Efficacy and safety of the weight-loss drug rimonabant: a meta-analysis of randomised trials

doi:10.1016/S0140-6736(07)61721-8

The Lancet

Volume 370, Issue 9600, 17–23 November 2007, Pages 1706-1713

https://doi.org/10.1016/S0140-6736(07)61721-8 Get rights and content

Summary

Background

Since the prevalence of obesity continues to increase, there is a demand for effective and safe anti-obesity agents that can produce and maintain weight loss and improve comorbidity. We did a meta-analysis of all published randomised controlled trials to assess the efficacy and safety of the newly approved anti-obesity agent rimonabant.

Methods

We searched The Cochrane database and Controlled Trials Register, Medline via Pubmed, Embase via WebSpirs, Web of Science, Scopus, and reference lists up to July, 2007. We collected data from four double-blind, randomised controlled trials (including 4105 participants) that compared 20 mg per day rimonabant with placebo.

Findings

Patients given rimonabant had a 4·7 kg (95% CI 4·1–5·3 kg; p<0·0001) greater weight reduction after 1 year than did those given placebo. Rimonabant caused significantly more adverse events than did placebo (OR=1·4; p=0·0007; number needed to harm=25 individuals [95% CI 17–58]), and 1·4 times more serious adverse events (OR=1·4; p=0·03; number needed to harm=59 [27–830]). Patients given rimonabant were 2·5 times more likely to discontinue the treatment because of depressive mood disorders than were those given placebo (OR=2·5; p=0·01; number needed to harm=49 [19–316]). Furthermore, anxiety caused more patients to discontinue treatment in rimonabant groups than in placebo groups (OR=3·0; p=0·03; number needed to harm=166 [47–3716]).

Interpretation

Our findings suggest that 20 mg per day rimonabant increases the risk of psychiatric adverse events—ie, depressed mood disorders and anxiety—despite depressed mood being an exclusion criterion in these trials. Taken together with the recent US Food and Drug Administration finding of increased risk of suicide during treatment with rimonabant, we recommend increased alertness by physicians to these potentially severe psychiatric adverse reactions.

Introduction

The prevalence of obesity continues to increase worldwide,¹ and there is a demand for effective and safe anti-obesity agents that can produce and maintain weight loss and improve comorbidities. Obesity is producing several health-related consequences.2, 3 Weight loss of 5–10% of bodyweight, irrespective of how it is achieved, is associated with improvements in cardiovascular risk profiles and reduced incidence of type 2 diabetes.2, 4, 5 Non-pharmacological treatment can be effective, but success rate in the long term is low.6, 7 Obesity guidelines recommend that anti-obesity pharmacotherapy is to be regarded as a potentially important adjunctive treatment to non-pharmacological therapy for patients with a body-mass index (BMI) greater than or equal to 30 kg/m², or a BMI of 27·0–29·9 kg/m² with one or more major obesity-related comorbidities.² The anti-obesity agent rimonabant (acomplia, Sanofi-Aventis, Paris, France), has been approved by the European Agency for the Evaluation of Medicinal Products (EMEA) in June, 2006, and is available in Argentina, Austria, Denmark, Finland, Germany, Ireland, Norway, Sweden, Greece, and the UK.

Rimonabant is a selective antagonist of the cannabinoid type 1 receptor, and it is the first member of a new class of compounds that targets the endocannabinoid system, which has been shown to be involved in the central and peripheral regulation of food intake and the CNS rewarding system.8, 9 So far, four clinical trials on rimonabant have been published,10, 11, 12, 13 and all show an increased weight loss compared with placebo of 4–6 kg over 6–12 months, with few tolerability or safety concerns. In the Rimonabant in Obesity (RIO)-Europe study,¹⁰ the investigators concluded that rimonabant was generally well tolerated with mild and transient side-effects. However, the individual trials showed trends to increases in depressed mood, depression, and severe adverse events. Furthermore, because patients with serious mental illness were excluded from the RIO programme, the estimates of the potential psychiatric side-effects of the drug are conservative.¹⁴ Rimonabant was recently assessed by the US Food and Drug Administration (FDA), and coinciding with the submission of this paper, the FDA's Advisory Committee unanimously concluded that more detailed safety information about rimonabant in larger patient numbers over the long term was needed before the drug could be approved.¹⁵

We aimed to do a meta-analysis of rimonabant studies to assess efficacy and safety of the drug, emphasising psychiatric adverse events such as depressive disorders that could potentially lead to suicide.

Section snippets

Search strategy and selection criteria

Five bibliographic databases (Medline from mid-1950s, Embase from 1980, Web of Science from 1945–54, Scopus from 1966, and the Cochrane Library) were searched up to November, 2006, for randomised controlled trials investigating rimonabant and weight loss. Search terms were (“rimonabant” OR “Acomplia” OR [“antagonist” AND “cannabinoid” AND “receptor”]) AND (“obesity” OR “weight loss” OR “overweight” OR “weight reduction” OR “slimming”) AND “controlled”. All clinical trials relating rimonabant to

Results

We identified 227 studies in the database searches (figure 1). If a study contained phases for both weight loss and weight maintenance, we included only data from the weight loss phase. After review of the identified studies, 57 were identified and retrieved for further scrutiny. We included only four randomised placebo-controlled, double-blind trials,10, 11, 12, 13 which were of high quality (Jadad assessment score of about 5) and met the inclusion criteria. All included trials were in the RIO

Discussion

Four trials in the RIO programme assessed the efficacy and safety of the anti-obesity agent rimonabant compared with placebo, and our meta-analysis has shown that rimonabant therapy produced a greater weight loss than did placebo. Patients who were allocated to rimonabant were much more likely to achieve a 10% weight reduction after 1 year compared with those allocated to placebo. These figures are in agreement with the outcome of a Cochrane meta-analysis,²⁷ and suggest that rimonabant is

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ArticlesEfficacy and safety of the weight-loss drug rimonabant: a meta-analysis of randomised trials

Summary

Background

Methods

Findings

Interpretation

Introduction

Section snippets

Search strategy and selection criteria

Results

Discussion

Lancet

Lancet

Lancet

Lancet

Control Clin Trials

Lancet

Surg Clin North Am

Am J Geriatr Psychiatry

Lancet

Systematic review of the long-term effects and economic consequences of treatments for obesity and implications for health improvement

Health Technol Assess

Treatment of obesity

Beneficial health effects of modest weight loss

Int J Obes Relat Metab Disord

Lessons from obesity management programmes: greater initial weight loss improves long-term maintenance

Obes Rev

Treatment of obesity by moderate and severe caloric restriction. Results of clinical research trials

Ann Intern Med

Endocannabinoid control of food intake and energy balance

Nat Neurosci

SR147778 [5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-N-(1-piperidinyl)-1H-pyr azole-3-carboxamide], a new potent and selective antagonist of the CB1 cannabinoid receptor: biochemical and pharmacological characterization

J Pharmacol Exp Ther

Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia

N Engl J Med

Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients: RIO-North America: a randomized controlled trial

JAMA

FDA briefing document: Zimulti (rimonabant) Tablets, 20 mg

Articles
Efficacy and safety of the weight-loss drug rimonabant: a meta-analysis of randomised trials