A Randomised Double-Blind Study of Weight Reducing Effect and Safety of Rimonabant in Obese Patients with or without Comorbidities A Randomised Double-Blind Study of Weight Reducing Effect and Safety of Rimonabant in Obese Patients with or without Comorbidities Presented at American College of Cardiology Scientific Sessions 2005 Presented by Dr. Luc Van Gaal RIO EUROPE Trial

www. Clinical trial results.org Rimonabant A selective cannabinoid type 1 receptor antagonist  20 mg  n=599 Rimonabant A selective cannabinoid type 1 receptor antagonist  20 mg  n=599 Endpoints:  Primary: Absolute change in weight from baseline to one year.  Secondary: Weight loss relative to baseline weight (≥5% and ≥10%), waist circumference, and change in metabolic parameter. Endpoints:  Primary: Absolute change in weight from baseline to one year.  Secondary: Weight loss relative to baseline weight (≥5% and ≥10%), waist circumference, and change in metabolic parameter. Presented at ACC Scientific Sessions ,507 patients with body mass index (BMI) ≥30 kg/m 2, or BMI >27 kg/m 2 with dyslipidemia or hypertension, and stable weight during the prior three months Randomized, Blinded, Parallel 1,507 patients with body mass index (BMI) ≥30 kg/m 2, or BMI >27 kg/m 2 with dyslipidemia or hypertension, and stable weight during the prior three months Randomized, Blinded, Parallel Placebo  n=305 Placebo  n=305 Rimonabant A selective cannabinoid type 1 receptor antagonist  5 mg  n=603 Rimonabant A selective cannabinoid type 1 receptor antagonist  5 mg  n=603 RIO EUROPE Trial Treatment for 2 Years

www. Clinical trial results.org RIO EUROPE Trial Weight Loss at 1 Year Presented at ACC Scientific Sessions 2004 Weight loss at one year was greater in the rimonabant 20 mg group and the rimonabant 5 mg group than in the placebo group. The weight loss results were maintained at 2 years,in an intent-to-treat analysis. Among patients who completed the duration of the study, the weight loss at 2 years was even larger. Mild side effects were higher in the 20 mg rimonabant group, including nausea, diarrhea, and dizziness, but were mostly mild and transient. 20mg 5mg Placebo 20mg 5mg Placebo 20mg 5mg Placebo Weight Loss at 2 Years Intent-To-Treat Analysis Weight Loss at 2 Years Patients who completed study duration p<0.001 p=0.038 p<0.001 p=0.0002

www. Clinical trial results.org Presented at ACC Scientific Sessions 2004 RIO EUROPE Trial Loss of ≥5% Initial Body Weight at 1 Year 20mg 5mg Placebo 20mg 5mg Placebo 20mg Placebo Loss of ≥10% Initial Body Weight at 1 Year Loss of ≥10% Initial Body Weight at 2 Years p<0.001 p=0.002 p<0.001 Loss of ≥5% of initial body weight at 1 year was more frequent in both rimonabant arms compared with placebo, and similar results were reported for loss of ≥10% of initial body weight at 1 year and 2 years. Waist circumference reduction at 1 year was greater in the rimonabant arms (8.5 cm for 20 mg and 5.3 cm for 5 mg) than placebo (4.5 cm; p<0.001 and p=0.002, respectively). At 2 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).

www. Clinical trial results.org RIO EUROPE Trial High Density Lipoprotein (HDL) Increase at 1 Year Presented at ACC Scientific Sessions 2004 Metabolic syndrome was reduced in the 20 mg rimonabant group at two years compared to placebo. At one year, high-density lipoprotein (HDL) increased in the 20 mg rimonabant group versus placebo, and triglycerides were reduced. Increases in HDL and reductions in triglycerides were maintained at 2 years. Both of these improvements were shown to be independent of weight loss. Additionally, insulin response on oral glucose tolerance test at 1 year was improved in the 20 mg rimonabant group vs. placebo (reduction compared to baseline of 11.0 µU/ml vs. 2.3 µU/ml, p=0.019). 20mg 5mg Placebo 20mg 5mg Placebo Baseline 1 Yr 2 Yrs Triglycerides Reduction at 1 Year Metabolic Syndrome in 20mg Group p<0.001 vs. Placebo p<0.001

www. Clinical trial results.org Among obese patients, treatment with the cannabinoid type 1 receptor antagonist rimonabant was associated with a greater reduction in weight, waist circumference, and presence of metabolic syndrome through two years compared with placebo. Among obese patients, treatment with the cannabinoid type 1 receptor antagonist rimonabant was associated with a greater reduction in weight, waist circumference, and presence of metabolic syndrome through two years compared with placebo. Both the present study and the RIO-LIIPIDS study demonstrated an improvement in lipids, as noted by higher HDL and lower triglycerides, a finding that was independent of weight reduction in the present study.Both the present study and the RIO-LIIPIDS study demonstrated an improvement in lipids, as noted by higher HDL and lower triglycerides, a finding that was independent of weight reduction in the present study. While some of the early 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. While some of the early 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. RIO EUROPE Trial