[en] BACKGROUND: 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. METHODS: 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 ClinicalTrials.gov, number NCT00029848. FINDINGS: 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. INTERPRETATION: 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.
Disciplines :
Endocrinology, metabolism & nutrition
Author, co-author :
Scheen, André ; Université de Liège - ULiège > Département des sciences cliniques > Diabétologie, nutrition et maladie métaboliques - Médecine interne générale
Finer, Nick
Hollander, Priscilla
Jensen, Michael D
Van Gaal, Luc F
Language :
English
Title :
Efficacy and tolerability of rimonabant in overweight or obese patients with type 2 diabetes: a randomised controlled study.
Alexander C., Landsman P., Teutsch S., and Haffner S. 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
National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). 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
Haffner S., Lehto S., Ronnemaa T., Pyorala K., and Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 339 (1998) 229-234
Booth G., Kapral M., Fung K., and Tu J. Relation between age and cardiovascular disease in men and women with diabetes compared with non-diabetic people: a population-based retrospective cohort study. Lancet 368 (2006) 29-36
Scheen A. Current management strategies for coexisting diabetes mellitus and obesity. Drugs 63 (2003) 1165-1184
Yusuf S., Hawken S., Ôunpuu S., et al. Obesity and the risk of myocardial infarction in 27 000 participants from 52 countries: case-control study. Lancet 366 (2005) 1640-1649
Chan J., Rimm E., Colditz G., Stampfer M., and Willett W. Obesity, fat distribution, and weight gain as risk factors for clinical diabetes in men. Diabetes Care 17 (1994) 961-969
Wing R., Marcus M., Epstein L., and Salata R. Type II diabetic subjects lose less weight than their overweight nondiabetic spouses. Diabetes Care 10 (1987) 563-566
Howlett A., Breivogel C., Childers S., Deadwyler S., Hampson R., and Porrino L. Cannabinoid physiology and pharmacology: 30 years of progress. Neuropharmacology 47 suppl 1 (2004) 345-358
Di Marzo V., Goparaju S., Wang L., et al. Leptin-regulated endocannabinoids are involved in maintaining food intake. Nature 410 (2001) 822-825
Ravinet Trillou C., Arnone M., Menet C., et al. 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
Poirier B., Bidouard J., Cadrouvele C., et al. The anti-obesity effect of rimonabant is associated with an improved serum lipid profile. Diabetes Obes Metab 7 (2005) 65-72
Bensaid M., Gary-Bobo M., Esclangon A., 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 63 (2003) 908-914
Osei-Hyiaman D., DePetrillo M., Pacher P., et al. Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. J Clin Invest 115 (2005) 1298-1305
Liu Y., Connoley I., Wilson C., and Stock M. Effects of the cannabinoid CB1 receptor antagonist SR141716 on oxygen consumption and soleus muscle glucose uptake in Lep(ob)/Lep(ob) mice. Int J Obes Relat Metab Disord 29 (2005) 183-187
Matias I., Gonthier M., Orlando P., et al. Regulation, function, and dysregulation of endocannabinoids in models of adipose and β-pancreatic cells and in obesity and hyperglycemia. J Clin Endocrinol Metab 91 (2006) 3171-3180
Van Gaal L., Rissanen A., Scheen A., Ziegler O., and Rössner S. 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. Lancet 365 (2005) 1389-1397
Pi-Sunyer F., Aronne L., Heshmati H., Devin J., Rosenstock J., and RIO-North America Study Group. 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 295 (2006) 761-775
Després J., Golay A., Sjöström L., and Rimonabant in Obesity-Lipids Study Group. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med 353 (2005) 2121-2134
Matthews D., Hosker J., Rudenski A., Naylor B., Treacher D., and Turner R. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28 (1985) 412-419
Ware J., and Sherbourne C. The MOS 36-item short-form health survey (SF-36). Med Care 30 (1992) 473-483
Kolotkin R., Crosby R., Kosloski K., and Williams G. Development of a brief measure to assess quality of life in obesity. Obes Res 9 (2001) 102-111
