Best Practice & Research Clinical Endocrinology & Metabolism
Volume 23, Issue 1 , Pages 103-116 , February 2009

Use of cannabinoid CB1 receptor antagonists for the treatment of metabolic disorders

  • André J. Scheen, MD, PhD (Professor and Doctor)

      Affiliations

    • Corresponding Author InformationCorresponding author. Tel.: +32 4 3667238; Fax: +32 4 3667068.
    • ,
  • Nicolas Paquot, MD, PhD (Professor and Doctor)

References 

  1. Di Marzo V, Bifulco M, De Petrocellis L. The endocannabinoid system and its therapeutic exploitation. Nature Reviews. Drug Discovery. 2004;3:771–784
  2. Pagotto U, Marsicano G, Cota D, et al. The emerging role of the endocannabinoid system in endocrine regulation and energy balance. Endocrine Reviews. 2006;27:73–100
  3. Matias I, Di Marzo V. Endocannabinoids and the control of energy balance. Trends in Endocrinology and Metabolism: TEM. 2007;18:27–37
  4. Cota D. Role of the endocannabinoid system in energy balance regulation and obesity. Frontiers of Hormone Research. 2008;36:135–145
  5. Di Marzo V. The endocannabinoid system in obesity and type 2 diabetes. Diabetologia. 2008;51:1356–1367
  6. Di Marzo V. Endocannabinoids: synthesis and degradation. Reviews of Physiology, Biochemistry and Pharmacology. 2008;160:1–24
  7. Alexander SPH, Kendall DA. The complications of promiscuity: endocannabinoid action and metabolism. British Journal of Pharmacology. 2007;152:602–623
  8. Mendizabal VE, Adler-Graschinsky E. Cannabinoids as therapeutic agents in cardiovascular disease: a tale of passions and illusions. British Journal of Pharmacology. 2007;151:427–440
  9. Di Marzo V. Targeting the endocannabinoid system: to enhance or reduce?. Nature Reviews. Drug Discovery. 2008;7:438–455
  10. Harrold JA, Williams G. The cannabinoid system: a role in both the homeostatic and hedonic control of eating?. The British Journal of Nutrition. 2003;90:729–734
  11. Matias I, Gonthier MP, Orlando P, et al. Regulation, function, and dysregulation of endocannabinoids in models of adipose and β-pancreatic cells and in obesity and hyperglycemia. The Journal of Clinical Endocrinology and Metabolism. 2006;91:3171–3180
  12. Pagano C, Rossato M, Vettor R. Endocannabinoids, adipose tissue and lipid metabolism. Journal of Neuroendocrinology. 2008;20(Suppl. 1):124–129
  13. Massa F, Storr M, Lutz B. The endocannabinoid system in the physiology and pathophysiology of the gastrointestinal tract. Journal of Molecular Medicine. 2005;83:944–954
  14. Kunos G, Osei-Hyiaman D. Endocannabinoids and liver disease. IV. Endocannabinoid involvement in obesity and hepatic steatosis. American Journal of Physiology. Gastrointestinal and Liver Physiology. 2008;294:G1101–G1104
  15. Cavuoto P, McAinch AJ, Hatzinikolas G, et al. Effects of cannabinoid receptors on skeletal muscle oxidative pathways. Molecular and Cellular Endocrinology. 2007;267:63–69
  16. Bermudez-Silva FJ, Suarez J, Baixeras E, et al. Presence of functional cannabinoid receptors in human endocrine pancreas. Diabetologia. 2008;51:476–487
  17. Lafontan M, Piazza PV, Girard J. Effects of CB1 antagonist on the control of metabolic functions in obese type 2 diabetic patients. Diabetes & Metabolism. 2007;33:85–95
  18. Nogueiras R, Rohner-Jeanrenaud F, Woods SC, et al. The endocannabinoid system and the control of glucose homeostasis. Journal of Neuroendocrinology. 2008;20(Suppl. 1):147–151
  19. Scheen AJ, Paquot N. Inhibitors of cannabinoid receptors and glucose metabolism. Current Opinion in Clinical Nutrition and Metabolic Care. 2008;11:505–511
