Skip Navigation
Skip to contents

Diabetes Metab J : Diabetes & Metabolism Journal

Search
OPEN ACCESS

Articles

Page Path
HOME > Diabetes Metab J > Volume 36(6); 2012 > Article
Letter
Letter: The Risk of Bladder Cancer in Korean Diabetic Subjects Treated with Pioglitazone (Diabetes Metab J 2012;36:371-8)
Sang-Yong Kim
Diabetes & Metabolism Journal 2012;36(6):460-461.
DOI: https://doi.org/10.4093/dmj.2012.36.6.460
Published online: December 12, 2012
  • 2,945 Views
  • 25 Download
  • 1 Crossref
  • 1 Scopus

Division of Endocrinology and Metabolism, Chosun University School of Medicine, Gwangju, Korea.

Corresponding author: Sang Yong Kim. Department of Internal Medicine, Chosun University Hospital, 365 Pilmun-daero, Dong-gu, Gwangju 501-717, Korea. diabetes@chosun.ac.kr

Copyright © 2012 Korean Diabetes Association

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Type 2 diabetes mellitus is characterized by insulin resistance as well as progressive pancreatic β-cell dysfunction. Thiazolidinediones (TZDs) are a class of hypoglycemic medications that influence insulin sensitivity in peripheral tissue [1]. Pioglitazone is a TZD, peroxisome proliferator-activated receptor (PPAR)-γ ligand used in the treatment of type 2 diabetic patients [2].
Many preclinical trials have demonstrated that PPAR-γ is a potential molecular target for the development of bladder cancer. Yoshimura et al. [3] found PPAR-γ mRNA in bladder cancer samples. Furthermore, immunohistochemistry revealed that the protein expression of PPAR-γ was significantly higher with increasing grade and increasing stage of bladder cancer [3]. In male rats exposed to muraglitazar, a dual human PAPR-α/γ agonist, there was a dose-related increased incidence of transitional cell papilloma and carcinoma of the urinary bladder [4]. Lubet et al. [5] also reported that another PPAR-γ agonist, rosiglitazone, enhanced bladder tumors in rats pretreated with N-(4-hydroxybutyl)-N-(butyl)-nitrosamine (BBN), a known DNA-reactive bladder carcinogen in several species. However, the mechanisms underlying this pro-tumor potential of pioglitazone for bladder cancer are not fully understood.
In the large prospective pioglitazone clinical trial in macrovascular events (PROactive) study, 14 bladder cancers occurred in the pioglitazone arm (0.5%) versus 6 in the placebo arm (0.2%) [6], and in September 2010, the U.S. Food and Drug Administration (FDA) announced an ongoing investigation on the possible risk in humans [7]. In July 2011, the European Medicines Agency issued a warning about the potential for bladder cancer with pioglitazone [8]. Subsequent studies also suggested that pioglitazone treatment appears to be associated with a significantly increased risk of bladder cancer in patients with type 2 diabetes [9,10]. However, meta-analysis has demonstrated that this association was not significant [11,12].
Song et al. recently reported the risk of bladder cancer in Korean diabetic patients treated with pioglitazone. In this study, development of bladder cancer in Korean diabetic patients was more related to smoking and hemoglobin level rather than pioglitazone use. However, odds ratio of pioglitazone use was relatively high, although it was not significant (2.09, P=0.484). Many factors may be related to this difference between Caucasian and Korean patients. As noted by the authors, ethnic and dose differences may be important factors between Korean and Caucasian studies. In addition, concomitant drug use could be possible confounding factor in those studies. Because pioglitazone is a second-line drug after metformin in the Korean medication system, pioglitazone users usually administer metformin concomitantly. Although the mechanisms underlying the protective potential of metformin are not completely understood, many population studies have shown that metformin is associated with a significant reduction of cancer incidence in general [13]. Also, in contrast to the many Western diabetic patients who receive pioglitazone with insulin, only limited Korean patients use pioglitazone with insulin.
Although it is unable to clearly exclude the possibility of a relationship between pioglitazone and bladder cancer, this study provides the meaningful result that the risk of bladder cancer in Korean diabetic patients treated with pioglitazone might be different from that of Caucasians. Pioglitazone is effective in reducing blood glucose and is the only useful TZD that improves insulin sensitivity. However, all therapeutic choices need to be based on the balance of potential risks and benefits. Treatment decisions are not always easy and are best achieved when considering all available evidence. Because the authors are currently analyzing the data from 3,500 patients with bladder cancer across several university hospitals, this result will provide a more definitive conclusion about the relationship between pioglitazone and bladder cancer in Korean diabetic patients.

No potential conflict of interest relevant to this article was reported.

