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.
Van Gaal, Luc F; Rissanen, Aila M; Scheen, Andréet al.
[en] 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.
Scheen, André ; Université de Liège - ULiège > Département des sciences cliniques > Diabétologie, nutrition et maladie métaboliques - Médecine interne générale
Ziegler, Olivier
Rossner, Stephan
Language :
English
Title :
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.
PT James, N Rigby, R Leach The obesity epidemic, metabolic syndrome and future prevention strategies Eur J Cardiovasc Prev Rehabil 11 2004 3 8
DA York, S Rossner, I Caterson American Heart Association. Prevention conference VII: obesity, a worldwide epidemic related to heart disease and stroke: Group I: worldwide demographics of obesity Circulation 110 2004 e463 e470
WHO Integrated management of cardiovascular risk: report of a WHO meeting 2002 World Health Organisation Geneva
D Cota, G Marsicano, M Tschop The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis J Clin Invest 112 2003 423 431
V Di Marzo, M Bifulco, L De Petrocellis The endocannabinoid system and its therapeutic exploitation Nat Rev Drug Discov 3 2004 771 784
V Di Marzo, SK Goparaju, L Wang Leptin-regulated endocannabinoids are involved in maintaining food intake Nature 410 2001 822 825
T Croci, L Manara, G Aureggi In vitro functional evidence of neuronal cannabinoid CB1 receptors in human ileum Br J Pharmacol 125 1998 1393 1395
M Bensaid, M Gary-Bobo, A Esclangon 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 63 2003 908 914
AC Howlett, CS Breivogel, SR Childers, SA Deadwyler, RE Hampson, LJ Porrino Cannabinoid physiology and pharmacology: 30 years of progress Neuropharmacology 47 suppl 1 2004 345 358
C Ravinet Trillou, M Arnone, C Delgorge Anti-obesity effect of SR141716, a CB1 receptor antagonist, in diet-induced obese mice Am J Physiol Regul Integr Comp Physiol 284 2003 R345 R353
R Gomez, M Navarro, B Ferrer A peripheral mechanism for CB1 cannabinoid receptor-dependent modulation of feeding J Neurosci 22 2002 9612 9617
TC Kirkham Endogenous cannabinoids: a new target in the treatment of obesity Am J Physiol Regul Integr Comp Physiol 284 2003 R343 R344
TL Horvath Endocannabinoids and the regulation of body fat: the smoke is clearing J Clin Invest 112 2003 323 326
G Kunos, S Batkai Novel physiologic functions of endocannabinoids as revealed through the use of mutant mice Neurochem Res 26 2001 1015 1021
D Cota, G Marsicano, B Lutz Endogenous cannabinoid system as a modulator of food intake Int J Obes Relat Metab Disord 27 2003 289 301
Laboratory Test Handbook 4th edn. 1996 Lexi-Comp Hudson
Third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III) final report Circulation 106 2002 3143 3421
DR Matthews, JP Hosker, AS Rudenski, BA Naylor, DF Treacher, RC Turner Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man Diabetologia 28 1985 412 419
AS Zigmond, RP Snaith The hospital anxiety and depression scale Acta Psychiatr Scand 67 1983 361 370
DJ Goldstein Beneficial health effects of modest weight loss Int J Obes Relat Metab Disord 16 1992 397 415
LF Van Gaal, MA Wauters, IH De Leeuw The beneficial effects of modest weight loss on cardiovascular risk factors Int J Obes Relat Metab Disord 21 suppl 1 1997 S5 S9
S Zhu, Z Wang, S Heshka, M Heo, MS Faith, SB Heymsfield Waist circumference and obesity-associated risk factors among whites in the third National Health and Nutrition Examination Survey: clinical action thresholds Am J Clin Nutr 76 2002 743 749
I Janssen, P Katzmarzyk, R Ross Waist circumference and not body mass index explains obesity-related health risk Am J Clin Nutr 79 2004 379 384
JP Després, I Lemieux, D Prud'homme Treatment of obesity: need to focus on high risk abdominally obese patients BMJ 322 2001 716 720
DJ Gordon, JL Probstfield, RJ Garrison High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies Circulation 79 1989 8 15
LA Matsuda, SJ Lolait, MJ Brownstein, AC Young, TI Bonner Structure of a cannabinoid receptor and functional expression of the cloned cDNA Nature 346 1990 561 564
S Munro, KL Thomas, M Abu-Shaar Molecular characterization of a peripheral receptor for cannabinoids Nature 365 1993 61 65
AC Howlett The cannabinoid receptors Prostaglandins Other Lipid Mediat 68-69 2002 619 631
LD Petrocellis, MG Cascio, VD Marzo The endocannabinoid system: a general view and latest additions Br J Pharmacol 141 2004 765 774
Y Liu, I Connoley, C Wilson, M Stock Effects of the cannabinoid CB1 receptor antagonist SR141716 on oxygen consumption and soleus muscle glucose uptake in Lepob/Lepob mice Int J Obes Relat Metab Disord 29 2004 183 187
M Arnone, J Maruani, F Chaperon Selective inhibition of sucrose and ethanol intake by SR 141716, an antagonist of central cannabinoid (CB1) receptors Psychopharmacology (Berl) 132 1997 104 106
J Simiand, M Keane, PE Keane, P Soubrie SR 141716, a CB1 cannabinoid receptor antagonist, selectively reduces sweet food intake in marmoset Behav Pharmacol 9 1998 179 181
AH Berg, TP Combs, X Du, M Brownlee, PE Scherer The adipocyte-secreted protein Acrp30 enhances hepatic insulin action Nat Med 7 2001 947 953
TP Combs, AH Berg, S Obici, PE Scherer, L Rossetti Endogenous glucose production is inhibited by the adipose-derived protein Acrp30 J Clin Invest 108 2001 1875 1881
J Fruebis, TS Tsao, S Javorschi Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice Proc Natl Acad Sci USA 98 2001 2005 2010
T Yamauchi, J Kamon, H Waki The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity Nat Med 7 2001 941 946
S Yusuf, S Hawken, S Ounpuu Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study Lancet 364 2004 937 952
JB Meigs, PW Wilson, DM Nathan, RB D'Agostino Sr, K Williams, SM Haffner Prevalence and characteristics of the metabolic syndrome in the San Antonio Heart and Framingham Offspring Studies Diabetes 52 2003 2160 2167
CM Alexander, PB Landsman, SM Teutsch, SM Haffner NCEP-defined metabolic syndrome, diabetes, and prevalence of coronary heart disease among NHANES III participants age 50 years and older Diabetes 52 2003 1210 1214
