Printable Version

Home > Abstracts of Current Literature > Effects of Rimonabant

Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study

Background: Preliminary information has revealed a possible role of cannabinoid-1 (CB-1) receptors in regulation of energy balance and body weight. This presents a physiological foundation for the clinical development of rimonabant (a CB-1 receptor blocker) for the management of obesity and related cardiovascular risk factors.

Objective: This trial was conducted to assess the efficacy and safety of rimonabant in weight reduction and improving cardiovascular risk factors in overweight or obese patients.

Methods: This was a randomized, double-blind, placebo-controlled, parallel group trial. One thousand five hundred and seven patients enrolled in the study and had either a body-mass index of 30 kg/m2 or greater, or a body-mass index of greater than 27 kg/m2 with treated or untreated hypertension, dyslipidemia, or both. An inclusion criterion was less than a 5 kg variation in body weight during the 3 months prior to the start of the study. Exclusion criteria included endocrine disease, cardiovascular or pulmonary disease, renal or hepatic disorders, substantial neurological illness, or substantial psychological illness. Also if the patient had a history of depression, suicide attempts, or weight-loss surgical procedures they were excluded from the study. Certain medications like anti-obesity drugs, corticosteroids, antidepressants, neuroleptics, non-selective systemic antihistamines, nicotine substitutes, and antidiabetic drugs were not permitted during the study. Patients who wanted to quit smoking were not permitted in the study nor was a dosage change in dyslipidemia agents permitted. Marijuana users were also excluded from the study. Placebo, 5 mg of rimonabant, or 20 mg of rimonabant were administered once daily for one year. In addition, patient’s basal metabolic rate was estimated, and a dietician subtracted 600 kcal from that to calculate a recommended energy intake for each patient. At each study visit, patients received dietary counseling and were encouraged to increase physical activity. The primary efficacy endpoint was the absolute weight change from baseline at the end of one year, which also included the proportion of patients who achieved 5% or more and 10% or more weight loss. Secondary endpoints were changes from baseline in waist circumference, concentrations of fasting glucose and insulin, lipid profiles, and the prevalence of the metabolic syndrome. All safety and efficacy analyses were done using the intent-to-treat (ITT) population. Also, the per protocol results were noted for the primary and secondary efficacy endpoints.

Results: The change in body weight in the per protocol group was –4.8 kg (6.2) (p=0.042) in the 5 mg group and –8.6 kg (7.3) (p<0.001) in the 20 mg group. Also the change in waist circumference from baseline was –5.3 kg (6.4) (not significant) for the 5 mg group and –8.5 kg (7.4) (p<0.001) in the 20 mg group. The change in body weight in the ITT population and change in waist circumference from baseline were both significant vs. placebo in the 5 mg and 20 mg rimonabant arms where –3.4 kg (5.7) (p=0.002) and –3.9 cm (6.6) (p=0.002) for both findings in the 5 mg arm and –6.6 kg (7.2) (p<0.001) and –6.5 cm (7.4) (p<0.001) for both findings in the 20 mg arm. There was a change in HDL cholesterol for both 5 and 20 mg rimonabant arms where 0.19 mmol/L (0.23) p=0.048 and 0.26 mmol/L (0.26) p<0.001, respectively. For the 20 mg rimonabant group only, there was a change in triglycerides –0.20 mmol/L (0.64) p<0.001, in total cholesterol to HDL cholesterol ratio –0.71 (0.78) p<0.001, in fasting glucose –0.09 mmol/L (0.65) p=0.026, in fasting insulin –1.0 mU/mL (8.8) p<0.001, and in insulin resistance –0.3% (2.4) p=0.002. The most common adverse effects included nausea, dizziness, arthralgia, diarrhea, and depressed mood disorders. The authors concluded that blocking CB1 receptors with rimonabant 20 mg, combined with a low caloric diet (600 kcal/day deficit) for 1 year, contributed to a significant reduction in weight and waist circumference, and improvements in cardiovascular risk factors.

Strengths: All safety and efficacy analyses were done using the ITT population, which provides more true-to-life data. The study also provided the per protocol results which provides more absolute data. The parallel study design is appropriate for determining the efficacy of a drug, provided the patients in the experimental and control groups are truly comparable which is accurate for this study. The inclusion and exclusion criteria for this study were representative of the patient population of interest, obese and overweight patients with potentially related cardiovascular risk factors.

Weaknesses: Possible conflicts of interest may exist since a major supporter of the study is the pharmaceutical company that manufactures rimonabant. Although precautions were taken, the occurrence of known adverse events could indirectly lead to unblinding. There were no methods for monitoring patient compliance in regards to caloric intake and medication adherence. Also, there does not seem to be a measure of standardization between the 80 different test sites, which could lead to increased variability.

Conclusion: While it is currently under investigation for the treatment of obesity and smoking cessation, if approved, rimonabant may possibly create a new treatment option for obese and nicotine dependent populations. It is important to mention that although psychiatric adverse effects were noted during the study, there was not a significant change after one year from baseline in the HAD scale used to evaluated depression and anxiety in patients. Depression and anxiety were two anticipated side effects due to the drug’s mechanism of action. The results of this study based on the HAD scale might erase some of the concern for the drug’s expected mood-changing adverse effects. Also an important factor, the patient’s hypocaloric diet during the study could have aided the weight reducing capability of rimonabant while it is still unclear what its weight loss ability is in patients who do not follow a low calorie diet. If additional safety and efficacy studies confirm the results of this trial, rimonabant could be an effective therapeutic option for the treatment of obesity because few safe and effective drugs are currently available to combat this challenging clinical epidemic.

Van Gaal LF, Rissanen AM, Scheen AJ, Ziegler O, Rossner S. Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet. 2005 April 16;365:1389-97.

Heather B. Fouse, Pharm.D. Candidate