Study examines link between use of diabetes drug pioglitazone and increased risk of bladder cancer

Although some previous studies have suggested an increased risk of bladder cancer with use of the diabetes drug pioglitazone, analyses that included nearly 200,000 patients found no statistically significant increased risk, however a small increased risk could not be excluded, according to a study in the July 21 issue of JAMA.

Assiamira Ferrara, M.D., Ph.D., of Kaiser Permanente Northern California, Oakland, and colleagues studied with several groups of persons with diabetes: a bladder cancer cohort that followed 193,099 persons (40 years or older in 1997-2002) until December 2012; 464 case patients and 464 matched controls were surveyed about additional confounders (factors that can influence outcomes that may improperly skew the results); and a cohort analysis of 10 additional cancers included 236,507 persons (40 years or older in 1997-2005) and followed until June 2012. The additional cancers were prostate, female breast, lung/bronchus, endometrial, colon, non-Hodgkin lymphoma, pancreas, kidney/renal pelvis, rectum, and melanoma. All cohorts were from Kaiser Permanente Northern California.

Among the persons in the bladder cancer cohort, 34,181 (18 percent) received pioglitazone (median duration, 2.8 years) and 1,261 had incident bladder cancer. Ever use of pioglitazone was not associated with bladder cancer risk. Results were similar in case-control analyses (pioglitazone use: 19.6 percent among case patients and 17.5 percent among controls).

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 and pancreatic cancer. No clear patterns of risk for any cancer were observed for time since initiation, duration, or dose.

"These studies were conducted to address safety concerns related to the risk of cancer after treatment with pioglitazone," the authors write.

"There was no statistically significant increased risk of bladder cancer associated with pioglitazone use. However, a small 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 the observed associations are causal or due to chance, residual confounding, or reverse causality."

Joshua M. Sharfstein, M.D., of the Johns Hopkins Bloomberg School of Public Health, Baltimore, and Aaron S. Kesselheim, M.D., J.D., M.P.H., of Brigham and Women's Hospital, Boston, comment on the findings of this study in an accompanying editorial.

"That these data from the report by Lewis et al shed new light on the safety of pioglitazone reflects the dynamic nature of many drug safety questions. As in this case, caution and further review are the appropriate responses to many safety signals. But when emerging available data—clinical, laboratory, observational, and even population-based studies— create a compelling picture of risk in excess of potential benefit to patients, the FDA should act to protect the public."

In an accompanying editorial, Phil B. Fontanarosa, M.D., M.B.A., Executive Deputy Editor, JAMA, Chicago, and colleagues discuss the responsibility of medical journals to the health of the public in reviewing studies evaluating the potential relationship between drugs, devices, or vaccines and adverse outcomes.

"The findings of the study by Lewis et al demonstrating no statistically significant association between the use of pioglitazone and the risk of bladder cancer are important because of the prevalence of type 2 diabetes, fairly widespread use of pioglitazone, and safety concerns about this drug."

"Even though no observational study examining the relationship between an exposure and an outcome can definitively establish 'positive' cause-and-effect results, and no observational study can definitively prove 'negative' results, each study adds to the totality of evidence regarding the safety of drugs, devices, and vaccines. By publishing the results of these studies, JAMA will continue to provide information physicians can use in discussions with patients and regulatory bodies can use in policy decisions about the benefits and risks of various therapies."