Pioglitazone Use and Risk of Bladder Cancer and Other Common Cancers in Persons With Diabetes

Abstract

IMPORTANCE Studies suggest pioglitazone use may increase risk of cancers. OBJECTIVE To examine whether pioglitazone use for diabetes is associated with risk of bladder and 10 additional cancers. DESIGN, SETTING, AND PARTICIPANTS Cohort and nested case-control analyses among persons with diabetes. A bladder cancer cohort followed 193 099 persons aged 40 years or older in 1997-2002 until December 2012; 464 case patients and 464 matched controls were surveyed about additional confounders. A cohort analysis of 10 additional cancers included 236 507 persons aged 40 years or older in 1997-2005 and followed until June 2012. Cohorts were from Kaiser Permanente Northern California. EXPOSURES Ever use, duration, cumulative dose, and time since initiation of pioglitazone as time dependent. MAIN OUTCOMES AND MEASURES Incident cancer, including bladder, prostate, female breast, lung/bronchus, endometrial, colon, non-Hodgkin lymphoma, pancreas, kidney/renal pelvis, rectum, and melanoma. RESULTS Among 193 099 persons in the bladder cancer cohort, 34 181 (18%) received pioglitazone (median duration, 2.8 years; range, 0.2-13.2 years) and 1261 had incident bladder cancer. Crude incidences of bladder cancer in pioglitazone users and nonusers were 89.8 and 75.9 per 100 000 person-years, respectively. Ever use of pioglitazone was not associated with bladder cancer risk (adjusted hazard ratio [HR], 1.06; 95% CI, 0.89-1.26). Results were similar in case-control analyses (pioglitazone use: 19.6% among case patients and 17.5% among controls; adjusted odds ratio, 1.18; 95% CI, 0.78-1.80). In adjusted analyses, there was no association with 8 of the 10 additional cancers; ever use of pioglitazone was associated with increased risk of prostate cancer (HR, 1.13; 95% CI, 1.02-1.26) and pancreatic cancer (HR, 1.41; 95% CI, 1.16-1.71). Crude incidences of prostate and pancreatic cancer in pioglitazone users vs nonusers were 453.3 vs 449.3 and 81.1 vs 48.4 per 100 000 person-years, respectively. No clear patterns of risk for any cancer were observed for time since initiation, duration, or dose. CONCLUSIONS AND RELEVANCE Pioglitazone use was not associated with a statistically significant increased risk of bladder cancer, although an increased risk, as previously observed, could not be excluded. The increased prostate and pancreatic cancer risks associated with ever use of pioglitazone merit further investigation to assess whether they are causal or are due to chance, residual confounding, or reverse causality.

Cancer risks of anti-hyperglycemic drugs for type 2 diabetes treatment – a clinical appraisal

“…During the initial double-blind treatment period of PROactive (mean observation time of 34.5 months), there was a higher number bladder malignancies reported in the pioglitazone group compared with the placebo group (n=14 versus 6); however, a ten-year follow-up of 3,599 patients who completed PROactive found no significant difference in bladder malignancies between the two groups (Erdmann, et al, 2016). Although five-year interim analysis results of a ten-year epidemiology study conducted by the University of Pennsylvania and Division of Research at Kaiser Permanente Northern California showed a small but statistically significant elevated risk of bladder cancer among patients receiving more than 2 years of pioglitazone treatment, the final ten-year results of this study found no statistically significant association between use of pioglitazone and bladder cancer risk, irrespective of duration and dose of treatment (Lewis, et al, 2015).…”

Pioglitazone after Ischemic Stroke or Transient Ischemic Attack

“…46 , 47 However, more recent studies 48 , 49 showed no significant association for any dose or duration of therapy. 49 Other research suggests that PPAR-γ agonists might prevent certain cancers. 50 , 51 Although we did not observe a significant effect of treatment on the incidence of total or any specific cancer, our study was not powered to address these questions.…”

Do We Still Need Pioglitazone for The Management of Type 2 Diabetes Mellitus? A Peep In To Risk of Bladder Cancer in Diabetic Population

“…Despite the beneficial effect of pioglitazone use in glycemic control, its extended use has been allied with various adverse events and questioned owing to safety concerns. Bladder cancer is one of the risk factors associated with the pioglitazone use [2]. According to American Cancer Society, 79,030new cases causing about 16,870 deaths were reported from bladder cancer in the United State (US) for 2017.…”