  20. Isoldi KK, Aronne LJ. The challenge of treating obesity: the endocannabinoid system as a potential target. Journal of the American Dietetic Association. 2008;108:823–831
  21. Perkins JM, Davis SN. Endocannabinoid system overactivity and the metabolic syndrome: prospects for treatment. Current Diabetes Reports. 2008;8:12–19
  22. Vemuri VK, Janero DR, Makriyannis A. Pharmacotherapeutic targeting of the endocannabinoid signaling system: drugs for obesity and the metabolic syndrome. Physiology & Behavior. 2008;93:671–686
  23. Szmitko PE, Verma S. The endocannabinoid system and cardiometabolic risk. Atherosclerosis. 2008;199:248–256
  24. Scheen AJ. CB1 blockade, insulin resistance and type 2 diabetes. In: Desprès JP & Di Marzo V (eds.). Abdominal obesity and the endocannabinoid system. in press.
  25. Christensen R, Kristensen PK, Bartels EM, et al. Efficacy and safety of the weight-loss drug rimonabant: a meta-analysis of randomised trials. Lancet. 2007;370:1706–1713
  26. Van Gaal LF, Pi-Sunyer X, Després JP, et al. Efficacy and safety of rimonabant for improvement of multiple cardiometabolic risk factors in overweight/obese patients: pooled 1-year data from the RIO program. Diabetes Care. 2008;31(Suppl. 2):S229–S240
  27. Scheen AJ, Paquot N, Castillo MJ, et al. How to measure insulin action in vivo. Diabetes/Metabolism Reviews. 1994;10:151–188
  28. Engeli S. Dysregulation of the endocannabinoid system in obesity. Journal of Neuroendocrinology. 2008;20(Suppl. 1):110–115
  29. Bluher M, Engeli S, Kloting N, et al. Dysregulation of the peripheral and adipose tissue endocannabinoid system in human abdominal obesity. Diabetes. 2006;55:3053–3060
  30. Cote M, Matias I, Lemieux I, et al. Circulating endocannabinoid levels, abdominal adiposity and related cardiometabolic risk factors in obese men. International Journal of Obesity. 2007;31:692–699
  31. D'Eon TM, Pierce KA, Roix JJ, et al. The role of adipocyte insulin resistance in the pathogenesis of obesity-related elevations in endocannabinoids. Diabetes. 2008;57:1262–1268
  32. Pacher P, Batkai S, Kunos G. The endocannabioid system as an emerging target of pharmacotherapy. Pharmacological Reviews. 2006;58:389–462
  33. Pertwee RG. Inverse agonism and neutral antagonism at cannabinoid CB1 receptors. Life Sciences. 2005;76:1307–1324
  34. Xie S, Furjanic MA, Ferrara JJ, et al. The endocannabinoid system and rimonabant: a new drug with a novel mechanism of action involving cannabinoid CB1 receptor antagonism – or inverse agonism – as potential obesity treatment and other therapeutic use. Journal of Clinical Pharmacy and Therapeutics. 2007;32:209–231
  35. Curioni C, Andre C. Rimonabant for overweight or obesity. Cochrane Database of Systematic Reviews. 2006;4:4
  36. Gelfand EV, Cannon CP. Rimonabant: a selective blocker of the cannabinoid CB1 receptors for the management of obesity, smoking cessation and cardiometabolic risk factors. Expert Opinion on Investigational Drugs. 2006;15:307–315
  37. Available from: http://www.emea.eu.int/humandocs/Humans/EPAR/acomplia/acomplia.htm.
  38. Hagmann WK. The discovery of taranabant, a selective cannabinoid-1 receptor inverse agonist for the treatment of obesity. Archiv der Pharmazie. 2008;341:405–411
  39. Addy C, Wright H, Van Laere K, et al. The acyclic CB1R inverse agonist taranabant mediates weight loss by increasing energy expenditure and decreasing caloric intake. Cell Metabolism. 2008;7:68–78
  40. Scheen AJ. CB1 receptor blockade and its impact on cardiometabolic risk factors: overview of the RIO programme with rimonabant. Journal of Neuroendocrinology. 2008;20(Suppl. 1):139–146
