OBJECTIVE: Sibutramine favors a negative energy balance and also has the potential to increase heart rate and blood pressure. We investigated if a progressive supervised sibutramine–diet–exercise clinical intervention could increase the body weight loss previously reported while minimizing the potential cardiostimulatory effects of this drug.DESIGN AND SUBJECTS: The tri-therapy intervention was divided into two phases of 6 weeks each in which sibutramine (10 mg) was taken once daily by eight obese men (body mass index (BMI) between 30 and 40 kg/m2). Part A consisted of a dietary follow-up with an energy restriction, whereas in part B an aerobic exercise program combined with a low-fat diet was introduced. Systolic (SBP) and diastolic (DBP) blood pressure, resting heart rate (RHR) and body weight were measured every 2 weeks while body density, resting metabolic rate (RMR) and respiratory quotient (RQ) were determined before and after the intervention.RESULTS: This clinical intervention produced a substantial body weight loss (−10.7 kg, P<0.01) which was about twice as much as other 12-week studies. In part A, both RHR (+4 beats/min) and DBP (+5 mmHg, P<0.01) were increased. However, after part B, RHR (−8 beats/min, P=0.02) and DBP (−3 mmHg, P<0.01) were significantly decreased. RMR was decreased at the end of the program but this effect did not persist after adjustments for fat-free mass. RQ was also reduced (−0.05, P<0.01) following the clinical tri-therapy.CONCLUSION: In conclusion, these observations suggest that this clinical tri-therapy favored a satisfactory benefit–risk profile since it enhanced weight loss without inducing increases in heart rate and blood pressure or detrimental changes in RMR and substrate oxidation.