ORLANDO, FLA. — The outstanding weight loss and cardiovascular-risk reduction previously reported after 1 year of rimonabant therapy were maintained after 2 years of treatment in the phase III Rimonabant in Obesity-Europe trial, Luc Van Gaal, M.D., reported at the annual meeting of the American College of Cardiology.
The safety and tolerability profiles of rimonabant, the first in a new class of selective endocannabinoid type 1-receptor blockers, also remained reassuring after 2 years' treatment, added Dr. Van Gaal, professor of diabetology, metabolism, and clinical nutrition at the University of Antwerp (Belgium) and principal investigator for Rimonabant in Obesity (RIO)-Europe.
The new 2-year study results are virtually superimposable on the 2-year outcomes of the phase III RIO-North America trial presented last fall at the annual scientific sessions of the American Heart Association (INTERNAL MEDICINE NEWS, Jan. 15, 2005, p. 52).
Armed with data from over 6,600 overweight and obese participants in the two trials, plus two Sanofi-Aventis-sponsored 1-year phase III trials, the company plans to file before midyear for Food and Drug Administration and European Commission approval of rimonabant 20 mg/day for weight loss, a spokesman told this newspaper. Simultaneously, Sanofi-Aventis will file for a smoking cessation indication, the subject of another extensive phase III rimonabant clinical trials program.
RIO-Europe was a randomized, double-blind, placebo-controlled study involving 1,507 overweight or obese patients with a mean baseline body mass index (BMI) of 37 kg/m2 and a mean age of 45 years. As is typical in weight loss trials, 80% were women. Participants were strongly encouraged by dietitians and counselors to adopt a 600-kcal/day-deficit diet and increase their physical activity.
In RIO-Europe, 20 mg/day of rimonabant resulted in a mean 7.2-kg weight loss among those who completed 2 years of treatment, compared with a mean 2.5-kg loss in those taking placebo. In an intent-to-treat analysis, the mean weight loss was 5.5 kg in the rimonabant arm and 1.2 kg with placebo.
At baseline, more than 42% of study participants met National Cholesterol Education Program criteria for metabolic syndrome. After 2 years on rimonabant 20 mg/day, the prevalence of metabolic syndrome fell by 57%, compared with a 34% drop with placebo.
Mean waist circumference—a measure of intraabdominal obesity—was reduced by 7.5 cm after 2 years on rimonabant, from a baseline of 110 cm, and by 3.4 cm in the placebo group. More than 32% of patients who completed 2 years of rimonabant treatment lost at least 10% of their baseline body weight—a medically meaningful threshold—as compared with 11% on placebo. HDL-cholesterol levels climbed by 28.2%, compared with 16.8% with placebo. Triglycerides fell by an average of 8.8% with rimonabant while rising 6.3% in the placebo group.
Rimonabant also significantly improved insulin sensitivity. Only about half of the observed improvement in lipids could be explained by the weight loss, implying that rimonabant exerts direct metabolic effects beyond weight loss, Dr. Van Gaal continued.
As was the case after 1 year, rimonabant resulted in no significant changes in heart rate, blood pressure, or QT interval at the 2-year mark. The most common treatment side effects were nausea and other GI symptoms and dizziness, all of which were more frequent in year 1 and mostly mild.
Discussant Julius M. Gardin, M.D., called RIO-Europe “a remarkable study—really a landmark study in the field of obesity.”
He singled out the 57% decrease in prevalence of metabolic syndrome as particularly impressive in terms of future likely cases of cardiovascular disease and diabetes prevented. He also called the 2-year safety data “heartening.” But he sounded a note of caution: “If you look at the weight-loss data, at 2 years the curves are starting to head upward. And we all know that obesity is not just a 2-year problem. … We'll want to see postmarketing studies to see if this effect is maintained long-term.”
Dr. Gardin also raised several philosophical issues that have been on the minds of many physicians who endured the litigious frenzy that followed the fen-phen (fenfluramine-phentermine) controversy.
“Hypothetically, what if rimonabant is approved, hits the market, we have 5 million prescriptions out there, and we get all of the wonderful positive effects described in the study—but it turns out one person per million dies related to the drug? What should reasonable people do about this? Should they say that's an acceptable risk-benefit ratio? Or should we handle it the way previous anorexigens were handled, with punitive measures?” asked Dr. Gardin, chief of cardiology at St. John Hospital and Medical Center, Detroit.
Another societal issue is whether rimonabant should be considered in anyone who meets a BMI criterion, or if additional risk factors ought to be required. “I would hate to see prescription of a medication subvert efforts … to encourage prudent eating, reduction of calories, exercise, and other healthful lifestyle measures,” Dr. Gardin said.