  41. Van Gaal LF, Rissanen AM, Scheen AJ, et al. 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. 2005;365:1389–1397
  42. Van Gaal LF, Scheen AJ, Rissanen AM, et al. Long-term effect of CB1 blockade with rimonabant on cardiometabolic risk factors: 2-year results from the RIO-Europe study. European Heart Journal. 2008;29:1761–1771
  43. Pi-Sunyer FX, Aronne LJ, Heshmati HM, et al. 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 : The Journal of the American Medical Association. 2006;295:761–775
  44. Després JP, Golay A, Sjöström L, Rimonabant in Obesity-Lipids Study Group . Effects on metabolic risk factors in overweight patients with dyslipidemia. The New England Journal of Medicine. 2005;353:2121–2134
  45. Scheen AJ, Finer N, Hollander P, et al., for the RIO-Diabetes Study Group  Efficacy and tolerability of rimonabant in overweight or obese patients with type 2 diabetes: a randomised controlled study. Lancet. 2006;368:1660–1672
  46. Scheen AJ. Cannabinoid-1 receptor antagonists in type-2 diabetes. Best Practice & Research. Clinical Endocrinology & Metabolism. 2007;21:535–553
  47. Lihn AS, Pedersen SB, Richelsen B. Adiponectin: action, regulation and association to insulin sensitivity. Obesity Reviews. 2005;6:13–21
  48. Scheen AJ, Paquot N, Van Gaal LF. Inhibition des récepteurs CB1 et métabolisme du glucose: rimonabant dans le diabète de type 2. Revue Médicale Suisse. 2008;4:1812–1817
  49. Després JP. ADAGIO-Lipids: an international study of rimonabant in Dyslipidemia with AtheroGenic risk In abdominally obese patients. Late breaking presentation, 77th European Atherosclerosis Society Congress, April 29th, 2008, Istanbul, Turkey.
  50. Rosenstock J. The potential of rimonabant in prediabetes: pooled 1-year results from the RIO-Lipids, RIO-Europe and RIO- North America studies. [abstract] Diabetologia. 2005;48(Suppl. 1):A16;37
  51. Scheen AJ, Van Gaal LF, Després JP. Efficacy of rimonabant in improving glucose tolerance in overweight/obese non-diabetic patients: analysis of pooled data from the randomised placebo-controlled RIO-Lipids and RIO-Europe studies. Submitted for publication.
  52. Scheen A, Van Gaal L, for the RIO-Europe Study Group . Long-term efficacy of rimonabant in improving glucose tolerance in overweight/obese non-diabetic patients: 2-year results from RIO-Europe. [abstract] Diabetes. 2008;57(Suppl. 1):A1;101-OR
  53. Scheen AJ. Current management strategies for coexisting diabetes mellitus and obesity. Drugs. 2003;63:1165–1184
  54. Scheen AJ. Diabetes, obesity, and metabolic syndrome. In:  Meckling KA editors. Nutrient-drug interactions. Boca Raton, FL, US: CRC Press Taylor & Francis; 2007;p. 1–30
  55. Scheen AJ. Antidiabetic agents in subjects with mild dysglycaemia: prevention or early treatment of type 2 diabetes?. Diabetes & Metabolism. 2007;33:3–12
  56. Scheen AJ, Ernest Ph. Antiobesity treatment in type 2 diabetes: results of clinical trials with orlistat and sibutramine. Diabetes & Metabolism. 2002;28:437–445
  57. Rucker D, Padwal R, Li SK, et al. Long term pharmacotherapy for obesity and overweight: updated meta-analysis. BMJ (Clinical Research Ed.). 2007;335:1194–1199
  58. Bloomgarden ZT, Dodis R, Viscoli CM, et al. Lower baseline glycemia reduces apparent oral agent glucose-lowering efficacy. A meta-regression analysis. Diabetes Care. 2006;29:2137–2139
  59. Rosenstock J, Iranmanesh A, Hollander PA. Improved glycemic control with weight loss plus beneficial effects on atherogenic dyslipidemia with rimonabant in drug-naïve type 2 diabetes: the SERENADE trial. [abstract] Diabetes. 2007;56(Suppl. 1):A49–A50
