All statistical tests were two-tailed, with significance determined by reference to the 5% level. The null hypothesis was that the treatments were equivalent. The principal measure of efficacy was analyzed using the Kruskal-Wallis test,36 including a factor for treatment group. Given that this result was significant at the 5% level, pairwise comparisons between the treatment groups were made by the large-sample normal approximation to the Wilcoxon rank sum test.35
The methods we used to analyze differences between treatment groups were analysis of variance (ANOVA)34 with factors for treatment group, center, and treatment group-by-center interaction for weight loss, waist and hip circumference, waist/hip ratio, vital signs, glucose and triglycerides, and ranked ANOVA for BMI, cholesterol, and uric acid. The differences between groups in the proportion of patients losing at least 5% and 10% of their baseline body weight were analyzed by logistic regression with factors for treatment group and center. All efficacy analyses were performed using the last observation carried forward (LOCF) to replace missing data. All data collected were included except for assessments performed more than 14 days after the last dose of study medication. After 14 days postdose, it was thought body weights could have changed significantly.
Results
Of 510 patients who entered the run-in period, 485 continued into the double-blind phase Figure 1. This occurred because of a lack of a gold-standard definition of obesity at the outset of this study; a protocol amendment allowed data from these patients to be included in the analysis. No clinically significant differences were noted between treatment groups at baseline with respect to demographic profile or characteristics of obesity Table 1. Four patients had BMIs at screening that fell out of the original trial protocol, all in the sibutramine 10-mg treatment group (1 patient <27 and 3 patients >40 kg/m2). Reanalysis of the data excluding these 4 patients was carried out, and no differences affecting the results, outcomes, or conclusions of our study were found.
Our analysis takes the patients who withdrew from the study into account.32 Pooled rates of withdrawal for any reason were similar in the 3 treatment groups: placebo, 83 patients (51%); sibutramine 10 mg, 79 (49%); and sibutramine 15 mg, 67 (42%). The completion rate for the 1-year study was 53%, which is generally consistent with weight loss programs.37 Regarding the primary outcome analysis, fewer patients in the sibutramine groups than in the placebo group withdrew for lack of efficacy or adverse events. Using the log-rank test, there was no statistically significant difference between treatment groups in time to withdrawal, overall withdrawal rate, or withdrawal rate due to adverse events or lack of efficacy. Both sibutramine-treated groups had more patients in each category of weight loss above 5% (P=.001; Table 2. Pairwise comparisons showed a statistically significant difference versus placebo in favor of sibutramine 10 mg (P=.04) and sibutramine 15 mg (P <.001).
A significantly greater proportion of patients in the 2 sibutramine groups lost at least 5% and 10% of their baseline body weight Table 2. Mean weight reduction was significantly greater in the sibutramine groups than in the placebo group. Mean reductions in BMI reflected those in body weight and were significantly greater with 10 mg sibutramine (1.7 kg/m2) and 15 mg sibutramine (2.4 kg/m2) than with placebo (0.6 kg/m2; P <.001). The reduction in BMI was significantly greater with 15 mg sibutramine than 10-mg sibutramine (P <.05).
Patients treated with 10 mg or 15 mg sibutramine once daily lost more weight at each monthly assessment than those treated with placebo Figure 2. Weight loss was dose related, and maximal weight loss occurred by month 6 in all treatment groups. During the 4 weeks after treatment cessation (at whatever time this occurred), there were small weight increases in all treatment groups. Ten (6%) patients in the placebo group withdrew because of lack of efficacy compared with 5 (3%) in the sibutramine 10 mg group and 2 (1%) in the sibutramine 15-mg group.
Dose-related reductions in mean waist and hip circumferences achieved by month 6 were maintained at month 12. In the placebo group at month 12 (LOCF), the reductions were similar for waist and hip (2.4 cm and 2.6 cm, respectively), while in the 10- and 15-mg sibutramine groups, waist reduction was greater than hip reduction (6.4 cm and 3.8 cm at 10 mg and 7.4 cm and 5.2 cm at 15 mg). The reductions on active treatment were significantly greater than with placebo (P <.05 for overall comparison). The mean reduction in waist/hip ratio at month 12 (LOCF) was significantly greater with 10 mg sibutramine (-0.04) and 15 mg sibutramine (-0.03) than with placebo (-0.01; P <.05; least significant difference, .02).