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Pioglitazone use and risk of bladder cancer
AbstractObjectiveTo determine whether pioglitazone compared with other antidiabetic drugs is associated with an increased risk of bladder cancer in people with type 2 diabetes.ParticipantsA cohort of 145806 patients newly treated with antidiabetic drugs between 1 January 2000 and 31 July 2013, with follow up until 31 July 2014.Main outcome measuresThe use of pioglitazone was treated as a time varying variable, with use lagged by one year for latency purposes. Cox proportional hazards models were used to estimate adjusted hazard ratios with 95% confidence intervals of incident bladder cancer associated with pioglitazone overall and by both cumulative duration of use and cumulative dose. Similar analyses were conducted for rosiglitazone, a thiazolidinedione not previously associated with an increased risk of bladder cancer.ResultsThe cohort generated 689616 person years of follow up, during which 622 patients were newly diagnosed as having bladder cancer (crude incidence 90.2 per 100000 person years). Compared with other antidiabetic drugs, pioglitazone was associated with an increased risk of bladder cancer (121.0 v 88.9 per 100000 person years; hazard ratio 1.63, 95% confidence interval 1.22 to 2.19). Conversely, rosiglitazone was not associated with an increased risk of bladder cancer (86.2 v 88.9 per 100000 person years; 1.10, 0.83 to 1.47). Duration response and dose response relations brown hermes belt replica were observed for pioglitazone but not for rosiglitazone.ConclusionThe results of this large population based study indicate that pioglitazone is associated with an increased risk of bladder cancer. The absence of an association with rosiglitazone suggests that the increased risk is drug specific and not a class effect.IntroductionPioglitazone, an antidiabetic drug belonging to the thiazolidinedione class, has been shown to improve glycaemic levels in people with type 2 diabetes.1 However, in 2005 the PROactive randomised controlled trial unexpectedly showed an imbalance in the number of cases of bladder cancer with pioglitazone compared with placebo.2 In contrast, this imbalance was never observed in randomised controlled trials of rosiglitazone, the other approved drug belonging to the thiazolidinedione class.1 3The findings of the PROactive trial were subsequently corroborated in some,4 5 6 7 8 9 10 but not all, observational studies.11 12 13 14 15 16 17 18 19 Indeed, in the five year interim analysis of a large observational study using the Kaiser Permanente Northern California database,4 the use of pioglitazone for 24 months or more was associated with an increased risk of bladder cancer (hazard ratio 1.4, 95% confidence interval 1.03 to 2.0). However, in the final analysis of the Kaiser Permanente Northern California study, which used the same cohort4 with follow up extended to 10 years, the use of pioglitazone was no longer significantly associated with an increased risk of bladder cancer in a duration response fashion.20 These null findings are also consistent with those of another large multicohort study.19 The apparent heterogeneity in this literature may be due to methodological limitations, such as the inclusion of prevalent users,5 6 10 11 12 13 14 18 time lag bias,15 immortal time bias,10 14 18 and no consideration of disease latency.8 10 12 17 18Given these discrepant findings, the methodological shortcoming of previous studies examining this association, and the apparent loss of an association in studies with longer follow up,20 additional studies are needed to investigate further the association between pioglitazone and bladder cancer. In a large, population based study we assessed the association between the use of pioglitazone and bladder cancer in people with type Hermes belt replica paris 2 diabetes.MethodsData sourceThis study was conducted using the United Kingdom Clinical Practice Research Datalink (CPRD). The CPRD collects information on anthropometric variables such as body mass index and lifestyle variables such as smoking. Data collected in the CPRD have been previously validated and shown to be of high quality.22 23 Furthermore, cancer diagnoses have been found to be highly consistent with those recorded in the UK national cancer data repository.24Study populationBase cohortWe assembled a base cohort composed of all people newly treated for type 2 diabetes, defined as receiving a first ever prescription for a non insulin antidiabetic drug (metformin, sulfonylureas, prandial glucose regulators, thiazolidinediones, acarbose, dipeptidyl peptidase 4 (DPP 4) inhibitors, glucagon like peptide (GLP 1) agonists, sodium glucose cotransporter 2 (SGLT2) inhibitors) between 1 January 1988 and 31 July 2013. Patients were required to be at least 40 years of age and to have at least one year of CPRD medical history before that first prescription. We excluded patients prescribed insulin any time before their first non insulin antidiabetic prescription (as these may represent those with an advanced form of type 2 diabetes), and patients with a