Pioglitazone use and risk of bladder cancer: population based cohort studyBMJ 2016; 352 doi: https://doi.org/10.1136/bmj.i1541 (Published 30 March 2016) Cite this as: BMJ 2016;352:i1541
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PIOGLITAZONE AND BLADDER CANCER: REPORTING STAGE AND GRADE MAY HELP UNDERSTAND CAUSATION AND CLINICAL RELEVANCE
We thank Tuccori et al. for their retrospective analysis of the association between pioglitazone use and bladder cancer. Their conclusion that pioglitazone use is associated with an increased risk of developing bladder cancer adds weight to this longstanding and controversial topic (1, 2).
The grades and stages of bladder cancers detected are of particular interest to clinicians treating urothelial carcinoma of the bladder (UCB). For many years, UCB has been thought of in the context of two pathways to pathogenesis. One pathway consisted of low-grade (WHO 2004 classification) (3), stage Ta non-muscle-invasive bladder cancers (4), which frequently recur (31-62%) (5), but seldom progress to muscle invasive disease (0-17%) (5). Patients with this type of UCB can expect a 5-year survival of close to 90% (6). Their cancers can be effectively controlled by endoscopic resection, adjuvant intravesical therapy and close cystoscopic follow-up. By contrast, high-grade bladder cancers (WHO 2004) (3) often progress to muscle invasion or are muscle invasive at diagnosis. Muscle-invasive bladder cancer (MIBC) has poor 5-year survival (~50%) (7) despite aggressive therapy (neoadjuvant chemotherapy, then either radical cystectomy and lymph node resection, or radical radiotherapy).
More recently, genomic and transcription analysis of UCB has suggested that bladder cancer consists of more than the 2 classical molecular sub-groups, with some advocating the further sub-classification of MIBC (8-11). Interestingly, the PPAR pathway has been implicated in “luminal” MIBC subtypes with, high-levels of PPARγ expression having been reported in human bladder cancers (9). Of note, rosiglitazone has been used to selectively activate PPARγ to investigate the role of PPAR pathway activation in human bladder cancer cell-lines to help understand its role in controlling luminal gene expression (9). It would therefore, be of profound clinical relevance to report bladder cancer grade and stage from this and in future association studies. If there is a real link between pioglitazone and bladder cancer, understanding which sort (grade) of cancers are involved and molecular characterisation of these cancers, could help to shed light on the mechanism. If it affects high-grade cancers only, that would imply that UBC resulting from pioglitazone use was much more clinically significant than if all grades of cancer were affected.
1. Tuccori M, Filion KB, Yin H, Yu OH, Platt RW, Azoulay L. Pioglitazone use and risk of bladder cancer: population based cohort study. BMJ. 2016;352. doi: 10.1136/bmj.i1541.
2. Korhonen P, Heintjes EM, Williams R, Hoti F, Christopher S, Majak M, et al. Pioglitazone use and risk of bladder cancer in patients with type 2 diabetes: retrospective cohort study using datasets from four European countries. BMJ. 2016;354. doi: 10.1136/bmj.i3903.
3. Eble JN, Sauter G, Epstein JI, Sesterhenn IA. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Urinary System and Male Genital Organs. IARC Press Lyon, 2004.
4. (UICC) UIClC. TNM Classification of Malignant Tumors. 7 ed: UICC; 2009.
5. Babjuk M, Böhle A, Burger M, Compérat E, Kaasinen E, Palou J, et al. Guidelines on Non-muscle-invasive Bladder Cancer (Ta, T1 and CIS). European Association of Urology; 2014.
6. CRUK. Bladder cancer statistics: Cancer Reaserch UK; 2016 (24/11/2016). Available from: http://www.cancerresearchuk.org/health-professional/cancer-statistics/st... - heading-Three.
7. Stein J, Skinner D. Radical cystectomy for invasive bladder cancer: long-term results of a standard procedure. World journal of urology. 2006;24(3):296-304. doi: 10.1007/s00345-006-0061-7.
8. The Cancer Genome Atlas Research N. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature. 2014. Epub 2014/01/31. doi: 10.1038/nature12965. PubMed PMID: 24476821.
