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Supplementay Online Content Lewis JD, Habel LA, Quesenbey CP, et al.pioglitazone use and isk of bladde ca and othe common cas in pesons with diabetes. JAMA. doi:10.11/jama.2015.7996. Supplemental Methods. etable 1. Bladde ca stage by pioglitazone teatment etable 2. Hazad Ratios and Confide Intevals fo All Vaiables Included in the Analysis of Eve Exposue to Pioglitazone and the Risk of Bladde Caa: Kaise Pemanente Nothen Califonia Diabetes Registy etable 3. Hazad Ratios a Assessing the Association between Pioglitazone Teatment and Bladde Ca Risk by Sex and Smoking Status: Kaise Pemanente Nothen Califonia Diabetes Registy etable 4. Analysis of Bladde Ca Risk and Duation of Exposue to Pioglitazone with Altenative Categoies of Exposue Including the Categoies Used in the Pio Repot of this Cohot among 193,099 Patients: Kaise Pemanente Nothen Califonia Diabetes Registy etable 5. Analysis of Bladde Ca Risk and Duation of Diabetes Theapies among the 59,070 Patients Who Wee Newly Diagnosed with Diabetes at Cohot Enty: a Kaise Pemanente Nothen Califonia Diabetes Registy etable 6. Sensitivity Analysis of Bladde Ca Risk and Pioglitazone Exposue Censoing FollowUp If Pioglitazone Was Discontinued fo at Least 1 Yea: Kaise Pemanente Nothen Califonia Diabetes Registy etable 7. Sensitivity Analysis of Bladde Ca Risk and Pioglitazone Exposue Using Fine Gadation of the Oldest Age Categoy:a Kaise Pemanente Nothen Califonia Diabetes Registy etable 8. Sensitivity Analysis of Bladde Ca Risk and Pioglitazone Exposue Using Altenative FollowUp Peiods and Altenative Methods to Calculate Cumulative Dose and Duation: Kaise Pemanente Nothen Califonia Diabetes Registy etable 9. Compaison of Suvey Respondents and NonRespondents by CaseContol Status in Nested CaseContol Study of Bladde Ca and Pioglitazone Exposue: Kaise Pemanente Nothen Califonia Diabetes Registy etable 10 Cude of Ca at 10 Sites Accoding to Dose and Duation of Pioglitazone Exposue (n= 236,507)], Kaise Pemanente Nothen Califonia Diabetes Registy, 19972012 etable 11. Adjusted a Hazad Ratios fo Eve Use of Pioglitazone and othe diabetes medications and Risk of Ca of the Postate, Female Beast, Lung/Bonchus and Colon, nonhodgkin Lymphoma, Copus Utei, Paas, Kidney/Renal Pelvis, and Rectum and Melanoma: Kaise Pemanente Nothen Califonia Diabetes Registy, 19972012 etable 12. Hazad Ratio a,b Estimates fo the Risk of Ca at 10 sites Associated with Time si Initiation of Pioglitazone, Duation of Pioglitazone Use, and Dose of Pioglitazone used in Sensitivity Analysis 1 [individuals censoed at the time they stop using pioglitazone (n=236,507)], Kaise Pemanente Nothen Califonia Diabetes Registy,1997 2012 etable 13. Hazad Ratio a,b Estimates fo the Risk of Ca at 10 sites Associated with Time si Initiation of Pioglitazone, Duation of Pioglitazone Use, and Dose of Pioglitazone used in Sensitivity Analysis 2 [among individuals with complete infomation on pioglitazone pesciptions (n=196,401)], Kaise Pemanente Nothen Califonia Diabetes Registy, 19972012

etable 14a. Hazad Ratio a b c Confide Intevals) Estimates fo the Risk of Ca at 10 sites Associated with Time si Initiation of Pioglitazone, Duation of Pioglitazone Use, and Dose of Pioglitazone Used in Sensitivity Analysis 3 [among individuals with additional postal suvey data on height, weight and health behavios (n= 48,425)], Kaise Pemanente Nothen Califonia Diabetes Registy, 19972012 etable 14b. Hazad Ratio a b c Estimates fo the Risk of Ca at 10 Sites Associated with Time si Initiation of Pioglitazone, Duation of Pioglitazone use, and Dose of Pioglitazone Used in Sensitivity Analysis 3 [among individuals with additional postal suvey data on height, weight and health behavios (n= 