NEW ORLEANS — Evidence is mounting that rimonabant, shown effective for weight loss and smoking cessation, independently improves patients' cardiovascular risk profiles, F. Xavier Pi-Sunyer, M.D., reported at the annual scientific sessions of the American Heart Association.
In the wake of the highly favorable results of the Rimonabant In Obesity-North America (RIO-NA) trial that were presented, the company plans to file for marketing approval for the investigational drug in the second quarter of 2005, a Sanofi-Synthelabo spokesman told this newspaper.
A total of 3,040 obese patients participated in RIO-NA, a 2-year randomized double-blind trial conducted at 72 U.S. and Canadian centers. Subjects were randomized to rimonabant at 20 or 5 mg/day or to placebo in a 2:2:1 ratio for the first year. Those on rimonabant were then re-randomized to the same dose of the drug or placebo for the second year. All patients were also prescribed a mildly hypocaloric diet designed to create a 600 kcal/day deficit relative to energy requirements.
Patients on rimonabant at 20 mg/day experienced significant reductions in body weight and abdominal fat well in excess of what can be achieved with currently available weight-loss medications. They also developed an improved cardiovascular risk profile and a sharply decreased prevalence of the metabolic syndrome, said Dr. Pi-Sunyer, professor of medicine at Columbia University and chief of the department of endocrinology, diabetes, and nutrition at St. Luke's-Roosevelt Hospital, New York City.
Mean weight loss at 1 year was 8.7 kg in the 20 mg rimonabant group, compared with 2.8 kg with placebo. At 2 years the rimonabant group weighed a mean of 7.4 kg less than at baseline; the placebo group weighed 2.3 kg less. A total of 62.5% of patients on high-dose rimonabant lost more than 5% of their initial body weight and 32.8% lost more than 10%, compared with 33.2% and 16.4%, respectively, of the subjects on placebo.
After 2 years on rimonabant at 20 mg/day, mean waist circumference was reduced by 3.1 inches, compared with 1.9 inches on rimonabant 5 mg/day and 1.5 inches on placebo. HDL levels rose by a mean of 24.5%, while triglyceride levels fell by 9.9% in the 20 mg rimonabant group, compared with a 13.8% rise in HDL and 1.6% decline in triglycerides in the placebo arm, reported Dr. Pi-Sunyer, principal investigator for RIO-NA.
At baseline, 34.8% of patients met criteria for the metabolic syndrome. After 2 years on rimonabant at 20 mg/day, the prevalence of metabolic syndrome fell to 22.5%, a greater than one-third reduction. In contrast, there was no meaningful change in the prevalence of metabolic syndrome in the placebo arm.
Statistical analysis indicated that about half of the improvements in HDL cholesterol, triglycerides, insulin sensitivity, and fasting insulin seen with rimonabant were attributable to the weight loss, while the other half could be traced to an independent effect of the medication, he continued.
Depression, anxiety, irritability, and nausea were slightly more common in the rimonabant groups than the placebo group. But the three study arms did not differ significantly in terms of serial scores on the Hospital Anxiety and Depression Scale.
RIO-NA was the largest and longest study in a drug-development program, totaling more than 6,600 obese or overweight patients in phase III trials. First-year results of RIO-NA were remarkably consistent with those reported earlier in the year-long RIO-Europe and RIO-Lipids trials.
Discussant Robert H. Eckel, M.D., president-elect of the AHA, noted that rimonabant is the prototype of a new drug class targeting the endocannabinoid receptor within the brain's pleasure centers. More agents will likely follow.
“Rimonabant is of particular interest to me because the HDL effect appears to be much greater than would be expected from the amount of weight loss that occurred,” said Dr. Eckel, professor of medicine at the University of Colorado, Denver.
Although the 2-year data show very encouraging evidence of both safety and efficacy, the effects of longer-term therapy directed at the brain's pleasure center remain a question mark, he added.