Drug Safety

, Volume 36, Issue 8, pp 643–649 | Cite as

Risk of Bladder Cancer in Diabetic Patients Treated with Rosiglitazone or Pioglitazone: A Nested Case–Control Study

  • Fei-Yuan HsiaoEmail author
  • Pei-Hua Hsieh
  • Weng-Foung Huang
  • Yi-Wen Tsai
  • Churn-Shiouh GauEmail author
Original Research Article



Evidence has emerged that pioglitazone may increase the risk of bladder cancer, but the association has not been confirmed. This potential risk also has not been evaluated in users of rosiglitazone.


Using Taiwan’s National Health Insurance Research Database (NHIRD), this large population-based nested case–control study was conducted to explore the relationship between the use of rosiglitazone or pioglitazone and risk of bladder cancer in diabetic patients.


We identified 3,412 cases of newly diagnosed bladder cancer and 17,060 controls (1:5 matched by age and sex) among a diabetic patient cohort from the NHIRD. We defined an index date for each case as the date of first hospitalization for bladder cancer. Each control was assigned the index date of their corresponding case. Multivariable conditional logistic regressions were used to estimate the association between exposure (timing and duration) to rosiglitazone or pioglitazone and bladder cancer. We defined rosiglitazone or pioglitazone exposure as “current” if the prescription duration covered the index date or ended at 90 days before, as “recent” if it ended 91–180 days before the index date, or as “past” if the last prescription ended more than 180 days before. Duration of rosiglitazone or pioglitazone use was defined based on the cumulative days of exposure prior to the index date: <1, 1–2 and ≥2 years.


Rosiglitazone and pioglitazone use were associated with risk of bladder cancer and the associations were stronger with a longer term of exposure (pioglitazone <1 year odds ratio [OR] 1.45 [95 % CI 1.12–1.87, p < 0.01], 1–2 years OR 1.74 [95 % CI 1.05–2.90, p = 0.03] and ≥2 years OR 2.93 [95 % CI 1.59–5.38, p < 0.01]; rosiglitazone <1 year OR 0.98 [95 % CI 0.82–1.17, p = 0.81], 1–2 years OR 1.78 [95 % CI 1.31–2.39, p < 0.01] and ≥2 years OR 2.00 [95 % CI 1.37–2.92, p < 0.01]).


Long-term exposures to pioglitazone and rosiglitazone were associated with higher odds of bladder cancer, and the highest odds were seen in users with ≥2 years of exposure.


Chronic Obstructive Pulmonary Disease Bladder Cancer Rosiglitazone Pioglitazone Index Date 
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We thank the Bureau of National Health Insurance (BNHI) and National Health Research Institutes (NHRI) for making available the databases for this study. The content of this article, however, in no way represents any official position of the BNHI or NHRI. The authors bear all responsibility for the results and interpretation of the results. We thank Dr. C. Daniel Mullins of the University of Maryland and Dr. Susan Shur-Fen Gau of the National Taiwan University for providing consultation and assistance with the revised manuscript.

Author contributions

Dr F.Y. Hsiao, Ms P.H. Hsieh and Dr C.S. Gau were responsible for development of the study concept and design and the preparation of the manuscript. Dr F.Y. Hsiao and Ms P.H. Hsieh contributed to data acquisition and statistical analysis. All authors participated in the analysis and interpretation of the data of the manuscript. This manuscript has been read and approved by all authors.

Financial support

No sources of funding were used to conduct this study or prepare this manuscript.

Conflict of interest

Pei-Hua Hsieh received a part-time research assistantship from a research project (DOH100-FDA-41100) sponsored by the Food and Drug Administration, Taiwan. Fei-Yuan Hsiao, Weng-Foung Huang, Yi-Wen Tsai and Churn-Shiouh Gau have no conflicts of interest to declare that are directly relevant to the content of this study.