48,425)], Kaise Pemanente Nothen Califonia Diabetes Registy, 19972012 etable 15. Adjusted a Hazad Ratios Confide Intevals) fo Time Si Initiation of Pioglitazone, Duation of Pioglitazone Use, and Dose of Pioglitazone Used and Risk of Ca at 10 Sites Calculating Duation and Dose Stating with the Second Pesciption fo Pioglitazone, Kaise Pemanente Nothen Califonia Diabetes Registy, 19972012 etable 16. Hazad atios fo the isk of postate ca associated with eve use of pioglitazone, time si initiation, duation, and dose, with and without adjustment fo PSA sceening in the pevious 5 and 3 among a cohot of 123,880 men with diabetes: Kaise Pemanente Nothen Califonia, Januay 1, 1997June 30, 2012 a This supplementay mateial has been povided by the authos to give eades additional infomation about thei wok.

BLADDER CANCER STUDY SUPPLEMENTAL METHODS Data Souce The study was conducted within Kaise Pemanente Nothen Califonia (KPNC), which povides compehensive healthcae sevices to appoximately 3.2 million membes, epesenting appoximately 30% of the population in its catchment aea 1. The KPNC phamacy database ecods infomation on each outpatient pesciption dispensed at a KPNC phamacy and includes medication name, dose, egimen, numbe of pills and days supply. Pio eseach demonstated that 80% to 85% of KPNC membes fill all of thei pesciptions at Kaise phamacies; it is appoximately 95% fo those with a phamacy benefit 1. The souce population was identified fom the KPNC diabetes egisty, which was fist constucted in 1993 and has been updated annually si then. The egisty identifies patients pimaily fom fou data souces: pimay hospital dischage oses of diabetes mellitus (si 1971); two o moe outpatient visit oses of diabetes (si 1995); any pesciption fo a diabeteselated medication (si 1994); o any ecod of an abnomal hemoglobin A1c (HbA1c) test (>6.7%) (si 1991). The diabetes egisty gathes data fom a vaiety of KPNC electonic medical ecods (EMR) to build and follow the egisty cohot acoss time. These data include ca egisties, phamacy ecods, laboatoy ecods, and inpatient and outpatient medical oses. These data have been widely employed in pio epidemiological studies 1. Ceation of the Study Cohot The study cohot included both pesons with an established osis of diabetes mellitus pio to Januay 1, 1997 and those who wee newly osed pio to Decembe 31, 22. Patients wee eligible fo the study cohot if they met any of the following citeia: 1) as of Januay 1, 1997 they had been osed with diabetes mellitus, wee age 40 o olde and wee membes of KPNC, 2) they had been osed with diabetes mellitus, eached age 40 between Januay 1, 1997 and Decembe 31, 22 and wee KPNC membes on thei 40th bithday, o 3) had diabetes mellitus and wee age 40 o olde when they joined KPNC between Januay 1, 1997 and Decembe 31, 22. Fom this cohot of 207,378 we then excluded 823 pesons with a osis of bladde ca pio to enty in the cohot o within 6 of joining KPNC in ode to avoid misclassification of pevalent bladde cas as incident oses. Likewise, pesons without pesciption benefits at the time of enty into the cohot (n=6,674) o those with a gap of moe than fou in pesciption o membeship benefits whee the gap stated within the fist fou of enteing the cohot (n=6,782) wee excluded. These pesons would have an extemely limited oppotunity to meet ou exposue definition (descibed below). This esulted in 193,099 eligible men and women with diabetes mellitus, of whom 59,070 wee newly osed with diabetes mellitus between Januay 1, 1997 and Decembe 31, 22. Followup Peiod We included a total of 16 of data extending fom Januay 1, 1997 though Decembe 31, 2012. This epot includes an addition of 4 and 8 fom ou published inteim analysis 2. Followup stated on the fist date that the inclusion citeia