ANTWERP, Belgium, March 8 /PRNewswire/ -- The results of a two-year phase III study in 1,507 patients treated with rimonabant, the first in a new class of therapeutic agents called selective CB1 Blockers, demonstrated that the improvements in cardiovascular risk factors achieved with rimonabant 20 mg/day at the end of the first year of treatment were maintained in the second year. The study also demonstrated the safety and tolerability profile of rimonabant versus placebo.
The two-year results of the RIO-Europe trial were presented today at the Scientific Sessions of the American College of Cardiology in Orlando, Florida by Luc Van Gaal, M.D., Professor of Diabetology, Metabolism and Clinical Nutrition, University Hospital of Antwerp, Belgium and principal investigator of the study. The first-year results of the RIO-Europe study had been presented at the European Society of Cardiology meeting in August 2004.
The two-year findings of the RIO-Europe trial are consistent with those of the other two-year trial in the rimonabant phase III program, RIO-North America, results of which were announced at the scientific sessions of the American Heart Association in November 2004. "The RIO-Europe findings demonstrated that in addition to maintaining body weight loss, two-year treatment with rimonabant 20 mg/day compared with placebo reduced waist circumference improved metabolic profile and reduced the number of patients meeting the NCEP (National Cholesterol Education Program) criteria for metabolic syndrome, thus diminishing cardiovascular risk factors in patients studied," said Professor Van Gaal.
RIO-Europe objectives and design
The RIO-Europe trial is one of four phase III studies comprising the RIO program, which assesses the efficacy and safety of rimonabant in weight reduction and metabolic risk factor improvement in over 6,600 overweight and obese patients studied world-wide.
RIO-Europe is a phase III, multinational multicenter, randomized, double-blind, and placebo-controlled trial comparing two fixed-dose regimens of rimonabant (5 mg and 20 mg once daily) to placebo for a period of two years. The study was conducted on 1,507 patients at 40 centers in Europe and 20 centers in the US. The objectives of the trial were to assess the effects of rimonabant on weight loss for a period of one year and to determine rimonabant's potential to maintain weight loss during a second year of treatment. The study also assessed improvement in waist circumference and in metabolic risk factors (eg, dyslipidemia, glucose metabolism, and metabolic syndrome) and evaluated the safety and tolerability profile of rimonabant over the two-year period.
After a screening period of two weeks, patients were prescribed a hypocaloric diet (designed to reduce daily caloric intake by 600 kcal from the patients' energy requirements) and entered a four-week single-blind placebo run-in period. Afterward, patients were randomly assigned to one of the three treatment groups: rimonabant 20 mg or 5 mg or placebo for 104 weeks of double- blind treatment using a randomization ratio of 2:2:1.
The findings presented today demonstrated the two-year benefits of rimonabant 20 mg/day treatment vs placebo in the study population. Among patients completing the study, waist circumference, was reduced by 7.5 cm (2.9 inches) in patients treated with rimonabant 20 mg/day for the full two year period vs. 3.4 cm (1.3 inches) for patients in the placebo group (P<.001). Among all patients who entered the study, waist circumference was reduced by 5.7 cm (2.24 inches) and 1.8 cm (0.71 inches) in patients treated with rimonabant 20 mg/day and the placebo group (P<.001), respectively. Among patients completing the study, 59.7% of patients treated with rimonabant 20 mg/day lost more than 5% of their initial body weight vs 23.4%of those in the placebo group (P<.001). Among all patients who entered the study, 44.4% of patients treated with rimonabant 20 mg/day lost more than 5% of their initial body weight vs 15.6% of those in the placebo group (P<.001). Among patients completing the study, 32.1% of patients treated with rimonabant 20 mg/day lost more than 10% of their initial body weight, vs 10.9% of those in the placebo group (P<.001). Among all patients who entered the study, 22.0% of patients treated with rimonabant 20 mg/day lost more than 10% of their initial body weight vs 6.3% of those in the placebo group (P<.001).
