Pioglitazone Use Not Linked to Bladder Cancer at 10 Years

Miriam E Tucker

July 21, 2015

The diabetes drug pioglitazone does not appear to be associated with an increased risk of bladder cancer, as had been previously suggested, but new data indicate a possible increased risk of prostate and pancreatic cancer.

The new 10-year findings, from three large database analyses, were published July 21 in the Journal of the American Medical Association by James D Lewis, MD, of the Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, and colleagues.

"Pioglitazone is currently used by up to a quarter of diabetes patients in the United States. In a large, 10-year study, we found no statistically significant association between the use of pioglitazone and the increased risk of bladder cancer, which should be reassuring to clinicians and patients," lead investigator Assiamira Ferrara, MD, PhD, section chief for Women's and Children's Health and research scientist with the Kaiser Permanente Northern California Division of Research, Oakland, told Medscape Medical News.

However, she added, "a small increased risk of bladder cancer could not be excluded. Our study was able to examine 4 years or more of pioglitazone use, but we were not able to address bladder-cancer risks associated with longer-term use.

"Pioglitazone helps people with type 2 diabetes to make better use of insulin. Like all drugs for diabetes and all medications, there will always be risks and benefits," Dr Ferrara said. "The decision to use pioglitazone is dependent on the balance of these factors for any individual. This study can help doctors and patients with diabetes to better understand the risks of pioglitazone, allowing a better understanding when choosing treatments."

Balancing Risk

The new findings represent 10 years of observational follow-up requested by both the US Food and Drug Administration (FDA) and European Medicines Agency (EMA). A 5-year interim analysis had shown a small but significant 1.4-fold elevated risk of bladder cancer among patients receiving pioglitazone for longer than 2 years. In response, both the FDA and EMA revised the drug's label but allowed for continued marketing, pending the current results.

In one of two accompanying editorials, Joshua M Sharfstein, MD, of Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, and Aaron S Kesselheim, MD, JD, of the division of pharmacoepidemiology and pharmacoeconomics, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, cite the pioglitazone case as an example of the need for the FDA to develop a standardized framework for regulatory decisions about drug safety in situations of uncertainty.

"It may not be feasible for the FDA to reconcile all competing interests and opinions about complex questions of drug safety. A more realistic goal is a rigorous, fair, and transparent framework that will make drug safety less a recurrent crisis and more just another difficult task facing a very important agency," Sharfstein and Kesselheim write.

In the second editorial, JAMA executive deputy editor Phil B Fontanarosa, MD, and two other JAMA editors declare that the journal "will continue to review studies evaluating the potential relationship between drugs, devices, or vaccines and adverse outcomes. Each manuscript will be considered based on its scientific validity, as well as the importance of the results and merits of the main study message."

By publishing the results of these studies, the editors say, "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."

10-Year Results Reassuring, but Risk Can't Be Ruled Out

The three studies were a cohort analysis of 193,099 people with diabetes aged 40 years and older, a nested study of 464 bladder-cancer patients compared with 464 matched controls, and a separate cohort study of 236,507 individuals with diabetes, that analyzed the risk of 10 additional cancers based on use vs nonuse of pioglitazone. All data were from Kaiser Permanente Northern California.

Of the 193,099 adults with diabetes, 34,181 received pioglitazone during follow-up and 1261 (0.65%) received a diagnosis of bladder cancer.

The crude incidence of bladder cancer was 89.8 and 75.9 per 100,000 person-years in pioglitazone users and nonusers, respectively. Cancer stage did not differ between pioglitazone users and nonusers. After adjustment for potential confounders, there was no association between ever use of pioglitazone and bladder cancer, with a hazard ratio (HR) of 1.06. Use of other diabetes medications was also not associated with bladder cancer risk.

Results were similar in the case-control analysis, which included adjustments for self-reported race/ethnicity, smoking history, occupations associated with bladder cancer, frequency of urinary-tract infections, and HbA1c. In this analysis, the odds ratio for ever use of pioglitazone was a nonsignificant 1.18 (95% confidence interval [CI], 0.78 – 1.80).

In the third analysis, 16% (38,190) of 236,507 individuals had ever used pioglitazone and 6.8% (15,992) had received a diagnosis of some type of cancer. Pioglitazone use was associated with an increased risk of prostate cancer, with a crude incidence of 453 vs 449 per 100,000 person-years (HR, 1.13; 95% CI, 1.02 – 1.26), and pancreatic cancer (81 vs 48 per 100,000 person-years; HR, 1.41; 95% CI, 1.16 – 1.71). Other cancers were not significantly related to pioglitazone use.

However, the authors note that other diabetes medications were also associated with pancreatic cancer, which suggests reverse causality, because hyperglycemia is an early manifestation of pancreatic cancer. This explanation is supported by the observation that risk of pancreatic cancer lowered with time since initiation.

"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," Lewis and colleagues conclude.

The study was funded by a grant from Takeda Development Center Americas. Dr Lewis has reported consulting for Takeda Development Center Americas, Janssen, and Lilly; receiving personal fees and grants from Bayer; serving on the Data and Safety Monitoring Board for Pfizer; receiving personal fees from Merck and AstraZeneca; and receiving grants from Centocor and Nestle Health Science. Dr Ferrara has reported receiving grants from Takeda Development Center Americas and Sanofi. Disclosures for the coauthors are listed in the article. Dr Kesselheim's work is funded by the Greenwall Foundation and Harvard Program in Therapeutic Science. Dr Kesselheim also has reported receiving grants from the FDA for work unrelated to the article. Dr Sharfstein and the JAMA editors reported no relevant financial relationships.

JAMA. 2015;314:265-277, 233-234, 235-236. Abstract, Sharfstein editorial, Fontanarosa editorial

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