Diabetology International

, Volume 10, Issue 1, pp 24–36 | Cite as

Pioglitazone use and risk of bladder cancer: a systematic literature review and meta-analysis of observational studies

  • Juha Mehtälä
  • Houssem Khanfir
  • Dimitri Bennett
  • Yizhou Ye
  • Pasi Korhonen
  • Fabian HotiEmail author
Original Article



Studies investigating bladder cancer risk in pioglitazone-treated type 2 diabetes mellitus patients report conflicting results. Previous meta-analyses on this topic utilized publications prior to 2013. More long-term observational studies have been published since then. We reviewed the accumulated evidence and updated findings from previous meta-analyses.


This meta-analysis was based on a systematic review of peer-reviewed observational studies published prior to September 30, 2016. Eligible studies were identified using a specified MEDLINE search. References from included studies and from previous meta-analyses were screened for additional records. Meta-analysis hazards ratios were derived using a random-effects model. Several sensitivity analyses including hierarchical Bayesian meta-analysis with country-specific effects were conducted.


Of 363 identified records, 23 studies were included in this review and 18 in the actual meta-analyses. For bladder cancer outcome, the estimated effect size for ever vs. never use of pioglitazone was 1.16 [95% confidence interval (CI), 1.04–1.28]. In the cumulative dose and duration analyses, highest effect was observed in the highest/longest exposure group, but substantial heterogeneity was present. In the sensitivity analysis, only studies adjusted for lifestyle-related factors were included and the frequentist effect size was 1.18 (95% CI, 1.00–1.40, p = 0.054). However, the risk was not verified in the Bayesian framework with an effect size of 1.17 [95% credible interval (CrI), 0.94–1.54].


In line with previous meta-analyses, we observed a small but statistically significant association between ever (vs. never) use of pioglitazone and bladder cancer risk; however, causality is not established and alternative explanations cannot be ruled out.


Bladder cancer Meta-analysis Pioglitazone Review Observational studies 



This study was sponsored by Takeda Pharmaceuticals Company Limited.

Author contributions

DB and YY conceived and designed the study and wrote a first protocol outline. JM, HK, PK, and FH critically reviewed the outline and developed a full protocol. JM, HK, PK, YY, and FH participated in the development of the literature search strategy, conducted literature search, and abstracted and compiled the data. JM, HK, PK, and FH performed the analyses. All authors participated in the discussion and interpretation of the study findings. JM, HK, PK, and FH drafted the manuscript. All authors critically reviewed, revised, and approved the final version submitted for publication.

Compliance with ethical standards

Conflict of interest

YY and DB are employees of Takeda Pharmaceutical Company Limited. JM, HK, FH, and PK are employees of EPID Research Oy, which is a contract research organization that performs commissioned pharmacoepidemiologic studies, and thus its employees have been and currently are working in collaboration with several pharmaceutical companies.

Ethics approval

This systematic literature review does not involve any animal or human subjects, including research on identifiable human material and data.

Supplementary material

13340_2018_360_MOESM1_ESM.docx (767 kb)
Supplementary material 1 (DOCX 766 kb)


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Copyright information

© The Japan Diabetes Society 2018

Authors and Affiliations

  1. 1.EPID Research OyEspooFinland
  2. 2.Takeda Pharmaceutical Company LimitedCambridgeUSA

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