Rimonabant Maintains Both Weight and Waist Reductions at 2 Years

Peggy Peck

November 10, 2004

Nov. 10, 2004 (New Orleans) -- Daily treatment with 20 mg of rimonabant, an investigational endocannabinoid type I blocker, was associated with a significant reduction in weight and waist circumference as well as improvements in high-density lipoprotein (HDL) cholesterol levels, triglyceride levels, and insulin sensitivity, according to results of the Rimonabant In Obesity (RIO)-North America trial reported here at the American Heart Association 2004 Scientific Sessions.

The release of the RIO-North America results completes the trilogy of rimonabant for weight loss studies that started in this city nine months ago. RIO-Lipids, presented at the American College of Cardiology meeting here on March 9, reported similar weight loss and circumference reductions in 1,036 patients with dyslipidemia and a BMI between 27 and 40 kg/m 2. In addition, RIO-Europe, a 1,501-patient study presented at the European Society of Cardiology meeting in late August this year, also reported weight loss, lipid profile benefits, and reductions in waist size.

With 3,040 patients randomized to rimonabant or placebo in RIO-North America, it is the largest rimonabant study to date, said lead investigator Xavier Pi-Sunyer, MD, chief of the division of endocrinology at St. Luke's-Roosevelt Medical Center and Columbia University in New York City.

Moreover, this is the first study to report two-year results of daily rimonabant. Dr. Pi-Sunyer told Medscape that the benefits -- an average weight loss of 19 lb and a 3.1-inch average reduction in waist circumference -- were sustained after two years. Weight loss was steady over the first year and "reached a plateau and then maintained that plateau," he said.

The study was conducted at 72 centers in the U.S. and eight centers in Canada. Of the subjects, 81.4% were women, and all subjects had to have a baseline BMI of 30 kg/m 2 or more or a baseline BMI of 27 kg/m 2 and at least one cardiovascular risk factor.

Patients were randomized to 5 mg or 20 mg of rimonabant or to placebo. After one year of treatment, those treated with the rimonabant were rerandomized to either the same dose of the drug or placebo; patients initially randomized to the control group remained on placebo treatment for the second year of the study. In addition, patients were asked to maintain diets that were 600 kcal less than their diets at baseline.

After two years, "62.5% of the patients on rimonabant 20 mg lost 5% or more of their body weight and 33% lost 10% or more," Dr. Pi-Sunyer said. These findings were not observed in patients treated with 5 mg or in those randomized to placebo.

Moreover, in the 20-mg group "HDL increased by 24.5% compared to a 13.8% increase in the placebo arm," Dr. Pi-Sunyer said. That was significant at P < .001. He also reported that in the 20-mg group triglyceride levels decreased by 9.9% compared with a 1.6% decrease in the placebo group, which was also significant at P < .05.

The investigators reported, however, that those patients who were rerandomized from the 20-mg group of the study to placebo gained back most of the weight they reportedly lost. Such findings prompted concerns that the effectiveness of the drug was contingent on its chronic and continued use, and some uncertainty regarding potential long-term adverse effects still remains.

For example, because the drug blunts a pleasure center in the brain there was concern about depression, but Dr. Pi-Sunyer said there were no differences in depression scores among the three groups.

The results remain impressive. "To maintain weight loss for two years is pretty good," said Robert Bono, MD, chief of cardiology at Northwestern University in Chicago, Illinois, and a past president of the American Heart Association. Moreover, he told Medscape that it is significant that the weight reduction was "was also accomplished in a sizeable number of patients."

While Dr. Pi-Sunyer said that the safety profile of the drug was good, he added that the drug has been tested only in adults. With the obesity epidemic reaching into grade schools, he said that interest in the drug is high, but it is too soon to speculate about use in adolescents. "We have begun discussions with authorities in the United States and Europe about trials with adolescents," he said.

Douglas Greene, MD, vice president of corporate medical and regulatory affairs for Sanofi-Aventis, the developer of rimonabant, told Medscape that the company plans to file for U.S. Food and Drug Administration approval in the second quarter of 2005.

AHA 2004 Scientific Sessions: Late-breaking clinical trials. Presented Nov. 9, 2004.

Reviewed by Gary D. Vogin, MD

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