Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Paper
  • Published:

A randomized double-blind placebo-controlled study of the long-term efficacy and safety of topiramate in the treatment of obese subjects

International Journal of Obesity volume 28, pages 1399–1410 (2004)Cite this article

Abstract

BACKGROUND: Treatment of obese subjects with topiramate has recently been associated with significant weight loss in a 6-month dose-ranging study.

OBJECTIVE: To investigate the long-term efficacy and safety of topiramate in obese subjects.

DESIGN: Randomised, double-blind, placebo-controlled study investigating three doses of topiramate: 96, 192, and 256 mg/day. All subjects also participated in a nonpharmacological weight-loss programme.

SUBJECTS: The study included 1289 subjects 18–75 y with a body mass index ≥30 kg/m2 and <50 kg/m2 in the absence of comorbidities, or ≥27 kg/m2 and <50 kg/m2 in the presence of controlled hypertension and/or dyslipidaemia.

DURATION: The original study design was for a 6-week, single-blind, placebo run-in phase followed by an 8-week titration phase and 2 y of maintenance at the assigned dose. Sponsor ended study early in order to develop a new controlled-release formulation with the potential to enhance tolerability and simplify dosing in this patient population. Therefore, none of the subjects completed the full 2 y of treatment. Efficacy results are based on subjects who were enrolled early enough to have had an opportunity to complete 1 y at their assigned dose (modified intent-to-treat population, MITT) before learning of the decision to terminate the study. Safety results are based on all subjects who took at least one dose of study medication.

RESULTS: The safety population consisted of 1282 subjects, and the MITT efficacy population was 854 subjects. At 60 weeks, subjects in the placebo group lost 1.7% of their baseline body weight, while subjects in the topiramate 96, 192, and 256 mg/day treatment groups lost 7.0, 9.1, and 9.7%, respectively (P<0.001, MITT, last observation carried forward). Weight loss ≥5% of baseline weight was achieved by 18% of subjects in the placebo arm vs 54, 61, and 67% of subjects receiving topiramate 96, 192, and 256 mg/day, respectively; weight loss ≥10% was achieved by 6 vs 29, 40, and 44%, respectively (P<0.001). Weight loss was accompanied by significant improvements in blood pressure (systolic/diastolic changes of +0.4/+1.0, −3.1/−1.3, −5.7/−3.4, and −4.6/−2.4 mmHg were observed for placebo, topiramate 96 mg/day, 192 mg/day, and 256 mg/day, respectively, P<0.001) and glucose and insulin. The most common adverse events more frequently observed in topiramate-treated subjects occurred mostly during the titration phase and were related to the central or peripheral nervous system and included paresthesia, difficulty with concentration/attention, depression, difficulty with memory, language problems, nervousness, and psychomotor slowing.

CONCLUSION: Topiramate treatment of obese subjects over the course of 1 y resulted in clinically significant weight loss. Improvements were also observed in blood pressure and glucose tolerance.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. James PT, Leach R, Kalamara E, Shayeghi M . The worldwide obesity epidemic. Obes Res 2001; 9 (Suppl 4): S228–S233.

    Article  Google Scholar 

  2. Seidell JC . Obesity, insulin resistance and diabetes—a worldwide epidemic. Br J Nutr 2000; 83 (Suppl 1): S5–S8.

    CAS  Google Scholar 

  3. Mokdad AH, Bowman BA, Ford ES, Vinicor F, Marks JS, Koplan JP . The continuing epidemics of diabetes and obesity in the United States. JAMA 2001; 286: 1195–1200.

    Article  CAS  Google Scholar 

  4. Flegal KM, Carroll MD, Ogden CL, Johnson CL . Prevalence and trends in obesity among US adults, 1999–2000. JAMA 2002; 288: 1723–1727.

    Article  Google Scholar 

  5. National Task Force on the Prevention and Treatment of Obesity. Overweight, obesity, and health risk. Arch Intern Med 2000; 160: 898–904.