diagnosis of gestational diabetes and polycystic ovary syndrome (as these are other indications for metformin).Study cohortUsing the base cohort, we identified all patients who hermes belt price replica initiated a new antidiabetic drug class on or after 1 January 2000 (the year pioglitazone and rosiglitazone entered the UK market) until 31 July 2013. These patients included those newly treated with an antidiabetic drug class, as well as those who switched to or added on an antidiabetic drug class not previously used in their treatment. Cohort entry was defined by the date of this new prescription. We excluded all patients with a diagnosis of bladder cancer (including malignant, in situ, and benign lesions) at any time before cohort entry, as well as those with less than one year of follow up after cohort entry. The latter was necessary for latency considerations, as short term drug use are unlikely to cause incident bladder cancer.All patients were followed from the year after cohort entry until a first ever diagnosis of bladder cancer (malignant and in situ), or censored on death from any cause, end of registration with the general practice, or end of the study period (31 July 2014), whichever occurred first.Use of thiazolidinedionesIn the models we entered the use of thiazolidinediones as a time varying variable and classified it according to one of the four mutually exclusive categories: pioglitazone use, rosiglitazone use, pioglitazone and rosiglitazone use (mainly switchers), and no thiazolidinedione use. Patients were considered unexposed to thiazolidinediones until the time of the first thiazolidinedione prescription and thereafter considered exposed, after accounting for a one year lag period. This lag period was necessary to take into account a latency time window and to minimise possible detection bias around the time of treatment initiation. This was considered the primary exposure definition.In secondary analyses, we determined whether there was a duration response and dose response relation between pioglitazone and incidence of bladder cancer. The duration response relation was assessed in terms of cumulative duration of use, which was defined, in a time dependent fashion, as the total number of years of use, calculated by summing the durations of all prescriptions received between cohort entry and the time of the event. This variable was then classified using the same categories used in the interim analysis of the Kaiser Permanente Northern California study4: 2 years of use. We also assessed cumulative duration on a continuous scale using a restricted cubic spline model with five knots.25 Dose response was assessed in terms of cumulative dose, which was calculated in a time dependent fashion as the sum of all doses received up until the date of the event. This variable was also categorised using the same cut offs used in previous studies4 5: 10500 mg, 10501 28000 mg, and >28000 mg. We assessed the linear trend for cumulative duration of use and dose by considering these variables as continuous in the models.For comparison purposes we also assessed whether there was a duration response and dose response relation with rosiglitazone, in terms of cumulative duration of use (categorically (2 years) and continuously using restricted cubic spline modelling) and cumulative dose (categorised on the basis of the distribution of use in thirds in the cohort). We also conducted two secondary analyses to assess whether there were duration response and dose response relations with pioglitazone and risk of bladder cancer in terms of cumulative duration of use and cumulative dose (as defined previously). Identical analyses were done for rosiglitazone. For all models we used the model proposed by Fine and Gray to account for competing risks due to death from any cause.27 We examined the Schoenfeld residuals for the time fixed covariates and found no important departures from the proportional hazards assumption.Sensitivity analysesWe conducted nine sensitivity analyses to assess the robustness of our findings. Firstly, given uncertainties related to the latency time window, we repeated the primary analysis with lag periods of zero and two years. Secondly, we repeated the primary analysis after considering a stricter definition for drug use based on receiving at least four prescriptions within a 12 month window. Thirdly, we repeated the analysis after excluding patients with a history of bladder conditions at any time before cohort entry and censoring on a new diagnosis during follow up. Fourthly, we repeated the primary analysis after additionally censoring on a new diagnosis of benign bladder lesions, in situ bladder cancer, liver failure, and heart failure (the last two were also additional exclusion criteria). Indeed, thiazolidinediones are contraindicated or not recommended for the two last conditions, the presence of which may lead to thiazolidinedione discontinuation or may influence treatment decisions. Fifthly, in 2011 several regulatory actions were issued because of the potential association between pioglitazone and bladder cancer.28 We performed a