9. Choi W, Porten S, Kim S, Willis D, Plimack ER, Hoffman-Censits J, et al. Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy. Cancer Cell. 2014;25(2):152-65. doi: 10.1016/j.ccr.2014.01.009. PubMed PMID: 24525232; PubMed Central PMCID: PMCPMC4011497.
10. Sjodahl G, Lauss M, Gudjonsson S, Liedberg F, Hallden C, Chebil G, et al. A systematic study of gene mutations in urothelial carcinoma; inactivating mutations in TSC2 and PIK3R1. PloS one. 2011;6(4):e18583. Epub 2011/05/03. doi: 10.1371/journal.pone.0018583. PubMed PMID: 21533174; PubMed Central PMCID: PMC3077383.
11. Knowles MA, Hurst CD. Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity. Nature reviews Cancer. 2015;15(1):25-41. doi: 10.1038/nrc3817. PubMed PMID: 25533674.
Competing interests: No competing interests
We thank Drs. Gallagher, Winocour, Ryder, Blann, and Davidson for their interest in our work. As noted by Gallagher and Winocour, the previous pioglitazone trials were designed and powered to assess efficacy and not safety endpoints. This is particularly true for endpoints such as bladder cancer, which are both rare and have long latency periods. Given these limitations of trials regarding the assessment of such safety outcomes, the presence of an imbalance between the randomized groups necessitates further enquiry. With respect to the Insulin Resistance Intervention after Stroke (IRIS) trial, there was indeed an imbalance in the number of bladder cancer events in the in the pioglitazone versus placebo groups (12 events (0.6%) vs 8 events (0.4%), respectively) (1). Although this imbalance did not achieve statistical significance, its importance is strengthened by that also observed in the PROactive trial (2). Importantly, while we acknowledge that some early events were subsequently excluded from the bladder cancer analysis of PROactive and agree with Gallagher and Winocour that such events are unlikely to be causally associated with the recently initiated treatment, the imbalance in bladder cancer events remained after the exclusion of these early events (6 vs 3) (2). With the presence of this imbalance in bladder cancer in the two largest and longest pioglitazone trials published to date, we believe that these trial data are both consistent with our observed results (3) and should raise some concerns regarding the safety of pioglitazone with respect to bladder cancer.
With respect to the IRIS trial (1), it is important to note that this trial differed from the PROactive trial (2) in that it randomized non-diabetic patients (and thus involved a population at a lower risk of bladder cancer), and that there was a concerted effort (for ethical and safety reasons) to exclude patients with history of or at high risk of bladder cancer. Moreover, more patients in the pioglitazone group than in the placebo group were “removed for safety reasons” after randomization, which included the presence “of or risk factors for bladder cancer” (146 vs. 117 patients, respectively) (1). Unfortunately, it is unclear if the reported number of bladder cancer events includes patients who developed bladder cancer after they have been removed from the study.
Drs. Gallagher, Winocour, Ryder and Blann are also concerned that our findings are due to residual confounding. However, these concerns ignore the robust pharmacoepidemiologic approach employed that specifically aimed at circumventing the methodological limitations of the previous studies. This approach included the use of a new-user design, a time-dependent exposure definition, lagging exposure to deal with latency and detection bias, marginal structural modeling to deal with potential time-dependent confounding, and a head-to-head comparison of pioglitazone versus rosiglitazone with adjustment for high-dimensional propensity scores. All of these approaches generated results that were consistent with those of our primary analysis. While the observational nature of our study is still subject to some residual confounding from an unknown and/or unmeasured confounder, we show in Supplementary Figure 3 that the observed association would only be fully explained by a very strong confounder (i.e., one strongly associated with both the exposure and outcome); it is unclear if such a hypothetical confounder actually exists, suggesting that residual confounding is an unlikely explanation for our observed results.
One of the key findings of our study is the absence of an association with rosiglitazone, a thiazolidinedione introduced the same year and for the same target population as pioglitazone. However, Drs. Ryder and Blann claim that it is not possible to assume that users of pioglitazone and rosiglitazone were similar; this is based on their hypothesis of preferential prescribing of pioglitazone to patients with “more advanced” disease given the cardiovascular concerns that were raised with rosiglitazone. We are not aware of any studies that have documented this preferential prescribing pattern in the UK or elsewhere. Furthermore, this hypothesis is not supported by our data. Indeed, as shown in Supplementary Table 5, pioglitazone and rosiglitazone users were remarkably similar on nearly all characteristics, including Charlson comorbidity score (a variable that captures several cardiovascular conditions).
