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.

  • Original Article
  • Published:

A clinical trial assessing the safety and efficacy of the CB1R inverse agonist taranabant in obese and overweight patients: low-dose study

Abstract

Objective:

To evaluate the weight loss efficacy, safety and tolerability of taranabant, a CB1R inverse agonist, in obese and overweight patients.

Design:

Multicenter, double-blind, randomized, placebo-controlled study.

Subjects:

Patients 18 years old, BMI 27–43 kg m−2, were randomized to placebo (n=209) or taranabant 0.5 mg (n=207), 1 mg (n=208) or 2 mg given orally once daily (n=417) for 52 weeks.

Measurements:

Key efficacy measurements included body weight (BW), waist circumference (WC), lipid endpoints and glycemic endpoints.

Results:

Based on a last observation carried forward analysis of the all-patients-treated population, mean change in BW for taranabant 0.5, 1, and 2 mg and placebo was −5.4, −5.3, −6.7 and −1.7 kg, respectively (P<0.001 for all doses vs placebo). The proportions of patients who lost at least 5 and 10% of their baseline BW at week 52 were significantly higher for all taranabant doses vs placebo (P<0.001 for all doses). Reductions in WC, percentage of body fat, and triglycerides were significant for taranabant 2 mg and in triglycerides for taranabant 1 mg vs placebo. There was no effect of taranabant vs placebo on other lipid or glucose-related endpoints. Incidences of adverse experiences classified in the gastrointestinal (diarrhea and nausea), nervous system (dizziness/dizziness postural), psychiatric-related (irritability and anger/aggression) and vascular (flushing/hot flush) organ systems were higher and statistically significant in the taranabant 2-mg group compared with the placebo group. Irritability was higher and statistically significant in all taranabant groups compared with the placebo group.

Conclusion:

All three doses of taranabant-induced clinically meaningful and statistically significant weight loss. Incidences of adverse experiences in organ systems known to express CB1R were higher in taranabant groups.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Clinical guidelines on the identification, evaluation treatment of overweight obesity in adults—the evidence report national institutes of health. Obes Res 1998; 6 (Suppl 2): 51S–209S.

  2. WHO. Obesity:preventing and managing the global epidemic. Report of a WHO consultant. World Health Organ Tech Rep Ser 2000 2008; 894: 1–253.

    Google Scholar 

  3. Bray GA . Medical Mangement of Obesity. In: Bray GA, Bouchard C. (eds). Handbook of Obesity: Clinical Applications. Informa Healthcare: New York, NY, 2008. pp 227–484.

    Chapter  Google Scholar 

  4. Li Z, Maglione M, Tu W, Mojica W, Arterburn D, Shugarman LR et al. Meta-analysis: pharmacologic treatment of obesity. Ann Intern Med 2005; 142: 532–546.

    Article  CAS  PubMed  Google Scholar 

  5. Despres JP, Golay A, Sjostrom L . Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med 2005; 353: 2121–2134.

    Article  CAS  PubMed  Google Scholar 

  6. Pi-Sunyer FX, Aronne LJ, Heshmati HM, Devin J, Rosenstock J . 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 2006; 295: 761–775.

    Article  CAS  PubMed  Google Scholar 

  7. Rucker D, Padwal R, Li SK, Curioni C, Lau DC . Long term pharmacotherapy for obesity and overweight: updated meta-analysis. BMJ 2007; 335: 1194–1199.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Scheen AJ, Finer N, Hollander P, Jensen MD, Van Gaal LF . Efficacy and tolerability of rimonabant in overweight or obese patients with type 2 diabetes: a randomised controlled study. Lancet 2006; 368: 1660–1672.

    Article  CAS  PubMed  Google Scholar 

  9. Van Gaal LF, Rissanen AM, Scheen AJ, Ziegler O, Rossner 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 2005; 365: 1389–1397.

    Article  CAS  PubMed  Google Scholar 

  10. Van Gaal LF, Scheen AJ, Rissanen AM, Rossner S, Hanotin C, Ziegler O . Long-term effect of CB1 blockade with rimonabant on cardiometabolic risk factors: two year results from the RIO-Europe Study. Eur Heart J 2008; 29: 1761–1771.

