Scheen, A. J., Finer, N., Hollander, P., Jensen, M. D. & Van Gaal, L. F. Efficacy and tolerability of rimonabant in overweight or obese patients with type 2 diabetes: a randomised controlled study. Lancet 368, 1660-1672

University of Cambridge, Cambridge, England, United Kingdom
The Lancet (Impact Factor: 45.22). 12/2006; 368(9548):1660-72. DOI: 10.1016/S0140-6736(06)69571-8
Source: PubMed


Rimonabant, a selective cannabinoid type 1 receptor blocker, reduces bodyweight and improves cardiovascular and metabolic risk factors in non-diabetic overweight or obese patients. The aim of the RIO-Diabetes trial was to assess the efficacy and safety of rimonabant in overweight or obese patients with type 2 diabetes that was inadequately controlled by metformin or sulphonylureas.
1047 overweight or obese type 2 diabetes patients (body-mass index 27-40 kg/m2) with a haemoglobin A1c (HbA1c) concentration of 6.5-10.0% (mean 7.3% [SD 0.9] at baseline) already on metformin or sulphonylurea monotherapy were given a mild hypocaloric diet and advice for increased physical activity, and randomly assigned placebo (n=348), 5 mg/day rimonabant (360) or 20 mg/day rimonabant (339) for 1 year. Two individuals in the 5 mg/day group did not receive double-blind treatment and were thus not included in the final analysis. The primary endpoint was weight change from baseline after 1 year of treatment. Analyses were done on an intention-to-treat basis. This trial is registered at, number NCT00029848.
692 patients completed the 1 year follow-up; numbers in each group after 1 year were much the same. Weight loss was significantly greater after 1 year in both rimonabant groups than in the placebo group (placebo: -1.4 kg [SD 3.6]; 5 mg/day: -2.3 kg [4.2], p=0.01 vs placebo; 20 mg/day: -5.3 kg [5.2], p<0.0001 vs placebo). Rimonabant was generally well tolerated. 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.
These data indicate that 20 mg/day rimonabant, in combination with diet and exercise, can produce a clinically meaningful reduction in bodyweight and improve HbA1c and a number of cardiovascular and metabolic risk factors in overweight or obese patients with type 2 diabetes inadequately controlled by metformin or sulphonylureas.

