Pioglitazone use and risk of bladder cancer: a systematic literature review and meta-analysis of observational studies
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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.
KeywordsBladder cancer Meta-analysis Pioglitazone Review Observational studies
This study was sponsored by Takeda Pharmaceuticals Company Limited.
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.
This systematic literature review does not involve any animal or human subjects, including research on identifiable human material and data.
- 1.World Health Organization. Global Report on Diabetes. 2016. http://apps.who.int/iris/bitstream/10665/204871/1/9789241565257_eng.pdf?ua=1. Accessed 23 Aug 2016.
- 2.Centers for Disease Control and Prevention. National Diabetes Statistics Report: Estimates of Diabetes and Its Burden in the United States, 2014. http://www.cdc.gov/diabetes/pubs/statsreport14/national-diabetes-report-web.pdf. Accessed 23 Aug 2016.
- 10.Takeda Pharmaceuticals America, Inc. Actos (Pioglitazone Hydrochloride) Tablets: Full Prescribing Information. 2009. http://www.actos.com/actospro/home.aspx. Accessed 12 Aug 2016.
- 37.Shapiro S. Causation, bias and confounding: a hitchhiker’s guide to the epidemiological galaxy part 2. Principles of causality in epidemiological research: confounding, effect modification and strength of association. J Fam Plann Reprod Health Care. 2008;34:185–90. https://doi.org/10.1783/147118908784734873.CrossRefPubMedGoogle Scholar
- 48.Lewis JD, Habel L, Quesenberry C, et al. Proteinuria testing among patients with diabetes mellitus is associated with bladder cancer diagnosis: potential for unmeasured confounding in studies of pioglitazone and bladder cancer: proteinuria and bladder cancer diagnosis. Pharmacoepidemiol Drug Saf. 2014;23:636–45. https://doi.org/10.1002/pds.3619.CrossRefPubMedGoogle Scholar