title: Pioglitazone use and risk of bladder cancer in patients with type 2 diabetes: retrospective cohort study using datasets from four European countries.
abstract: OBJECTIVE
  To evaluate the association between pioglitazone use and bladder cancer risk in patients with type 2 diabetes.
  
  
  METHODS
  Retrospective cohort study using propensity score matched cohorts.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
  
  
  BACKGROUND
  Registered to the European Union electronic register of post-authorisation studies (EU PAS register no EUPAS3626).
authors.affiliation: EPID Research, FI-02130 Espoo, Finland pasi.korhonen@epidresearch.com.
authors.forename: Pasi
authors.initials: P
authors.lastname: Korhonen
authors.affiliation: PHARMO Institute, Utrecht, Netherlands.
authors.forename: Edith M
authors.initials: EM
authors.lastname: Heintjes
authors.affiliation: Clinical Practice Research Datalink, London, UK.
authors.forename: Rachael
authors.initials: R
authors.lastname: Williams
authors.affiliation: EPID Research, FI-02130 Espoo, Finland.
authors.forename: Fabian
authors.initials: F
authors.lastname: Hoti
authors.affiliation: EPID Research, FI-02130 Espoo, Finland.
authors.forename: Solomon
authors.initials: S
authors.lastname: Christopher
authors.affiliation: EPID Research, FI-02130 Espoo, Finland.
authors.forename: Maila
authors.initials: M
authors.lastname: Majak
authors.affiliation: PHARMO Institute, Utrecht, Netherlands.
authors.forename: Leanne
authors.initials: L
authors.lastname: Kool-Houweling
authors.affiliation: Clinical Practice Research Datalink, London, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Strongman
authors.affiliation: Centre for Pharmacoepidemiology, Karolinska Institute, Stockholm, Sweden.
authors.forename: Marie
authors.initials: M
authors.lastname: Linder
authors.affiliation: Takeda Development Centre Europe, London , UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Dolin
authors.affiliation: Centre for Pharmacoepidemiology, Karolinska Institute, Stockholm, Sweden.
authors.forename: Shahram
authors.initials: S
authors.lastname: Bahmanyar
mesh_terms: D000368:Aged; D066264:Datasets as Topic; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D005260:Female; D005387:Finland / Q000453:epidemiology; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009426:Netherlands / Q000453:epidemiology; D000077205:Pioglitazone; D057216:Propensity Score; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D012307:Risk Factors; D013548:Sweden / Q000453:epidemiology; D045162:Thiazolidinediones / Q000009:adverse effects* / Q000627:therapeutic use; D006113:United Kingdom / Q000453:epidemiology; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced* / Q000453:epidemiology
chemical_list: D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D000077205:Pioglitazone