  6. Garrison RJ, Castelli WP . Weight and thirty-year mortality of men in the Framingham Study. Ann Intern Med 1985; 103: 1006–1009.

    Article  CAS  Google Scholar 

  7. Allison DB, Fontaine KR, Manson JE, Stevens J, VanItallie TB . Annual deaths attributable to obesity in the United States. JAMA 1999; 282: 1530–1538.

    Article  CAS  Google Scholar 

  8. Resnick HE, Valsania P, Halter JB, Lin X . Relation of weight gain and weight loss on subsequent diabetes risk in overweight adults. J Epidemiol Community Health 2000; 54: 596–602.

    Article  CAS  Google Scholar 

  9. Brown CD, Higgins M, Donato KA, Rohde FC, Garrison R, Obarzanek E, Ernst ND, Horan M . Body mass index and the prevalence of hypertension and dyslipidemia. Obes Res 2000; 8: 605–619.

    Article  CAS  Google Scholar 

  10. Kaufman JS, Durazo-Arvizu RA, Rotimi CN, McGee DL, Cooper RS, for the Investigators of the International Collaborative Study on Hypertension in Blacks. Obesity and hypertension prevalence in populations of African origin. Epidemiology 1996; 7: 398–405.

    Article  CAS  Google Scholar 

  11. Rimm EB, Stampfer MJ, Giovannucci E, Ascherio A, Spiegelman D, Colditz GA, Willett WC . Body size and fat distribution as predictors of coronary heart disease among middle-aged and older US men. Am J Epidemiol 1995; 141: 1117–1127.

    Article  CAS  Google Scholar 

  12. Rexrode KM, Hennekens CH, Willett WC, Colditz GA, Stampfer MJ, Rich-Edwards JW, Speizer FE, Manson JE . A prospective study of body mass index, weight change, and risk of stroke in women. JAMA 1997; 277: 1539–1545.

    Article  CAS  Google Scholar 

  13. Hochberg MC, Lethbridge-Cejku M, Scott Jr WW, Reichle R, Plato CC, Tobin JD . The association of body weight, body fatness and body fat distribution with osteoarthritis of the knee: data from the Baltimore Longitudinal Study of Aging. J Rheumatol 1995; 22: 488–493.

    CAS  PubMed  Google Scholar 

  14. Tuomilehto J, Lindström J, Eriksson JG, Valle TT, Hämäläinen H, Ilanne-Parikka P, Keinänen-Kiukaanniemi S, Laakso M, Louheranta A, Rastas M, Salminen V, Uusitupa M, for the Finnish Diabetes Prevention Study Group. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001; 344: 1343–1350.

    Article  CAS  Google Scholar 

  15. Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002; 346: 393–403.

  16. Cutler JA . Randomized clinical trials of weight reduction in nonhypertensive persons. Ann Epidemiol 1991; 1: 363–370.

    Article  CAS  Google Scholar 

  17. Ard JD, Rosati R, Oddone EZ . Culturally-sensitive weight loss program produces significant reduction in weight, blood pressure, and cholesterol in eight weeks. J Natl Med Assoc 2000; 92: 515–523.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Topiramate (Topamax®) tablets. Physicians' Desk Reference. Medical Economics Co., Inc: Montvale, NJ; 2002. pp 2590–2595.

  19. Richard D, Ferland J, Lalonde J, Samson P, Deshaies Y . Influence of topiramate in the regulation of energy balance. Nutrition 2000; 16: 961–966.

    Article  CAS  Google Scholar 

  20. Bray GA, Hollander P, Klein S, Kushner R, Levy B, Fitchet M, Perry BH, for the US Topiramate Research Group. A 6-month randomized, placebo-controlled dose-ranging trial of topiramate for weight loss in obesity. Obes Res 2003; 11: 722–733.

