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Aim: The Sibutramine Cardiovascular OUTcomes trial showed that sibutramine produced greater mean weight loss than placebo but increased cardiovascular morbidity but not mortality. The relationship between 12-month weight loss and subsequent cardiovascular outcomes is explored., Methods: Overweight/obese subjects (N = 10 744), ≥55 years with cardiovascular disease and/or type 2 diabetes mellitus, received sibutramine plus weight management during a 6-week Lead-in Period before randomization to continue sibutramine (N = 4906) or to receive placebo (N = 4898). The primary endpoint was the time from randomization to first occurrence of a primary outcome event (non-fatal myocardial infarction, non-fatal stroke, resuscitated cardiac arrest or cardiovascular death)., Results: For the total population, mean weight change during Lead-in Period (sibutramine) was -2.54 kg. Post-randomization, mean total weight change to Month 12 was -4.18 kg (sibutramine) or -1.87 kg (placebo). Degree of weight loss during Lead-in Period or through Month 12 was associated with a progressive reduction in risk for the total population in primary outcome events and cardiovascular mortality over the 5-year assessment. Although more events occurred in the randomized sibutramine group, on an average, a modest weight loss of approximately 3 kg achieved in the Lead-in Period appeared to offset this increased event rate. Moderate weight loss (3-10 kg) reduced cardiovascular deaths in those with severe, moderate or mild cardiovascular disease., Conclusions: Modest weight loss over short-term (6 weeks) and longer-term (6-12 months) periods is associated with reduction in subsequent cardiovascular mortality for the following 4-5 years even in those with pre-existing cardiovascular disease. While the sibutramine group experienced more primary outcome events than the placebo group, greater weight loss reduced overall risk of these occurring in both groups., (© 2011 Blackwell Publishing Ltd.)

Background: The long-term effects of sibutramine treatment on the rates of cardiovascular events and cardiovascular death among subjects at high cardiovascular risk have not been established., Methods: We enrolled in our study 10,744 overweight or obese subjects, 55 years of age or older, with preexisting cardiovascular disease, type 2 diabetes mellitus, or both to assess the cardiovascular consequences of weight management with and without sibutramine in subjects at high risk for cardiovascular events. All the subjects received sibutramine in addition to participating in a weight-management program during a 6-week, single-blind, lead-in period, after which 9804 subjects underwent random assignment in a double-blind fashion to sibutramine (4906 subjects) or placebo (4898 subjects). The primary end point was the time from randomization to the first occurrence of a primary outcome event (nonfatal myocardial infarction, nonfatal stroke, resuscitation after cardiac arrest, or cardiovascular death)., Results: The mean duration of treatment was 3.4 years. The mean weight loss during the lead-in period was 2.6 kg; after randomization, the subjects in the sibutramine group achieved and maintained further weight reduction (mean, 1.7 kg). The mean blood pressure decreased in both groups, with greater reductions in the placebo group than in the sibutramine group (mean difference, 1.2/1.4 mm Hg). The risk of a primary outcome event was 11.4% in the sibutramine group as compared with 10.0% in the placebo group (hazard ratio, 1.16; 95% confidence interval [CI], 1.03 to 1.31; P=0.02). The rates of nonfatal myocardial infarction and nonfatal stroke were 4.1% and 2.6% in the sibutramine group and 3.2% and 1.9% in the placebo group, respectively (hazard ratio for nonfatal myocardial infarction, 1.28; 95% CI, 1.04 to 1.57; P=0.02; hazard ratio for nonfatal stroke, 1.36; 95% CI, 1.04 to 1.77; P=0.03). The rates of cardiovascular death and death from any cause were not increased., Conclusions: Subjects with preexisting cardiovascular conditions who were receiving long-term sibutramine treatment had an increased risk of nonfatal myocardial infarction and nonfatal stroke but not of cardiovascular death or death from any cause. (Funded by Abbott; ClinicalTrials.gov number, NCT00234832.)

