Pioglitazone and bladder cancer risk: a multipopulation pooled, cumulative exposure analysis

Daniel Levin, Samira Bell (Lead / Corresponding author), Reijo Sund, Sirpa A. Hartikainen, Jaakko Tuomilehto, Eero Pukkala, Ilmo Keskimäki, Ellena Badrick, Andrew G. Renehan, Iain E. Buchan, Samantha L. Bowker, Jasjeet K. Minhas-Sandhu, Zafar Zafari, Carlo Marra, Jeffrey A. Johnson, Bruno H. Stricker, Andrè G. Uitterlinden, Albert Hofman, Rikje Ruiter, Catherine E. de KeyserThomas M. MacDonald, Sarah H. Wild, Paul M. McKeigue, Helen M. Colhoun, on behalf of the Scottish Diabetes Research Network Epidemiology Group and the Diabetes and Cancer Research Consortium

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    Abstract

    AIMS/HYPOTHESIS: The evidence on the association between pioglitazone use and bladder cancer is contradictory, with many studies subject to allocation bias. The aim of our study was to examine the effect of exposure to pioglitazone on bladder cancer risk internationally across several cohorts. The potential for allocation bias was minimised by focusing on the cumulative effect of pioglitazone as the primary endpoint using a time-dependent approach.

    METHODS: Prescription, cancer and mortality data from people with type 2 diabetes were obtained from six populations across the world (British Columbia, Finland, Manchester, Rotterdam, Scotland and the UK Clinical Practice Research Datalink). A discrete time failure analysis using Poisson regression was applied separately to data from each centre to model the effect of cumulative drug exposure on bladder cancer incidence, with time-dependent adjustment for ever use of pioglitazone. These were then pooled using fixed and random effects meta-regression.

    RESULTS: Data were collated on 1.01 million persons over 5.9 million person-years. There were 3,248 cases of incident bladder cancer, with 117 exposed cases and a median follow-up duration of 4.0 to 7.4 years. Overall, there was no evidence for any association between cumulative exposure to pioglitazone and bladder cancer in men (rate ratio [RR] per 100 days of cumulative exposure, 1.01; 95% CI 0.97, 1.06) or women (RR 1.04; 95% CI 0.97, 1.11) after adjustment for age, calendar year, diabetes duration, smoking and any ever use of pioglitazone. No association was observed between rosiglitazone and bladder cancer in men (RR 1.01; 95% CI 0.98, 1.03) or women (RR 1.00; 95% CI 0.94, 1.07).

    CONCLUSIONS/INTERPRETATION: The cumulative use of pioglitazone or rosiglitazone was not associated with the incidence of bladder cancer in this large, pooled multipopulation analysis.

    Original languageEnglish
    Pages (from-to)493-504
    Number of pages12
    JournalDiabetologia
    Volume58
    Issue number3
    Early online date7 Dec 2014
    DOIs
    Publication statusPublished - Mar 2015

    Keywords

    • Bladder cancer
    • Epidemiology
    • Meta-analysis
    • Pioglitazone
    • Rosiglitazone
    • Thiazeolidinedione

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    Cite this

    Levin, D., Bell, S., Sund, R., Hartikainen, S. A., Tuomilehto, J., Pukkala, E., Keskimäki, I., Badrick, E., Renehan, A. G., Buchan, I. E., Bowker, S. L., Minhas-Sandhu, J. K., Zafari, Z., Marra, C., Johnson, J. A., Stricker, B. H., Uitterlinden, A. G., Hofman, A., Ruiter, R., ... on behalf of the Scottish Diabetes Research Network Epidemiology Group and the Diabetes and Cancer Research Consortium (2015). Pioglitazone and bladder cancer risk: a multipopulation pooled, cumulative exposure analysis. Diabetologia, 58(3), 493-504. https://doi.org/10.1007/s00125-014-3456-9