wee met. Followup fo pesons in the cohot ended when the fist of the following occued: 1) a gap of geate than 4 in eithe membeship o pesciption benefits, 2) a new osis of bladde ca, 3) death fom any cause, o 4) end of followup (Decembe 31, 2012). Outcome The outcome fo this study was an incident osis of bladde ca. nt bladde cas wee identified fom the KPNC ca egisty (one of seveal sites that submit data to the Suveilla, Epidemiology, and End Results [SEER] pogam) fom Januay 1, 1997 to Decembe 31, 2012. This was supplemented by case identification though suveilla of electonic pathology epots within KPNC fo the peiod fom Januay 1, 25 to Mach 23, 2012, the time peiod of inteviewing fo the linked nested casecontol study 2. We did not make any distinction egading the histology of the bladde ca and included pesons osed with in situ bladde ca as well as papillay uethal neoplasm of low malignant potential (PUNLMP) fom 25 onwad 3,4. Exposue Definition The pimay exposue of inteest in this study was teatment with pioglitazone, defined as having filled at least two pesciptions fo the dug within a 6month peiod accoding to the KPNC phamacy database. Followup fo eve use began with the second of 2 pesciptions defining eve use such that pesons wee consideed unexposed until the second pesciption was filled. Identical definitions wee used to detemine exposue to othe categoies of diabetes medications. Exposue to pioglitazone and all othe diabetes medications wee teated as unidiectional time dependent vaiables, i.e., o a peson met the exposue definition the peson was consideed exposed fom that point fowad, even if they discontinued the medication. Diabetes medications wee categoized as pioglitazone, othe TZDs, metfomin, sulfonylueas, insulin, and othe (e.g., miglitol and acabose). In addition, indicato vaiables wee ceated sepaately fo pesons who had not eceived any diabetes medication

pesciptions and fo those who eceived at least one pesciption but had not met the definition of exposue (i.e., did not fill two pesciptions fo the same medication within a 6month peiod). Each of these was consideed as a sepaate vaiable. Due to the numeous combinations of diabetes medications that ae used by pesons within the cohot and the abse of an a pioi hypothesis that cetain combinations would be moe o less hamful, we did not attempt to ceate vaiables to descibe the diffeent combinations (e.g., sulfonyluea plus pioglitazone). Cumulative duation of exposue was measued by counting the numbe of days between pesciptions. If the next pesciption was filled within 30 days of the expected end date of the pevious pesciption, we assumed that theapy was uninteupted. Howeve, if thee wee no efills within the 30 days afte the expected end date of the pevious pesciption, we assumed a gap in theapy stating 30 days afte the date that the pevious pesciption should have ended (based on days supply vaiable in pesciption database). Cumulative dose of pioglitazone was calculated in a simila fashion. Fo any pesciption that was completed pio to an event date, the total pescibed dose (i.e., numbe of pills in the pesciption multiplied by the dose of the pills) was assumed to have been consumed. Fo pesciptions that wee still active on the date of an event, the total consumed dose was educed to eflect the popotion of pills expected to have been consumed by that date. Potential Confounding Vaiables fo the Cohot Study Fo the cohot study, data on the potential confoundes listed in Table 1 wee extacted fom the EMR. We selected as potential confoundes vaiables believed to be associated with one o moe of the following: the isk of bladde ca (e.g., age, ace, sex, smoking, socioeconomic status), the possibility of detection of bladde ca (e.g., uinay diseases o symptoms