Rimonabant: Unique and Promising

Abstract

The global pandemic of overweight has evoked increasing alarm as a risk factor for multiple adverse health outcomes. Prominent among these are obesity, metabolic syndrome, and diabetes, all of which promote the development of cardiovascular disease. The magnitude of the problem is reflected by estimates that on a worldwide scale, overweight (body mass index >25 kg/m2) and frank obesity (body mass index >30 kg/m2) affect 1 billion and 300,000 persons, respectively,1 and in this country 97 million people are categorized as overweight or obese.2 This situation prompted The Surgeon Generals' Call to Action to Prevent and Decrease Overweight and Obesity.3 It is well known that overnutrition and underactivity play important roles in the development of obesity. Together with the persistence of cigarette smoking, these unfavorable lifestyles are prime examples of the extent to which adverse health outcomes are a result of self-imposed practices. Although it has been established that favorable lifestyle modifications exert beneficial effects on obesity and its clinical aftermaths, alteration of personal habits has proved a daunting challenge to individuals, health care providers, and society. In such circumstances, the search for pharmacologic alleviation has been our practice, often with gratifying results, as exemplified by the statin class of drugs.4 Enter rimonabant—a unique drug with therapeutic potential in obesity, smoking, and the metabolic syndrome. Rimonabant is the first of a new class of drugs that acts as a selective inhibitor of cannabinoid-1 receptors in the endocannabinoid system. Stimulation of these receptors, which are densest in the brain, appears to influence 1) lipid and glucose metabolism in adipose tissue; and 2) regulation of appetite, energy balance, and nicotine dependence.5 Through these mechanisms, the endocannabinoid system appears to be involved in weight gain and the urge to smoke. Rimonabant has a high affinity for central cannabinoid receptors, blocks the actions of cannabinoid receptor agonists, and has induced weight loss in animal investigations. Evidence that the drug can induce decreased appetite and weight loss has been extended to humans in phase 1 and 2 trials, which have led to the current phase 3 prospective, randomized, placebo-controlled trials on obesity and smoking cessation. The phase 3 trials on obesity (Rimonabant in Obesity) include RIO-Lipids, RIO-Diabetes, RIO-Europe, and RIO-America. Preliminary results have shown favorable effects of rimonabant compared with placebo on weight loss, multiple factors of the metabolic syndrome, and incidence of the metabolic syndrome.6 The effect of the drug is dose-related, and approximately 60% of study patients have lost 5%-10% of body weight. The results in the metabolic syndrome are unique in that there is currently no single drug aimed at the cluster of factors comprising this condition. RIO-Europe was recently published and confirmed the preliminary findings.7 The effects of rimonabant on smoking cessation are currently being investigated in the three STRATUS trials (Studies with Rimonabant and Tobacco Use). Initial findings suggest a significantly higher quit rate compared with placebo. Adverse effects of rimonabant have been dose-related and generally mild, including gastrointestinal disturbances, nausea, dizziness, and upper respiratory tract infections.7 These promising results suggest that rimonabant may afford a unique approach to combating two of the major health hazards of our society: obesity and smoking. Multiple, long-term studies are in progress to determine whether the early promise will translate into enduring fulfillment.