Dr. Davidson is concerned that our percentage of bladder cancer events was high (5.86%) among patients exposed to pioglitazone compared to what has been reported in other observational studies (<0.50%). Unfortunately, Dr. Davidson’s calculation was incorrect as it was based on the number of patients who were exposed to pioglitazone at cohort entry only (921 patients) rather than the total number of patients who were exposed during the entire study period (10,951 patients). When using the correct denominator (n=10,951), the percentage of bladder cancer events in pioglitazone users drops to 0.49% (i.e., 54/10,951). That being said, the incidence rate and not percentage should be the metric on which studies are compared, as the latter ignores the duration of follow-up.
Finally, Drs. Gallagher, Winocour, Ryder, and Blann discuss the relatively low cost of pioglitazone and its potential benefits on other outcomes, either along or when used in combination with other antidiabetic drugs. Our study was not designed to examine the cost-effectiveness of pioglitazone or its effects on these other endpoints. Rather, it was designed to determine the bladder cancer risk of pioglitazone, and we believe that it has provided strong evidence that pioglitazone is associated with an increased risk of bladder cancer. This evidence now must be considered when weighing the potential benefits and harms of pioglitazone relative to other currently available antidiabetic drugs.
Ultimately, the pioglitazone-bladder cancer controversy will not be resolved with a randomized controlled trial as it would be unethical to design and conduct a trial for a safety issue such as bladder cancer. This is where well-conducted observational studies, together with safety signals generated by randomized controlled trials, can provide critical information to relevant stakeholders.
1. Kernan WN, Viscoli CM, Furie KL, Young LH, Inzucchi SE, Gorman M, Guarino PD, Lovejoy AM, Peduzzi PN, Conwit R, Brass LM, Schwartz GG, Adams HP, Jr., Berger L, Carolei A, Clark W, Coull B, Ford GA, Kleindorfer D, O'Leary JR, Parsons MW, Ringleb P, Sen S, Spence JD, Tanne D, Wang D, Winder TR: Pioglitazone after Ischemic Stroke or Transient Ischemic Attack. N Engl J Med 2016;374:1321-1331
2. Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, Massi-Benedetti M, Moules IK, Skene AM, Tan MH, Lefebvre PJ, Murray GD, Standl E, Wilcox RG, Wilhelmsen L, Betteridge J, Birkeland K, Golay A, Heine RJ, Koranyi L, Laakso M, Mokan M, Norkus A, Pirags V, Podar T, Scheen A, Scherbaum W, Schernthaner G, Schmitz O, Skrha J, Smith U, Taton J: 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
3. Tuccori M, Filion KB, Yin H, Yu OH, Platt RW, Azoulay L: Pioglitazone use and risk of bladder cancer: population based cohort study. BMJ 2016;352:i1541
Competing interests: No competing interests
Tuccori et al conclude that the use of pioglitazone is associated with an increased risk of bladder cancer (1). The authors also suggest that their findings are consistent with the recently published Insulin Resistance Intervention after Stroke (IRIS) trial (2) where pioglitazone was compared with placebo in participants with cerebrovascular disease, but not Type 2 diabetes, and the risk of further macrovascular events investigated. In the IRIS trial there were 12 cases of incident bladder cancer out of 1939 participants in the pioglitazone arm after 4.8 years compared with 8 cases out of 1937 in the placebo group (P=0.37). The IRIS trial was not powered to answer the question of whether pioglitazone use was associated with bladder cancer but it is misleading to claim that the negative result with regard to bladder cancer incidence elicited in the IRIS trial supports the findings of Tuccori and colleagues.
A further concern in this observational study is that the pioglitazone and non-pioglitazone users were not matched (3). Pioglitazone users were older, had been diagnosed with Type 2 diabetes for longer and had worse glycaemic control than the non-pioglitazone users. The pioglitazone users were also more likely to have a history of bladder problems and undergo urine protein testing. Although adjustment for these variables took place it is possible that these factors could be implicated in the causation of bladder cancer in the pioglitazone treated group.
