No strong association is found between pioglitazone and bladder cancerBMJ 2015; 351 doi: https://doi.org/10.1136/bmj.h3934 (Published 22 July 2015) Cite this as: BMJ 2015;351:h3934
The diabetes drug pioglitazone is not associated with a statistically significant increased risk of bladder cancer, although a small increased risk cannot be excluded, new research published in JAMA has found.1
The researchers also found that the use of pioglitazone was associated with a higher risk of prostate and pancreatic cancer, although they said that further investigation is needed to assess whether the associations are causal or due to other factors.
The safety of pioglitazone, an oral antidiabetic agent in the thiazolidinedione class, is controversial. Preclinical studies of the drug in the 1990s showed an increase in bladder cancer in male rats, and early clinical studies showed a possible safety risk in humans. In 2012 a retrospective cohort study published in The BMJ concluded that the use of pioglitazone was associated with a higher risk of bladder cancer in people with type 2 diabetes.2
In 2011, because of concerns about the risk of bladder cancer, the US Food and Drug Administration issued a warning advising doctors not to use pioglitazone in patients with active bladder cancer and to use it with caution in patients who had a prior history of bladder cancer. The European Medicines Agency, after carrying out a safety review, also found a small increased risk of bladder cancer with pioglitazone. However, the agency decided that it should remain as a treatment option but that prescribers should carefully select patients and monitor their response to treatment.
In April this year the drug company Takeda reportedly agreed to pay $2.4bn (£1.5bn; €2.2bn) to settle numerous lawsuits involving patients who had been exposed to pioglitazone and had developed bladder cancer.3
The latest research, funded by a grant from Takeda, included a cohort study that looked at 193 099 people who were aged 40 or older in 1997-2002 and followed them until December 2012. Among 34 181 patients who had ever used pioglitazone the study found 186 cases of bladder cancer, and among 158 918 patients who had never used pioglitazone it found 1075 cases. Ever having used pioglitazone was not associated with bladder cancer risk (hazard ratio 1.06 (95% confidence interval 0.89 to 1.26)).
The results differed from the five year interim analysis, which, although it showed no increased risk of bladder cancer overall, found that people who received more than two years of pioglitazone treatment had a small but statistically significant 1.4-fold elevated risk of bladder cancer.
In a case-control study the researchers also found no statistically significant increased risk. Among 373 patients with bladder cancer 91 had been exposed to pioglitazone, and among 383 controls without bladder cancer 81 had been exposed to pioglitazone (adjusted odds ratio 1.18 (0.78 to 1.80)).
In addition, the researchers followed a second cohort of 236 507 people, including 38 190 who had ever been treated with pioglitazone, which focused on the risk of 10 other cancers. During follow-up 15 992 patients had an incident cancer diagnosed at one or more sites, ranging from 629 people with rectal cancer to 3777 with prostate cancer. Ever having used pioglitazone was associated with a higher risk of prostate cancer (hazard ratio 1.13 (1.02 to 1.26)) and pancreatic cancer (1.41 (1.16 to 1.71)).
Cite this as: BMJ 2015;351:h3934