title: Thiazolidinediones and associated risk of bladder cancer: a systematic review and meta-analysis.
abstract: OBJECTIVE
  To determine whether thiazolidinedione use is associated with a risk of bladder cancer.
  
  
  METHODS
  We searched MEDLINE and EMBASE in June 2012 (with PubMed update to July 2013) and conducted meta-analysis on the overall risks of bladder cancer with pioglitazone or rosiglitazone and the risk with different categories of cumulative dose or duration of drug use.
  
  
  RESULTS
  We screened 230 citations and included 18 studies, comprising five randomized controlled trials (RCTs) and 13 observational studies. Meta-analysis showed a significantly higher overall risk of bladder cancer with pioglitazone in RCTs [7878 participants; odds ratio (OR) 2.51, 95% confidence interval (CI) 1.09-5.80] and observational studies (>2.6 million patients; OR for 'ever' users vs. non-users 1.21, 95% CI 1.09-1.35). Subgroup analysis of observational studies by cumulative dose showed the risk of bladder cancer to be greatest with >28.0 g of pioglitazone (OR 1.64, 95% CI 1.28-2.12). A significantly increased risk was found with both 12-24 months (OR 1.41, 95% CI 1.16-1.71) and >24 months (OR 1.51, 95% CI 1.26-1.81) cumulative durations of pioglitazone exposure. No significant risk was seen with rosiglitazone in RCTs (OR 0.84, 95% CI 0.35-2.04) or 'ever' users vs. non-users in observational studies (OR 1.03, 95% CI 0.94-1.12); the evidence for any relationship between bladder cancer risk and rosiglitazone cumulative duration is limited and inconsistent. Direct comparison of pioglitazone to rosiglitazone 'ever' users yielded an OR of 1.25 (95% CI 0.91-1.72).
  
  
  CONCLUSIONS
  A modest but clinically significant increase in the risk of bladder cancer with pioglitazone was found, which appears to be related to cumulative dose and duration of exposure. We recommend that prescribers limit pioglitazone use to shorter durations.
authors: Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK; Royal Liverpool University Hospital, Liverpool, UK.
authors: Richard M
authors: RM
authors: Turner
authors: Chun S
authors: CS
authors: Kwok
authors: Chen
authors: C
authors: Chen-Turner
authors: Chinedu A
authors: CA
authors: Maduakor
authors: Sonal
authors: S
authors: Singh
authors: Yoon K
authors: YK
authors: Loke
mesh_terms: D003627:Data Interpretation, Statistical; D004305:Dose-Response Relationship, Drug; D006801:Humans; D012306:Risk; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced*
chemical_list: D045162:Thiazolidinediones
keywords: diabetes mellitus; meta-analysis; pioglitazone; rosiglitazone; thiazolidinedione; urinary bladder neoplasm