including uinay tact infections, uinay incontine, uolithiasis, and pio histoy of othe cas), o the likelihood of being pescibed pioglitazone (e.g., diabetes duation, HbA1c levels, congestive heat failue, and enal insufficiency). Most confoundes othe than smoking wee measued using data ecoded on o befoe the stat of followup. The following vaiables wee teated as time updating covaiates: use of statins, angiotensin conveting enzyme inhibitos o angiotensin ecepto blockes, o medications used to teat benign postatic hypetophy, uinay incontine, uinay tact infection o pyelonephitis, uolithiasis, othe bladde conditions, postatic specific antigen (PSA) testing, HbA1c contation, and complications of diabetes. Complications of diabetes included diabetic etinopathy, peipheal neuopathy, diabetic nephopathy, micoalbuminuia o poteinuia, and coonay atey disease. This vaiable was analyzed both as a composite vaiable and as its individual components. Race was categoized as ecoded in the electonic health ecods. Whee appopiate, categoical vaiables included an additional categoy fo missing data. Although body mass index was poposed as a potential confounde in the potocol, this was not analyzed si the vaiable was missing in appoximately 50% of the pesons. Smoking status was categoized as cuent, not cuent, o missing. Data on smoking have been ecoded in the electonic databases si the middle of 1998. Fo pesons who enteed the cohot pio to this time, electonic smoking data is incomplete. To account fo this, we also used data on smoking fom a patient suvey that was completed duing the 1994 to 1996 by membes of the diabetes egisty, which included 65,282 (34%) pesons fom the bladde ca cohot.. Thus, pesons wee categoized as smokes if they wee identified as cuent smokes in the outpatient EMR (14.8%) o by the suvey (3.1%). Patients who wee censoed pio to July 1, 1998, had not completed the suvey, and lacked smoking data in the electonic ecod wee consideed to have missing data on smoking (n=6,905, 3.6%). In the multivaiable analyses descibed below, pesons with missing data on smoking wee gouped with nonsmokes. Analyses excluding pesons with missing smoking data yielded nealy identical esults (data not shown). Similaly, diabetes duation was assessed fom a patient suvey that was completed duing the 1994 to 1996 by membes of the diabetes egisty. Using this souce we obtained diabetes duation at the baseline (o date of enty in the cohot) fo 47,051 (24.4%) people. Fo the emaining people we attempted to calculate diabetes duation at the baseline using the date of enty in the diabetes egisty. We wee able to do so fo the 106,281 (55.0%) diabetes egisty membes who had been in the health plan fo at least two pio to the date of enty in the diabetes egisty. Howeve, fo the emaining 39,778 (20.6%) people who had been in the health plan fo less than two befoe the date of enty in the diabetes egisty, we wee unable to assess diabetes duation. Renal insufficiency was detemined fom measued ceatinine contations. We used the sexspecific theshold levels suggested as a containdication to metfomin theapy to define enal insufficiency ( 1.5 mg/dl in males and 1.4 mg/dl in females) 5. Diabetic nephopathy was defined as a ceatinine contation >2.0 mg/dl fo both men and women. Median annual household income in the census block was used as a measue of socioeconomic status. We dichotomized this measue as high o low, based on whethe the census block median annual household income was above o below the aveage census block median income fo the cohot ($59,0) at the time of the fist inteim analysis. Statistical Analyses fo the Cohot Study Continuous and categoical vaiables wee compaed with the Wilcoxon ank sum test and chisquae test o Fishe s exact test, espectively.

