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Rimonabant May Reduce Weight and Cardiovascular Risk Factors CME
News Author: Laurie Barclay, MD | CME Author: Charles Vega, MD, FAAFP Release Date: April 18, 2005; Reviewed and Renewed: April 18, 2006; Valid for credit through April 18, 2007
April 18, 2005 — Rimonabant reduces weight and cardiovascular risk factors in obese people, according to the results of a randomized trial published in the April 16 issue of The Lancet.
"In this study, treatment with rimonabant over one year led to sustained, clinically meaningful weight loss, reduction in waist circumference, and associated improvements in several cardiovascular and metabolic risk factors," lead author Luc Van Gaal, MD, from University Hospital in Antwerp, Belgium, says in a news release.
Animal studies suggest that cannabinoid-1 receptor (CB1) blockade produces a lean phenotype, with resistance to diet-induced obesity and associated dyslipidemia. The multinational Rimonabant In Obesity (RIO)-Europe study evaluated the effect of rimonabant, a selective CB1 blocker, on weight and cardiovascular risk factors in overweight or obese patients.
In the RIO-Europe study, 1,507 patients with body mass index (BMI) of at least 30 kg/m2 or BMI more than 27 kg/m2 with treated or untreated dyslipidemia, hypertension, or both were randomized to receive double-blind treatment with placebo, 5 mg of rimonabant, or 20 mg of rimonabant once daily in addition to a mild hypocaloric diet (600 kcal/day deficit). The main outcome measure was weight change from baseline after one year of treatment based on intent-to-treat analysis.
At one year, weight loss was greater in patients receiving rimonabant, 5 mg (mean, -3.4 ± 5.7 kg; P = .002 vs placebo) and 20 mg (-6.6 ± 7.2 kg; P < .001 vs placebo) compared with placebo (-1.8 ± 6.4 kg). Weight loss in the rimonabant groups was sustained for around 36 to 40 weeks.
Compared with the placebo group, more patients in the group receiving rimonabant, 20 mg, achieved weight loss of 5% or more (67% of patients; P < .001) and 10% or more (39% of patients; P < .001). This group also had significantly greater improvements than placebo in waist circumference (average reduction, 4 cm), high-density lipoprotein (HDL) cholesterol and triglyceride levels, insulin resistance, and prevalence of the metabolic syndrome.
The effects of rimonabant, 5 mg, were not as marked. Overall, rimonabant was well-tolerated, and adverse effects were mild and transient. In all treatment groups, the most common adverse events leading to study discontinuation were depressed mood disorders. Compared with the other groups, withdrawals for nausea, vomiting, diarrhea, headache, dizziness, and anxiety were more frequent in the 20-mg rimonabant group.
"CB1 blockade with rimonabant 20 mg, combined with a hypocaloric diet over one year, promoted significant decrease of body weight and waist circumference, and improvement in cardiovascular risk factors," the authors write. "The large number of patients treated with CB1 blockade who achieved the 10% target for weight loss or had a marked improvement in the top risk factors established by the world-wide INTERHEART study, suggests that rimonabant can be considered as a valuable adjunct therapy for weight and waist reduction in patients at high cardiovascular risk."
Sanofi-Aventis, maker of rimonabant, funded the study and provided honoraria to five of the authors.
In an accompanying comment, Uberto Pagotto, MD, and Renato Pasquali, MD, from Sant Orsola-Malpighi General Hospital in Bologna, Italy, note that these findings suggest a weight-independent effect of rimonabant on lipid parameters. Whether the mechanism is related to a rise in adiponectin or other mechanisms is still unknown.
"These data, and those from the other ongoing clinical trials with rimonabant, might presumably help us to better tackle obesity and related metabolic and cardiovascular disease," Drs. Pagotto and Pasquali write. "When additional drugs are available, we will also have the possibility to individually target the therapeutic strategies according to phenotype characteristics and to the pathophysiological mechanism inducing the disease."
Dr. Pagotto has financial arrangements with Sanofi-Aventis, Abbott, Eli Lilly, and the European Commission. Dr. Pasquali has received honoraria, speaker's fees, and research grants from Sanofi-Aventis, Abbott, and Roche.
Lancet. 2005;365:1363-1364, 1389-1397 Clinical Context
As research yields new data on the complex metabolic underpinnings of obesity, the promise of new agents to fight this problem grows. Cannabinoid receptors have been found in a wide variety of human tissue, and overactivation of the endocannabinoid system appears to contribute to obesity.
Rimonabant represents a new class of CB1 antagonist, and it appears to target multiple organs. It may exert an anorexic effect on the central nervous system while also acting on the gut to increase the sensation of satiety. In addition, this drug may inhibit lipogenesis within adipose tissue and promote glucose uptake into skeletal muscle.
The authors of the current study compare rimonabant with placebo in a double-blind trial that examines not only weight but metabolic factors as well.
