An overview of the metabolic effects of rimonabant in randomized controlled trials: potential for other cannabinoid 1 receptor blockers in obesity

Abstract

Rimonabant, a cannabinoid receptor blocker, has recently been used in clinical practice for weight loss and weight maintenance. Our aim was to review the results of trials of the drug in relation to weight loss and maintenance, and its impact on cardio-metabolic risk factors. Randomized controlled trials with rimonabant were selected, through a Medline search, using the terms: rimonabant, endocannabinoid antagonist and obesity. Reports of studies on large numbers of patients and covering the topics related to this review were included. In all the trials, there was a considerable reduction in body weight in subjects taking 20 mg rimonabant daily varying from 2.6 to 6.3 kg (placebo-subtracted changes). Rimonabant was also associated with haemoglobin A(₁c) (HbA(₁c) ) reduction. In the Rimonabant in obesity (RIO)-diabetes study, diabetic patients taking metformin or sulphonylureas showed decrease in HbA(₁c) levels by 0.5-0.6 ± 0.8% when rimonabant was added, whereas in the Serenade trial patients with untreated diabetes showed a reduction in HbA(₁c) of 0.8% vs. 0.3% with placebo. Similar results were obtained in diabetic patients under insulin treatment. The lipidemic profile also improved in patients taking rimonabant 20 mg daily; levels of high density lipoprotein cholesterol (HDL-c) increased significantly while levels of triglycerides (TRG) decreased in all trials, and positive effects were also observed in patients with atherogenic or untreated dyslipidaemia. In all the RIO studies, prevalence of the metabolic syndrome decreased significantly. In addition, patients treated with 20 mg rimonabant daily exhibited increase in adiponectin. The metabolic changes observed were partly independent of the weight loss and could be attributed to independent peripheral effect of rimonabant. All these beneficial metabolic effects of rimonabant could lead to progress in the prevention of cardiovascular disease. However, in all the trials the incidence of adverse events leading to discontinuation was greater in the rimonabant treated patients than placebo, mainly because of psychiatric disorders (depression and anxiety), nausea and dizziness. Rimonabant is effective in reducing weight in the obese but may lead to intolerable adverse effects most notably psychiatric effects, which make it unsuitable for routine use. However, the drug provides useful proof of principle for this approach to weight loss. Novel cannabinoid type 1 receptor blockers with selectivity for peripheral receptors, may achieve similar metabolic results with decreased prevalence of psychiatric adverse effects.