Pimay analysis Fo the cohot study, Cox popotional hazads models wee used fo all calculations of the elative hazad (HR) of bladde ca with pioglitazone, adjusted fo the covaiates. The efee goup fo calculation of the elative hazad associated with eve use of pioglitazone was neve use of pioglitazone. Neve use of pioglitazone includes pesons on no diabetes medications, with < 2 fills fo pioglitazone in a 6 month peiod, and with use of medications othe than pioglitazone. Identical methods wee used to detemine elative hazads associated with exposue to othe categoies of diabetes medications. We decided a pioi to include age (categoized as 4049, 5059, 6069, and 70 o olde) and sex in all baseline models, given the known association of these vaiables with iased isk of bladde ca. Calenda yea of cohot enty was included in the baseline model to account fo tends in teatment pattens. Othe categoies of diabetes medications wee included in the baseline model to assess both fo confounding and the association of the othe medications with bladde ca. To test fo confounding, we pefomed analyses that included smoking and othe vaiables measued at baseline in an adjusted Cox egession model. This adjusted model included the following as covaiates: age, sex, ace/ethnicity, yea of cohot enty, othe diabetes medications, smoking, othe bladde conditions, median household income, congestive heat failue, ca othe than bladde ca, enal insufficiency, HbA1c and the inteaction with new osis of diabetes, duation of diabetes. Patients who ae newly osed with diabetes will always have an elevated HbA1c contation but this usually impoves quickly when theapy is initiated. This is diffeent fom a peson who is on teatment and despite this has an elevated HbA1c contation. This latte goup eflects poo contol of diabetes despite theapy. The inteaction tem allows fo this distinction. The fully adjusted model did not include the time updating vaiables, as it was not infeasible to include so many time updating vaiables in a single model. Rathe, we tested each time updating vaiable sepaately by adding the vaiable to the base model to detemine whethe inclusion of the vaiable changed the HR fo the association with pioglitazone by 10% o moe. None of the vaiables esulted in a 10% o geate change, and as such none meet ou definition of confounding. Howeve, the lagest changes in the HR wee seen when the vaiables elated to poteinuia o diabetic nephopathy wee included. Thus, we ceated an additional model that included the vaiables measued at baseline, smoking, and the esults of testing fo micoalbuminuia. As descibed peviously 6, the latte vaiable excluded uine tests that included testing fo hematuia and was categoized as positive, negative, o no testing duing the past yea. Seconday Analysis Assessment of Relation between Pioglitazone Dose and Duation and Bladde Ca Additional analyses wee pefomed to exploe fo evide of an iasing isk of bladde ca with iasing exposue to pioglitazone as compaed to neve use of pioglitazone. We measued exposue in tems of the following: time si initiation of theapy, cumulative dose of pioglitazone, and cumulative duation of theapy. Calculation of the total dose o duation of teatment was computed stating with the fist pesciption that defined eve use of pioglitazone. Each of these vaiables was categoized into thee levels (tetiles) such that we had thee goups of appoximately simila size. The efee goup fo these analyses was neve use of pioglitazone. Test fo effect modification We also examined whethe the association between bladde ca and pioglitazone exposue (eve vs. neve and by duation, dose, and time si initiation of pioglitazone) diffeed accoding to sex o by smoking status. Sex was selected to examine fo effect modification based on the appaent diffee in bladde ca isk among male and female ats teated with pioglitazone. Smoking was selected because of the stong association between smoking and bladde ca isk. Additional pespecified analyses of pesons with complete histoy of dug exposue and association of othe diabetes medications with bladde ca isk An analysis limited to pesons who wee newly osed with diabetes duing the un in peiod fom 1997 to 22. The definition of newly osed diabetes equied that the peson was a membe of KPNC fo a minimum of 2 befoe thei fist diabetes osis. This analysis eliminated the potential fo left censoing. This analysis also allowed us to examine the duation effect of othe medications. Additional post hoc analyses We designed a numbe of post hoc analyses, lagely geaed at undestanding diffees in the 5yea inteim analysis and the 10yea final analysis and checking fo potential bias in ou design. These included the following: 1) An analysis that tuncated followup afte Apil 30, 28 (the end of followup in the published inteim analysis) but used the cuent cut points fo exposue duation. This analysis allowed us to assess whethe small changes in the computational methods o updates to the clinical and ca egisty data could have impacted the esults. 2) An analysis that futhe divided the longest exposue duation categoy into 4.1 to 6 and moe than 6, fully adjusted as in the pimay analyses. This analysis allowed us to assess fo a duation esponse using fine gadation of the

