title: Association between longer therapy with thiazolidinediones and risk of bladder cancer: a cohort study.
abstract: BACKGROUND
  The use of pioglitazone, a thiazolidinedione (TZD), may increase the risk of bladder cancer in patients with type 2 diabetes. In this study, we assessed the risk of bladder cancer associated with the use of TZDs and between pioglitazone and rosiglitazone, an alternative TZD.
  
  
  METHODS
  We conducted a retrospective cohort study of patients with type 2 diabetes mellitus who initiated treatment with a TZD (n = 18 459 patients) or a sulfonylurea (SU) (n = 41 396 patients) between July 1, 2000, and August 31, 2010, using The Health Improvement Network database in the United Kingdom. Incident cancers were identified for 196 708 person-years of follow-up. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of bladder cancer in the TZD cohort compared with the SU cohort (referent), adjusted for potential confounders. Risk associated with increasing duration of drug exposure was also examined. All statistical tests were two-sided.
  
  
  RESULTS
  We identified 60 incident bladder cancers in the TZD cohort and 137 cancers in the SU cohort. No difference in bladder cancer risk was found between the two cohorts (TZD vs SU, HR = 0.93, 95% CI = 0.68 to 1.29) in analyses that did not account for duration of exposure. However, the risk of bladder cancer was increased among patients with the longest duration of TZD vs SU therapy (≥ 5 years of use, HR = 3.25, 95% CI = 1.08 to 9.71) and among those with the longest time since initiation of therapy (≥ 5 years since first use, HR = 2.53, 95% CI = 1.12 to 5.77). Risk of bladder cancer also increased with increasing time since initiation of pioglitazone (P (trend) < .001) and rosiglitazone (P (trend) = .006). Comparison of pioglitazone to rosiglitazone use did not demonstrate difference in cancer risk (P = .49).
  
  
  CONCLUSIONS
  Long-term TZD therapy (≥ 5 years) in patients with type 2 diabetes may be associated with an increased risk of bladder cancer, which may be common to all TZDs.
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Ronac
authors.initials: R
authors.lastname: Mamtani
authors.forename: Kevin
authors.initials: K
authors.lastname: Haynes
authors.forename: Warren B
authors.initials: WB
authors.lastname: Bilker
authors.forename: David J
authors.initials: DJ
authors.lastname: Vaughn
authors.forename: Brian L
authors.initials: BL
authors.lastname: Strom
authors.forename: Karen
authors.initials: K
authors.lastname: Glanz
authors.forename: James D
authors.initials: JD
authors.lastname: Lewis
mesh_terms: D000368:Aged; D015331:Cohort Studies; D015986:Confounding Factors, Epidemiologic; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D000077205:Pioglitazone; D016016:Proportional Hazards Models; D012107:Research Design; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000008:administration & dosage* / Q000009:adverse effects*; D006113:United Kingdom / Q000453:epidemiology; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced* / Q000453:epidemiology*
chemical_list: D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D000077205:Pioglitazone