Figure 1 summarises the results of the search (fig 1). We identified 27 potentially relevant trials, and five orlistat, five sibutramine, and four rimonabant studies met final inclusion criteria. These were added to the 11 orlistat and five sibutramine trials previously identified.8
Cohen’s κ coefficient for inter-rater agreement measured 0.95 for trial selection and 0.85 for study quality.
Fig 1 Results of search for relevant studies
Description of studies
Thirty double blind placebo controlled randomised controlled trials were included in the final review: 16 orlistat (n=10 631 participants), 10 sibutramine (n=2623), and four rimonabant (n=6635) (tables 1-3).w1-30 Twenty seven of these studies received funding from the drug manufacturer.
Table 1 Included studies on effect of orlistat on weight loss
Table 2 Included studies on effect of sibutramine on weight loss
Table 3 Included studies on effect of rimonabant on weight loss
Nine orlistat studies limited enrolment to higher risk populations: four recruited patients with type 2 diabetesw2 w8 w9 w12 and five enrolled obese patients with at least one cardiovascular risk factor (hypertension, dyslipidaemia, diabetes, or impaired glucose tolerance).w1 w3 w5 w11 w15 In the largest study, which used orlistat (Xenical in the prevention of diabetes in obese subjects, XENDOS), 21% of patients had impaired glucose tolerance.w16
Two sibutramine studies limited enrolment to patients with hypertension with controlled blood pressurew22 w23 and three enrolled patients with type 2 diabetes.w20 w24 w25
One rimonabant study enrolled patients with dyslipidaemia (rimonabant in obesity (RIO)-lipids),w29 one enrolled patients with diabetes (rimonabant in obesity-diabetes),w27 and the other two commonly included patients with dyslipidaemia or hypertension (rimonabant in obesity-Europe; rimonabant in obesity-North America).w28 w30
Twenty seven studies (16 orlistat, seven sibutramine, and four rimonabant) were weight loss trials, in which drug treatment was used in conjunction with a weight loss diet for one to four years. Of these, one rimonabant and four orlistat studies also contained a second weight maintenance year.w4 w7 w13 w14 w30 The three remaining sibutramine trials were weight maintenance studies, in which randomisation was performed after a one to six month induction phase with reduced energy intake.w17 w19 w21 A standardised, low fat, low energy diet and encouragement to exercise were the main cointerventions in most weight loss studies.
Inclusion and exclusion criteria
Trials generally enrolled selected patients with few comorbidities who were able to adhere to a run-in phase protocol. Patients had similar demographic profiles across trials of all three drugs: about two thirds to three quarters of participants were women, about 90% were white, mean age was 45-50 years, mean weight was about 100 kg, and mean body mass index was 35-36 (class 2 obesity).7
In most studies exclusion criteria were obesity of endocrine origin, uncontrolled hypertension, treatment with drugs affecting body weight, pregnancy or lactation, relevant psychiatric or medical illness, previous bariatric surgery, and considerable weight loss before screening.
Studies were all of similar quality,7
and the most important methodological limitation was high attrition rates, which averaged 30% for orlistat studies and 40% for sibutramine and rimonabant studies. The most common reasons for premature withdrawal were refusal of treatment, loss to follow-up, and adverse effects. Most studies did not describe the randomisation process or comment on allocation concealment. No study specifically mentioned blinding of outcome assessors. All studies reported eligibility criteria, and cointerventions were similar in intervention and control arms. Although all included studies described using an intention to treat analysis, the validity of this approach was compromised by the high attrition rates. Because there was little variation in quality and weight loss results, we did not perform sensitivity analyses according to study quality.
Secondary end points were inconsistently reported, sometimes in only a subgroup of patients, or were not reported in an extractable manner. Our analysis includes only those data that were extractable from a given study.
Significant heterogeneity (I2 ≥50%) was present in several anthropometric outcomes but was not judged to be clinically relevant. Substantial heterogeneity (I2 >80%) was also present when we pooled the effects of orlistat and rimonabant on glycaemic control. For orlistat, this heterogeneity was attenuated and did not seem clinically relevant when we limited pooling to patients with diabetes alone. For rimonabant, we have reported glycaemic control results only for the single trial involving patients with type 2 diabetes.
The number of patients included in a given endpoint analysis may be lower that the overall total number of patients studied because we extracted data only for the highest dose of a given drug and the end point may not have been reported at all or not reported in an extractable manner. None of the trials reported total mortality, cardiovascular morbidity, and cardiovascular mortality as end points.
