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

ABSTRACT 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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Available from: Nick Finer, Aug 22, 2015
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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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    • "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 · 3.43 Impact Factor
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    • "Cannabinoid CB1 receptor antagonists and inverse agonists, such as rimonabant, AM 4113, and AM251 (e.g., [23] [24] [25]) have drawn attention as drugs that can be used to treat behavioral disorders involved with overeating, such as obesity, by reducing food intake (see [26] [27] for reviews). Rimonabant is probably the most well researched of these drugs to date, and indeed has been shown to reduce free food intake in animal studies [28] [29] [30] [31] [32] [33] [34] [35] [36] [37], as well as reduce weight in clinical trials studies with obese humans [38] [39] [40] [41] [42] [43]. Though rimonabant has side effects that have called into question its application for weight loss [44] [45], the cannabinoid drug class is still of interest in treating disorders in which excessive contact with a reinforcing stimulus, such as food or drugs, is relevant [26,45–48]. "
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    ABSTRACT: Research on free-food intake suggests that cannabinoids are implicated in the regulation of feeding. Few studies, however, have characterized how environmental factors that affect food procurement interact with cannabinoid drugs that reduce food intake. Demand analysis provides a framework to understand how cannabinoid blockers, such as rimonabant, interact with effort in reducing demand for food. The present study examined the effects rimonabant had on demand for sucrose in obese Zucker rats when effort to obtain food varied and characterized the data using the exponential ("essential value") model of demand. Twenty-nine male (15 lean, 14 obese) Zucker rats lever-pressed under eight fixed ratio (FR) schedules of sucrose reinforcement, in which the number of lever-presses to gain access to a single sucrose pellet varied between 1 and 300. After behavior stabilized under each FR schedule, acute doses of rimonabant (1-10mg/kg) were administered prior to some sessions. The number of food reinforcers and responses in each condition was averaged and the exponential and linear demand equations were fit to the data. These demand equations quantify the value of a reinforcer by its sensitivity to price (FR) increases. Under vehicle conditions, obese Zucker rats consumed more sucrose pellets than leans at smaller fixed ratios; however, they were equally sensitive to price increases with both models of demand. Rimonabant dose-dependently reduced reinforcers and responses for lean and obese rats across all FR schedules. Data from the exponential analysis suggest that rimonabant dose-dependently increased elasticity, i.e., reduced the essential value of sucrose, a finding that is consistent with graphical depictions of normalized demand curves.
    Physiology & Behavior 02/2012; 105(3):734-41. DOI:10.1016/j.physbeh.2011.10.009 · 3.03 Impact Factor
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