OBJECTIVE

To analyze the association between pioglitazone use and bladder cancer through a spontaneous adverse event reporting system for medications.

RESEARCH DESIGN AND METHODS

Case/noncase bladder cancer reports associated with antidiabetic drug use were retrieved from the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) between 2004 and 2009 and analyzed by the reporting odds ratio (ROR).

RESULTS

Ninety-three reports of bladder cancer were retrieved, corresponding to 138 drug-reaction pairs (pioglitazone, 31; insulin, 29; metformin, 25; glimepiride, 13; exenatide, 8; others, 22). ROR was indicative of a definite risk for pioglitazone (4.30 [95% CI 2.82–6.52]), and a much weaker risk for gliclazide and acarbose, with very few cases being treated with these two drugs (6 and 4, respectively).

CONCLUSIONS

In agreement with preclinical and clinical studies, AERS analysis is consistent with an association between pioglitazone and bladder cancer. This issue needs constant epidemiologic surveillance and urgent definition by more specific studies.

A link between pioglitazone and bladder cancer first appeared in preclinical studies and was first reported on the U.S. pioglitazone label in 1999, but experimental studies recently suggested that it might be a rat-specific phenomenon (1). In the large PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events) study, 14 bladder cancers occurred in the pioglitazone arm (0.5%) versus 6 in the placebo arm (0.2%) (2,3), and in September 2010, the U.S. Food and Drug Administration (FDA) announced an ongoing investigation on the possible risk in humans (4). Accordingly, the drug manufacturer is conducting a 10-year observational study to address the long-term risk of bladder cancer associated with pioglitazone (4).

Very recently, the European Medicines Agency (EMA) suspended the marketing authorization of rosiglitazone (5), and the FDA largely restricted its use because of an increased cardiovascular risk (6). These measures will increase the prescription of pioglitazone; thus, the definition of its benefit/risk profile becomes all the more pressing.

Our aim was to contribute to defining the safety profile of pioglitazone, focusing on cases of bladder cancer recorded in the FDA Adverse Event Reporting System (AERS) database associated with antidiabetic drug treatment.

The reports recorded in FDA AERS from January 2004 to December 2009 were downloaded from the FDA website. The system contains all reports of adverse drug events spontaneously reported by health care professionals, manufacturers, and consumers from the U.S. and serious and unlabeled spontaneous reports from non–U.S. countries. The adverse events are codified by Medical Dictionary for Regulatory Activities (MedDRA) terminology. Reports concerning antidiabetic drugs were selected, provided that age, sex, and event date were available. Duplicates and multiple records, a well-known drawback of FDA AERS (7), were excluded by a semiautomated multistep process (8).

The association between antidiabetic drugs and bladder cancer was analyzed by the case/noncase methodology (9). Cases were the reports retrieved under the MedDRA high-level term “bladder neoplasms” for any given drug; noncases were all of the other reports related to the same drug. The association between the drug and bladder cancer was calculated by the adverse drug reaction reporting odds ratio (ROR) as a measure of disproportionality. The ratio cases/noncases for each drug were compared with the ratio of cases/noncases for all other antidiabetic drugs. Stratified analyses weighed the influence of male sex and old age. The possible effect of notoriety bias was tested by a year-by-year analysis. Epi Info 3.4.3-2007 software (Centers for Disease Control and Prevention, Atlanta, GA) was used for statistical analyses.

From 2004 to 2009, 86,987 reports involving antidiabetic drugs were recorded in FDA AERS, corresponding to 599,085 drug-reaction pairs (obtained by splitting comedications and multiple reactions reported for each case), with 37,841 reports concerning pioglitazone. Overall, 93 reports of bladder cancer were retrieved, corresponding to 138 drug-reaction pairs, with 31 concerning pioglitazone; 29 insulin; 25 metformin; 13 glimepiride; 8 exenatide; 6 gliclazide; 5 glipizide; 4 sitagliptin, acarbose and rosiglitazone; 3 glibenclamide; 2 nateglinide and repaglinide; and 1 phenformin and voglibose.

The ROR of bladder cancer was significantly >1 for pioglitazone (ROR 4.30 [95% CI 2.82–6.52]; P < 0.001) as well as for gliclazide and acarbose (Table 1). Among the 31 cases of bladder cancer reported in pioglitazone users (mean age, 70 years; range 53–84), 23 occurred in men (3.86 [2.37–6.26]; Supplementary Table A1) and 8 were in women (5.19 [2.15–12.11]). When stratified by age (cutoff, 65), ROR for pioglitazone was only significant in older patients (5.10 [3.14–8.23]). Four cases of bladder cancer were reported in 2004, three in 2005, nine in 2006, five in 2007, six in 2008, and four in 2009 (ROR not statistically significant in 2005 and 2009; Supplementary Table A2).

