bladder cancer risk

Bladder cancer risk not increased with pioglitazone therapy

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Through an analysis of nearly 200,000 patients, no statistically significant increased risk for bladder cancer was found with the use of Actos, according to recent study findings published in JAMA.

Assiamira Ferrara, MD, PhD, of Kaiser Permanente Northern California, and colleagues conducted a bladder cancer cohort analysis of 193,099 people aged 40 years or older in 1997 to 2002 until December 2012; evaluated 464 case patients and 464 matched controls for additional confounders; and performed a cohort analysis for 10 additional cancers on 236,507 people aged 40 years or older in 1997 to 2005 until June 2012. All participants were members of Kaiser Permanente Northern California.

Assiamira Ferrera

Assiamira Ferrara

The additional cancers included prostate, female breast, lung/bronchus, endometrial, colon, non-Hodgkin’s lymphoma, pancreas, kidney/renal pelvis, rectum and melanoma.

Among the bladder cancer cohort, 34,181 participants received Actos (pioglitazone, Takeda) during follow-up. Overall, 0.65% of participants were diagnosed with bladder cancer. No significant association was found between ever use of pioglitazone and bladder cancer (HR = 1.06; 95% CI, 0.89-1.26).

Through the case-control analysis, researchers found similar rates of bladder cancer between ever use (19.6%) and nonusers (17.5%).

In the study analyzing additional cancers, 16% of participants had received pioglitazone by the end of follow-up. The researchers found no association between most of the cancers and pioglitazone use; however, there was an increased risk for prostate cancer (HR = 1.13; 95% CI, 1.02-1.26) and pancreatic cancer (HR = 1.41; 95% CI, 1.16-1.71).

“There was no statistically significant increased risk of bladder cancer associated with pioglitazone use,” the researchers wrote. “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 change, residual confounding, or reverse causality.”

In an accompanying editorial, Joshua M. Sharfstein, MD, of Johns Hopkins Bloomberg School of Public Health, andAaron S. Kesselheim, MD, JD, MPH, of Brigham and Women’s Hospital, wrote that the results “shed new light on the safety of pioglitazone reflecting the dynamic nature of many drug safety questions.

“As in this case, caution and further review are the appropriate responses to many safety signals,” they wrote. “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 another editorial, Phil B. Fontanarosa, MD, MBA, executive deputy editor of JAMA, and colleagues wrote that medical journals have a responsibility to review studies evaluating the potential relationship between drugs, devices or vaccines and adverse outcomes.

“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,” they wrote. “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.”

Pioglitazone, rosiglitazone did not increase bladder cancer risk in patients with type 2 diabetes

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The cumulative use of pioglitazone or rosiglitazone to treat type 2 diabetes was not associated with bladder cancer in a pooled analysis of six populations, according to research published in Diabetologia

“These data challenge the idea that pioglitazone causes bladder cancer,”Helen Colhoun, MD, of the University of Dundee, United Kingdom, toldEndocrine Today. “We find no evidence of such an effect, at least in the time span of the study we have conducted, which was longer than many previously published.”

Helen Colhoun

Helen Colhoun

Colhoun, with Daniel Levin, MD, also of the University of Dundee, and colleagues examined drug effects on bladder cancer risk using data from British Columbia, Finland, Manchester, Rotterdam, Scotland and UK Clinical Practice Research Datalink.

The investigators gathered prescription, cancer and mortality data from patients with type 2 diabetes. Data collected from six centers included 1.01 million patients during 5.9 million person-years; the mean age of the patients at entry into the centers was 60 to 64 years.

To model the effect of cumulative exposure on cancer incidence, a discrete time failure analysis was applied separately to data from each center with Poisson regression; time-dependent adjustments were made for ever use of pioglitazone; results were pooled using fixed and random effects meta-regression.

During a median follow-up of 4 to 7.4 years, there were 3,248 cases of incident bladder cancer, with 117 exposed cases.

No evidence was demonstrated for any association between cumulative exposure to pioglitazone and bladder cancer in men (RR per 100 days of cumulative exposure=1.01; 95% CI, 0.97-1.06) or women (RR=1.04; 95% CI, 0.97-1.11) with adjustments for age, calendar year, diabetes duration, smoking and any ever use of pioglitazone.

Further, no association seen between rosiglitazone and bladder cancer in men (RR=1.01; 95% CI, 0.98-1.03) or women (RR=1; 95% CI, 0.94-1.07).

“The decision to use any drug needs to weigh the risks and benefits associated with that drug,” Colhoun said. “We do not find evidence of bladder cancer being a concern with pioglitazone, but the decision to use the drug should be taken in the context of other known side effects, including fracture risk.”

Calhoun underscored that these data should provide reassurance for patients who have already used the drug and were worried by previous reports about bladder cancer.

The strengths of this particular research, according to investigators, were that “most observational pharmacoepidemiological studies are limited by allocation bias” and that they also “considered exposure to other glucose-lowering drugs in the models.”

Limitations to the study included short-term follow-up duration and absence of data on ethnicities other than white Europeans, BMI and smoking, the researchers conceded.

“Longer-term studies observational of real world exposure to diabetes drugs remain important, not just for this class of drugs, but other diabetes drugs too,” Colhoun said. “Such studies need to be careful to use methods that minimize biases.” – by Allegra Tiver

Pioglitazone and bladder cancer risk: Examining the evidence

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In 2011, accumulating evidence on a possible link between pioglitazone and bladder cancer led to an FDA warning.