sensitivity analysis censoring follow up to 31 December 2010, as it is possible that patients starting or continuing pioglitazone after that date may have been more carefully screened for bladder cancer. Sixthly, we repeated the primary analysis using multiple imputation for variables with missing values (that is, body mass index, smoking, and haemoglobin A1c).29 30 Seventhly, we additionally adjusted the models for the time dependent use of other antidiabetic drugs (metformin, sulfonylureas, incretin based drugs (GLP 1 analogues or DPP 4 inhibitors), insulin, and other oral hypoglycaemic drugs) during follow up, lagged by one year for latency considerations. Eighthly, to account for potential time dependent confounding during the 14.5 year study period, we repeated the primary analysis using a marginal structural Cox proportional hazards model with inverse probability of treatment and censoring weighting (see the supplementary file for a detailed description of this method). Finally, we assessed the strength of an unmeasured confounder needed to move the estimated hazard ratio to the null using the "rule out" method proposed by Schneeweiss.31Head to head comparison of pioglitazone with rosiglitazoneTo assess further whether an association between pioglitazone and bladder cancer is a drug specific compared with a class effect, we conducted two additional analyses that directly compared pioglitazone with rosiglitazone. In the first approach, we contrasted the use of pioglitazone with the use of rosiglitazone by repeating our primary analysis with the latter as the reference category. In the second approach, we used the study cohort to assemble a subcohort of patients starting pioglitazone or rosiglitazone between 1 January 2000 and 31 July 2013, with follow up until 31 July 2014. As with the primary analysis, all patients were required to have at least one year of follow up after their first prescription for a thiazolidinedione. Consequently, cohort entry was set as the year after the first thiazolidinedione prescription during the study period. All patients were followed until a first ever diagnosis of bladder cancer, or censored on death from any cause, switching to another thiazolidinedione, end of registration with the general practice, or end of the study period, Hermes belts replica paris whichever occurred first. The model was adjusted for high dimensional propensity scores,32 which included the prespecified variables listed previously along with another 500 empirically defined variables measured at the time of the first thiazolidinedione prescription. All analyses were conducted with SAS version 9.4 (SAS Institute, Cary, NC).Patient involvementNo patients were involved in setting the research question or the outcome measure, nor were they involved in developing plans for design or implementation of the study. No patients were asked to advise on interpretation or writing up of results. There are no plans to disseminate the results of the research to study participants or the relevant patient community.ResultsA total of 145806 patients met the study inclusion criteria (see supplementary figure 1). Overall, the cohort was followed for a mean of 4.7 (SD 3.4) years, generating 689616 person years of follow up. Overall, 622 patients received a diagnosis of bladder cancer during follow up, yielding a crude incidence rate of 90.2 (95% confidence interval 83.2 to 97.6) per 100000 person years. Among patients with an event, the median time between cohort entry and an incident diagnosis of bladder cancer was 4.4 (interquartile range 2.5 6.5) years.Table 1 presents the characteristics of the cohort overall and stratified by pioglitazone users versus non thiazolidinedione users at baseline. Compared with non thiazolidinedione users, pioglitazone users were less likely to be obese but more likely to have increased haemoglobin A1c levels, to have undergone urine protein testing before cohort entry, had a longer duration of treated diabetes, and were more likely to have previous bladder conditions. Pioglitazone users were also more likely to have used sulfonylureas and less likely to have received metformin compared with non users of thiazolidinediones. The baseline characteristics of rosiglitazone users are similar and shown in supplementary table 1.Table 1 Baseline characteristics of cohort overall and stratified by users and non users of pioglitazone at cohort entry. Values are numbers (percentages) unless stated otherwiseView this table:View popupView inlineOverall, the use of rosiglitazone was not associated with an increased risk of incident bladder cancer (86.2 v 88.9 per 100000 person years, adjusted hazard ratio 1.10, 95% confidence interval 0.83 to 1.47; see supplementary table 2). Similarly, there was no evidence of a duration response relation in terms of cumulative duration of use when it was classified as a categorical variable (P=0.7 for trend; see supplementary table 2) or when it was considered as a continuous variable (see supplementary figure 2). Finally, there was no evidence of a dose response relation in terms of cumulative dose (P=0.7 for trend; see supplementary table 2).