  • 1. Yki-Jarvinen H. Thiazolidinediones. N Engl J Med 2004;351:1106-1118. ArticlePubMed
  • 2. Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, Zinman B. American Diabetes Association. European Association for Study of Diabetes. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2009;32:193-203. ArticlePubMedPMCPDF
  • 3. Yoshimura R, Matsuyama M, Segawa Y, Hase T, Mitsuhashi M, Tsuchida K, Wada S, Kawahito Y, Sano H, Nakatani T. Expression of peroxisome proliferator-activated receptors (PPARs) in human urinary bladder carcinoma and growth inhibition by its agonists. Int J Cancer 2003;104:597-602. ArticlePubMed
  • 4. Tannehill-Gregg SH, Sanderson TP, Minnema D, Voelker R, Ulland B, Cohen SM, Arnold LL, Schilling BE, Waites CR, Dominick MA. Rodent carcinogenicity profile of the antidiabetic dual PPAR alpha and gamma agonist muraglitazar. Toxicol Sci 2007;98:258-270. PubMed
  • 5. Lubet RA, Fischer SM, Steele VE, Juliana MM, Desmond R, Grubbs CJ. Rosiglitazone, a PPAR gamma agonist: potent promoter of hydroxybutyl(butyl)nitrosamine-induced urinary bladder cancers. Int J Cancer 2008;123:2254-2259. ArticlePubMed
  • 6. Dormandy J, Bhattacharya M, van Troostenburg. Safety and tolerability of pioglitazone in high-risk patients with type 2 diabetes: an overview of data from PROactive. Drug Saf 2009;32:187-202. PubMed
  • 7. U.S. Food and Drug Administration. FDA drug safety communication: ongoing safety review of actos (pioglitazone) and potential increased risk of bladder cancer after two years exposure updated 2010 Sep 17. Available from: http://www.fda.gov/Drugs/DrugSafety/ucm226214.htm.
  • 8. European Medicines Agency. European Medicines Agency recommends new contraindications and warnings for pioglitazone to reduce small increased risk of bladder cancer updated 2011 Jul 21. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2011/07/WC500109176.pdf.
  • 9. Zhu Z, Shen Z, Lu Y, Zhong S, Xu C. Increased risk of bladder cancer with pioglitazone therapy in patients with diabetes: a meta-analysis. Diabetes Res Clin Pract 2012;98:159-163. ArticlePubMed
  • 10. Mamtani R, Haynes K, Bilker WB, Vaughn DJ, Strom BL, Glanz K, Lewis JD. Association between longer therapy with thiazolidinediones and risk of bladder cancer: a cohort study. J Natl Cancer Inst 2012;104:1411-1421. ArticlePubMedPMC
  • 11. Colmers IN, Bowker SL, Johnson JA. Thiazolidinedione use and cancer incidence in type 2 diabetes: a systematic review and meta-analysis. Diabetes Metab 2012 Epub 2012 Oct 4. DOI: 10.1016/j.diabet.2012.06.003.Article
  • 12. Tseng CH. Pioglitazone and bladder cancer: a population-based study of Taiwanese. Diabetes Care 2012;35:278-280. PubMedPMC
  • 13. Papanas N, Maltezos E, Mikhailidis DP. Metformin and cancer: licence to heal? Expert Opin Investig Drugs 2010;19:913-917.ArticlePubMed

Figure & Data

References

    Citations

    Citations to this article as recorded by  
    • Thiazolidinedione drugs in the treatment of type 2 diabetes mellitus: past, present and future
      Melissa A. Davidson, Donald R. Mattison, Laurent Azoulay, Daniel Krewski
      Critical Reviews in Toxicology.2018; 48(1): 52.     CrossRef

    • PubReader PubReader
    • Cite this Article
      Cite this Article
      export Copy Download
      Close
      Download Citation
      Download a citation file in RIS format that can be imported by all major citation management software, including EndNote, ProCite, RefWorks, and Reference Manager.

      Format:
      • RIS — For EndNote, ProCite, RefWorks, and most other reference management software
      • BibTeX — For JabRef, BibDesk, and other BibTeX-specific software
      Include:
      • Citation for the content below
      Letter: The Risk of Bladder Cancer in Korean Diabetic Subjects Treated with Pioglitazone (Diabetes Metab J 2012;36:371-8)
      Diabetes Metab J. 2012;36(6):460-461.   Published online December 12, 2012
      Close
    • XML DownloadXML Download
    Kim SY. Letter: The Risk of Bladder Cancer in Korean Diabetic Subjects Treated with Pioglitazone (Diabetes Metab J 2012;36:371-8). Diabetes Metab J. 2012;36(6):460-461.
    DOI: https://doi.org/10.4093/dmj.2012.36.6.460.

    Diabetes Metab J : Diabetes & Metabolism Journal
    Close layer