The results of a two-year Phase III study in 3040 patients with rimonabant (Acomplia), the first in a new class of therapeutic agents called selective CB1 Blockers, demonstrate that the benefits achieved with rimonabant 20mg at the end of the first year of the study were sustained in the second year of therapy with a good safety and tolerability profile versus placebo.
Patients treated with twenty milligrams of rimonabant for two years experienced a reduction in body weight and in waist circumference, demonstrating a significant reduction in abdominal fat, a key marker for cardiovascular disease. Patients treated over the two year period also achieved a significant increase in HDL-cholesterol (good cholesterol), a reduction in triglycerides and an improvement in insulin sensitivity. The RIO-North America study is the largest of all rimonabant studies presented to date. The results from this study data are consistent with the findings from two previous large-scale studies on rimonabant. Acomplia is currently being developed for the management of cardiovascular risk factors including reduction of abdominal obesity, improving lipid and glucose metabolism, and as an aid to smoking cessation.
Obesity is a major public health burden and one of the most frequent causes of death worldwide mainly through cardiovascular disease. Obesity is typically measured by body mass index (BMI). However, recent findings have shown that visceral (abdominal) fat (simply measured by waist circumference) is a better predictor for heart attack than weight or BMI. 44% of adult Americans have a waist circumference size exceeding the at-risk level (40 inches for men and 35 inches for women). Visceral fat is associated with the cause of metabolic risk factors such as dyslipidemia or insulin resistance that may lead to diabetes, heart attack, stroke and other cardiovascular disease. Reducing abdominal fat is a recognized priority for preventing cardiovascular disease.
"As the cardiovascular risk factors associated with obesity have become more manifest, it has become increasingly apparent that current approaches are insufficient. Excess abdominal fat in particular is increasingly recognized as one of the most telling harbingers of future cardiovascular complications," said Professor Pi-Sunyer. "The two-year results of the RIO-North America trial confirm that rimonabant is an innovative and promising tool for the long-term management of weight and associated cardiovascular risk factors in abdominally obese patients," he added.
RIO-North America was a Phase III, multinational multicenter, randomized, double-blind, placebo-controlled trial comparing two fixed-dose regimens of rimonabant (5mg and 20mg once daily) to placebo for a period of two years. The study was conducted on 3,040 patients at 72 centers in the United States and Canada.
The objectives of the trial were to assess the effect of rimonabant on weight loss over a period of one year and to determine the ability of rimonabant to prevent weight regain during a second year of treatment. The study objectives also included an assessment of improvement in risk factors associated with abdominal obesity (as measured by waist circumference) such as dyslipidemia, glucose metabolism, and the metabolic syndrome, and an evaluation of the safety and tolerability of rimonabant over a period of two years.
Rimonabant 20mg proved to be safe and tolerable vs. placebo throughout the two year study period. Side effects were mainly minor and short-lived. Overall discontinuation rates for adverse events in the first year of the study were 7.2%, 9.4% and 12.8% in placebo, rimonabant 5mg and rimonabant 20mg groups. The discontinuation rates for patients randomly assigned to continue their first-year treatment for a second year were 6.7%, 8.3% and 6.0% in placebo, rimonabant 5mg and 20mg groups. No differences were noted in the three groups with regards to scores measured by the Hospital Anxiety Depression scale. In this trial and in two preceding studies, rimonabant was also shown to have no significant EKG or heart rate changes.
The EC System is a newly discovered, physiological system in the body that is believed to play a key role in the central and peripheral regulation of energy balance, glucose and lipid metabolism as well as in the control of tobacco dependence.
CB1 receptors are found in the brain as well as in peripheral tissues of the body such as adipocytes (or "fat cells") which are associated with lipid and glucose metabolism. Excessive food intake or chronic tobacco use result in an overactive EC System. This can trigger a cycle of increased eating and fat storage, or, in the case of smoking, sustained tobacco dependence.
Rimonabant is the first in a new class of drugs called cannabinoid type 1 (CB1) blockers. By selectively blocking both centrally and peripherally the CB1 receptors, rimonabant modulates the overactive EC System. The results have been seen in reducing cardiovascular risk factors through reduction in abdominal fat and a corresponding improvement in metabolic parameters that is beyond that expected through weight reduction.
The new clinical results from the study suggests that rimonabant may become an important tool in cardiovascular risk factor reduction.
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