AbstractObjectiveTo determine whether pioglitazone compared with other antidiabetic drugs is associated with an increased risk of bladder cancer in people with type 2 diabetes.ParticipantsA cohort of 145806 patients newly treated with antidiabetic drugs between 1 January 2000 and 31 July 2013, with follow up until 31 July 2014.Main outcome measuresThe use of pioglitazone was treated as a time varying variable, with use lagged by one year for latency purposes. Cox proportional hazards models were used to estimate adjusted hazard ratios with 95% confidence intervals of incident bladder cancer associated with pioglitazone overall and by both cumulative duration of use and cumulative dose. Similar analyses were conducted for rosiglitazone, a thiazolidinedione not previously associated with an increased risk of bladder cancer.ResultsThe cohort generated 689616 person years of follow up, during which 622 patients were newly diagnosed as having bladder cancer (crude incidence 90.2 per 100000 person years). Compared with other antidiabetic drugs, pioglitazone was associated with an increased risk of bladder cancer (121.0 v 88.9 per 100000 person years; hazard ratio 1.63, 95% confidence interval 1.22 to 2.19). Conversely, rosiglitazone was not associated with an increased risk of bladder cancer (86.2 v 88.9 per 100000 person years; 1.10, 0.83 to 1.47). Duration response and dose response relations brown hermes belt replica were observed for pioglitazone but not for rosiglitazone.ConclusionThe results of this large population based study indicate that pioglitazone is associated with an increased risk of bladder cancer. The absence of an association with rosiglitazone suggests that the increased risk is drug specific and not a class effect.IntroductionPioglitazone, an antidiabetic drug belonging to the thiazolidinedione class, has been shown to improve glycaemic levels in people with type 2 diabetes.1 However, in 2005 the PROactive randomised controlled trial unexpectedly showed an imbalance in the number of cases of bladder cancer with pioglitazone compared with placebo.2 In contrast, this imbalance was never observed in randomised controlled trials of rosiglitazone, the other approved drug belonging to the thiazolidinedione class.1 3The findings of the PROactive trial were subsequently corroborated in some,4 5 6 7 8 9 10 but not all, observational studies.11 12 13 14 15 16 17 18 19 Indeed, in the five year interim analysis of a large observational study using the Kaiser Permanente Northern California database,4 the use of pioglitazone for 24 months or more was associated with an increased risk of bladder cancer (hazard ratio 1.4, 95% confidence interval 1.03 to 2.0). However, in the final analysis of the Kaiser Permanente Northern California study, which used the same cohort4 with follow up extended to 10 years, the use of pioglitazone was no longer significantly associated with an increased risk of bladder cancer in a duration response fashion.20 These null findings are also consistent with those of another large multicohort study.19 The apparent heterogeneity in this literature may be due to methodological limitations, such as the inclusion of prevalent users,5 6 10 11 12 13 14 18 time lag bias,15 immortal time bias,10 14 18 and no consideration of disease latency.8 10 12 17 18Given these discrepant findings, the methodological shortcoming of previous studies examining this association, and the apparent loss of an association in studies with longer follow up,20 additional studies are needed to investigate further the association between pioglitazone and bladder cancer. In a large, population based study we assessed the association between the use of pioglitazone and bladder cancer in people with type Hermes belt replica paris 2 diabetes.MethodsData sourceThis study was conducted using the United Kingdom Clinical Practice Research Datalink (CPRD). The CPRD collects information on anthropometric variables such as body mass index and lifestyle variables such as smoking. Data collected in the CPRD have been previously validated and shown to be of high quality.22 23 Furthermore, cancer diagnoses have been found to be highly consistent with those recorded in the UK national cancer data repository.24Study populationBase cohortWe assembled a base cohort composed of all people newly treated for type 2 diabetes, defined as receiving a first ever prescription for a non insulin antidiabetic drug (metformin, sulfonylureas, prandial glucose regulators, thiazolidinediones, acarbose, dipeptidyl peptidase 4 (DPP 4) inhibitors, glucagon like peptide (GLP 1) agonists, sodium glucose cotransporter 2 (SGLT2) inhibitors) between 1 January 1988 and 31 July 2013. Patients were required to be at least 40 years of age and to have at least one year of CPRD medical history before that first prescription. We excluded patients prescribed insulin any time before their first non insulin antidiabetic prescription (as these may represent those with an advanced form of type 2 diabetes), and patients with a diagnosis of gestational diabetes and polycystic ovary syndrome (as these