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Rimonabant on Weight Reduction and Weight Maintenance: RIO-NORTH AMERICA - RIO-NA
Description:
The goal of the trial was to evaluate the efficacy and safety of Rimonabant, the first selective cannabinoid type 1 (CB1) receptor antagonist, compared with placebo for weight reduction out to two years.
Hypothesis:
Treatment with Rimonabant will be associated with a greater weight loss than placebo through two years.
Study Design
Study Design:
Patients Screened: 4,604
Patients Enrolled: 3,040
Mean Follow Up: Two years
Mean Patient Age: Mean age 45 years
Female: 81
Patient Populations:
Body mass index (BMI) ≥30 kg/m2 or BMI >27 with comorbidity, defined as dyslipidemia or hypertension, and stable weight during the prior three months
Exclusions:
Body weight fluctuation of >5 kg in prior 3 months; clinically significant cardiac, renal, hepatic, gastrointestinal tract, neuropsychiatric, or endocrine disorders; drug-treated or diagnosed type 1 or type 2 diabetes; use of medications that alter body weight or appetite; a history or current substance abuse; or changes in smoking habits or smoking cessation in prior 6 months
Primary Endpoints:
Absolute change in weight from baseline to one year, and prevention of weight regain after re-randomization through year two
Secondary Endpoints:
Weight loss relative to baseline weight (≥5% and ≥10%), waist circumference, and change in metabolic parameter
Drug/Procedures Used:
Patients were randomized in a 2:2:1 manner to a fixed daily dose of Rimonabant 5 mg, Rimonabant 20 mg, or placebo. After one year of treatment, patients originally randomized to the Rimonabant 5 mg and 20 mg were re-randomized to either the same dose of Rimonabant or placebo for an additional year. The goal of the re-randomization was to evaluate whether weight loss in the Rimonabant arms could be maintained following cessation of the drug. Patients in all groups were instructed to reduce caloric intake by 600 calories, and physical activity was encouraged.
Principal Findings:
The study was completed through one year in 51% of the placebo group and the 5 mg Rimonabant group and 55% of the 20 mg Rimonabant group. Weight loss at one year was greater in the Rimonabant 20 mg group (6.3 kg) and the Rimonabant 5 mg group (~3 kg) than the placebo group (1.6 kg; p<0.001 for 20 mg comparison, p<0.05 for 5 mg comparison). Additionally, waist circumference reduction was greater in the Rimonabant 20 mg compared with placebo (6.1 cm for 20 mg vs. 2.5 cm for placebo; p<0.001 for 20 mg vs. placebo). Metabolic syndrome was reduced in the 20 mg Rimonabant group from 34.8% at baseline to 21.2% at one year.
Weight loss at two years was greatest in patients who were randomized to Rimonabant 20 mg for the full two years (7.4 kg; p<0.001 vs placebo). Patients originally randomized to Rimonabant in the first year, but re-randomized to placebo the second year, did not maintain as large of a weight loss at the end of two years. Waist circumference reduction at two years was greater in patients who were randomized to Rimonabant 20 mg for the full two years compared with placebo (5 cm for 20 mg vs. 2.2 cm for placebo; p<0.001 for 20 mg vs. placebo). Loss of ≥5% of initial body weight was more frequent in patients randomized to Rimonabant 20 mg for two years compared with placebo (40% for 20 mg vs. 19% for placebo, p<0.001). Similar results were reported for loss of ≥10% of initial body weight (17% for 20 mg [p<0.001 vs. placebo] vs. 8% for placebo). At two years, high-density lipoprotein (HDL) increases and triglyceride reductions were greatest in patients who were randomized to Rimonabant 20 mg for the full two years.
Dropout rates due to adverse events by one year higher in the Rimonabant 20 mg group (12.8% in 20 mg Rimonabant group, 9.4% for 5 mg, and 7.2% in placebo group). However, rates during year two of treatment among patients re-randomized to the same groups were similar (4.2% in 20 mg Rimonabant group, 6.3% for 5 mg, and 4.0% in placebo group).
Interpretation:
Among obese patients, treatment with the CB1 receptor antagonist Rimonabant was associated with a greater reduction in weight, waist circumference, and presence of metabolic syndrome at one year compared with placebo. Weight loss through two years was maintained in patients who continued to receive high-dose Rimonabant, but was not as great in those who discontinued Rimonabant after one year.
Obesity has been shown to be a risk factor for a variety of comorbidities, including increased coronary heart disease, diabetes, and hyperlipidemia. The one-year data are similar to the results reported in the RIO-EUROPE and RIO-LIPIDS trials, which also showed a greater weight reduction with Rimonabant 20 mg compared with placebo. While weight loss was maintained through two years in patients who were re-randomized to Rimonabant 20 mg for the full two years, weight loss was not maintained as well in patients who were randomized to Rimonabant the first year, but placebo the second year, suggesting the need for maintenance therapy. Study drug discontinuation by one year was high in all three groups (>50%).
References:
Pi-Sunyer XP, et al. Effect of Rimonabant, a Cannabinoid-1 Receptor Blocker, on Weight and Cardiometabolic Risk Factors in Overweight or Obese Patients: RIO-North America. JAMA. 2006;295:761-775.
Presented by F. Xavier Pi-Sunyer at the American Heart Association Scientific Sessions, November 2004, New Orleans, LA.
Keywords: Hyperlipidemias, Weight Loss, Overweight, Lipids, Comorbidity, Coronary Disease, Risk Factors, Pyrazoles, Metabolic Syndrome, Waist Circumference, Piperidines, Cannabinoid Receptor Antagonists, Motor Activity, Receptor, Cannabinoid, CB1, Obesity, Energy Intake, Triglycerides, Lipoproteins, HDL, Diabetes Mellitus
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