A Randomized Double-Blind Study of Weight Reducing Effect and Safety of Rimonabant in Obese Patients With or Without Comorbidities - RIO-Europe

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.

Hypothesis:

Treatment with rimonabant will be associated with a greater weight loss than placebo.

Study Design

Patients Screened: 2,168
Patients Enrolled: 1,507
Mean Follow Up: Two years
Mean Patient Age: Mean age 45 years
Female: 20

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:

Clinical disorders, such as substantial endocrine disease, diabetes, cardiovascular or pulmonary disease, hepatic and renal disorders, or substantial neurological or psychological illness

Primary Endpoints:

Absolute change in weight from baseline to one year

Secondary Endpoints:

Weight loss relative to baseline weight (≥5% and ≥10%)
Waist circumference
Change in metabolic parameter

Drug/Procedures Used:

Patients were randomized to a fixed daily dose of rimonabant 5 mg (n=603), rimonabant 20 mg (n=599), or placebo (n=305) treatment for two years. Patients in all groups were instructed to reduce diet by 600 calories, and physical activity was encouraged.

Principal Findings:

Weight loss at one year was greater in the rimonabant 20 mg group (6.6 kg) and the rimonabant 5 mg group (3.4 kg) than the placebo group (1.8 kg; p<0.001 for 20 mg comparison, p=0.002 for 5 mg comparison). The weight loss results were maintained at two years, with loss of 5.5 kg in the 20 mg group, 2.9 kg in the 5 mg group, and 1.2 kg in the placebo group in an intent-to-treat analysis (p<0.001 for 20 mg vs. placebo, p=0.0002 for 5 mg vs. placebo).

Among patients who completed the duration of the study, the weight loss at two years was even larger (7.2 kg for 20 mg, 4.9 kg for 5 mg, and 2.5 kg for placebo). Among patients on study drug at 1 year, loss of ≥5% of initial body weight at one year was more frequent in both rimonabant arms compared with placebo (67.4% for 20 mg and 44.2% for 5 mg vs. 30.5% for placebo, p<0.001 and p=0.002, respectively). Similar results were reported for loss of ≥10% of initial body weight at one year (39.0% for 20 mg [p<0.001 vs. placebo] and 15.3% for 5 mg vs. 12.4% for placebo) and two years (32.1% for 20 mg group vs. 10.9 for placebo group).

Waist circumference reduction at one year was greater in the rimonabant arms (6.5 cm for 20 mg and 3.9 cm for 5 mg) than placebo (2.4 cm; p<0.001 and p=0.002, respectively). At two years, results were similar in the cohort of patients who completed the study (reduction of 7.5 cm in the 20 mg group, 5.3 cm in the 5 mg group, and 3.4 cm in the placebo group).

Metabolic syndrome was reduced in the 20 mg rimonabant group from 42.2% at baseline to 19.6% at one year and 21.5% at two years (p<0.001 compared to placebo). At one year, high-density lipoprotein (HDL) increased by 27% in the 20 mg rimonabant group (p<0.001 vs. placebo), 19% in the 5 mg rimonabant group, and 17% in the placebo group, and triglycerides were reduced (reduction of 10.6% for 20 mg, p<0.001 vs. placebo; 4.9% for 5 mg, and 6.6% for placebo). Increases in HDL and reductions in triglycerides were maintained at two years. Both of these improvements were shown to be independent of weight loss. Additionally, insulin response on oral glucose tolerance test at one year was improved in the 20 mg rimonabant group versus placebo (reduction compared to baseline of 11.0 µU/ml vs. 2.3 µU/ml, p=0.019).

Mild side effects were higher in the 20 mg rimonabant group, including nausea, diarrhea, and dizziness, but were mostly mild and transient. Dropout rates by one year were similar in all three groups (39.4% in 20 mg rimonabant group, 37.3% for 5 mg, and 41.6% in placebo group). Discontinuation due to an adverse event from year one to two was slightly higher in the 20 mg group (18.9%) compared with the 5 mg group (10.9%) or placebo group (13.1%).

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 through two years compared with placebo.

These data are similar to the results reported in the RIO-LIPIDS trial, which evaluated rimonabant in patients with abdominal obesity and abnormal lipid profiles and also showed a greater weight reduction with rimonabant compared with placebo. Both studies showed an improvement in lipids, as noted by higher HDL and lower triglycerides, a finding that was independent of weight reduction in the present study.

Obesity has been shown to be a risk factor for a variety of comorbidities, including increased coronary heart disease, diabetes, and hyperlipidemia. The two-year follow-up data demonstrate that while some of the benefit was lost, the majority of the weight loss, reduction in waist circumference, and increase in HDL was maintained over the longer follow-up period.

References:

Van Gaal LF, et al. Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet 2005; 365: 1389–97.

Presented by Dr. Luc Van Gaal at the March 2005 ACC Annual Scientific Session, Orlando, FL.

Van Gaal L. RIO-EUROPE: a randomised double-blind study of weight reducing effect and safety of rimonabant in obese patients with or without comorbidities. Paper presented at the European Society of Cardiology Congress 2004, 29 August-1 September, Munich, Germany.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, Hypertriglyceridemia, Lipid Metabolism, Diet

Keywords: Obesity, Abdominal, Follow-Up Studies, Hyperlipidemias, Comorbidity, Coronary Disease, Risk Factors, Waist Circumference, Piperidines, Cannabinoid Receptor Antagonists, Dizziness, Glucose Tolerance Test, Motor Activity, Receptor, Cannabinoid, CB1, Nausea, Insulin, Weight Loss, Body Weight, Lipids, Diarrhea, Pyrazoles, Metabolic Syndrome X, Diet, Triglycerides, Lipoproteins, HDL, Diabetes Mellitus


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