Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
권호 표지
DOI QR코드

DOI QR Code

Pharmacological Therapies of Obesity: A Review of Current Treatment Options

  • Bacher, H.Peter (Abbott Laboratories, Department of Global Research and Development) ;
  • Shepherd, Gillian M. (Abbott Laboratories, Department of Global Research and Development) ;
  • Legler, Udo F. (Abbott GmbH & Co. KG, Department of Global Research and Development)
  • Published : 2009.10.31
Download PDF
⟨ Previous Next ⟩

Abstract

Over the last decade, the incidence of overweight and obesity has nearly doubled in many countries and is considered a pandemic. Obesity was identified as a major risk factor for cardiovascular disease as the same level as smoking and diabetes. Visceral fat is considered one of the key contributors to outcome and certain ethnic groups such as Asians seem to be more affected than others. Weight reduction through lifestyle changes was found to be impactful to improve overall health, but weight loss and maintenance thereof is limited and difficult to sustain. Surgical intervention demonstrated a greater weight loss in the severely obese and was associated with improved all-cause mortality. Despite numerous pharmacological targets and a high medical need, only few drugs have been successfully developed. Earlier studies with amphetamine-derived compounds showed significant weight loss but their critical safety profiles led to market withdrawals and disappointment. More recent compounds; orlistat - a lipase inhibitor, rimonabant - a cannaboid-1-receptor antagonist, and sibutramine - a combined serotonin/norepinephrine re-uptake inhibitor, all demonstrated similar significant efficacy; however, they carry specific safety profiles making them unsuitable for every patient. The main limitation of pharmacotherapy is the absence of clear benefit-risk assessments through outcome studies. Such a study - the SCOUT trial - was designed to compare sibutramine versus placebo and the effect on morbidity and mortality in nearly 10,000 obese patients with additional risk factors. Such studies could provide new scientific evidence for obesity treatment and may support future pharmacological approaches.