  60. Hollander PA, Amod A, Litwak LE. Rimonabant improves glycemic control in insulin-treated type 2 diabetes: the ARPEGGIO trial. [abstract] Diabetes. 2008;57(Suppl. 1):A95
  61. Nissen SE, Nicholls SJ, Wolski K, et al. Effect of rimonabant on progression of atherosclerosis in patients with abdominal obesity and coronary artery disease. The STRADIVARIUS randomized controlled trial. JAMA : The Journal of the American Medical Association. 2008;299:1547–1560
  62. Scheen AJ. The endocannabinoid system, a promising target for the management of type 2 diabetes. Current Protein & Peptide Science, in press.
  63. Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults . 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. 2002;106:3143–3421
  64. Barter P, Gotto AM, LaRosa JC, et al., Treating to New Targets Investigators  HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. The New England Journal of Medicine. 2007;357:1301–1310
  65. Després JP, Lemieux I, Bergeron J, et al. Abdominal obesity and the metabolic syndrome: contribution to global cardiometabolic risk. Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:1039–1049
  66. Després JP, Van Gaal L, Scheen A, et al. Rimonabant improves cardiometabolic risk factors in overweight/obese patients irrespective of treatment with statins: pooled data from the RIO program. [abstract] Atherosclerosis. 2006;(Suppl. 7):329
  67. Després JP, Lemieux I. Abdominal obesity and metabolic syndrome. Nature. 2006;444:881–887
  68. Van Gaal LF, Mertens IL, De Block CE. Mechanisms linking obesity with cardiovascular disease. Nature. 2006;444:875–880
  69. Ruilope LM, Després JP, Scheen A, et al. Effect of rimonabant on blood pressure in overweight/obese patients with/without co-morbidities: analysis of pooled Rimonabant In Obesity (RIO) study results. Journal of Hypertension. 2007;26:357–367
  70. Scheen A, Van Gaal L. The CB1 blocker rimonabant reduces liver enzyme levels in overweight/obese people with type 2 diabetes: the RIO diabetes study. [abstract] Diabetic Medicine. 2006;23(Suppl. 4):251–252A685
  71. Luyckx FH, Scheen AJ, Lefèbvre PJ. Non-alcoholic steatohepatitis: association with obesity and insulin resistance, and influence of weight loss. Diabetes & Metabolism. 2000;26:98–106
  72. McFarlane SI, Banerji M, Sowers JR. Insulin resistance and cardiovascular disease. The Journal of Clinical Endocrinology and Metabolism. 2001;86:713–718
  73. Yki-Järvinen H. Fat in the liver and insulin resistance. Annals of Medicine. 2005;37:347–356
  74. Ridker PM. Inflammatory biomarkers and risks of myocardial infarction, stroke, diabetes, and total mortality: implications for longevity. Nutrition Reviews. 2007;65(Pt 2):S253–S259
  75. Bifulco M, Grimaldi C, Gazzerro P, et al. Rimonabant: just an anti-obesity drug? Current evidence on its pleiotropic effects. Molecular Pharmacology. 2007;71:1445–1456
  76. Scheen AJ. The future of obesity: new drugs versus lifestyle interventions?. [Editorial] Expert Opinion on Investigational Drugs. 2008;17:263–267
  77. CRESCENDO Comprehensive Rimonabant Evaluation Study of Cardiovascular ENDpoints and Outcomes . Available from: http://www.clinicaltrials.gov/ct/show/NCT00263042?order=2[accessed 1.02.07]

PII: S1521-690X(08)00098-5

doi: 10.1016/j.beem.2008.09.001

Best Practice & Research Clinical Endocrinology & Metabolism
Volume 23, Issue 1 , Pages 103-116 , February 2009

Article Tools

* Image Usage & Resolution