duation categoies, whethe those with the longest exposue to pioglitazone had the highest isk of bladde ca, and whethe the smalle hazad atio fo long tem exposue to pioglitazone in the final analysis was unifom acoss all duations of exposue o unique to only those with vey long duation of use. 3) An analysis that censoed followup afte pesons discontinue pioglitazone fo 1 yea. This examined whethe ou design that consideed pesons exposed foeve even if they discontinued theapy could have biased the esults. 4) An analysis that futhe divided the uppe most age categoy into fine goups to account fo potential bias elated to less use of pioglitazone among eldely pesons, fully adjusted as in the pimay analysis. 5) Pioglitazone is typically used only in pesons fo whom fist line theapy with diet and metfomin is inadequate An analysis was completed that excluded the fist 6 afte cohot enty to account fo possible iased detection of bladde ca in those newly osed with diabetes mellitus 7 (etable 8). Patients who eceived one o moe pesciptions fo pioglitazone duing the fist 6 in the cohot wee excluded fom the analysis to avoid immotal time bias. Models wee un in the entie cohot and those who wee newly osed with diabetes duing the followup peiod. 6) In the pimay analysis, dose and duation included the fist pesciption that was pat of the equiement fo two pesciptions within 6 to define eve exposue. This appoach povides a moe accuate estimate of the tue duation of exposue, howeve it also includes a small amount of immotal time when it would not have been possible fo the peson to have developed bladde ca (i.e. had they been osed with bladde ca between the fist and second pesciption, they would have been categoized as a case fo the unexposed cohot). Stating the calculation of dose and duation with the second pesciption eliminates the isk of immotal time bias but povides an inaccuate estimate of the cumulative dose and duation of exposue. To addess this, we epeated the analysis stating the calculation of dose and duation at the time of the 2 nd pesciption that met the definition of exposue (etable 8). Nested casecontol study To account fo incomplete o missing EMR data on ace/ethnicity, smoking histoy, duation of diabetes, and occupational exposues, we supplemented the cohot study with a casecontol study nested within the study cohot. Fom the souce cohot, we identified all incident oses of bladde ca fo the peiod fom Octobe 1, 22 to Mach 23, 2012. The index date was defined as the date of bladde ca osis. Fo each individual with bladde ca, one contol was andomly selected afte matching on sex, age ( 2.5 ), and time fom enty into the diabetes egisty to index date (± 6 ). In addition, each contol subject could not have been osed with bladde ca o have been censoed fom the cohot fo othe easons pio to the date of fist osis with bladde ca of the matched case subject. When a contol subject could not be eached fo inteview (see below) o efused to paticipate, additional contol subjects wee selected until a matched contol could be enolled. A minimum of 15 attempts that included a vaiety of days and times wee made to each all cases and contol subjects befoe detemining that the subject was uneachable. The date that the case subject was fist osed with bladde ca seved as the efee date fo both the case subject and fo the matched contol. The additional data fo the casecontol study (e.g., ace/ethnicity, duation of diabetes, smoking, use of indwelling cathetes, fequency of uinay tact infections, and occupational exposues) wee collected up to the efee date though telephone inteviews using a standadized questionnaie administeed by tained inteviewes. The questionnaie was administeed using computeassisted telephone inteviews (CATI) with diect data enty by inteviewe. Fo a small numbe of case subjects who wee unable to complete the full inteview (n=46), a shote inteview was completed by a poxy. Fo 23 of these case subjects, the matched contol subject also completed the shote poxy vesion of the suvey. In 7 cases with full inteviews, the contol had a poxy inteview. In the casecontol study, smoking was categoized accoding to total pack consumed pio to the efee date. Ciga and/o pipe smoking among noncigaette smokes wee combined as a dichotomous vaiable fo having eve smoked 1 o moe cigas o pipes pe week fo six o longe. Duation of diabetes was categoized as less than 5, 6 to 10, moe than 10, and unknown. Pevious and/o cuent employment in pofessions associated with iased bladde ca isk wee teated as dichotomous vaiables. Highisk occupational exposues wee defined as any pio histoy of wok as a painte, dive o haidesse 8 10. Pevious uinay tact infection was categoized as none, one to two pio infections, o moe than two pio infections. Statistical analyses fo the Nested CaseContol Study We examined the chaacteistics of the paticipants and nonpaticipants in the nested casecontol study using desciptive statistics (etable 9). Analysis of the casecontol study was conducted in a simila fashion as the cohot study except that conditional logistic egession was used to calculate odds atios (ORs) and 95% confide intevals (CIs). Within the casecontol study, potential confoundes that wee deived exclusively fom EMR data wee defined as descibed fo the cohot study (e.g., congestive heat failue was assessed at the stat of followup in the cohot).