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    • "The pathophysiology of type 2 diabetes is closely related to these disorders. Clinical studies investigated that, treatment of overweight type 2 diabetic patients with rimonabant (CB1 antagonism) (20 mg/day for 1year) significantly reduced body weight and improved glycemic control and HbA1C levels in comparison to placebo (Scheen et al., 2006). The aim of this study was to determine whether G1359A polymorphism of CNR1 is associated with coronary artery disease (CAD) with and without type 2 diabetes mellitus (T2DM) and with T2DM patients free of CAD and to elucidate the association of G1359A polymorphism of CNR1 with lipid profile and other cardiovascular risk factors. "
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    ABSTRACT: Emerging evidence that the cannabinoid type 1 receptor (CB1) and its endogenous ligands, endocannabinoids, involved in regulation of feeding behavior and body weight. Over-activation of ECS is associated with metabolic diseases as dyslipidemia and insulin resistance involved in CAD and diabetes. The aim was to determine whether G1359A polymorphism of CNR1 associated with CAD with and without T2DM, and with T2DM patients free of CAD and elucidate the association of CNR1 polymorphism with CAD risk factors. The study was carried on 50 patients with CAD (25 patients with and 25 patients without T2DM), 25 patients with T2DM free of CAD and a group of 20 healthy subjects as a control group. Coronary artery angiography for patient group, serum lipid profile (TG, TC, LDL and HDL) and assessment of G1359A polymorphism of CNR1 by RFLP method were done. CAD patients with and without T2DM had significantly higher age, fasting blood glucose, systolic and diastolic blood pressure, male gender, smoking, and body mass index (BMI) compared with control. GG genotype and G allele of G1359A polymorphism were significantly associated with CAD patients with T2DM (p<0.05). G allele increased risk of occurrence of CAD with diabetes by 5.22 (OR) 95% CI (1.32-20.54). GG genotype was significantly associated with higher TC (p<0.01), LDLc (p<0.001) and BMI (p=0.001). Association of G1359A polymorphism with BMI and disordered lipid may explain in part its association with CAD patients with T2DM and may encourage use of cannabinoid receptor antagonist in treatment of these disorders. Copyright © 2013 Safaa I. Tayel, et al., This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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    • "The efficacy and safety of Rimonabant in weight reduction and improving metabolic syndrome parameters in different populations have been assessed in several trials. The four large ‘Rimonabant in obesity’ (RIO) studies involved over 6600 participants, composed of four separate trials: RIO North America,[60] RIO Europe,[61] RIO Diabetes[62] and RIO Lipids,[63] in addition to other randomized double-blind Rimonabant-placebo controlled trials, namely the Serenade,[64] Stradivarius,[65] Arpeggio[66] and Adagio-lipids studies.[67] "
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    ABSTRACT: Non-alcoholic fatty liver disease (NAFLD) is a major cause of liver morbidity and mortality with no proven effective therapy as of yet. Its prevalence is increasing globally in parallel with obesity and metabolic syndrome pandemic. The endocannabinoid (EC) system has been implicated in the pathogenesis of several diseases, including fatty liver diseases. This system refers to the cannabinoid receptors type 1 (CB1) and type 2 (CB2), with both their endogenous ligands and machinery dedicated to EC synthesis and degradation. There is accumulating evidence on the role CB1 as a key mediator of insulin resistance and liver lipogenesis in both animals and humans. On the other hand, CB2 receptors have been shown to promote inflammation with anti-fibrogenic properties. The pharmacological modulation of the EC system activity for the treatment of metabolic syndrome and NAFLD are promising yet premature. The initial limited success due to deleterious central nervous system side-effects are likely to be bypassed with the use of peripherally restricted drugs.
    Saudi Journal of Gastroenterology 03/2013; 19(4):144-151. DOI:10.4103/1319-3767.114505 · 1.12 Impact Factor
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    • "In addition to obesity, CB 1 antagonists have been in particular proposed as therapeutic agents for smoking cessation [16], drug abuse [24e26], liver fibrosis [27], obesity-associated hepatic steatosis [28], sexual dysfunction [29], metabolic syndrome and dyslipidemia [30]. Cardiovascular and metabolic risk factor improvements due to the administration of CB 1 antagonists have been also highlighted in type 2 diabetes patients [31]. Despite initial enthusiasm in drug discovery for the identification and the selection of first CB 1 antagonist candidates able to reach the pharmaceutical market, with reference to the well known history "
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    ABSTRACT: In spite of rimonabant's withdrawal from the European market due to its adverse effects, interest in the development of drugs based on CB(1) antagonists is revamping on the basis of the peculiar properties of this class of compounds. In particular, new strategies have been proposed for the treatment of obesity and/or related risk factors through CB(1) antagonists, i.e. by the development of selectively peripherally acting agents or by the identification of neutral CB(1) antagonists. New compounds based on the lead CB(1) antagonist/inverse agonist rimonabant have been synthesized with focus on obtaining neutral CB(1) antagonists. Amongst the new derivatives described in this paper, the mixture of the two enantiomers (±)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-3-(2-cyclohexyl-1-hydroxyethyl)-4-methyl-1H-pyrazole ((±)-5), and compound 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-3-[(Z)-2-cyclohexyl-1-fluorovinyl]-4-methyl-1H-pyrazole ((Z)-6), showed interesting pharmacological profiles. According to the preliminary pharmacological evaluation, these novel pyrazole derivatives showed in fact both neutral CB(1) antagonism behaviour and significant in vivo activity towards food intake.
    European Journal of Medicinal Chemistry 01/2013; 62C:256-269. DOI:10.1016/j.ejmech.2012.12.056 · 3.45 Impact Factor
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