title: Pioglitazone and bladder cancer risk: a multipopulation pooled, cumulative exposure analysis.
abstract: OBJECTIVE
  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
  The cumulative use of pioglitazone or rosiglitazone was not associated with the incidence of bladder cancer in this large, pooled multipopulation analysis.
authors.affiliation: Diabetes Epidemiology Group, Population Health Sciences, University of Dundee, Dundee, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Levin
authors.forename: Samira
authors.initials: S
authors.lastname: Bell
authors.forename: Reijo
authors.initials: R
authors.lastname: Sund
authors.forename: Sirpa A
authors.initials: SA
authors.lastname: Hartikainen
authors.forename: Jaakko
authors.initials: J
authors.lastname: Tuomilehto
authors.forename: Eero
authors.initials: E
authors.lastname: Pukkala
authors.forename: Ilmo
authors.initials: I
authors.lastname: Keskimäki
authors.forename: Ellena
authors.initials: E
authors.lastname: Badrick
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Renehan
authors.forename: Iain E
authors.initials: IE
authors.lastname: Buchan
authors.forename: Samantha L
authors.initials: SL
authors.lastname: Bowker
authors.forename: Jasjeet K
authors.initials: JK
authors.lastname: Minhas-Sandhu
authors.forename: Zafar
authors.initials: Z
authors.lastname: Zafari
authors.forename: Carlo
authors.initials: C
authors.lastname: Marra
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Johnson
authors.forename: Bruno H
authors.initials: BH
authors.lastname: Stricker
authors.forename: Andrè G
authors.initials: AG
authors.lastname: Uitterlinden
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.forename: Rikje
authors.initials: R
authors.lastname: Ruiter
authors.forename: Catherine E
authors.initials: CE
authors.lastname: de Keyser
authors.forename: Thomas M
authors.initials: TM
authors.lastname: MacDonald
authors.forename: Sarah H
authors.initials: SH
authors.lastname: Wild
authors.forename: Paul M
authors.initials: PM
authors.lastname: McKeigue
authors.forename: Helen M
authors.initials: HM
authors.lastname: Colhoun
mesh_terms: D000368:Aged; D001955:British Columbia / Q000453:epidemiology; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D005260:Female; D005387:Finland / Q000453:epidemiology; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects*; D015994:Incidence; D008297:Male; D008875:Middle Aged; D000077205:Pioglitazone; D000077154:Rosiglitazone; D012606:Scotland / Q000453:epidemiology; D045162:Thiazolidinediones / Q000009:adverse effects*; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced* / Q000453:epidemiology*
chemical_list: D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D000077205:Pioglitazone