are other indications for metformin).Study cohortUsing the base cohort, we identified all patients who hermes belt price replica initiated a new antidiabetic drug class on or after 1 January 2000 (the year pioglitazone and rosiglitazone entered the UK market) until 31 July 2013. These patients included those newly treated with an antidiabetic drug class, as well as those who switched to or added on an antidiabetic drug class not previously used in their treatment. Cohort entry was defined by the date of this new prescription. We excluded all patients with a diagnosis of bladder cancer (including malignant, in situ, and benign lesions) at any time before cohort entry, as well as those with less than one year of follow up after cohort entry. The latter was necessary for latency considerations, as short term drug use are unlikely to cause incident bladder cancer.All patients were followed from the year after cohort entry until a first ever diagnosis of bladder cancer (malignant and in situ), or censored on death from any cause, end of registration with the general practice, or end of the study period (31 July 2014), whichever occurred first.Use of thiazolidinedionesIn the models we entered the use of thiazolidinediones as a time varying variable and classified it according to one of the four mutually exclusive categories: pioglitazone use, rosiglitazone use, pioglitazone and rosiglitazone use (mainly switchers), and no thiazolidinedione use. Patients were considered unexposed to thiazolidinediones until the time of the first thiazolidinedione prescription and thereafter considered exposed, after accounting for a one year lag period. This lag period was necessary to take into account a latency time window and to minimise possible detection bias around the time of treatment initiation. This was considered the primary exposure definition.In secondary analyses, we determined whether there was a duration response and dose response relation between pioglitazone and incidence of bladder cancer. The duration response relation was assessed in terms of cumulative duration of use, which was defined, in a time dependent fashion, as the total number of years of use, calculated by summing the durations of all prescriptions received between cohort entry and the time of the event. This variable was then classified using the same categories used in the interim analysis of the Kaiser Permanente Northern California study4: 2 years of use. We also assessed cumulative duration on a continuous scale using a restricted cubic spline model with five knots.25 Dose response was assessed in terms of cumulative dose, which was calculated in a time dependent fashion as the sum of all doses received up until the date of the event. This variable was also categorised using the same cut offs used in previous studies4 5: 10500 mg, 10501 28000 mg, and >28000 mg. We assessed the linear trend for cumulative duration of use and dose by considering these variables as continuous in the models.For comparison purposes we also assessed whether there was a duration response and dose response relation with rosiglitazone, in terms of cumulative duration of use (categorically (2 years) and continuously using restricted cubic spline modelling) and cumulative dose (categorised on the basis of the distribution of use in thirds in the cohort). We also conducted two secondary analyses to assess whether there were duration response and dose response relations with pioglitazone and risk of bladder cancer in terms of cumulative duration of use and cumulative dose (as defined previously). Identical analyses were done for rosiglitazone. For all models we used the model proposed by Fine and Gray to account for competing risks due to death from any cause.27 We examined the Schoenfeld residuals for the time fixed covariates and found no important departures from the proportional hazards assumption.Sensitivity analysesWe conducted nine sensitivity analyses to assess the robustness of our findings. Firstly, given uncertainties related to the latency time window, we repeated the primary analysis with lag periods of zero and two years. Secondly, we repeated the primary analysis after considering a stricter definition for drug use based on receiving at least four prescriptions within a 12 month window. Thirdly, we repeated the analysis after excluding patients with a history of bladder conditions at any time before cohort entry and censoring on a new diagnosis during follow up. Fourthly, we repeated the primary analysis after additionally censoring on a new diagnosis of benign bladder lesions, in situ bladder cancer, liver failure, and heart failure (the last two were also additional exclusion criteria). Indeed, thiazolidinediones are contraindicated or not recommended for the two last conditions, the presence of which may lead to thiazolidinedione discontinuation or may influence treatment decisions. Fifthly, in 2011 several regulatory actions were issued because of the potential association between pioglitazone and bladder cancer.28 We performed a sensitivity analysis censoring follow up to 31 December 2010, as it is possible