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CB1 antagonists for obesity—what lessons have we learned from rimonabant?

Abstract

When compared with other modifiable cardiovascular risk factors, such as hypertension, dyslipidemia and smoking, obesity remains a surprisingly puzzling condition to prevent and treat. The history of the development of anti-obesity drugs has known more defeats than even partial victories. With very few drugs on the market, and bad publicity related to adverse events, obesity remains an almost completely unmet challenge for the pharmaceutical industry. In light of past experience with endocannabinoid-system antagonists, such as rimonabant, we propose that a major paradigm shift in clinical practice might be necessary to justify the use of pharmacotherapy for obesity. Furthermore, we suggest that the criteria currently used by regulatory authorities to evaluate and approve anti-obesity drugs should be rigorously re-examined. Finally, we discuss how pharmacological approaches that aim to counteract overactivity of the endocannabinoid system should be revisited in the future to treat visceral (intra-abdominal) obesity and its metabolic consequences.

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Figure 1: Endocannabinoid biosynthesis, action and inactivation.

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References

  1. Howlett, A. C. et al. Cannabinoid physiology and pharmacology: 30 years of progress. Neuropharmacology 47 (Suppl. 1), 345–358 (2004).

    Article  CAS  Google Scholar 

  2. Devane, W. A. et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258, 1946–1949 (1992).

    Article  CAS  Google Scholar 

  3. Di Marzo, V. The endocannabinoid system in obesity and type 2 diabetes. Diabetologia 51, 1356–1367 (2008).

    Article  CAS  Google Scholar 

  4. Foltin, R. W., Brady, J. V. & Fischman, M. W. Behavioral analysis of marijuana effects on food intake in humans. Pharmacol. Biochem. Behav. 25, 577–582 (1986).

    Article  CAS  Google Scholar 

  5. Van Gaal, L. F. 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 365, 1389–1397 (2005).

    Article  CAS  Google Scholar 

  6. Després, J. P. et al. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N. Engl. J. Med. 353, 2121–2134 (2005).

    Article  Google Scholar 

  7. Scheen, A. J. et al. Efficacy and tolerability of rimonabant in overweight or obese patients with type 2 diabetes: a randomised controlled study. Lancet 368, 1660–1672 (2006).

    Article  CAS  Google Scholar 

  8. Pi-Sunyer, F. X. 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 295, 761–775 (2006).

    Article  CAS  Google Scholar 

  9. Cahill, K. & Ussher, M. Cannabinoid type 1 receptor antagonists (rimonabant) for smoking cessation. Cochrane Database of Systematic Reviews, Issue 3. Art. No.: CD005353 10.1002/14651858.CD005353.pub3 (2009).

    Google Scholar 

  10. Prospective Studies Collaboration. Body-mass index and cause-specific mortality in 900,000 adults: collaborative analyzes of 57 prospective studies. Lancet 373, 1083–1096 (2009).

  11. Després, J. P. & Lemieux, I. Abdominal obesity and metabolic syndrome. Nature 444, 881–887 (2006).

    Article  Google Scholar 

  12. Després, J. P. et al. Abdominal obesity and the metabolic syndrome: contribution to global cardiometabolic risk. Arterioscler. Thromb. Vasc. Biol. 28, 1039–1049 (2008).

    Article  Google Scholar 

  13. Després, J. P., Lemieux, I. & Prud'homme, D. Treatment of obesity: need to focus on high risk abdominally obese patients. BMJ 322, 716–720 (2001).

    Article  Google Scholar 

  14. Després, J. P. Drug treatment for obesity. We need more studies in men at higher risk of coronary events. BMJ 322, 1379–1380 (2001).

    Article  Google Scholar 

  15. Rucker, D., Padwal, R., Li, S. K., Curioni, C. & Lau, D. C. Long term pharmacotherapy for obesity and overweight: updated meta-analysis. BMJ 335, 1194–1199 (2007).

    Article  CAS  Google Scholar 

  16. Ritchie, S. A. & Connell, J. M. The link between abdominal obesity, metabolic syndrome and cardiovascular disease. Nutr. Metab. Cardiovasc. Dis. 17, 319–326 (2007).

    Article  CAS  Google Scholar 

  17. Fabricatore, A. N. et al. Attrition from randomized controlled trials of pharmacological weight loss agents: a systematic review and analysis. Obes. Rev. 10, 333–341 (2009).

    Article  CAS  Google Scholar 

  18. Blüher, M. et al. Dysregulation of the peripheral and adipose tissue endocannabinoid system in human abdominal obesity. Diabetes 55, 3053–3060 (2006).

    Article  Google Scholar 

  19. Di Marzo, V. et al. Changes in plasma endocannabinoid levels in viscerally obese men following a 1 year lifestyle modification program and waist circumference reduction: associations with changes in metabolic risk factors. Diabetologia 52, 213–217 (2009).

    Article  CAS  Google Scholar 

  20. Nissen, S. E. et al. Effect of rimonabant on progression of atherosclerosis in patients with abdominal obesity and coronary artery disease: the STRADIVARIUS randomized controlled trial. JAMA 299, 1547–1560 (2008).

    Article  CAS  Google Scholar 

  21. Carr, R. D. et al. A two-year study to assess the efficacy, safety, and tolerability of taranabant in obese patients: 52 week results. Atherosclerosis 9, 12 (2008).

    Article  Google Scholar 

  22. Pacher, P. & Steffens, S. The emerging role of the endocannabinoid system in cardiovascular disease. Semin. Immunopathol. 31, 63–77 (2009).

    Article  CAS  Google Scholar 

  23. Van Gaal, L. F. et al. Long-term effect of CB1 blockade with rimonabant on cardiometabolic risk factors: two year results from the RIO-Europe Study. Eur. Heart J. 29, 1761–1771 (2008).

    Article  CAS  Google Scholar 

  24. Osei-Hyiaman, D. et al. Hepatic CB1 receptor is required for development of diet-induced steatosis, dyslipidemia, and insulin and leptin resistance in mice. J. Clin. Invest. 118, 3160–3169 (2008).

    Article  CAS  Google Scholar 

  25. Buettner, C. et al. Leptin controls adipose tissue lipogenesis via central, STAT3-independent mechanisms. Nat. Med. 14, 667–675 (2008).

    Article  CAS  Google Scholar 

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Acknowledgements

The authors thank Isabelle Lemieux (Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec, Canada) for valuable help during preparation of the manuscript.

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Correspondence to Vincenzo Di Marzo.

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Competing interests

Vincenzo Di Marzo has declared associations with the following companies: GW Pharmaceuticals (consultant and research support) and Sanofi-Aventis (speakers bureau and research support).

Jean-Pierre Després has declared associations with the following companies: Abbott Laboratories (speakers bureau), AstraZeneca (speakers bureau), Eli Lilly (research support), GlaxoSmithKline (speakers bureau and research support), INNODIA (consultant), Merck Sharp & Dohme (consultant), Novartis (consultant), Pfizer Canada (speakers bureau), Sanofi-Aventis (consultant, speakers bureau and research support) and Solvay (speakers bureau).

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Di Marzo, V., Després, JP. CB1 antagonists for obesity—what lessons have we learned from rimonabant?. Nat Rev Endocrinol 5, 633–638 (2009). https://doi.org/10.1038/nrendo.2009.197

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