Elsevier

The Lancet

Volume 365, Issue 9468, 16–22 April 2005, Pages 1389-1397
The Lancet

Articles
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

https://doi.org/10.1016/S0140-6736(05)66374-XGet rights and content

Summary

Background

In animal models, cannabinoid-1 receptor (CB1) blockade produces a lean phenotype, with resistance to diet-induced obesity and associated dyslipidaemia. We assessed the effect of rimonabant, a selective CB1 blocker, on bodyweight and cardiovascular risk factors in overweight or obese patients.

Methods

patients with body-mass index 30 kg/m2 or greater, or body-mass index greater than 27 kg/m2 with treated or untreated dyslipidaemia, hypertension, or both, were randomised to receive double-blind treatment with placebo, 5 mg rimonabant, or 20 mg rimonabant once daily in addition to a mild hypocaloric diet (600 kcal/day deficit). The primary efficacy endpoint was weight change from baseline after 1 year of treatment in the intention-to-treat population.

Findings

Weight loss at 1 year was significantly greater in patients treated with rimonabant 5 mg (mean −3·4 kg [SD 5·7]; p=0·002 vs placebo) and 20 mg (−6·6 kg [7·2]; p<0·001 vs placebo) compared with placebo (−1·8 kg [6·4]). Significantly more patients treated with rimonabant 20 mg than placebo achieved weight loss of 5% or greater (p<0·001) and 10% or greater (p<0·001). Rimonabant 20 mg produced significantly greater improvements than placebo in waist circumference, HDL-cholesterol, triglycerides, and insulin resistance, and prevalence of the metabolic syndrome. The effects of rimonabant 5 mg were of less clinical significance. Rimonabant was generally well tolerated with mild and transient side effects.

Interpretation

CB1 blockade with rimonabant 20 mg, combined with a hypocaloric diet over 1 year, promoted significant decrease of bodyweight and waist circumference, and improvement in cardiovascular risk factors.

Introduction

The prevalence of obesity continues to increase, with more than 50% of Europeans currently classified as overweight and up to 30% as clinically obese.1, 2 WHO has estimated that, yearly, about a quarter of a million deaths in Europe and more than 2·5 million deaths worldwide are weight-related, with cardiovascular disease as the leading cause.3 Because few safe and effective drugs are available, the treatment of obesity remains one of the greatest unmet clinical needs of our time.

The newly discovered endocannabinoid system contributes to the physiological regulation of energy balance, food intake, and lipid and glucose metabolism through both central and peripheral effects.4, 5, 6 This system consists of endogenous ligands and two types of G-protein-coupled cannabinoid receptors: CB1, located in several brain areas and in a variety of peripheral tissues including adipose tissue, the gastrointestinal tract, the pituitary and adrenal glands, sympathetic ganglia, heart, lung, liver, and urinary bladder;7, 8 and CB2, in the immune system.9 The endocannabinoid system is overactivated in genetic animal models of obesity5 and in response to exogenous stimuli such as excessive food intake.10 Preclinical studies implicate the endocannabinoid system in the modulation of food intake and adipogenesis,11, 12, 13 through peripheral mechanisms. The system might provide a possible treatment target for high-risk overweight or obese patients. Insights into the endocannabinoid system have been derived from studies in animals with genetic deletion of CB1, which have a lean phenotype and are resistant to diet-induced obesity and associated insulin resistance produced by a highly palatable high-fat diet.14 Further evidence comes from investigation of pharmacological blockade of CB1 receptors with the selective CB1 blocker rimonabant, which produces weight loss and ameliorates metabolic abnormalities in obese animals.10, 15 Preclinical findings support the role of the CB1 receptor in both central and peripheral regulation of energy balance and body weight,5 providing a mechanistic basis for the clinical development of rimonabant for the management of obesity and associated cardiovascular risk factors.

We undertook a large, multicentre, multi-national, randomised, placebo-controlled trial—the RIO (Rimonabant In Obesity) Europe trial—to assess the efficacy and safety of rimonabant in reducing body weight and improving cardiovascular risk factors in overweight or obese patients.

Section snippets

Patients

Men and women aged 18 years or older, with body-mass index (BMI) 30 kg/m2 or greater, or BMI greater than 27 kg/m2 with treated or untreated hypertension or treated or untreated dyslipidaemia, were recruited from 60 sites in Europe and the USA between October, 2001, and April, 2002. Although RIO-Europe was planned to be done in Europe only, difficulties in meeting recruitment targets led to the extension of the study to 20 sites in the USA with an enrolment, of 276 US patients.

Eligible patients

Results

309 men and 1198 women were randomised to double-blind treatment. 920 patients (61%) completed the 1-year follow-up: 178 (58·4%) in the placebo group, 379 (62·7%) in the rimonabant 5 mg group, and 363 (60·6%) in the rimonabant 20 mg group (figure 1).

The treatment groups had similar demographic and baseline characteristics (table 1). 346 patients with a BMI of 40 kg/m2 or greater were enrolled. At baseline, 617 (40·9%) patients had hypertension, 915 (60·8%) had dyslipidaemia, and 615 (41·4%) met

Discussion

In this study, treatment with rimonabant over 1 year led to sustained, clinically meaningful weight loss, reduction in waist circumference, and associated improvements in several cardiovascular and metabolic risk factors, including HDL-cholesterol and triglyceride concentrations, HOMA-IR, and prevalence of the metabolic syndrome. About half of the effect of rimonabant on HDL-cholesterol and triglycerides was independent of weight loss. Despite a significant effect on bodyweight, rimonabant 5 mg

References (39)

  • V Di Marzo et al.

    Leptin-regulated endocannabinoids are involved in maintaining food intake

    Nature

    (2001)
  • T Croci et al.

    In vitro functional evidence of neuronal cannabinoid CB1 receptors in human ileum

    Br J Pharmacol

    (1998)
  • M Bensaid et al.

    The cannabinoid CB1 receptor antagonist SR141716 increases Acrp30 mRNA expression in adipose tissue of obese fa/fa rats and in cultured adipocyte cells

    Mol Pharmacol

    (2003)
  • C Ravinet Trillou et al.

    Anti-obesity effect of SR141716, a CB1 receptor antagonist, in diet-induced obese mice

    Am J Physiol Regul Integr Comp Physiol

    (2003)
  • R Gomez et al.

    A peripheral mechanism for CB1 cannabinoid receptor-dependent modulation of feeding

    J Neurosci

    (2002)
  • TC Kirkham

    Endogenous cannabinoids: a new target in the treatment of obesity

    Am J Physiol Regul Integr Comp Physiol

    (2003)
  • TL Horvath

    Endocannabinoids and the regulation of body fat: the smoke is clearing

    J Clin Invest

    (2003)
  • G Kunos et al.

    Novel physiologic functions of endocannabinoids as revealed through the use of mutant mice

    Neurochem Res

    (2001)
  • D Cota et al.

    Endogenous cannabinoid system as a modulator of food intake

    Int J Obes Relat Metab Disord

    (2003)
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