Comparative safety of pioglitazone versus clinically meaningful treatment alternatives concerning the risk of bladder cancer in older US adults with type 2 diabetes

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Abstract
Aims: To compare bladder cancer incidence between patients initiating pioglitazone treatment and patients initiating treatment with dipeptidyl‐peptidase‐4 inhibitors [DPP‐4s] or sulfonylureas. Methods: We identified M edicare beneficiaries aged >65 years who initiated treatment with pioglitazone ( N = 38 700), DPP‐4s ( N = 82 552) or sulfonylureas ( N = 126 104) between 2007 and 2014 after at least 6 months without prescriptions for these drug classes. Patients were followed from second prescription until bladder cancer outcome (2 claims within 60 days) using a 6‐month induction/latency period, censoring for treatment change, death or end of 2014. We used propensity score‐weighted C ox proportional‐hazards models to obtain adjusted hazard ratios (a HR ) and their 95% confidence intervals. Results: Overall mean age of participants was 75 years and 41% were men. Over a median of 1.2 treatment years, 727 beneficiaries developed bladder cancer. Pioglitazone initiators had an increased incidence of bladder cancer (308 vs 204 [DPP‐4s] or 231 [sulfonylureas] per 100 000 person‐years; aHR, 1.57 [1.23‐2.00] vs DPP‐4s and 1.32 [1.02‐1.70] vs sulfonylureas). The increased risk emerged within the first 2 years of treatment (aHR, 1.63 [1.22‐2.17] vs DPP‐4s and 1.32 [0.98‐1.78] vs sulfonylureas). If treatment was discontinued within the first 2 years, the risk after 2 years post initiation was attenuated (aHR, 0.89 [0.61‐1.28]) compared with patients treated for more than 2 years (aHR, 1.45 [0.93‐2.26]) both vs DPP‐4s. Findings were consistent across secondary and sensitivity analyses. Conclusions: Pioglitazone was associated with an elevated risk of bladder cancer compared with DPP‐4s and sulfonylureas. The elevated risk emerged within the first 2 years of treatment and was attenuated after discontinuing. Pioglitazone's relative effectiveness should be weighed against a small absolute increase in risk of bladder cancer.
Funding Information
  • Pharmacoepidemiology Gillings Innovation Lab (PEGIL) (200811.0010)
  • Center for Pharmacoepidemiology, Department of Epidemiology
  • University ofNorth Carolina (UNC) Gillings School of Global Public Health
  • CER Strategic Initiative of UNC's Clinical and Translational Science Award (UL1TR001111)
  • Cecil G. Sheps Center for Health Services
  • UNC School of Medicine
  • National Institute on Aging (RO1 AG023178)

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