    Article  CAS  Google Scholar 

  21. Energy and protein requirements: report of a Joint FAO/WHO/UNU Expert Consultation. Technical report series no. 724. World Health Organization: Geneva; 1985. p 71.

  22. Dunnett CW, Tamhane AC . Step-down multiple tests for comparing treatments with a control in unbalanced one-way layouts. Stat Med 1991; 10: 939–947.

    Article  CAS  Google Scholar 

  23. Wirth A, Krause J . Long-term weight loss with sibutramine: a randomized controlled trial. JAMA 2001; 286: 1331–1339.

    Article  CAS  Google Scholar 

  24. Smith IG, Goulder MA, on behalf of the Members of the Sibutramine Clinical Study 1047 Team. Randomized placebo-controlled trial of long-term treatment with sibutramine in mild to moderate obesity. J Fam Pract 2001; 50: 505–512.

    CAS  PubMed  Google Scholar 

  25. Davidson MH, Hauptman J, DiGirolamo M, Foreyt JP, Halsted CH, Heber D, Heimburger DC, Lucas CP, Robbins DC, Chung J, Heymsfield SB . Weight control and risk factor reduction in obese subjects treated for 2 years with orlistat: a randomized controlled trial. JAMA 1999; 281: 235–242.

    Article  CAS  Google Scholar 

  26. Torgerson JS, Hauptman J, Boldrin MN, Sjostrom L . 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 2004; 27: 155–161.

    Article  CAS  Google Scholar 

  27. Sjostrom L, Rissanen A, Andersen T, Boldrin M, Golay A, Koppeschaar HP, Krempf M . Randomised placebo-controlled trial of orlistat for weight loss and prevention of weight regain in obese patients. European Multicentre Orlistat Study Group. Lancet 1998; 352: 167–172.

    Article  CAS  Google Scholar 

  28. James WP, Astrup A, Finer N, Hilsted J, Kopelman P, Rossner S, Saris WH, Van Gaal LF . Effect of sibutramine on weight maintenance after weight loss: a randomised trial. STORM Study Group. Sibutramine Trial of Obesity Reduction and Maintenance. Lancet 2000; 356: 2119–2125.

    Article  CAS  Google Scholar 

  29. Bray GA, Blackburn GL, Ferguson JM, Greenway FL, Jain AK, Mendel CM, Mendels J, Ryan DH, Schwartz SL, Scheinbaum ML, Seaton TB . Sibutramine produces dose-related weight loss. Obes Res 1999; 7: 189–198.

    Article  CAS  Google Scholar 

  30. Carpenter KM, Hasin DS, Allison DB, Faith MS . Relationships between obesity and DSM-IV major depressive disorder, suicide ideation, and suicide attempts: results from a general population study. Am J Public Health 2000; 90: 251–257.

    Article  CAS  Google Scholar 

  31. Picard F, Deshaies Y, Lalonde J, Samson P, Richard D . Topiramate reduces energy and fat gains in lean (Fa/?) and obese (fa/fa) Zucker rats. Obes Res 2000; 8: 656–663.

    Article  CAS  Google Scholar 

  32. York DA, Singer L, Thomas S, Bray GA . Effect of topiramate on body weight and body composition of Osborne–Mendel rats fed a high-fat diet: alterations in hormones, neuropeptide, and uncoupling-protein mRNAs. Nutrition 2000; 16: 967–975.

    Article  CAS  Google Scholar 

  33. Richard D, Picard F, Lemieux C, Lalonde J, Samson P, Deshaies Y . The effects of topiramate and sex hormones on energy balance of male and female rats. Int J Obes Relat Metab Disord 2002; 26: 344–353.

    Article  CAS  Google Scholar 

  34. White HS, Brown SD, Woodhead JH, Skeen GA, Wolf HH . Topiramate enhances GABA-mediated chloride flux and GABA-evoked chloride currents in murine brain neurons and increases seizure threshold. Epilepsy Res 1997; 28: 167–179.