Kolotkin R., and Crosby R. Psychometric evaluation of the Impact Of Weight On Quality Of Life-Lite Questionnaire (IWQOL-Lite) in a community sample. Quality of Life Research 11 (2002) 157-171
Hill A., Rogers P., and Blundell J. Techniques for the experimental measurement of human being behaviour and food intake: a practical guide. Int J Obes Relat Metab Disord 19 (1995) 361-375
Zigmond A., and Snaith R. The hospital anxiety and depression scale. Acta Psychiatr Scand 67 (1983) 361-370
Hochberg Y. A sharper Bonferonni procedure for multiple tests of significance. Biometrika 75 (1988) 800-802
Gadbury G., Coffey C., and Allison D. Modern statistical methods for handling missing repeated measurements in obesity trial data: beyond LOCF. Obes Rev 4 (2003) 175-184
Wood A., White I., Hillsdon M., and Carpenter J. Comparison of imputation and modelling methods in the analysis of a physical activity trial with missing outcomes. Int J Epidemiol 34 (2005) 89-99
Buyse M., and Molenberghs G. Criteria for the validation of surrogate endpoints in randomized experiments. Biometrics 54 (1998) 1014-1029
International Diabetes Federation. Global guideline for type 2 diabetes. http://www.idf.org/home/index.cfm?node=1457 (accessed Oct 9, 2006)
American Diabetes Association. Clinical practice recommendations 2005. Diabetes Care 28 suppl 1 (2005) S1-S79
Klein S., Burke L., Bray G., et al. Clinical implications of obesity with specific focus on cardiovascular disease: a statement for professionals from the American Heart Association Council on Nutrition, Physical Activity, and Metabolism: endorsed by the American College of Cardiology Foundation. Circulation 110 (2004) 2952-2967
Stratton I., Adler A., Neil H., et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 321 (2000) 405-412
DeFronzo R., Ratner R., Han J., Kim D., Fineman M., and Baron A. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care 28 (2005) 1092-1100
Gaede P., Vedel P., Larsen N., Jensen G., Parving H., and Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 348 (2003) 383-393
Stumvoll M., Goldstein B., and van Haeften T. Type 2 diabetes: principles of pathogenesis and therapy. Lancet 365 (2005) 1333-1346
Eckel R., Grundy S., and Zimmet P. The metabolic syndrome. Lancet 365 (2005) 1415-1428
Danesh J., Wheeler J., Hirschfield G., et al. C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. N Engl J Med 350 (2004) 1387-1397
Cota D., Marsicano G., Tschop M., et al. The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis. J Clin Invest 112 (2003) 423-431
Chandran M., Phillips S., Ciaraldi T., and Henry R. Adiponectin: more than just another fat cell hormone?. Diabetes Care 26 (2003) 2442-2450
Sattar N., Wannamethee G., Sarwar N., et al. Adiponectin and coronary heart disease: a prospective study and meta-analysis. Circulation 114 (2006) 623-629
Williamson D., Thompson T., Thun M., Flanders D., Pamuk E., and Byers T. Intentional weight loss and mortality among overweight individuals with diabetes. Diabetes Care 23 (2000) 1499-1504
Guare J., Wing R., and Grant A. Comparison of obese NIDDM and nondiabetic women: short- and long-term weight loss. Obes Res 3 (1995) 329-335
Anon. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 352 (1998) 837-853
Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 346 (2002) 393-403
Wing R., Koeske R., Epstein L., Nowalk M., Gooding W., and Becker D. Long-term effects of modest weight loss in type II diabetic patients. Arch Intern Med 147 (1987) 1749-1753
Nathan D., Buse J., Davidson M., et al. Management of hyperglycaemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 29 (2006) 1963-1972
Norris S., Zhang X., Avenell A., et al. Efficacy of pharmacotherapy for weight loss in adults with type 2 diabetes mellitus: a meta-analysis. Arch Intern Med 164 (2004) 395-404
Padwal R., Li S., and Lau D. Long-term pharmacotherapy for overweight and obesity: a systematic review and meta-analysis of randomized controlled trials. Int J Obes Relat Metab Disord 27 (2003) 1437-1446