that patients starting or continuing pioglitazone after that date may have been more carefully screened for bladder cancer. Sixthly, we repeated the primary analysis using multiple imputation for variables with missing values (that is, body mass index, smoking, and haemoglobin A1c).29 30 Seventhly, we additionally adjusted the models for the time dependent use of other antidiabetic drugs (metformin, sulfonylureas, incretin based drugs (GLP 1 analogues or DPP 4 inhibitors), insulin, and other oral hypoglycaemic drugs) during follow up, lagged by one year for latency considerations. Eighthly, to account for potential time dependent confounding during the 14.5 year study period, we repeated the primary analysis using a marginal structural Cox proportional hazards model with inverse probability of treatment and censoring weighting (see the supplementary file for a detailed description of this method). Finally, we assessed the strength of an unmeasured confounder needed to move the estimated hazard ratio to the null using the "rule out" method proposed by Schneeweiss.31Head to head comparison of pioglitazone with rosiglitazoneTo assess further whether an association between pioglitazone and bladder cancer is a drug specific compared with a class effect, we conducted two additional analyses that directly compared pioglitazone with rosiglitazone. In the first approach, we contrasted the use of pioglitazone with the use of rosiglitazone by repeating our primary analysis with the latter as the reference category. In the second approach, we used the study cohort to assemble a subcohort of patients starting pioglitazone or rosiglitazone between 1 January 2000 and 31 July 2013, with follow up until 31 July 2014. As with the primary analysis, all patients were required to have at least one year of follow up after their first prescription for a thiazolidinedione. Consequently, cohort entry was set as the year after the first thiazolidinedione prescription during the study period. All patients were followed until a first ever diagnosis of bladder cancer, or censored on death from any cause, switching to another thiazolidinedione, end of registration with the general practice, or end of the study period, Hermes belts replica paris whichever occurred first. The model was adjusted for high dimensional propensity scores,32 which included the prespecified variables listed previously along with another 500 empirically defined variables measured at the time of the first thiazolidinedione prescription. All analyses were conducted with SAS version 9.4 (SAS Institute, Cary, NC).Patient involvementNo patients were involved in setting the research question or the outcome measure, nor were they involved in developing plans for design or implementation of the study. No patients were asked to advise on interpretation or writing up of results. There are no plans to disseminate the results of the research to study participants or the relevant patient community.ResultsA total of 145806 patients met the study inclusion criteria (see supplementary figure 1). Overall, the cohort was followed for a mean of 4.7 (SD 3.4) years, generating 689616 person years of follow up. Overall, 622 patients received a diagnosis of bladder cancer during follow up, yielding a crude incidence rate of 90.2 (95% confidence interval 83.2 to 97.6) per 100000 person years. Among patients with an event, the median time between cohort entry and an incident diagnosis of bladder cancer was 4.4 (interquartile range 2.5 6.5) years.Table 1 presents the characteristics of the cohort overall and stratified by pioglitazone users versus non thiazolidinedione users at baseline. Compared with non thiazolidinedione users, pioglitazone users were less likely to be obese but more likely to have increased haemoglobin A1c levels, to have undergone urine protein testing before cohort entry, had a longer duration of treated diabetes, and were more likely to have previous bladder conditions. Pioglitazone users were also more likely to have used sulfonylureas and less likely to have received metformin compared with non users of thiazolidinediones. The baseline characteristics of rosiglitazone users are similar and shown in supplementary table 1.Table 1 Baseline characteristics of cohort overall and stratified by users and non users of pioglitazone at cohort entry. Values are numbers (percentages) unless stated otherwiseView this table:View popupView inlineOverall, the use of rosiglitazone was not associated with an increased risk of incident bladder cancer (86.2 v 88.9 per 100000 person years, adjusted hazard ratio 1.10, 95% confidence interval 0.83 to 1.47; see supplementary table 2). Similarly, there was no evidence of a duration response relation in terms of cumulative duration of use when it was classified as a categorical variable (P=0.7 for trend; see supplementary table 2) or when it was considered as a continuous variable (see supplementary figure 2). Finally, there was no evidence of a dose response relation in terms of cumulative dose (P=0.7 for trend; see supplementary table 2).
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