The possible link between pioglitazone exposure and bladder cancer has been contentious for a number of years (4, 5) and has contributed to the fall from grace of pioglitazone in clinical practice. In their introduction, Tuccori and colleagues mention as justification for their study an “imbalance in the number of cases of bladder cancer with pioglitazone compared to placebo” in the PROactive study in 2005. In 2015, for the first time, details about the timing of the bladder cancer in these patients in the PROactive study that led to the imbalance were published (6). In one the bladder cancer was diagnosed after 13 days taking pioglitazone, in another after 14 days taking pioglitazone, in another after one month of taking pioglitazone, in another after 3 months taking pioglitazone, and in another after 4 months taking pioglitazone. These 5 bladder cancer cases could not possibly have been related to pioglitazone, and when they are excluded (which the authors of the original PROactive paper did) the suggestion of an increased incidence of bladder cancer in pioglitazone treated patients in the PROactive study was not upheld. A further recently published study of over a million patients across six different populations concluded that the cumulative use of pioglitazone was not associated with bladder cancer incidence (7). The KPNC study, considered by some to be the definitive study in this area, reviewed over 1200 cases of bladder cancer in pioglitazone users over a 10 year period and also did not find an association between pioglitazone use and bladder cancer incidence (8). Despite the emergence of these recent studies and a growing feeling of reassurance when pioglitazone safety is considered (9) current NICE guidance still states that the risk of bladder cancer with pioglitazone treatment is between 1-10 in 1000 cases (10). This advice predates recent evidence to the contrary (7, 8) and should now be reviewed by NICE. This would seem to be a priority for the newly convened clinical guideline update committee for diabetes.
Even if it is argued that pioglitazone is associated with an increased risk of bladder cancer then the study by Tuccori and colleagues suggests that the absolute risk of bladder cancer is small (1). This, and the other caveats of pioglitazone use, namely fluid retention, heart failure and fracture risk, should be balanced against the potential of pioglitazone to improve glycaemic control as well as tackle insulin resistance and reduce cerebrovascular and cardiovascular risk in high risk patients (2, 11).
New therapeutic possibilities involving metformin, pioglitazone, empagliflozin and potentially liraglutide are emerging in the quest to establish optimal therapeutic combinations that reduce macrovascular risk beyond that seen by lowering HbA1c alone (12, 13). The combination of pioglitazone and empagliflozin is particularly appealing given the diuretic potential of empagliflozin to combat the fluid retention caused by pioglitazone.
Pioglitazone is off patent and its cost, at around £11 for a 28 day supply, compares favourably to newer blood glucose lowering therapies. Despite pioglitazone causing a significant reduction in HbA1c the risk of hypoglycaemia is low. Pioglitazone undergoes hepatic metabolism and, therefore, also remains a useful treatment option in chronic kidney disease, particularly as this patient group is at high cardiovascular risk (14).
We believe that pioglitazone has a valuable role to play in the management of Type 2 diabetes that extends beyond blood glucose lowering. Its therapeutic potential should not be dismissed on the basis of a questionable bladder cancer risk.
1. Tuccori M, Filion KB, Yin H, et al. Pioglitazone use and risk of bladder cancer: population based cohort study. BMJ 2016;352:i1541.
2. Kernan WN, Viscoli CM, Furie KL, et al. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med 2016;374:1321-31.
3. Ryder RE, Blann A. http://www.bmj.com/content/352/bmj.i1541/rapid-responses
4. Gale EA. Pioglitazone: are rumours of its death exaggerated? Diabet Med 2015;32:431-7. doi: 10.1111/dme.12708.
5. Ryder REJ, DeFronzo RA. Rehabilitation of pioglitazone. Br J Diabetes Vasc Dis 2015; 15: 46-49.
6. Ryder REJ. Neither evidence from the PROactive study nor the KPNC supports pioglitazone as a tumour promoter. Diab Med 2015; 32: 438-439.
7. Levin D, et al. Scottish Diabetes Research Network Epidemiology Group Diabetes and Cancer Research Consortium. Pioglitazone and bladder cancer risk: a multipopulation pooled, cumulative exposure analysis. Diabetologia 2015;58:493-504.