Metabolic parameters, such as HDL-cholesterol and triglyercides, were significantly improved in patients treated with rimonabant 20 mg/day throughout the two-year period. Among patients completing the study, HDL-cholesterol increased by 28.2% in the rimonabant 20 mg/day group vs 16.8% in the placebo group (rimonabant 20 mg/day vs placebo (P<.001). Among all patients who entered the study, HDL-cholesterol increased by 22.6% in the rimonabant 20 mg/day group vs 12.6% in the placebo group (rimonabant 20 mg/day vs placebo (P<.001)). Among patients completing the study, triglycerides were reduced by 8.8% in patients treated with rimonabant 20 mg/day throughout the two-year period vs an increase of 6.3% in the placebo group (rimonabant 20 mg/day vs placebo (P<.001)). Among all patients who entered the study, triglycerides were reduced by 4.1% in patients treated with rimonabant 20 mg/day vs an increase of 10% in the placebo group (rimonabant 20 mg/day vs placebo (P<.001)). A statistical analysis of the data suggested that approximately half of the improvements in HDL cholesterol and triglyceride profiles observed in patients treated with rimonabant 20 mg/day were independent of the weight loss achieved in this group.
Although people with diabetes were not included in the study, patients on rimonabant 20 mg/day showed improved insulin sensitivity as measured by HOMA (Homeostasis Model Assessment) compared with those on placebo (P<.001). Of particular note is that the number of patients completing the study who met the diagnostic criteria for metabolic syndrome was reduced by approximately 50% in patients treated with rimonabant 20 mg/day vs a decrease of approximately 20.0% in the placebo group (P<0.001). Metabolic syndrome includes a series of health risks or conditions that increase a person's chances to develop heart disease, stroke and diabetes. (1)
Safety & tolerability
The safety and tolerability of rimonabant 20 mg vs placebo were assessed in this two-year study. Side effects were mainly mild and transient and appeared mainly in the first year. The most common side effects included nausea (13.7% for 20 mg/day, 6.0% for 5 mg/day, 5.2% for placebo), dizziness (9.3% for 20 mg/day, 8.1% for 5 mg/day, 5.2% for placebo), diarrhea (8.2% for 20 mg/day, 7.3% for 5 mg/day, 4.6% for placebo) and vomiting (5.2% for 20 mg/day, 2.5% for 5 mg/day, 1.6% for placebo). Overall discontinuation rates due to adverse events in the two years of the study were 13.1%, 10.9% and 18.9% in the placebo, rimonabant 5 mg/day and rimonabant 20 mg/day groups, respectively. In the RIO-Europe trial and in two preceding studies (RIO-Lipids 1-year and RIO-North America 2-year), rimonabant demonstrated a safe cardiovascular profile with no significant EKG, blood pressure or heart rate changes on average. (2)
Obesity is a major public health burden and a key risk factor for the development of cardiovascular disease, the leading cause of mortality worldwide. (3) Obesity is typically measured by body mass index (BMI); however, recent findings have shown that abdominal obesity is a much better predictor of heart attack than weight or BMI. (3) Abdominal obesity can be simply measured by waist circumference (4), and is an indicator of intra-abdominal adiposity, the hidden fat present deep within the abdomen (5). It is this intra-abdominal adiposity (inside the abdomen) which is one of the most significant contributors to the development of cardiovascular risk factors such as dyslipidemia, insulin resistance, or metabolic syndrome and which may lead to diabetes, heart attack, stroke or other cardiovascular disease. (5) Approximately 46% of adult Americans have a waist circumference that exceeds the at-risk level (40 inches for men and 35 inches for women). (6) The prevalence of abdominal obesity in the US has tripled in the last 40 years. (7)
Rimonabant and the Endocannabinoid (EC) System
The EC System is a physiological system in the body that is believed to play a key role in the central and peripheral regulation of energy balance, fat accumulation as well as in glucose and lipid metabolism. (8) CB1 receptors are found in the brain as well as in peripheral tissues of the body such as adipocytes (or "fat cells"), which are involved in lipid and glucose metabolism. (9) This system represents a promising target for intervention(s) aimed at reducing cardiovascular risk. (9) Rimonabant is the first in a new class of drugs called CB1 blockers. By selectively blocking both centrally and peripherally the CB1 receptors, rimonabant regulates the overactive EC System. (9) Results from clinical trials show that rimonabant reduces cardiovascular risk factors by reducing intra-abdominal adiposity and improving metabolic parameters beyond the level expected through weight reduction alone.
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University Hospital Antwerp Dept. Diabetology, Metabolism and Clinical