    Article  CAS  PubMed  Google Scholar 

  11. Addy C, Wright H, Van Laere K, Gantz I, Erondu N, Musser BJ et al. The acyclic CB1R inverse agonist taranabant mediates weight loss by increasing energy expenditure and decreasing caloric intake. Cell Metab 2008; 7: 68–78.

    Article  CAS  PubMed  Google Scholar 

  12. Kroenke K, Spitzer RL, Williams JB . The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med 2001; 16: 606–613.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Addy C, Cote J, Li S, Agrawal N, Majumdar A, Li H et al. Taranbant plasma concentrations are increased when co-administered with ketoconazole or ditiazem. Obesity, Program Abstract Supplement 2007; A147.

  14. Keller SD, Bayliss MS, Ware Jr JE, Hsu MA, Damiano AM, Goss TF . Comparison of responses to SF-36volume: health survey questions with one-week and four-week recall periods. Health Serv Res 1997; 32: 367–384.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Kolotkin RL, Crosby RD, Kosloski KD, Williams GR . Development of a brief measure to assess quality of life in obesity. Obes Res 2001; 9: 102–111.

    Article  CAS  PubMed  Google Scholar 

  16. Wechsler D . WAIS-III WMS-III Technical Manual. The Psychological Corporations, Harcout Brace and Company: San Antonia, TX, 1997.

    Google Scholar 

  17. McNair DM, Lorr M, Droppleman LF . Manual for the Profile of Mood States (POMS). Educational and Industrial Testing Service: San Diego, CA, 1971.

    Google Scholar 

  18. Spitzer RL, Kroenke K, Williams JB . Validation and utility of a self-report version of PRIME-MD: the PHQ primary care study. primary care evaluation of mental disorders patient health questionnaire. JAMA 1999; 282: 1737–1744.

    Article  CAS  PubMed  Google Scholar 

  19. Department of Health Human Services Public Health Service Food Drug Administration Center for Drug Evaluation Research Memorandum N12. Overview for December Meeting of Psychopharmacologic Drug Advisory Committee (PDAC) Appendix 2 Request to Sponsors—Advice for the pharmaceutical industry in exploring their placebo-controlled clinical trials databases for suicidality and preparing data sets for analysis by FDA. http://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4272b1-01-FDA.pdf 2006; 128–137.

  20. Posner K, Oquendo MA, Gould M, Stanley B, Davies M . Columbia classification algorithm of suicide assessment (C-CASA): classification of suicidal events in the FDA's pediatric suicidal risk analysis of antidepressants. Am J Psychiatry 2007; 164: 1035–1043.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Katz A, Nambi SS, Mather K, Baron AD, Follmann DA, Sullivan G et al. Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans. J Clin Endocrinol Metab 2000; 85/7: 2402–2410.

    Article  Google Scholar 

  22. Aronne LJ, Tonstad S, Moreno M, Gantz I, Erondu N, Suryawanshi S et al. A clinical trial assessing the safety and efficacy of taranabant, a CB1R inverse agonist, in obese and overweight patients: a high-dose study. Int J Obesity 2010 (in press).

Download references

Acknowledgements

We thank the staff and patients at the 72 clinical sites who participated in the clinical trial. We thank Carol Yacik, Barry Gumbiner and Bret Musser for their contributions to the taranabant clinical program, Ira Gantz for his contribution to the taranabant program and critical review of the article, and Kathleen Newcomb and Catherine Phillips for their help in the preparation of the article. We also extend our appreciation to the Data Safety and Monitoring Committee members, Julie Buring, SC D, Daniel Heijtan, Ph D, Edward Horton, MD (Chair), Robert Josse, MD, and Robert Spitzer, MD.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to J Proietto.

Ethics declarations

Competing interests

The study was funded by Merck & Co. The authors JBH, NE, QY, SS, MEJ, AOJ-L, SBH, KDK and JMA are employees of Merck & Co. Inc., and may hold stock in that company. JP is a member of a Merck Diabetes and Obesity Global Expert Committee.

Additional information

Supplementary Information accompanies the paper on International Journal of Obesity website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Proietto, J., Rissanen, A., Harp, J. et al. A clinical trial assessing the safety and efficacy of the CB1R inverse agonist taranabant in obese and overweight patients: low-dose study. Int J Obes 34, 1243–1254 (2010). https://doi.org/10.1038/ijo.2010.38

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ijo.2010.38

Keywords

This article is cited by

Search

Quick links