The blockade of the CB1 receptor as a treatment for obesity has been explored in several clinical trials. In one study, obese or overweight patients (BMI > 27
) with dyslipidaemia, and/or hypertension, were randomised to double-blind treatment with placebo or Rimonabant (5
mg or 20
mg once daily). All groups were also encouraged to follow a mild hypocaloric diet [9
]. Rimonabant at a dose of 20
mg/day, combined with a hypocaloric diet over 1 year, promoted a significant decrease in bodyweight and waist circumference and improvement in cardiovascular risk factors. After one year, patients treated with higher-dose Rimonabant had reduced glucose and insulin levels 2 hours after oral glucose tolerance testing compared with placebo. Interestingly, this benefit continued to be seen at 2 years, when weight stabilisation had occurred. In this study Rimonabant was reported as generally well tolerated with mild and transient side effects.
The Rimonabant in Obesity-Lipids (RIO-Lipids) trial also studied the effects of Rimonabant on metabolic risk factors in high-risk patients who were overweight or obese and had dyslipidaemia [10
]. The investigators randomly assigned over 1000 overweight or obese patients with untreated dyslipidaemia to double-blinded treatment with placebo or Rimonabant for 12 months in addition to a hypocaloric diet. Rimonabant at a dose of 20
mg was associated with a significant mean weight loss, reduction in waist circumference, increase in HDL cholesterol, and reduction in triglycerides, compared with placebo. Rimonabant at a dose of 20
mg also resulted in an increase in plasma adiponectin levels, a change that was partly independent of weight loss alone. The most frequent adverse events resulting in discontinuation of the drug were depression, anxiety, and nausea.
The RIO-North America Study Group also assessed the efficacy and safety of Rimonabant alongside lifestyle modification for sustained changes in weight and cardiometabolic risk factors over 2 years [11
]. Rimonabant treatment in addition to diet promoted modest but sustained reductions in weight and waist circumference and favourable changes in cardiometabolic risk factors. This trial was limited by a high drop-out rate. The most common drug-related adverse event in this study was nausea.
The RIO-Diabetes trial assessed the efficacy and safety of Rimonabant in overweight or obese patients with type 2 diabetes inadequately controlled by metformin or sulphonylureas. Over 1000 overweight or obese type 2 diabetes patients with a haemoglobin A1c of 6.5–10.0% already on metformin or sulphonylurea were randomly assigned to received placebo, 5
mg/day Rimonabant, or 20
mg/day Rimonabant for 1 year in addition to a hypocaloric diet and advice for increased physical activity [12
]. Rimonabant, at a dose of 20
mg/day, in combination with diet and exercise, produced a clinically meaningful reduction in bodyweight and improved HbA1c and a number of cardiovascular and metabolic risk factors. The incidence of adverse events that led to discontinuation was slightly greater in the 20
mg/day Rimonabant group, mainly due to depressed mood disorders, nausea, and dizziness [12
The SERENADE trial (The Study Evaluating Rimonabant Efficacy in Drug-Naive Diabetic Patients) assessed the glucose-lowering efficacy and safety of Rimonabant in drug-naive type 2 diabetic patients. In this 6-month, randomized double-blind placebo-controlled trial, Rimonabant resulted in improvements in glycaemic control, body weight, and lipid profile in drug-naive type 2 diabetic patients [13
Two meta-analyses [14
] confirmed that Rimonabant treatment led to clinically meaningful weight loss, reduction in waist circumference, and improvements in several metabolic risk factors. However, findings from a meta-analysis of all published randomised controlled trials suggested that 20
mg per day Rimonabant increases the risk of psychiatric adverse events (depressed mood disorders and anxiety) despite depressed mood being an exclusion criterion in these trials. Rimonabant caused significantly more adverse events than did placebo and 1.4 times more serious adverse events [15
]. Patients given Rimonabant were 2.5 times more likely to discontinue the treatment because of depressive mood disorders than were those given placebo. Furthermore, anxiety caused more patients to discontinue treatment in Rimonabant groups than in placebo groups.
In The US Food and Drug Administration analysis of the four major trials as well as unpublished trials, psychiatric adverse events were found to be more common with Rimonabant (20
mg/day) than placebo [16
]. Furthermore, two deaths from suicide were reported in patients taking Rimonabant. The drug was never approved in the United States for the treatment of obesity. The marketing approval for Rimonabant has since been removed by the European Regulatory Authorities.