  1. 1.
    Dormandy J, Bhattacharya M, van Troostenburg de Bruyn AR. Safety and tolerability of pioglitazone in high-risk patients with type 2 diabetes: an overview of data from PROactive. Drug Saf. 2009;32(3):187–202.PubMedCrossRefGoogle Scholar
  2. 2.
    Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, Massi-Benedetti M, Moules IK, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet. 2005;366(9493):1279–89.PubMedCrossRefGoogle Scholar
  3. 3.
    Azoulay L, Yin H, Filion KB, Assayag J, Majdan A, Pollak MN, et al. The use of pioglitazone and the risk of bladder cancer in people with type 2 diabetes: nested case–control study. BMJ. 2012;344:e3645.PubMedCrossRefGoogle Scholar
  4. 4.
    Lewis JD, Ferrara A, Peng T, Hedderson M, Bilker WB, Quesenberry CP Jr, et al. Risk of bladder cancer among diabetic patients treated with pioglitazone: interim report of a longitudinal cohort study. Diabetes Care. 2011;34(4):916–22.PubMedCrossRefGoogle Scholar
  5. 5.
    Neumann A, Weill A, Ricordeau P, Fagot JP, Alla F, Allemand H. Pioglitazone and risk of bladder cancer among diabetic patients in France: a population-based cohort study. Diabetologia. 2012;55(7):1953–62.PubMedCrossRefGoogle Scholar
  6. 6.
    Tseng CH. Pioglitazone and bladder cancer: a population-based study of Taiwanese. Diabetes Care. 2012;35(2):278–80.PubMedCrossRefGoogle Scholar
  7. 7.
    Piccinni C, Motola D, Marchesini G, Poluzzi E. Assessing the association of pioglitazone use and bladder cancer through drug adverse event reporting. Diabetes Care. 2011;34(6):1369–71.PubMedCrossRefGoogle Scholar
  8. 8.
    Mamtani R, Haynes K, Bilker WB, Vaughn DJ, Strom BL, Glanz K, et al. Association between longer therapy with thiazolidinediones and risk of bladder cancer: a cohort study. J Natl Cancer Inst. 2012;104(18):1411–21.PubMedCrossRefGoogle Scholar
  9. 9.
    Centers for Disease Control and Prevention. International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM). (Accessed 15 March 2013).
  10. 10.
    Hsiao FY, Yang CL, Huang YT, Huang WF. Using Taiwan’s national health insurance research databases for pharmacoepidemiology research. J Food Drug Anal. 2007;15(2):99–108.Google Scholar
  11. 11.
    Chang JS, Tsai CR, Tsai YW, Wiemels JL. Medically diagnosed infections and risk of childhood leukaemia: a population-based case–control study. Int J Epidemiol. 2012;41(4):1050–9.PubMedCrossRefGoogle Scholar
  12. 12.
    Chen YM, Chen DY, Chen LK, Tsai YW, Chang LC, Huang WF, et al. Alendronate and risk of esophageal cancer: a nationwide population-based study in Taiwan. J Am Geriatr Soc. 2011;59(12):2379–81.PubMedCrossRefGoogle Scholar
  13. 13.
    Yoshimura R, Matsuyama M, Segawa Y, Hase T, Mitsuhashi M, Tsuchida K, et al. Expression of peroxisome proliferator-activated receptors (PPARs) in human urinary bladder carcinoma and growth inhibition by its agonists. Int J Cancer. 2003;104(5):597–602.PubMedCrossRefGoogle Scholar
  14. 14.
    Nakashiro KI, Hayashi Y, Kita A, Tamatani T, Chlenski A, Usuda N, et al. Role of peroxisome proliferator-activated receptor gamma and its ligands in non-neoplastic and neoplastic human urothelial cells. Am J Pathol. 2001;159(2):591–7.PubMedCrossRefGoogle Scholar
  15. 15.
    Chaffer CL, Thomas DM, Thompson EW, Williams ED. PPARgamma-independent induction of growth arrest and apoptosis in prostate and bladder carcinoma. BMC Cancer. 2006;6:53.PubMedCrossRefGoogle Scholar
  16. 16.
    Suzuki S, Arnold LL, Pennington KL, Kakiuchi-Kiyota S, Wei M, Wanibuchi H, et al. Effects of pioglitazone, a peroxisome proliferator-activated receptor gamma agonist, on the urine and urothelium of the rat. Toxicol Sci. 2010;113(2):349–57.PubMedCrossRefGoogle Scholar
  17. 17.
    Sato K, Awasaki Y, Kandori H, Tanakamaru ZY, Nagai H, Baron D, et al. Suppressive effects of acid-forming diet against the tumorigenic potential of pioglitazone hydrochloride in the urinary bladder of male rats. Toxicol Appl Pharmacol. 2011;251(3):234–44.PubMedCrossRefGoogle Scholar
  18. 18.
    Diamant M, Heine RJ. Thiazolidinediones in type 2 diabetes mellitus: current clinical evidence. Drugs. 2003;63:1373–405.PubMedCrossRefGoogle Scholar
  19. 19.
    Burea of National Health Insurance, Taiwan. Special medical needs: catastrophic illness patients. (Accessed 15 May 2012).
  20. 20.
    Yang XL, Ma RC, So WY, Kong AP, Xu G, Chan JC. Addressing different biases in analysing drug use on cancer risk in diabetes in non-clinical trial settings—what, why and how? Diabetes Obes Metab. 2012;14(7):579–85.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2013

Authors and Affiliations

  1. 1.Graduate Institute of Clinical Pharmacy, College of MedicineNational Taiwan UniversityTaipeiTaiwan
  2. 2.Institute of Health and Welfare PolicyNational Yang-Ming UniversityTaipeiTaiwan
  3. 3.Center for Drug EvaluationTaipeiTaiwan
  4. 4.Food and Drug Administration, Department of HealthExecutive YuanTaiwan

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