    Article  CAS  Google Scholar 

  35. Gibbs III JW, Sombati S, DeLorenzo RJ, Coulter DA . Cellular actions of topiramate: blockade of kainate-evoked inward currents in cultured hippocampal neurons. Epilepsia 2000; 41 (Suppl 1): S10–S16.

    Article  CAS  Google Scholar 

  36. Taverna S, Sancini G, Mantegazza M, Franceschetti S, Avanzini G . Inhibition of transient and persistent Na+ current fractions by the new anticonvulsant topiramate. J Pharmacol Exp Ther 1999; 288: 960–968.

    CAS  PubMed  Google Scholar 

  37. Dodgson SJ, Shank RP, Maryanoff BE . Topiramate as an inhibitor of carbonic anhydrase isoenzymes. Epilepsia 2000; 41 (Suppl 1): S35–S39.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This trial was supported by Johnson & Johnson Pharmaceutical Research and Development, LLC. The members of the OBES-002 Study Group are: Dammann, Hanns-Gerd, Hamburg, Germany; Ditschuneit, Herwig H, Ulm, Germany; Eichler, Hans Georg, Vienna, Austria; Elte, Jan Willem, Rotterdam, The Netherlands; Finer, Nicholas, Luton, UK; Foerster, Hanns-Michael, Duisburg Baerl, Germany; Hamann, Andreas, Heidelberg, Germany; Hanefeld, Markolf, Dresden, Germany; Häring, Hans-Ulrich, Tübingen, Germany; Hoppichler, Friedrich, Salzburg, Austria; Klör, Hans-Ulrich, Giessen, Germany; Kopelman, Peter, London, UK; Laederach-Hofmann, Kurt, Bern, Switzerland; Lean, Michael, Glasgow, UK; Mathus-Vliegen, Elisabeth, Amsterdam, The Netherlands; Moore, Ray, Kwa-Zulu Natal, South Africa; Mustajoki, Pertti, Helsinki, Finland; Niskanen, Leo, Kuopio, Finland; Prager, Rudolf, Vienna, Austria; Rissanen, Aila, Helsinki, Finland; Rössner, Stephan, Huddinge, Sweden; Scheen, André, Sart Tilman, Liège, Belgium; Scheen, André, Quai Godefroid Kurth, Liège, Belgium; Sharma, Ayra Mitra, Berlin, Germany; Sjöström, Lars, Göteborg, Sweden; Usadel, Klaus-Henning, Frankfurt, Germany; Van der Merwe, Maria Teresa, Johannesburg, South Africa; Van Gaal, Luc, Edegem, Belgium; Wilding, John, Liverpool, UK; Zietz, Bettina, Regensburg, Germany.

Author information

Authors and Affiliations

  1. Diabetes and Endocrinology Research Group, Clinical Sciences Centre, University Hospital Aintree, Liverpool, UK

    J Wilding

  2. Department of Endocrinology, University Hospital, Antwerp, Belgium

    L Van Gaal

  3. Obesity Research Unit, Helsinki University Hospital, Helsinki, Finland

    A Rissanen

  4. Johnson & Johnson Pharmaceutical Research and Development, Beerse, Belgium

    F Vercruysse

  5. Johnson & Johnson Pharmaceutical Research and Development, Raritan, NJ, USA

    M Fitchet

Authors
  1. J Wilding
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. L Van Gaal
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A Rissanen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. F Vercruysse
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M Fitchet
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

for the OBES-002 Study Group

Corresponding author

Correspondence to J Wilding.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wilding, J., Gaal, L., Rissanen, A. et al. A randomized double-blind placebo-controlled study of the long-term efficacy and safety of topiramate in the treatment of obese subjects. Int J Obes 28, 1399–1410 (2004). https://doi.org/10.1038/sj.ijo.0802783

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.ijo.0802783

Keywords

This article is cited by

Search

Advanced search

Quick links