The World Health Organization estimates that more than 2.5 million deaths worldwide can be attributed to obesity each year, and the number continues to increase. Few safe and effective medications are available for obesity, but new understanding of the physiologic regulation of food intake and calorie storage have led to the development of therapies targeting the endocannabinoid system. This system is overactive in animal models of obesity and is believed to modulate food intake and adipogenesis through receptors (CB₁) in the brain and a variety of peripheral tissues. Van Gaal and colleagues studied a CB₁-blocking drug, rimonabant (Acomplia), in a large trial of adult obese patients.

The researchers recruited more than 1,500 obese adults from 60 European and U.S. centers. Inclusion criteria were a body mass index (BMI) of 30 or a BMI of 27 plus hypertension or dyslipidemia. Participants also were required to have experienced less than 11-lb (5-kg) variation in body weight in the three months before the study, and to be free from significant cardiovascular, pulmonary, hepatic, renal, neurologic, psychiatric, and endocrine disease, including diabetes. Participants were excluded if they had a history of surgical procedures for weight loss or of significant depression, were currently taking medications known to influence body weight, or intended to change their smoking status during the study period.

After extensive baseline assessment, including basal metabolic rate, body measurements, glucose tolerance testing, and other laboratory screening, 1,507 participants were randomly assigned to 5 mg per day of rimonabant, 20 mg per day of rimonabant, or placebo. All patients were advised on diet and exercise based on their personal basal metabolic rate. Patients were reassessed every 14 days for one month, then every 28 days for two years.

Patients in the three groups were comparable in all significant variables at baseline. Only 61 percent of participants completed the one-year follow-up: 379 (62.7 percent) in the 5-mg group, 363 (60.6 percent) in the 20-mg group, and 178 (58.4 percent) in the placebo group. Using intention-to-treat analysis, researchers found that patients taking rimonabant had significantly greater weight loss and improvement in lipids and insulin function after one year than those taking placebo. This effect was more pronounced if the analysis was limited to participants who completed one year of assigned therapy. In this analysis, the cumulative weight loss was 11 lb (5 kg) in the placebo group, compared with more than 22 lb (10 kg) in the 20-mg group. The percentage of patients with 10 percent or more weight loss was significantly greater in the 20-mg group (27.4 percent) than the placebo group (7.3 percent) but not in the 5-mg group (10.1 percent). If only those patients who completed the study were considered, these figures rose to 39 percent in the 20-mg group, 12.4 percent in the placebo group, and 15.3 percent in the 5-mg group. Waist circumference and lipid profile also improved significantly in patients taking rimonabant. The proportion of patients with metabolic syndrome decreased from 41.2 to 28.6 percent in those taking 5 mg and from 42.2 to 19.6 percent in those taking 20 mg, compared with a decrease from 39.9 to 31.4 percent in the placebo group. In about one half of participants, improvement in metabolic risk factors was independent of weight loss. Adverse effects were reported by more than 80 percent of patients in all three groups but most were mild and transitory. The greatest number of discontinuations (87) occurred in the 20-mg group, with almost one half (42) being attributed to psychiatric disturbance.

The authors conclude that rimonabant in conjunction with diet and exercise resulted in significant weight loss plus reduction in metabolic risk factors. Although understanding of the endocannabinoid system is incomplete, the system appears to play a significant role in food intake and energy homeostasis. Medications blocking receptors in this system have the potential to contribute significantly to antiobesity therapy.