Table 1

ROR of bladder cancer for antidiabetic drugs

Active substanceCases*All ADRROR95% CIP
Pioglitazone 31 37,841 4.30 2.82–6.52 <0.001 
Insulin 29 124,873 1.01 0.06–1.55 0.961 
Metformin 25 138,900 0.73 0.46–1.15 0.158 
Glimepiride 13 35,388 1.66 0.89–3.01 0.080 
Exenatide 100,946 0.30 0.14–0.64 0.001 
Gliclazide 7,560 3.56 1.42–8.39 0.001 
Glipizide 34,816 0.61 0.22–1.54 0.272 
Sitagliptin 11,638 1.51 0.48–4.22 0.416 
Acarbose 3,479 5.12 1.61–14.33 <0.001 
Rosiglitazone 44,006 0.38 0.12–1.05 0.045 
Glibenclamide 38,214 0.33 0.08–1.06 0.043 
Nateglinide 4,994 1.75 N.A. N.A. 
Repaglinide 6,060 1.44 N.A. N.A. 
Phenformin 65 68.30 N.A. N.A. 
Voglibose 2,938 1.48 N.A. N.A. 
Other antidiabetic drugs 7,367 N.A. N.A. N.A. 
Total 138 599,085    
Active substanceCases*All ADRROR95% CIP
Pioglitazone 31 37,841 4.30 2.82–6.52 <0.001 
Insulin 29 124,873 1.01 0.06–1.55 0.961 
Metformin 25 138,900 0.73 0.46–1.15 0.158 
Glimepiride 13 35,388 1.66 0.89–3.01 0.080 
Exenatide 100,946 0.30 0.14–0.64 0.001 
Gliclazide 7,560 3.56 1.42–8.39 0.001 
Glipizide 34,816 0.61 0.22–1.54 0.272 
Sitagliptin 11,638 1.51 0.48–4.22 0.416 
Acarbose 3,479 5.12 1.61–14.33 <0.001 
Rosiglitazone 44,006 0.38 0.12–1.05 0.045 
Glibenclamide 38,214 0.33 0.08–1.06 0.043 
Nateglinide 4,994 1.75 N.A. N.A. 
Repaglinide 6,060 1.44 N.A. N.A. 
Phenformin 65 68.30 N.A. N.A. 
Voglibose 2,938 1.48 N.A. N.A. 
Other antidiabetic drugs 7,367 N.A. N.A. N.A. 
Total 138 599,085    

ADR, adverse drug reaction; N.A., not available.

*Cases of bladder cancer.

†Mantel-Haenszel corrected.

Ten cases occurred during clinical studies. The length of drug use, which was recorded in 15 cases, was <6 months in 6 patients, 6–24 months in 5, and >24 months in 4. Antiplatelet agents (e.g., aspirin and clopidogrel), antihypertensive drugs (e.g., ACE inhibitors and diuretics), lipid-lowering agents (e.g., statins), other antidiabetic drugs (e.g., glimepiride, metformin, and acarbose), and glucocorticoid (fluticasone and mometasone) were the cotreatments most frequently recorded (24 patients). One patient was being treated with cytotoxic therapy (infliximab and methotrexate for psoriatic arthropathy), and one was treated with interferon-β-1α for multiple sclerosis.

Bladder cancer is the fourth most common cancer and the ninth leading cause of cancer death among U.S. men (10). Cigarette smoking, urinary tract infections, occupational exposure to aromatic amines and polycyclic aromatic hydrocarbons, and drugs (e.g., cyclophosphamide) are risk factors for the disease, as might be the systematic use of glucocorticoids (11).

We found a definite signal for bladder cancer associated with pioglitazone use. The demographic characteristics of the selected cases were consistent with bladder cancer epidemiology (male sex, old age) (10). A weaker signal was also associated with gliclazide, and a much weaker signal was associated with acarbose. Of note, the occurrence of fewer than five events, although resulting in a statistically significant ROR, may be considered clinically meaningless because it is too susceptible to reporting biases (12).

Although notoriety bias may have contributed to part of the association between pioglitazone use and bladder cancer (13), we also observed a significant relationship in 2004, which preceded publication of the PROactive study (2) and label revision. Therefore, we do not believe that our findings can be explained by notoriety bias alone. A greater use of pioglitazone could also have influenced this result (14).

Preliminary data found an increasing risk of bladder cancer with pioglitazone exposure, with statistical significance after 24 months (4). This issue could not be confirmed by our analysis, with only four cases of bladder cancer occurring in patients exposed to pioglitazone for more than 2 years and several missing data. In general, the association with bladder cancer does not seem to derive from concomitant drug use or comorbidity, with only two patients receiving treatments potentially favoring carcinogenesis and five patients receiving glucocorticoids.

