Thirteen (n=2839) double-blind, randomised controlled trials. Eleven studies (n=2561) were placebo controlled.
Effects in Obese Patients (n=2455):
Trials of less than six months (n=1584): Weight loss was dose related and was commonly significantly greater at doses of sibutramine greater or equal to 10 mg/day compared to placebo. Patients receiving sibutramine 10 to 20 mg/day lost approximately 5 to 7.5kg bodyweight (5 to 9.5% of initial bodyweight) over an 8- to 12- week period; correspondingly placebo recipients lost about 1.5 to 3.5kg (1.3 to 4.3%). In addition, a clinically significant 10% bodyweight loss was achieved after 24 weeks by 16 and 28% respectively, of patients receiving sibutramine 10 and 15 mg/day compared to none of the placebo recipients.
Comparative trials with denfenfluramine(n=278): Although actual weight loss appeared slightly greater with sibutramine than with dexfenfluramine in a comparative trial, the overall efficacy of the two treatments was considered equivalent, or not significantly different, after 12 weeks of treatment with once-daily sibutramine (10 mg) and twice-daily dexfenfluramine (15 mg) in a total of 278 obese patients.
Trials of at least one year (n=593): Maximal weight loss was apparent after about 6 months of sibutramine in two 1-year studies. Bodyweight remained below baseline values thereafter.
In the first study, long term use (12 months) of sibutramine at doses of 10 or 15 mg/day compared with placebo significantly reduced body weight in 53% of obese patients. A second study showed that additional significant weight loss was possible with sibutramine 10mg/day compared with placebo in obese patients who had already lost greater than or equal to 6kg during a 4-week very low calorie run-in period. Waist circumference was significantly reduced in sibutramine compared with placebo recipients after 12 months; however, the effect of treatment on waist to hip ratio was not clear.
Effects in Obese Patients with Concomitant Disease (n=384):
In obese patients with type 2 diabetes or hypertension, mean weight loss was significantly greater in once-daily sibutramine (10 or 15mg) than placebo after 12 weeks' therapy with concurrent dietary control, although weight loss appeared to be less than that reported in obese patients without comorbidities. Weight loss was increased or maintained during 12-week non-blind extension periods in obese patients with hypertension or type 2 diabetes who previously received placebo or sibutramine for 12 weeks.
In an 8-week study (n=60), the incidence of headache increased initially in sibutramine 20mg/day recipients (numbers not given) and remained at or above baseline incidence throughout the study. Sleeping difficulties, including problems falling asleep and staying asleep, and reduced duration of sleep, were reported a total of 27 times by 1 and 7 patients taking, respectively, sibutramine 5 and 20 mg/day. Increased irritability, impatience and excitation were reported by 6 of 21 patients in the sibutramine 20mg/day group. Dry mouth was common in both placebo- and drug-treated patients. Five of 60 patients were withdrawn because of adverse events: 1, 1 and 3 patients respectively from the placebo and sibutramine 5 and 20mg groups. Reasons included skin rash, headache, dizziness, nausea, depression, fatigue, panic attacks and numbness and tingling of the hands and feet.
In another study (n=173), 8% of patients receiving sibutramine 1 to 30 mg/day were withdrawn (11 were taking greater than 15mg daily). Not all withdrawals were directly related to the drug and reasons for withdrawal included threatened suicide, chest pain and elevated blood pressure.
In a comparative study of sibutramine and dexfenfluramine (n=226), there were twice as many patient withdrawals because of adverse events (type not defined) in the dexfenfluramine 15mg twice daily group (11 of 114; 10%) as in the sibutramine 10mg once daily group (6 of 112; 5%).
Cardiovascular issues: In one study (n=485) mean diastolic blood pressure (DBP) was increased in 176 normotensive obese patients who received sibutramine 10mg daily for 12 months (by 1.6mm Hg) but was reduced in 80 similar patients who received placebo (by 0.9mm Hg; p<0.01). Heart rate was increased more in sibutramine 15mg daily than in placebo recipients (by 3.5 vs 0.1 beats/min; p=0.007).
In a second 12-month study (n=108), the change in supine DBP from baseline was significantly different in sibutramine 10mg daily (1.5mm Hg increase) and placebo recipients (1.9mm Hg decrease). Mean heart rate was also increased to a greater extent in sibutramine 10mg than in placebo recipients (significant difference from baseline at month 6: 7.7 vs 1.4 beats/min). One month after treatment cessation, mean heart rate fell in sibutramine recipients but rose in placebo recipients (p=0.004 vs 12-month values).
In an 8-week study (n=60), 2 placebo recipients and 1 patient from each sibutramine group (5 or 20mg) had an increase in heart rate of 10 beats/min or to a resting rate of >90 beats/min. No clinically significant abnormal electrocardiographic parameters were observed in any patient.
In obese patients with hypertension (n=113), sibutramine for up to 24 weeks did not increase blood pressure.