Keywords

References

  1. Birkenfeld, A. L., Schroeder, C., Boschmann, M., Tank, J., Franke, G., Luft, F. C., Biaggioni, I., Sharma, A. M. and Jordan, J. (2002). Paradoxical effect of sibutramine on autonomic cardiovascular regulation. Circulation 106, 2459-2465. https://doi.org/10.1161/01.CIR.0000036370.31856.73
  2. Christensen, R., Kristensen, P. K., Bartels, E. M., Bliddal, H. and Astrup, A. (2007). Efficacy and safety of the weight-loss drug rimonabant: a meta-analysis of randomised trials. Lancet 370, 1706-1713. https://doi.org/10.1016/S0140-6736(07)61721-8
  3. Cota, D., Marsicano, G., Tschop, M., Grubler, Y., Flachskamm, C., Schubert, M., Auer, D., Yassouridis, A., Thone-Reineke, C., Ortmann, S., Tomassoni, F., Cervino, C., Nisoli, E., Linthorst, A. C. E., Pasquali, R., Lutz, B., Stalla, G. K. and Pagotto, U. (2003). The endogenous cannabinoid system affects energy balance via central orixegenic drive and peripheral lipogenesis. J. Clin. Invest. 112, 423-431. https://doi.org/10.1172/JCI17725.
  4. Després, J. P., Golay, A. and Sjöström, L. for the Rimonabant in Obesity-Lipids Study Group. (2005). Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N. Engl. J. Med., 353, 2121-2134. https://doi.org/10.1056/NEJMoa044537
  5. Eriksson, K. F. and Lindgarde, F. (1998). No excess 12-year mortality in men with impaired glucose tolerance who participated in the Malmo Preventive Trial with diet and exercise. Diabetologia 41, 1010-1016. https://doi.org/10.1007/s001250051024
  6. F.D.A. U.S. Food and Drug Administration Center for Drug Evaluation and Research. (1997). F.D.A. Analysis of Cardiac Valvular Dysfunction with Use of Appetite Suppressants. Available: http://www.fda.gov/cder/news/slides/index.htm [1997, Sep 17].
  7. Guerciolini, R. (1997). Mode of action of orlistat. Int. J. Obes. Relat. Metab. Disord. 21(Suppl 3), S12-23.
  8. Halford, J. C. G., Boyland, E. J., Cooper, S. J., Dovey, T. M., Huda, M. S. B., Dourish, C. T., Dawson, G. R. and Wilding, J. P. H. (2008). The effects of sibutramine on the microstructure of eating behaviour and energy expenditure in obese women. J. Psychopharmacology 1-11 (e-pub ahead of print). https://doi.org/10.1177/0269881108095195
  9. Hansen, D. L., Toubro, S., Stock, M. J., Macdonald, A. I. and Astrup, A. (1999). The effect of sibutramine on energy expenditure and appetite during chronic treatment without dietary restriction. Int. J. Obes. Relat. Metab. Disord., 23, 1016-1024. https://doi.org/10.1038/sj.ijo.0801059
  10. Hauner, H., Meier, M., Wendland, G., Kurscheid T., Lauterbach, K. and S.A.T. Study Group. (2004). Weight reduction by sibutramine in obese subjects in primary care medicine: the SAT Study. Exp. Clin. Endocrinol. Diabetes 112, 201-207. https://doi.org/10.1055/s-2004-817934
  11. Heusser, K., Tank, J., Diedrich, A., Engeli, S., Klaua, S., Krüger, N., Strauss, A., Stoffels, G., Luft, F. C. and Jordan, J. (2006). Influence of sibutramine treatment on sympathetic vasomotor tone in obese subjects. Clin. Pharmacol. Ther., 79, 500-508. https://doi.org/10.1016/j.clpt.2006.02.002
  12. Huxley, R., James, W. P., Barzi, F., Patel, J.V., Lear, S. A., Suriyawongpaisal, P., Janus E, Caterson, I., Zimmet, P., Prabhakaran, D., Reddy, S., Woodward, M. and The Obesity in Asia Collaboration. (2008). Obes. Reviews 9, S1, 53-61. https://doi.org/10.1111/j.1467-789X.2007.00439.x
  13. James, W. P. T., Astrup, A., Finer, N., Hilsted, J., Kopelman, P., Rössner, S., Saris, W. H. M. and Van Gaal, L. F. for the STORM Study Group. (2000). Effect of sibutramine on weight maintenance after weight loss: a randomised trial. Lancet 356, 2119-2125. https://doi.org/10.1016/S0140-6736(00)03491-7
  14. Lopez, A. D., Mathers, C. D., Ezzati, M., Jamison, D. T., Murray, C. L. J., (Eds.). (2006). Global Burden of Disease and Risk Factors. New York. Oxford University Press.
  15. McNulty, S. J., Ur, E. and Williams, G. for The Multicenter Sibutramine Study Group. (2003). A randomized trial of sibutramine in the management of obese type 2 diabetic patients treated with metformin. Diabetes Care 26, 125-131. https://doi.org/10.2337/diacare.26.1.125
  16. Neal, B., Chapman, N. and Patel, A. (2002). Managing the global burden of cardiovascular disease. Eur. Heart J., 4 (Suppl F), F2-F6. https://doi.org/10.1016/S1520-765X(02)90022-2
  17. Orexigen Company Press Release. (2009). Available at: http://ir.orexigen.com/phoenix.zhtml?c=207034&p=irolnewsArticle&ID=1308920&highlight=obesity.
  18. Padwal, R. S. and Majumdar, S. R. (2007). Drug treatments for obesity: orlistat, sibutramine, and rimonabant. Lancet 369, 71-77. https://doi.org/10.1016/S0140-6736(07)60033-6
  19. Pi-Sunyer, F. X., Aronne, L. J., Heshmati, H. M., Devin, J. and Rosenstock, J. for the RIO-North America Study Group. (2006). 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. J. Am. Med. Assoc., 295, 761-775. https://doi.org/10.1001/jama.295.7.761
  20. Prospective Studies Collaboration. (2009). Body-mass index and cause-specific mortality in 900 000 adults: collaborative analyses of 57 prospective studies. Lancet 373, 1083-1096. https://doi.org/10.1016/S0140-6736(09)60318-4
  21. Scheen, A. J., Finer, N., Hollander, P., Jensen, M. D. and Van Gaal, L. F. for the RIO-Diabetes Study Group. (2006). Efficacy and tolerability of rimonabant in overweight or obese patients with type 2 diabetes: a randomized controlled study. Lancet 368, 1660-1672. https://doi.org/10.1016/S0140-6736(06)69571-8
  22. Sjostrom, L., Narbro, K., Sjostrom, C.D., Karason, K., Larsson, B., Wedel, H., Lystig, T., Sullivan, M., Bouchard, C., Carlsson, B., Bengtsson, C., Dahlgren, S., Gummesson, A., Jacobson, P., Karlsson, J., Lindroos, A. K., Lonroth, H., Naslund, I., Olbers, T., Stenlof, K., Torgerson, J., Agren, G. and Carlsson, L. M. S. for the Swedish Obese Subjects Study. (2007). Effects of bariatric surgery on mortality in Swedish obese subjects. N. Engl. J. Med., 357, 741-752. https://doi.org/10.1056/NEJMoa066254
  23. Sjostrom, L., Rissanen, A., Andersen, T., Boldrin, M., Golay, A., Koppeschaar, H. P. and Krempf, M. (1998). Randomised placebo-controlled trial of orlistat for weight loss and prevention of weight regain in obese patients. European Multicentre Orlistat Study Group Lancet 352, 167-172. https://doi.org/10.1016/S0140-6736(97)11509-4
  24. Torgerson, J. S., Hauptman, J., Boldrin, M. N. and Sjöström, L. (2004). XENical in the Prevention of Diabetes in Obese Subjects (XENDOS) Study. A randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients. Diabetes Care 27, 155-161. https://doi.org/10.2337/diacare.27.1.155
  25. Walsh, K. M., Leen, E. and Lean, M.E. (1999). The effect of sibutramine on resting energy expenditure and adrenalineinduced thermogenesis in obese females. Int. J. Obes. Relat. Metab. Disord., 23, 1009-1015. https://doi.org/10.1038/sj.ijo.0801045
  26. W.H.O. Expert Consultation. (2004). Appropriate body-mass index for Asian populations and its implications for policy and intervention strategies. Lancet 363, 157-163. https://doi.org/10.1016/S0140-6736(03)15268-3
  27. Yusuf, S., Hawken, S., Ounpuu, S., Bautista, L., Franzosi, M. G., Commerford, P., Lang, C. C., Rumboldt, Z., Onen, C. L., Lisheng, L., Tanomsup, S., Wangai P., Razak, F., Sharma, A. M. and Anand, S. S. on behalf of the INTERHEART Study Investigators. (2005). Obesity and the risk of myocardial infarction in 27 000 participants from 52 countries: a case-control study. Lancet 366, 1640-1649. https://doi.org/10.1016/S0140-6736(05)67663-5
  28. Yusuf, S., Hawken, S., Ounpuu, S., Dans, T., Avezum, A., Lanas, F., McQueen, M., Budaj, A., Pais, P., Varigos, J. and Lisheng, L. on behalf of the INTERHEART Study Investigators. (2004). Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 364 (9438), 937-952. https://doi.org/10.1016/S0140-6736(04)17018-9

Cited by

  1. Food Ingredients as Anti-Obesity Agents: A Review vol.53, pp.9, 2013, https://doi.org/10.1080/10408398.2011.574215