The ROR analysis has several limitations: generic under-reporting, over-reporting generated by notoriety bias, dependence on the drug-marketing period (Weber effect), missing or misspelled data (7,13,15), and lack of information on patients’ habits (smoking) or occupational risks. Despite limitations, the higher-than-expected reporting of bladder cancer for pioglitazone users compared with users of other antidiabetic drugs should stimulate specific case--control studies aimed at verifying the magnitude of the hazard; until the final data of the FDA investigation are available, physicians should pay careful attention to this possible risk.

No potential conflicts of interest relevant to this article were reported.

C.P. researched data and wrote the manuscript. D.M. reviewed and edited the manuscript. G.M. contributed to discussion and reviewed and edited manuscript. E.P. researched data and wrote the manuscript.

Parts of this work were submitted in abstract form to the 10th Congress of the European Association for Clinical Pharmacology and Therapeutics, Budapest, Hungary, 26–29 June 2011.

1.
Suzuki
S
,
Arnold
LL
,
Pennington
KL
, et al
.
Effects of pioglitazone, a peroxisome proliferator-activated receptor gamma agonist, on the urine and urothelium of the rat
.
Toxicol Sci
2010
;
113
:
349
357
[PubMed]
2.
Dormandy
JA
,
Charbonnel
B
,
Eckland
DJ
, et al
;
PROactive investigators
.
Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial
.
Lancet
2005
;
366
:
1279
1289
[PubMed]
3.
Dormandy
J
,
Bhattacharya
M
,
van Troostenburg de Bruyn
AR
;
PROactive investigators
.
Safety and tolerability of pioglitazone in high-risk patients with type 2 diabetes: an overview of data from PROactive
.
Drug Saf
2009
;
32
:
187
202
[PubMed]
4.
Food and Drug Administration. FDA drug safety communication: ongoing safety review of actos (pioglitazone) and potential increased risk of bladder cancer after two years exposure [Internet], 2010. Silver Spring, MD, u.s. Food and Drug Administration. Available from http://www.fda.gov/Drugs/DrugSafety/ucm226214.htm. Accessed 21 October 2010
5.
European Medicines Agency. European Medicines Agency update on ongoing benefit-risk review of Avandia, Avandamet and Avaglim [Internet], 2010. London, U.K., European Medicines Agency. Available from http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2010/07/WC500094981.pdf. Accessed 25 October 2010
6.
Food and Drug Administration. FDA significantly restricts access to the diabetes drug Avandia [Internet], 2010. Silver Spring, MD, u.s. Food and Drug Administration. Available from http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm226956.htm. Accessed 25 October 2010
7.
Hauben
M
,
Reich
L
,
DeMicco
J
,
Kim
K
.
‘Extreme duplication’ in the US FDA Adverse Events Reporting System database
.
Drug Saf
2007
;
30
:
551
554
[PubMed]
8.
Poluzzi
E
,
Raschi
E
,
Motola
D
,
Moretti
U
,
De Ponti
F
.
Antimicrobials and the risk of torsades de pointes: the contribution from data mining of the US FDA Adverse Event Reporting System
.
Drug Saf
2010
;
33
:
303
314
[PubMed]
9.
Moore
N
,
Kreft-Jais
C
,
Haramburu
F
, et al
.
Reports of hypoglycaemia associated with the use of ACE inhibitors and other drugs: a case/non-case study in the French pharmacovigilance system database
.
Br J Clin Pharmacol
1997
;
44
:
513
518
[PubMed]
10.
Jemal
A
,
Siegel
R
,
Xu
J
,
Ward
E
.
Cancer statistics, 2010
.
CA Cancer J Clin
2010
;
60
:
277
300
[PubMed]
11.
Dietrich
K
,
Schned
A
,
Fortuny
J
, et al
.
Glucocorticoid therapy and risk of bladder cancer
.
Br J Cancer
2009
;
101
:
1316
1320
[PubMed]
12.
van Puijenbroek
EP
,
Bate
A
,
Leufkens
HG
,
Lindquist
M
,
Orre
R
,
Egberts
AC
.
A comparison of measures of disproportionality for signal detection in spontaneous reporting systems for adverse drug reactions
.
Pharmacoepidemiol Drug Saf
2002
;
11
:
3
10
[PubMed]
13.
Pariente
A
,
Gregoire
F
,
Fourrier-Reglat
A
,
Haramburu
F
,
Moore
N
.
Impact of safety alerts on measures of disproportionality in spontaneous reporting databases: the notoriety bias
.
Drug Saf
2007
;
30
:
891
898
[PubMed]
14.
Cohen
A
,
Rabbani
A
,
Shah
N
,
Alexander
GC
.
Changes in glitazone use among office-based physicians in the U.S., 2003-2009
.
Diabetes Care
2010
;
33
:
823
825
[PubMed]
15.
Almenoff
J
,
Tonning
JM
,
Gould
AL
, et al
.
Perspectives on the use of data mining in pharmaco-vigilance
.
Drug Saf
2005
;
28
:
981
1007
[PubMed]

Supplementary data