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

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 Medicare 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 Cox proportional‐hazards models to obtain adjusted hazard ratios (aHR) 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.