title: Pioglitazone and risk of bladder cancer among diabetic patients in France: a population-based cohort study.
abstract: OBJECTIVE
  Previous studies have suggested an increased risk of bladder cancer with pioglitazone exposure. We aimed to investigate the association between pioglitazone exposure and bladder cancer in France.
  
  
  METHODS
  This cohort study involved use of data from the French national health insurance information system (Système National d'Information Inter-régimes de l'Assurance Maladie; SNIIRAM) linked with the French hospital discharge database (Programme de Médicalisation des Systèmes d'Information; PMSI). The cohort included patients aged 40 to 79 years who filled a prescription for a glucose-lowering drug in 2006. The cohort was followed for up to 42 months. Pioglitazone exposure was modelled as a time-dependent variable and defined by having filled at least two prescriptions over a 6-month period. Incident cases of bladder cancer were identified by a discharge diagnosis of bladder cancer combined with specific aggressive treatment. Statistical analyses involved a multivariate Cox model adjusted for age, sex and exposure to other glucose-lowering drugs.
  
  
  RESULTS
  The cohort included 1,491,060 diabetic patients, 155,535 of whom were exposed to pioglitazone. We found 175 cases of bladder cancer among exposed patients and 1,841 among non-exposed patients. Incidence rates were 49.4 and 42.8 per 100,000 person-years, respectively. Pioglitazone exposure was significantly associated with bladder cancer incidence (adjusted HR 1.22 [95% CI 1.05, 1.43]). We observed a dose-effect relationship, with a significantly increased risk for high cumulative doses (≥ 28,000 mg, adjusted HR 1.75 [95% CI 1.22, 2.50]) and long duration of exposure (≥ 24 months, adjusted HR 1.36 [1.04, 1.79]).
  
  
  CONCLUSIONS
  In this cohort of diabetic patients from France, pioglitazone exposure was significantly associated with increased risk of bladder cancer.
authors.affiliation: Caisse Nationale de l'Assurance Maladie, 50 Avenue du Pr André Lemierre, 75986 Paris Cedex 20, France.
authors.forename: A
authors.initials: A
authors.lastname: Neumann
authors.forename: A
authors.initials: A
authors.lastname: Weill
authors.forename: P
authors.initials: P
authors.lastname: Ricordeau
authors.forename: J P
authors.initials: JP
authors.lastname: Fagot
authors.forename: F
authors.initials: F
authors.lastname: Alla
authors.forename: H
authors.initials: H
authors.lastname: Allemand
mesh_terms: D000328:Adult; D000368:Aged; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy*; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D005602:France / Q000453:epidemiology; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D015994:Incidence; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D000077205:Pioglitazone; D016016:Proportional Hazards Models; D012307:Risk Factors; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000009:adverse effects*; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced* / Q000453:epidemiology / Q000517:prevention & control
chemical_list: D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D000077205:Pioglitazone