First year results of the two year trial Rimonabant In Obesity - Europe (RIO-Europe), a Phase III clinical study comparing placebo to rimonabant, the first agent in a new therapeutic class known as selective cannabinoid type 1 (CB1) blockers, showed that overweight or obese people taking rimonabant 20mg once daily benefited from a significant reduction in their body weight, waist circumference – a marker of the dangerous abdominal obesity - and improvements in their lipid and glycemic profiles.
The improvement in lipids (HDL-cholesterol and triglycerides) was demonstrated to be partially independent from weight loss, implying a direct effect of the drug on these important metabolic cardiovascular risk parameters. The trial findings also revealed a significant decrease in the percentage of patients with metabolic syndrome1 in the rimonabant 20 mg/day group compared to placebo. These new results from the RIO-Europe study confirm rimonabant’s potential to become an important tool in the reduction of cardiovascular risk factors by lowering body weight, improving metabolic syndrome-associated parameters in overweight/obese subjects and aiding in smoking cessation as presented earlier this year.
RIO Europe, an international, multicentre, randomized, double-blind, placebo-controlled, parallel-group study compared rimonabant 20mg/day and 5mg/day to placebo in 1,507 overweight/obese patients (Body Mass Index (BMI) ? 30 kg/m2 or BMI > 27 with co-morbidity (e.g. dyslipidemia, hypertension) in 60 centres across Europe (Belgium, Finland, France, Germany, the Netherlands, Sweden) and the United States for a period of 2 years. The announcement made at the ESC 2004 concerns the first year data of the study.
Patients treated for one year with rimonabant 20mg/day lost an average of 8.6kg (about 19 lbs) (p<0.001 vs placebo) compared to 4.8kg (about 11 lbs)for patients on rimonabant 5mg/day (p=0.038 vs placebo) and 3.6kg (about 8 lbs) for those on placebo. Nearly 70% of patients treated with rimonabant 20mg/day lost more than 5% of their initial body weight (p< 0.001 vs placebo), compared to 44.2% of patients in the rimonabant 5mg/day group (p=0.002 vs placebo) and 30.5% in the placebo group. Moreover, 39% (p<0.001 vs placebo) of patients on rimonabant 20mg/day lost more than 10% of their initial body weight compared to 15.3% of those on rimonabant 5mg/day and 12.4% of those on placebo.
Patients on rimonabant 20mg/day also had an average decrease in their waist circumference of 8.5 cm (about 3.5 inches) (p< 0.001) versus 5.3 cm (2 inches) for those on rimonabant 5mg (p=0.002 vs placebo) and 4.5 cm (about 1.5 inches) for those on placebo.
The number of patients diagnosed as having metabolic syndrome at baseline (42.2%) was reduced by more than half (19.6%) after treatment with rimonabant 20mg (p<0.001 compared to placebo).
In addition to weight loss, a statistically significant improvement in metabolic risk factors with rimonabant 20mg vs. placebo was also observed.
In patients treated for one year with rimonabant 20 mg/day, HDL-cholesterol (good cholesterol) increased by 27.0% (p< 0.001 vs placebo), compared to 19% in the rimonabant 5mg/day group and 17.3% in the placebo group. Weight loss accounted for only approximately half the improvement in HDL seen with rimonabant 20mg vs. placebo, implying a significant direct effect of the drug on lipid metabolism, independent of weight loss (p=0.005).
In patients treated for one year with rimonabant 20mg, triglycerides were reduced by 10.6% in patients on rimonabant 20 mg (p < 0.001 vs. placebo), while increasing by 4.9% for rimonabant 5mg and by 6.6% for placebo.
As seen with HDL, weight loss accounted for only approximately half the improvement in triglycerides seen with rimonabant 20mg vs. placebo, implying a significant direct effect of the drug on lipid metabolism, independent of weight loss (p=0.005).
An improved insulin response as demonstrated by an Oral Glucose Tolerance Test was also observed. During the 2 hour test, patients on rimonabant 20 mg had to produce less insulin to metabolize their glucose compared to those on placebo (reduction by 11.0 µIU/ml vs baseline compared to 2.3 µIU/ml in the placebo group;p=0.019 ).
“The findings of the RIO-Europe trial are totally consistent with those of the RIO-Lipids trial announced earlier this year at the American College of Cardiology meeting. Patients on rimonabant 20mg/day experienced significant benefits in terms of weight loss, reduction in waist circumference and also experienced sizeable improvements in their lipid and glycemic profiles. What is even more interesting is the effect rimonabant 20mg has on metabolic cardiovascular risk factors, which is independent of weight loss,” said Luc Van Gaal, M.D., Professor of Diabetology, Metabolism and Clinical Nutrition, University Hospital Antwerp, Belgium, Principal Investigator of the RIO-Europe trial. “We are looking forward to the full 2 year findings of the RIO-Europe trial to see if these impressive results are maintained,” he added.
The RIO-Europe findings also confirmed the good safety profile of rimonabant. Side effects were mainly mild and transient and most frequently involved nausea (4.3 %, 5.1% and 12.9 % for placebo, rimonabant 5mg and rimonabant 20mg respectively), diarrhoea (3.0%, 6.0 % and 7.2% for placebo, rimonabant 5mg and rimonabant 20mg respectively) and dizziness (4.9 %, 7.0 %, 8.7 % for placebo, rimonabant 5mg and rimonabant 20mg respectively). Only in a very small number of cases did these side effects lead to discontinuation of drug use
Overall dropout rates in the three groups were similar (41.6% in the placebo group vs. 37.3% for rimonabant 5mg and 39.4%, for rimonabant 20mg). No difference was observed in the three groups with regards to scores measured by the Hospital anxiety depression scale. Importantly, rimonabant was also shown to have a good cardiovascular safety profile.
The RIO-Europe trial is one of four Phase III studies comprising the RIO programme, which assesses the efficacy and safety of rimonabant in weight reduction and metabolic risk factor improvement in over 6,600 overweight and obese patients world-wide. Rimonabant is also under investigation as an aid to smoking cessation in the STRATUS programme. The results of the STRATUS US trial presented earlier this year demonstrated that rimonabant 20mg doubled the odds of quitting smoking vs. placebo (p=0.002) without weight gain (on average patients lost 0.3kg (0.7 lb) on rimonabant 20mg vs. a 1.1kg (2.4 lb) weight gain for patients on placebo (p<0.001).
Preclinical studies have demonstrated the role of the endocannabinoid system (ECS), via the CB1 receptor, in the central and peripheral regulation of energy balance, as well as in the control of nicotine dependence. Rimonabant is the first selective cannabinoid type 1 (CB1) blocker to be developed for the management of cardiovascular risk factors including obesity, metabolic syndrome, dyslipidemia, type 2 diabetes and tobacco dependence. Metabolic parameter improvements observed with rimonabant are beyond those expected through weight reduction. The new clinical results from the RIO-Europe study confirm that by reducing body weight and improving metabolic parameters in overweight/obese subjects, rimonabant may become an important tool in the cardiovascular risk factor reduction armamentarium.