Pioglitazone use and risk of bladder cancer in patients with type 2 diabetes: retrospective cohort study using datasets from four European countriesBMJ 2016; 354 doi: https://doi.org/10.1136/bmj.i3903 (Published 16 August 2016) Cite this as: BMJ 2016;354:i3903
- Pasi Korhonen, research director1,
- Edith M Heintjes, scientific research manager2,
- Rachael Williams, senior researcher3,
- Fabian Hoti, head of statistics1,
- Solomon Christopher, statistician1,
- Maila Majak, statistician1,
- Leanne Kool-Houweling, researcher2,
- Helen Strongman, senior researcher3,
- Marie Linder, statistician4,
- Paul Dolin, head of pharmacoepidemiology5,
- Shahram Bahmanyar, associate professor4
- 1EPID Research, FI-02130 Espoo, Finland
- 2PHARMO Institute, Utrecht, Netherlands
- 3Clinical Practice Research Datalink, London, UK
- 4Centre for Pharmacoepidemiology, Karolinska Institute, Stockholm, Sweden
- 5Takeda Development Centre Europe, London , UK
- Correspondence to: P Korhonen
- Accepted 7 July 2016
Objective To evaluate the association between pioglitazone use and bladder cancer risk in patients with type 2 diabetes.
Design Retrospective cohort study using propensity score matched cohorts.
Settings Healthcare databases from Finland, the Netherlands, Sweden, and the United Kingdom. Data comprised country specific datasets of linked records on prescriptions, hospitals, general practitioners, cancer, and deaths.
Participants Patients with type 2 diabetes who initiated pioglitazone (n=56 337) matched with patients with type 2 diabetes in the same country exposed to diabetes drug treatments other than pioglitazone (n=317 109). Two matched cohorts were created, using a 1:1 fixed ratio (nearest match cohort) and a 1:10 variable ratio (multiple match cohort). Patients were matched on treatment history and propensity scores accounting for several variables associated with pioglitazone initiation.
Main outcome measures Hazard ratios and 95% confidence intervals were estimated by Cox’s proportional hazards model with adjustments for relevant confounders. To assess the robustness of the findings, several sensitivity and stratified analyses were performed.
Results In the cohort exposed to pioglitazone treatment, 130 bladder cancers occurred over a mean follow-up time of 2.9 years. In the nearest match and multiple match cohorts not exposed to pioglitazone treatment, 153 and 970 bladder cancers were recorded, with a mean follow‑up time of 2.8 and 2.9 years, respectively. With regards to bladder cancer risk, the adjusted hazard ratio for patients ever exposed versus never exposed to pioglitazone was 0.99 (95% confidence interval 0.75 to 1.30) and 1.00 (0.83 to 1.21) in the nearest and multiple match cohorts, respectively. Increasing duration of pioglitazone use and increasing cumulative dose were not associated with risk of bladder cancer (>48 months of pioglitazone use, adjusted hazard ratio 0.86 (0.44 to 1.66); >40 000 mg cumulative dose, 0.65 (0.33 to 1.26) in the nearest match cohort).
Conclusions This study shows no evidence of an association between ever use of pioglitzone and risk of bladder cancer compared with never use, which is consistent with results from other recent studies that also included a long follow-up period.
Trial registration Registered to the European Union electronic register of post-authorisation studies (EU PAS register no EUPAS3626).
Tim Williams and Susan Eaton (Clinical Practice Research Datalink (CPRD)) were involved in the study design. Irene Bezemer (PHARMO Institute) participated in analytical discussions, and Eline Houben (PHARMO Institute) contributed to construction of the analysis file. Shannon Kuismanen assisted in preparing this manuscript. The Swedish National Diabetes Register provided detailed data for this study. We thank all patients and participating staff who have contributed to the register.
Contributors: All authors planned and designed the study. SC, MM, ML, EMH, LK-H, RW, and HS performed the data management and data analysis, and all authors interpreted the data. All authors drafted the manuscript, revised the paper critically for important intellectual content, and approved the final version of the manuscript. PK supervised the study and is the guarantor.
Funding: The European Medicines Agency (EMA) mandated the marketing authorisation holder of Actos (pioglitazone) to conduct this study. The study protocol was reviewed and approved by the EMA, and the study was granted the ENCePP Seal, reflecting transparency and quality in research. The study was fully funded by Takeda Development Centre Europe.
Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: support from Takeda Development Centre Europe for the submitted work; PK, FH, SC, and MM are employed by EPID Research, EMH is and LK-H was employed by PHARMO Institute, RW and HS are employed by CPRD, and ML and SB are employed by the Karolinska Institute; EPID Research, PHARMO Institute, CPRD and Karolinska Institute perform commissioned pharmacoepidemiological studies and thus their employees have been and currently are working in collaboration with several pharmaceutical companies (including Takeda); PD is employed by Takeda.
Ethical approval: This register based study used anonymous data and had no patient contact. In Finland, the study protocol was approved by the ethical review board of the Hjelt Institute, University of Helsinki Medical Faculty (Dnro 96/13/00/2013). The research permission numbers to use the data were obtained from Statistics Finland (Dnro TK/53-373-13), National Institute for Health and Welfare (Dnro THL/388/5.05.00/2013), Social Insurance Institute (Dnro Kela 25/522/2013), Population Register Centre (Dnro 726/410/13). In Sweden, the study was approved by the regional ethical review board at the Karolinska Institute in Stockholm, Sweden (DNR 2011/82-31/3, 2011/752-323, and 2013/347-32). The participants did not give informed written consent because this was a register study and it is prohibited by Swedish law to backtrack registered individuals. In the UK, the study protocol was reviewed and approved by the Independent Scientific Advisory Committee (ISAC), which considers and provides advice to the Medicines and Healthcare products Regulatory Agency on research projects that propose the use of data obtained from the CPRD (ISAC protocol no 13_044 and 14_065). In the Netherlands, the PHARMO compliance committee approved use of the PHARMO Database Network for the study and confirmed no ethics approval was needed.
Data sharing: Criteria and process for sharing the analytical country specific datasets and meta-analysis dataset for third parties is defined in the study protocol, available at the ENCePP E-Register of Studies.
The lead author affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.
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