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. 2016 Aug 16:354:i3903.
doi: 10.1136/bmj.i3903.

Pioglitazone use and risk of bladder cancer in patients with type 2 diabetes: retrospective cohort study using datasets from four European countries

Pasi Korhonen  1 , Edith M Heintjes  2 , Rachael Williams  3 , Fabian Hoti  4 , Solomon Christopher  4 , Maila Majak  4 , Leanne Kool-Houweling  2 , Helen Strongman  3 , Marie Linder  5 , Paul Dolin  6 , Shahram Bahmanyar  5
Affiliations

Pioglitazone use and risk of bladder cancer in patients with type 2 diabetes: retrospective cohort study using datasets from four European countries

Pasi Korhonen et al. BMJ. .

Abstract

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).

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Conflict of interest statement

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.

Figures

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Fig 1 Adjusted risk estimates for bladder cancer for different pioglitazone exposures using the nearest matched cohort. Crude model=pioglitazone exposure variable and a dataset identifier. Adjusted model=crude model plus age, sex, metformin use, sulphonylurea use, insulin use, use of other diabetes drugs, all exact matching variables, propensity scores (divided into five equal groups), and all propensity score variables evaluated at cohort entry date. Ptrend=0.42 and 0.45 for increasing pioglitazone duration and dose, respectively, using the adjusted model. Incidence values measured over 10 000 person years
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Fig 2 Adjusted risk estimates for bladder cancer for different pioglitazone exposures using the multiple matched cohort. Crude model=pioglitazone exposure variable and a dataset identifier. Adjusted model=crude model plus age, sex, metformin use, sulphonylurea use, insulin use, use of other diabetes drugs, all exact matching variables, propensity scores (divided into five equal groups), and all propensity score variables evaluated at cohort entry date. Ptrend=0.85 and 0.81 for increasing pioglitazone duration and dose, respectively, using the adjusted model. Incidence values measured over 10 000 person years
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Fig 3 Adjusted hazard ratio estimates for bladder cancer in patients ever exposed to pioglitazone in the nearest matched cohort
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Fig 4 Adjusted hazard ratio estimates for bladder cancer in patients ever exposed to pioglitazone in the multiple matched cohort
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Fig 5 Adjusted hazard ratios in pioglitazone exposure groups (ever versus never) for stratified analysis of bladder cancer incidence, based on pooled dataset for the nearest matched cohort. NA=not available
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