8. Lewis JD, Habel LA, Quesenberry CP, et al. pioglitazone Use and Risk of Bladder Cancer and Other Common Cancers in Persons With Diabetes. JAMA 2015;314:265-77.
9. Davidson MB. Pioglitazone (Actos) and bladder cancer: legal system triumphs over the evidence. J Diabetes and its Complications. (in press).
10. NICE. Type 2 diabetes in adults: management. NG28. NICE, 2015.
11. Dormandy JA, Charbonnel B, Eckland DJA, et al. 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;366:1279-89.
12. Ryder REJ, DeFronzo RA. Diabetes medications with cardiovascular protection in the wake of EMPA-REG OUTCOME: the optimal combination may be metformin, pioglitazone and empagliflozin. Br J Diabetes Vasc Dis 2015;15:151-154.
13. DeFronzo RA, Chilton R, Norton L, et al. Revitalization of pioglitazone: The Optimal Agent to be Combined with an SGLT2 Inhibitor. Diabetes Obes Metab. 2016;18(5):454-62.
14. Brunelli SM, Thadhani R, Ikizler TA, Feldman HI. Thiazolidinedione use is associated with better survival in hemodialysis patients with non-insulin dependent diabetes. Kidney Int 2009;75:961–968.
Competing interests: No competing interests
Although pre-clinical developmental studies of pioglitazone in rats indicated a potential link with bladder cancer, there is now overwhelming evidence that no such effect is present in our own species (1,2). The problem is confined to male rats (but not female rats, mice, dogs or monkeys) and seems to be related to the high pH of male rat urine (1,2). Nevertheless the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) requested a large prospective 10 year safety study to establish whether there was any link between pioglitazone and bladder cancer in humans. This study reported in 2015 that there was no link between pioglitazone and bladder cancer (3), which confirmed the same result in a study of over one million persons also published in 2015 (4). Although Tuccori and colleagues allude to "an imbalance in the number of cases of bladder cancer with pioglitazone compared with placebo" in the PROactive study (5), we now know that the extra bladder cancer cases in the pioglitazone arm of the PROactive study could not possibly have been due to pioglitazone (6). It is important at this time to highlight this accumulated lack of evidence for a link between pioglitazone and bladder cancer, because there is now substantial evidence that suggests that pioglitazone reduces cardiovascular death and morbidity (1,7) and it may be a particularly effective agent alongside empagliflozin in this regard, with the two agents complementing each other in reducing cardiovascular outcomes by different, perhaps synergistic, mechanisms (7,8).
Tuccori and colleagues (5), in their cohort study of 145,806 patients in the United Kingdom (UK), effectively reproduced their previous report (9), in a nested case-control study of 115,727 patients, that pioglitazone is linked to bladder cancer. We believe that a flaw in these analyses is that diabetes in itself is associated with a higher risk of bladder cancer and it is likely that this risk increases in diabetes which is more severe and of longer duration and with poorer glycaemic control over longer duration (1). Indeed, Tuccori and colleagues in their paper deliberately exclude patients prescribed insulin as “these may represent those with a more advanced form of type 2 diabetes” (5). During the time period when most of the prescribing of pioglitazone was undertaken in the UK and accounting for the most of the patients in the study of Tuccori and others, the only other agents used to treat type 2 diabetes were metformin, sulphonylureas and insulin. During that era UK guidelines, including the NICE guidelines (1), considered pioglitazone to be a third line agent, for use when the metformin and sulphonylureas had failed – i.e. instead of insulin (1). Thus, UK patients prescribed pioglitazone were fundamentally different from those with whom they are being compared by Tuccori, having (at least) a longer duration of diabetes, and more poorly controlled diabetes for a longer time. This, and not necessarily the use of pioglitazone, would put them at higher risk of bladder cancer. This underlines the classic problem with analysis in retrospective observational databases, where one can so easily arrive at alternative conclusions when like is not being compared with like, and statistical associations may be found that reflect other factors. In support of this contention it can be seen in table 1 of Tuccori’s study (5) that, indeed, pioglitazone treated patients were more likely to have a HbA1c > 7.4% (58.3% v 46.6%) and had a considerably longer mean (SD) duration of diabetes (4.2 (4.6) v 0.3 (1.6) years) than those with whom they are being compared. Though Tuccori attempted to adjust for these confounders in a multivariate analysis (5), there remains an insurmountable difficulty - pioglitazone treated patients in the UK were fundamentally different from those not so treated - like was not being compared with like, and in that situation no amount of adjustment for confounders can create matching samples.