Body weight—Orlistat reduced weight by 2.9 kg (95% confidence interval 2.5 kg to 3.2 kg; 15 studies; fig 2) or 2.9% (2.5% to 3.4%; 13 studies) more than placebo and increased the absolute percentage of participants achieving 5% and 10% weight loss thresholds by 21% (54% v 33%; 18% to 24%; 14 studies) and 12% (26% v 14%; 9% to 14%; 13 studies), respectively (table 4). Placebo subtracted weight loss was 2.6% (2.1% to 3.2%; five studies) or 2.3 kg (1.6 kg to 3.0 kg; four studies) in patients with diabetes receiving orlistat. In the four studies with a second year of weight maintenance, both orlistat and placebo arms showed similar amounts of weight regain, though the weight differential observed after the weight loss phase was preserved.w4 w7 w13 w14
Fig 2 Placebo subtracted weight reduction (kg) with orlistat
Table 4 Summary of outcomes in studies of orlistat
Secondary end points—Orlistat reduced the incidence of type 2 diabetes from 9.0% to 6.2% (hazard ratio 0.63; 95% confidence interval 0.46 to 0.86) in one four year trial.w16 This benefit was observed primarily in patients with impaired glucose tolerance at baseline. Compared with placebo, orlistat also significantly reduced waist circumference, body mass index, systolic blood pressure, diastolic blood pressure, fasting glucose and haemoglobin A1C concentrations in patients with diabetes, and total cholesterol, low density lipoprotein cholesterol, and high density lipoprotein cholesterol concentrations (table 4). Fasting glucose concentrations were significantly reduced (P<0.05) in four of six studies that did not exclusively enrol patients with type 2 diabetes. There was no significant difference between orlistat and placebo in triglyceride concentrations or the change in Framingham cardiovascular risk score.w15
Adverse effects—Patients receiving orlistat were more likely to experience gastrointestinal adverse events and to discontinue because of this (table 4). The most commonly reported gastrointestinal events were fatty/oily stool, faecal urgency, and oily spotting, each occurring at frequency rates of 15% to 30% in most studies. Although concentrations of fat soluble vitamins were reportedly lowered, no study reported clinically relevant vitamin deficiency. Patients receiving orlistat were routinely advised to take daily multivitamins.
Weight loss—Patients receiving sibutramine lost 4.2 kg (3.6 kg to 4.7 kg; eight studies; fig 3) or 4.3% (3.7% to 5.0%; 10 studies) more weight than those taking placebo. In addition, sibutramine treatment increased the absolute percentage of 5% and 10% responders by 32% (55% v 27%; 27% to 37%; seven studies) and 18% (28% v 10%; 11% to 25%; seven studies), respectively (table 5). Placebo subtracted weight losses in patients with diabetes were 5.0% (3.8% to 6.2%) or 4.9 kg (3.6 kg to 6.2 kg). About 10-30% more sibutramine patients achieved successful weight maintenance compared with placebo (successful weight maintenance defined as maintaining 80-100% of the initial weight loss). This was significant (P<0.05) in all three studies but we did not combine data because of differing definitions of weight maintenance between studies.w17 w19 w21
Fig 3 Placebo subtracted weight reduction (kg) with sibutramine
Table 5 Summary of outcomes in studies of sibutramine
Secondary end points—Treatment with sibutramine significantly reduced body mass index, waist circumference, and triglyceride concentrations and increased concentrations of high density lipoprotein cholesterol (table 5). Change in glycaemic variables and concentrations of low density lipoprotein cholesterol and total cholesterol were inconsistently reported and, when reported, were not significantly different from values in the placebo group in any study.
Adverse effects—Compared with placebo, sibutramine increased systolic blood pressure by 1.7 mm Hg (0.1 mm Hg to 3.3 mm Hg; seven studies), diastolic blood pressure by 2.4 mm Hg (1.5 mm Hg to 3.3 mm Hg; seven studies), and pulse rate by 4.5 beats/min (3.5 beats/min to 5.6 beats/min; seven studies) (table 5). Insomnia, nausea, dry mouth, and constipation were more common in patients receiving sibutramine, occurring at frequency rates of 7-20%.
Weight loss—Patients receiving rimonabant lost 4.7 kg (4.1 kg to 5.3 kg; four studies; fig 4) more weight than those taking placebo. The average weight loss was 3.9 kg (3.2 kg to 4.6 kg) in the rimonabant in obesity-diabetes trial.w27 Rimonabant treatment also significantly increased the placebo subtracted absolute percentage of 5% and 10% responders by 33% (51% v 18%; 29% to 37%; four studies) and 19% (26% v 7%; 15% to 23%; seven studies), respectively (table 6). During the weight maintenance phase of the rimonabant in obesity-North America study, patients treated with rimonabant maintained the weight differential observed in the weight loss phase of the study.w30
Fig 4 Placebo subtracted weight reduction (kg) with rimonabant
Table 6 Summary of outcomes for rimonabant
Secondary end points—Rimonabant significantly reduced placebo subtracted waist circumference, systolic blood pressure, diastolic blood pressure, and triglyceride concentrations and increased high density lipoprotein cholesterol concentrations (table 6). Fasting glucose and haemoglobin A1C concentrations were significantly reduced in the rimonabant in obesity-diabetes studyw27 but not in the other rimonabant in obesity studies (table 6). Low density lipoprotein cholesterol and total cholesterol concentrations were not significantly reduced compared with placebo.
Adverse effects—The most worrying adverse effect was an increased incidence of psychiatric disorders (depression, anxiety, irritability, aggression), which occurred in 6% of patients receiving rimonabant and was 3% (2% to 5%; four studies) more likely in patients receiving rimonabant compared with placebo (table 6).