Around the same time, several European countries withdrew pioglitazone (Actos, Takeda Pharmaceuticals) from the market. The US package insert now states that data suggest an increased risk for bladder cancer in pioglitazone users. Data also suggest that the risk increases with duration of use. Other warnings state: Do not use pioglitazone in patients with active bladder cancer; use caution when using in patients with a prior history of bladder cancer; and tell patients to promptly report any sign of hematuria or other symptoms such as dysuria or urinary urgency, as these may be due to bladder cancer.

Concern about bladder cancer from pioglitazone first appeared in the PROactive study. In this study, bladder cancer developed more frequently in the pioglitazone group as compared with placebo (11 vs. six cases; P=.069). Eleven of the 20 patients developed bladder cancer within 1 year of beginning the study. After excluding these patients and those with known risk factors, researchers determined that pioglitazone did not increase the risk for bladder cancer.

Taylor_James
James R. Taylor

A retrospective study of US pharmacy claims by Oliveria and colleagues did not find any association between thiazolidinediones and colorectal, liver, bladder or pancreas cancers. The estimated RR for bladder cancer in this study was 1.05 (95% CI, 0.71-1.54). However, there were several limitations of the study because it was retrospective, could not discriminate between different thiazolidinediones, the number of documented bladder cancer cases was relatively small and other risk factors were unaccounted for.

A review of the FDA Adverse Event Reporting System (AERS) showed a high risk for bladder cancer in pioglitazone users (OR=4.3; 95% CI, 2.82-6.52). However, because there are potential biases associated with reporting, these data can be misleading.

Kaiser Permanente Northern California is conducting an observational study on pioglitazone and bladder cancer rates. An interim analysis showed an increased risk for bladder cancer with pioglitazone, with an HR of 1.2 (95% CI, 0.9-1.5). However, when looking at only those receiving pioglitazone for more than 24 months, the risk was increased by 40% with pioglitazone use (HR=1.4; 95% CI, 1.03-2.0). Concern over the time-dependent use design of this and the Oliveria study has been raised, as this may introduce a bias and thus make the results unreliable.

A study by Tseng and colleagues, published in Diabetes Care, reviewed insurance database information in Taiwan and found no significant increase in bladder cancer associated with the use of pioglitazone. There were, however, a relatively small number of cases.

Tseng also discussed some other confounding issues that must be considered. For example, diabetes itself may increase the risk for cancer. Also, pioglitazone is often used as a second- or third-line agent, and thus, the patient has likely had diabetes for a longer time, continues to have hypoglycemia and has been on other medications, all of which may increase the risk for bladder cancer.

Given the information to date, it is difficult to determine whether there is an association between pioglitazone use and bladder cancer. If such an association exists, further clarification on factors such as duration of use, ethnicity and concomitant bladder cancer risk factors must be clarified. Of course, when taking this information into consideration before prescribing pioglitazone, one should also consider the potential benefits of this agent such as reduced cardiovascular disease and improved glucose and lipids. Until better data are available, the FDA’s current precaution seems appropriate.

Pioglitazone, rosiglitazone did not increase bladder cancer risk in patients with type 2 diabetes

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The cumulative use of pioglitazone or rosiglitazone to treat type 2 diabetes was not associated with bladder cancer in a pooled analysis of six populations, according to research published in Diabetologia.

“These data challenge the idea that pioglitazone causes bladder cancer,”Helen Colhoun, MD, of the University of Dundee, United Kingdom, toldEndocrine Today. “We find no evidence of such an effect, at least in the time span of the study we have conducted, which was longer than many previously published.”

Helen Colhoun

Helen Colhoun

Colhoun, with Daniel Levin, MD, also of the University of Dundee, and colleagues examined drug effects on bladder cancer risk using data from British Columbia, Finland, Manchester, Rotterdam, Scotland and UK Clinical Practice Research Datalink.

The investigators gathered prescription, cancer and mortality data from patients with type 2 diabetes. Data collected from six centers included 1.01 million patients during 5.9 million person-years; the mean age of the patients at entry into the centers was 60 to 64 years.

To model the effect of cumulative exposure on cancer incidence, a discrete time failure analysis was applied separately to data from each center with Poisson regression; time-dependent adjustments were made for ever use of pioglitazone; results were pooled using fixed and random effects meta-regression.

During a median follow-up of 4 to 7.4 years, there were 3,248 cases of incident bladder cancer, with 117 exposed cases.

No evidence was demonstrated for any association between cumulative exposure to pioglitazone and bladder cancer in men (RR per 100 days of cumulative exposure=1.01; 95% CI, 0.97-1.06) or women (RR=1.04; 95% CI, 0.97-1.11) with adjustments for age, calendar year, diabetes duration, smoking and any ever use of pioglitazone.

Further, no association seen between rosiglitazone and bladder cancer in men (RR=1.01; 95% CI, 0.98-1.03) or women (RR=1; 95% CI, 0.94-1.07).

“The decision to use any drug needs to weigh the risks and benefits associated with that drug,” Colhoun said. “We do not find evidence of bladder cancer being a concern with pioglitazone, but the decision to use the drug should be taken in the context of other known side effects, including fracture risk.”

Calhoun underscored that these data should provide reassurance for patients who have already used the drug and were worried by previous reports about bladder cancer.

The strengths of this particular research, according to investigators, were that “most observational pharmacoepidemiological studies are limited by allocation bias” and that they also “considered exposure to other glucose-lowering drugs in the models.”

Limitations to the study included short-term follow-up duration and absence of data on ethnicities other than white Europeans, BMI and smoking, the researchers conceded.

“Longer-term studies observational of real world exposure to diabetes drugs remain important, not just for this class of drugs, but other diabetes drugs too,” Colhoun said. “Such studies need to be careful to use methods that minimize biases.” – by Allegra Tiver