It can also not be assumed that rosiglitazone treated patients were the same as pioglitazone treated patients. With the publications suggesting pioglitazone causes cardiovascular benefit (1,7,8,10) and those suggesting rosiglitazone causes cardiovascular harm (1,10), there was more use of pioglitazone in the more “cardiovascular” patients with type 2 diabetes – again, those with the “more advanced form of diabetes” that would be associated with bladder cancer. Also such “cardiovascular” patients on rosiglitazone were switched to pioglitazone. Thus, it is not surprising to find that bladder cancer is higher in pioglitazone treated patients because these are the ones with Tuccori’s “more advanced form of diabetes” – the “more advanced form of diabetes”” being the actual cause.
In summary, it is a question of balance. The balance of evidence is now overwhelmingly against there being a link between pioglitazone and bladder cancer (1-4,6,11), and any residual worries are surely very small. On the other hand, with type 2 diabetes being “more than anything a disease of people dying prematurely of cardiovascular disease” (1), we need medications that reduce death, myocardial infarctions and strokes and it would appear that pioglitazone is one such agent (1,7,8). Furthermore pioglitazone is a potent insulin sensitizer, improves pancreatic beta cell function, and causes a durable reduction in HbA1c and it should remain an important agent in the modern management of type 2 diabetes (2). The sad tale of the dubious link between pioglitazone and bladder cancer has recently been well described as “legal system triumphs over the evidence” (11).
1. Ryder REJ. Pioglitazone has a dubious bladder cancer risk but an undoubted cardiovascular benefit. Diab Med 2015; 32: 305-313.
2. Ryder REJ, DeFronzo RA. Rehabilitation of pioglitazone. Br J Diabetes Vasc Dis 2015; 15: 46-49
3. Lewis JD, Habel LA, Quesenberry CP, et al. pioglitazone Use and Risk of Bladder Cancer and Other Common Cancers in Persons With Diabetes. JAMA 2015;314:265-77.
4. Levin D, Bell S, Sund R, et al. Scottish Diabetes Research Network Epidemiology Group Diabetes and Cancer Research Consortium. pioglitazone and bladder cancer risk: a multipopulation pooled, cumulative exposure analysis. Diabetologia 2015;58:493-504.
5. Tuccori M, Filion KB, Yin H, et al. Pioglitazone use and risk of bladder cancer: population based cohort study. BMJ 2016;352:i1541.
6. Ryder REJ. Neither evidence from the PROactive study nor the KPNC supports pioglitazone as a tumour promoter. Diab Med 2015; 32: 438-439
7. Ryder REJ, DeFronzo RA. Diabetes medications with cardiovascular protection in the wake of EMPA-REG OUTCOME: the optimal combination may be metformin, pioglitazone and empagliflozin. Br J Diabetes Vasc Dis 2015; 15: 151-154
8. DeFronzo RA, Chilton R, Norton L, et al. Revitalization of pioglitazone: The Optimal Agent to be Combined with an SGLT2 Inhibitor. Diabetes Obes Metab. 2016 May;18(5):454-62.
9. Azoulay L, Yin H, Filion KB, et al. The use of pioglitazone and the risk of bladder cancer in people with type 2 diabetes: nested case-control study.
10. Ryder REJ. Rosiglitazone versus pioglitazone in relation to cardiovascular disease in type 2 diabetes – primum non nocere. Pract Diab Int 2007; 24: 422-425.
