The diabetes medication pioglitazone did not increase the risk of bladder cancer to a statistically significant degree in a large cohort study with a nested case-control substudy, but “a small increased risk” could not be ruled out, according to a report published online July 21 in JAMA.

Moreover, pioglitazone was linked to increased risks of prostate cancer and pancreatic cancer in a second cohort assessed in this study, a finding that “merits further investigation to assess whether the observed associations are causal or due to chance, residual confounding, or reverse causality,” said Dr. James D. Lewis of the center for clinical epidemiology and biostatistics, University of Pennsylvania, Philadelphia, and his associates.

Preclinical studies of pioglitazone showed an increase in bladder cancer in male rats, and early clinical studies detected a possible safety signal for bladder cancer in humans. The Food and Drug Administration and Takeda, the developer of pioglitazone, agreed to a 10-year observational study to assess a possible link to the disease, using data from the electronic health records of diabetes patients aged 40 and older enrolled in a large California health plan.

The study cohort comprised 193,099 patients, including 34,181 who took pioglitazone, who were followed for a median of 6-7 years (range, 1-16 years) for the development of bladder cancer. A total of 1,261 participants developed the disease, representing 0.65% of the entire cohort. There was no statistically significant association between the use of pioglitazone and bladder cancer (HR, 1.06), although the crude incidence of the disease was higher with exposure to pioglitazone (89.8 cases per 100,000 person-years) than without such exposure (75.9 cases per 100,000 person-years). The risk of bladder cancer also showed no clear association with duration of treatment or cumulative dose, the investigators said (JAMA 2015 July 21 [ doi:10.1001/jama.2015.7996 ]).

The findings were similar in a nested, case-control substudy involving 464 patients who developed bladder cancer and 464 control subjects matched for age, sex, and date of study entry. The rate of pioglitazone use was identical between these two groups, at 16%.

However, given the confidence intervals of the data concerning more than 4 years of pioglitazone use, “this study cannot exclude up to a 54% increased risk of bladder cancer,” Dr. Lewis and his associates noted.

The researchers also analyzed data from a second observational cohort of 236,507 diabetes patients aged 40 and older who were followed for the development of 10 other cancers from enrollment in 1997-2005 until 2012. Unlike the first cohort, the data from this cohort were adjusted to account for several potential confounding factors such as race/ethnicity, diabetes duration, smoking history, and occupational exposures. A total of 15,993 patients had incident cancers of the prostate, pancreas, breast, lung/bronchus, endometrium, colon, rectum, or kidney/renal pelvis, or non-Hodgkin lymphoma or melanoma. Pioglitazone was associated with an increased risk of prostate cancer (HR, 1.13) and pancreatic cancer (HR, 1.41), but not with the other cancers.