis, 134 contributed to the mortality analysis, and 128 contributed to the complications analysis. Studies could contribute to one or more surgery analyses.

Data Extraction:

We abstracted information about study design, intervention, co-interventions (diet, exercise), population, and outcomes. We also collected data on randomization, dropouts, blinding, and allocation, to assess methodological quality. We abstracted weight loss, control of comorbidities, and adverse events from controlled trials of medication, controlled trials of surgery, and surgery case series.

Data Synthesis:

A recent meta-analysis of sibutramine efficacy reported a mean difference in weight loss (compared to placebo) of 3.43 kg at 6 months. At 12 months, the difference was 4.45 kg. Treatment with sibutramine was associated with modest increases in heart rate and blood pressure, very small improvements in glycemic control among diabetics, and (based on the longest-duration and best-quality studies) small improvements in HDL cholesterol and triglycerides.

In our own meta-analysis on orlistat, the pooled random-effects estimate of the mean weight loss for orlistat-treated patients, compared to placebo-treated patients, was 2.51 kg at 6 months; at 12 months, it was 2.75 kg. We found an increase in diarrhea, flatulence, and bloating/ abdominal pain/dyspepsia in orlistat-treated patients compared to placebo, with relative risks (RR) of 3.4, 3.1, and 1.5, respectively.

We identified a published review on phentermine and diethylpropion for weight loss. Our literature review identified no new RCTs of these drugs since publication. Compared to placebo, subjects treated with phentermine lost on average 3.6 additional kg of weight at 6 months, while subjects treated with diethylpropion lost on average 3.0 additional kg of weight (but this difference had only borderline statistical significance). This review did not report side effects or adverse-event data.

Our meta-analysis of fluoxetine studies showed a mean weight loss, compared to placebo-treated patients, of 4.74 kg at 6 months and 3.05 kg at 12 months. There was an increase in nervousness/sweating/tremors, nausea/vomiting, fatigue/asthenia/ hypersomnia/somnolence, insomnia, and diarrhea in fluoxetine-treated patients compared to placebo, with RR of 6.4, 2.7, 2.4, 2.0, and 1.7, respectively.

We identified three studies of bupropion for weight loss that were suitable for meta-analysis. The pooled result at 6 to12 months, compared to placebo treated patients, was 2.8 kg. Bupropion causes dry mouth (RR = 2.99) and insomnia.

We identified six studies (all available only as abstracts) of topiramate for weight loss that were suitable for meta-analysis. The pooled result at 6 months, compared to placebo-treated patients, was an additional 6.5 percent of pretreatment weight lost. Parasthesias (RR = 4.9) and taste perversion (RR = 9.2) are the most commonly reported side effects attributable to topiramate.

We found single studies for each of the following: zonisamide and sertraline.

We identified one large matched cohort analysis that established that surgery results in greater weight loss than does medical treatment in obese individuals with a BMI of 40 kg/m² or greater. Surgery resulted in a 20 to 30 kg weight loss, maintained up to 8 years and accompanied by significant improvements in several comorbidities. For patients with a BMI between 35 and 40 kg/m², the data strongly support the superiority of surgical therapy but cannot yet be considered conclusive. Bariatric surgical procedures in current use have been performed with an overall postoperative mortality rate of less than 1 percent. The average postoperative mortality rate is probably twice this number. Laparoscopic procedures result in fewer wound complications or incisional hernias than open procedures.

Conclusions:

Sibutramine, orlistat, phentermine, diethylpropion (probably), bupropion, fluoxetine, and topiramate all promote weight loss when given along with recommendations for diet. Sibutramine and orlistat are the two most-studied drugs. The amount of extra weight loss attributable to these medications is modest (less than 5 kg at one year), but this amount still may be clinically significant. No evidence indicates that any particular drug promotes more weight loss than another drug. All of these drugs have side effects. The choice of drug may be made on an individual basis, based on tolerance to the expected side effects.

Surgical treatment is more effective than nonsurgical treatment for weight loss and the control of some comorbidities in patients with a body mass index of 40 kg/m² or greater. More data are needed to confirm or refute the relative efficacy of surgery for less severely obese persons. Perioperative mortality rates of less than 1 percent have been achieved by some surgeons and surgical centers. The perioperative mortality rates in other settings may be higher. Surgical treatment is associated with a substantial number of complications and adverse events, although most of these are minor.

The existing literature is almost bereft of data regarding either pharmaceutical or surgical treatment of adolescent and pediatric patients. To the extent that existing data on adults are judged to be inapplicable to adolescents or children, new studies will need to be performed.