Background: Increased prevalence of adolescent obesity requires effective treatment options beyond behavior therapy., Objective: To see whether sibutramine reduced weight more than placebo in obese adolescents who were receiving a behavior therapy program., Design: 12-month, 3:1 randomized, double-blind trial conducted from July 2000 to February 2002., Setting: 33 U.S. outpatient clinics., Participants: 498 participants 12 to 16 years of age with a body mass index (BMI) that was at least 2 units more than the U.S. weighted mean of the 95th percentile based on age and sex, to the upper limit of 44 kg/m2., Interventions: Site-specific behavior therapy plus 10 mg of sibutramine or placebo. Blinded study medication dose was uptitrated to 15 mg or placebo at month 6 if initial BMI was not reduced by 10%., Measurements: Body mass index, waist circumference, body weight, fasting lipid and glycemic variables, safety, and tolerability., Results: Seventy-six percent of patients in the sibutramine group and 62% of patients in the placebo group completed the study. The estimated mean treatment group difference at month 12 (linear mixed-effects model) favored sibutramine for change from baseline in BMI (-2.9 kg/m2 [95% CI, -3.5 to -2.2 kg/m2]) and body weight (-8.4 kg [CI, -9.7 to -7.2 kg]) (P < 0.001 for both). The sibutramine group had greater improvements in triglyceride levels, high-density lipoprotein cholesterol levels, insulin levels, and insulin sensitivity (P < or = 0.001 for all). The rate of tachycardia was greater with sibutramine vs. placebo (12.5% vs. 6.2%; difference, 6.3 percentage points [CI, 1.0 to 11.7 percentage points]) but did not lead to increased withdrawal (2.4% vs. 1.5%; difference, 0.9 percentage point [CI, -1.7 to 3.5 percentage points])., Limitations: The 1-year study duration precluded assessment of long-term weight maintenance and putative health benefits and harms, and 24% and 38% of the sibutramine and placebo groups, respectively, did not complete follow-up., Conclusions: Sibutramine added to a behavior therapy program reduced BMI and body weight more than placebo and improved the profile of several metabolic risk factors in obese adolescents.

Background: Early weight loss is generally considered to predict long-term weight outcome in obese patients, and this is reflected in prescribing guidelines for antiobesity drugs. For example, the current prescribing guidelines for the antiobesity drug, sibutramine, indicate that if patients have not lost 2 kg (or 4 lb) in the first 4 weeks of treatment with sibutramine 10 mg, the physician should re-evaluate the therapy, which may result in increasing the dose to 15 mg or discontinuation. This regimen may deny treatment to a large group of patients who might otherwise benefit, particularly patients with type 2 diabetes who often find it more difficult to lose weight than non-diabetic obese individuals., Materials: We have re-analysed pooled data from seven randomized, controlled studies of sibutramine-induced weight loss and maintenance in which patients (n = 928; 75% female) had taken sibutramine 10 or 15 mg continuously for 12 months, in order to determine the predictors of success in weight loss (defined as loss of at least 5% of initial body weight at Month 12) in both diabetic and non-diabetic patients. Sensitivity and specificity analyses were used to calculate optimal predictive values., Results: In both diabetic and non-diabetic patients, weight loss of 4 kg at 3 months was identified as the optimal predictor for achieving at least 5% weight loss at 12 months. This target was associated with the best average values for sensitivity, specificity and accuracy, as well as high positive (78% vs. 84% for non-diabetics and 76% vs. 85% for diabetics, compared to existing guidelines target of 2 kg after 1 month treatment) and negative predictive values (63% vs. 71% for non-diabetics; 52% vs. 70% for diabetics)., Conclusion: Sibutramine, in conjunction with diet and exercise, should be continued for at least 3 months (providing there are no adverse effects) to determine whether or not patients are likely to achieve a clinically valid outcome at 1 year. This highlights the need to ensure that regulatory restrictions reflect the needs of clinical practice.