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RIO-Diabetes - RIO-Diabetes
Description:
The goal of the trial was to evaluate the efficacy and safety of rimonabant, a selective cannabinoid type 1 (CB1) receptor antagonist, compared with placebo for weight reduction among overweight or obese patients with type 2 diabetes.
Hypothesis:
Treatment with rimonabant will be associated with a greater weight loss than placebo among overweight or obese patients with type 2 diabetes.
Study Design
Study Design:
Patients Screened: 2,405
Patients Enrolled: 1,045
Mean Follow Up: 1 year
Mean Patient Age: Mean age 56 years
Female: 51
Patient Populations:
Ages 18-70 years; type 2 diabetes treated with metformin or sulphonylurea monotherapy for ≥6 months but who remained inadequately controlled; body mass index 27-40 kg/m2; HbA1c 6.5%-10.0%; and fasting glucose concentration of 5.55-15.04 mmol/L
Exclusions:
Unstable bodyweight (>5 kg variation within past 3 months); any clinically significant disorder; systolic blood pressure >160 mm Hg or diastolic blood pressure >95 mm Hg; pregnancy or lactation; recent or planned changes in smoking status; use of anti-obesity drugs within the past 3 months; or use of any medication known to affect body weight
Primary Endpoints:
Weight change from baseline after 1 year of treatment
Secondary Endpoints:
Changes in HbA1c, high-density lipoprotein cholesterol, triglyceride, fasting glucose, fasting insulin, high-sensitivity C-reactive protein, and leptin concentrations; prevalence of metabolic syndrome; waist circumference; and blood pressure
Drug/Procedures Used:
Diabetic patients already on metformin or sulphonylurea monotherapy were randomized in a double-blind manner to rimonabant 5 mg (n = 358), rimonabant 20 mg (n = 339), or placebo (n = 348) for 1 year. Patients in all groups were instructed to reduce caloric intake and to increase physical activity.
Principal Findings:
The mean weight at screening was 96.3 kg. The study was completed through 1 year in 66.2% of the trial, with little variation by randomization group. Weight loss at 1 year was greater in the rimonabant 20 mg group (5.3 kg) and the rimonabant 5 mg group (2.3 kg) than the placebo group (1.4 kg; p < 0.001 for 20 mg comparison, p = 0.01 for 5 mg comparison). Compared with placebo (14.5%), loss of ≥5% of initial body weight was more frequent in patients randomized to rimonabant 20 mg (49.4%; p < 0.001) and rimonabant 5 mg (21.7%; p = 0.02). Similar results were reported for loss of ≥10% of initial body weight (16.4% for 20 mg, 6.2% for 5 mg, 2.0% for placebo; p < 0.001 for 20 mg vs. placebo and p = 0.01 for 5 mg vs. placebo). Additionally, waist circumference reduction was greater in the rimonabant groups compared with placebo (5.2 cm for 20 mg, 2.9 cm for 5 mg, 1.9 cm for placebo; p < 0.001 for 20 mg vs. placebo and p = 0.02 for 5 mg vs. placebo).
Glycosylated hemoglobin (HbA1c) at 1 year was reduced by 0.6% in the rimonabant 20 mg and by 0.1% in the 5 mg group, but increased by 0.1% in the placebo group (p < 0.001 for 20 mg vs. placebo and p = 0.03 for 5 mg vs. placebo). Fasting glucose at 1 year was reduced in the rimonabant 20 mg group compared with placebo (-0.64 mmol/L vs. +0.33 mmol/L, p < 0.001), but did not differ for the 5 mg group (+0.33 mmol/L, p = 0.86 vs. placebo).
Discontinuations due to adverse events by 1 year were higher in the rimonabant 20 mg group (15% in 20 mg rimonabant group, 8% for 5 mg, and 5% in placebo group). Psychiatric causes leading to discontinuation included depressed mood disorder (3% for rimonabant 20 mg, 0.9% for placebo), anxiety (0.6% for rimonabant 20 mg), and aggression (0.6% for rimonabant 5 mg).
Interpretation:
Among overweight or obese patients with type 2 diabetes inadequately controlled by metformin or sulphonylurea monotherapy, treatment with the CB1 receptor antagonist rimonabant was associated with a greater reduction in weight, waist circumference, and HbA1c at 1 year compared with placebo, with the 20 mg dose showing somewhat greater efficacy than the 5 mg dose.
Obesity is a risk factor for a variety of comorbidities, including increased coronary heart disease and diabetes. To further the problem, medications used to treat diabetic patients are often associated with weight gain, making diabetics a particularly difficult population for weight management.
The 1-year data are similar to the results reported in nondiabetic patients in the RIO-NA, RIO-EUROPE, and RIO-LIPIDS trials, which also showed a greater weight reduction with rimonabant 20 mg compared with placebo. In RIO-NA, weight loss was maintained through 2 years in patients who were re-randomized at 1 year to rimonabant 20 mg for the full 2 years, but 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. Adverse events leading to study drug discontinuation were higher in the rimonabant 20 mg, a finding similar to earlier rimonabant studies. Depression remains a frequent reason for rimonabant study drug withdraw.
References:
Scheen AJ, Finer N, Hollander P, Jensen MD, Van Gaal LF, on behalf of the RIO-Diabetes Study Group. Efficacy and tolerability of rimonabant in overweight or obese patients with type 2 diabetes: a randomised controlled study. Lancet 2006;368:1660-72.
Keywords: Receptors, Cannabinoid, Overweight, Diabetes Mellitus, Type 2, Comorbidity, Coronary Disease, Risk Factors, Weight Gain, Glucose, Glycated Hemoglobin A, Waist Circumference, Piperidines, Cannabinoid Receptor Antagonists, Metformin, Motor Activity, Obesity, Receptor, Cannabinoid, CB1, Depression, Weight Loss, Mood Disorders, Lipids, Pyrazoles, Energy Intake, Fasting
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