11. Davidson MB. Pioglitazone (Actos) and bladder cancer: legal system triumphs over the evidence. J Diabetes Complications. 2016, in press. http://dx.doi.org/10.1016/j.jdiacomp.2016.04.004 (accessed 29 April 2016)
Competing interests: No competing interests
To the Editor:
In the recent population based cohort study examining pioglitazone use and the risk of bladder cancer by Toucon et al1, there were 54 cases of bladder cancer in the 921 patients exposed to the drug yielding a prevalence of 5.86% compared to 497 cases in 142,758 non-exposed patients yielding a prevalence of 0.35%. Wei et al2 studying the same population several years earlier found a prevalence of 0.28% in patients exposed to pioglitazone and 0.44% in those not exposed. Furthermore, mean prevalences of bladder cancer in 12 other studies were 0.37% and 0.36%, respectively, in patients exposed and not exposed to pioglitazone.3 Do the authors have any explanation for the large difference in the prevalence of their patients exposed to pioglitazone and the prevalences in the rest of the literature?
1. Tuccon M, Filion KB, Yin H, Yu OH, Platt RW, Azoulay L. Pioglitazone use and risk of bladder cancer: population based cohort study. BMJ 2016;352:i1541.
2. Wei L. Pioglitazone and bladder cancer: a propensity score matched cohort study. Br J Clin Pharmacol 2012;75:254-9.
3. Davidson MB. Pioglitazone (Actos) and bladder cancer: legal system triumphs over the evidence. J Diabetes and its Complications. (in press).
Competing interests: No competing interests
In their retrospective cohort study, Tuccori  and colleagues used the United Kingdom Clinical Research Datalink to examine the risk of pioglitazone and bladder cancer. This study was undertaken due to the plethora of conflicting evidence on this topic over the years with seven studies showing a positive association while nine studies showi a null association.
Tuccori’s study identified four major biases that might occur more often in drug safety studies that use large population-based studies, namely immortal time bias, prevalent user bias, lag time bias and latency-time bias . When the analysis controlled for these biases, the study showed an elevated risk of bladder cancer with pioglitazone (RR= 1.63, 95%: 1.22 to 2.19) but not with rosiglitazone. These results were in contrast to a study from California published in the Journal of the American Medical Association  which had shown an increase in risk during the earlier years of follow up but no association was found when the follow up was extended to ten years, possibly due to prevalent user bias .
Tuccori’s study is yet another example of how results from a pharmacoepidemiologic study that appropriately identifies and control for biases specific to these types of studies might contradict previously published studies that used less rigorous methodology. Clinicians, patients and stakeholders might be excused for the constant bombardment of contradictory drug safety studies that are published in medical journals. We believe that it is the time for the high impact medical journals such as the BMJ to spearhead an initiative to improve the quality of pharmacoepidemiologic studies that are submitted to the journal. One solution may be the creation of a checklist specific to pharmacoepidemiologic studies that use big data. Such checklists exist for many other study designs. For example, checklists that are required by various medical journals for clinical trials have shown to improve the quality of reporting and possibly validity of published trials . Unlike available checklists for general observational studies that use large population-based databases such as RECORD (The REporting of studies Conducted using Observational Routinely-collected health Data RECORD) , this checklist should target biases more likely to occur in pharmacoepidemiologic studies. Specific biases need to be mentioned by their common names so that investigators can identify and address them in their research. Currently, RECORD has one section on bias that asks the user to “Describe any efforts to address potential sources of bias”. This non-specific statement does not explicitly specify immortal time bias, lag-time, bias or prevalent user bias which might be better addressed by investigators had the checklist explicitly stated “Was immortal time bias controlled for in the cohort study?”
The explosion of pharmacoepidemiologic studies using large population-based databases will undoubtedly lead to publication of drug safety studies with conflicting messages. Use of pharmacoepidemiology-specific reporting check lists has the potential to improve quality of published drug safety studies.
1. Tuccori Marco, Filion Kristian B, Yin Hui, Yu Oriana H, Platt Robert W, Azoulay Laurent et al. Pioglitazone use and risk of bladder cancer: population based cohort study BMJ 2016;352 :i1541
2. Lewis JD, Habel LA, Quesenberry CP, et al. Pioglitazone Use and Risk of Bladder Cancer and Other Common Cancers in Persons With Diabetes. JAMA2015;314:265-77.
3. Moher D, Jones A, Lepage L, Group C. Use of the CONSORT statement and quality of reports of randomized trials: a comparative before-and-after evaluation. JAMA 2001;285:1992–5
Competing interests: No competing interests