PROSTATE CANCER SUPPLEMENTAL METHODS To assess the potential fo detection bias seconday to diffeential use of postatespecific antigen (PSA) testing by pioglitazone use, in a post hoc analysis, the isk of postate ca associated with eve use, time si initiation, duation and dose of pioglitazone, was estimated with and without adjustment fo PSA sceening the pevious 5. Similaly, to examine the potential impact of osis with and teatment fo BPH, the isk of postate ca associated with eve use, time si initiation, duation and dose of pioglitazone was estimated with additional adjustment fo BPH teatment [classified as having had a BPH pocedue [i.e., tansuethal esection of the postate (TURP)], dug teatment fo BPH (alpha blocke o 5ARI), had BPH but not teated, o no BPH (efee). Results of these analyses ae included in etable 16. Refees 1. Fiedman G, Habel L, Boles M, et al. Kaise Pemanente Medical Cae Pogam: Division of Reseach, Nothen Califonia, and Cente fo Health Reseach, Nothwest Division. In: Stom BL, ed. Phamacoepidemiology. Thid ed. West Sussex: John Wiley & Sons, Ltd; 20:263 283. 2. Lewis JD, Feaa A, Peng T, et al. Risk of bladde ca among diabetic patients teated with pioglitazone: inteim epot of a longitudinal cohot study. Diabetes cae. Ap 2011;34(4):916 922. 3. Samaatunga H, Makaov DV, Epstein JI. Compaison of WHO/ISUP and WHO classification of noninvasive papillay uothelial neoplasms fo isk of pogession. Uology. Aug 22;60(2):315 319. 4. Cheng L, Neumann RM, Bostwick DG. Papillay uothelial neoplasms of low malignant potential. Clinical and biologic implications. Ca. Nov 15 1999;86(10):2102 2108. 5. Glucophage and Glucophage XR (metfomin HCl). Glucophage (metfomin HCl) Tablets and Glucophage XR (metfomin HCl extended elease) Tablets [Full Pescibing Infomation (US only)]. Piton, NJ, Bistol Myes Squibb Company; 29. 6. Lewis JD, Habel L, Quesenbey C, et al. Poteinuia testing among patients with diabetes mellitus is associated with bladde ca osis: potential fo unmeasued confounding in studies of pioglitazone and bladde ca. Phamacoepidemiology and dug safety. Ap 25 2014. 7. Colmes IN, Majumda SR, Yasui Y, Bowke SL, Maa CA, Johnson JA. Detection bias and oveestimation of bladde ca isk in type 2 diabetes: a matched cohot study. Diabetes cae. Oct 2013;36(10):3070 3075. 8. Chen R, Seaton A. A meta analysis of painting exposue and ca motality. Ca Detect. Pev. 1998;22(6):533 539. 9. Kunze E, Chang Claude J, Fentzel Beyme R. Life style and occupational isk factos fo bladde ca in Gemany. A casecontol study. Ca. Ap 1 1992;69(7):1776 1790. 10. Takkouche B, Regueia Mendez C, Montes Matinez A. Risk of ca among haidesses and elated wokes: a metaanalysis. Int. J. Epidemiol. Sep 14 29.

etable 1. Bladde ca stage by pioglitazone teatment Ca Stage Eve Use of Pioglitazone a Neve Use of Pioglitazone (n=186 Cases) (n=1,075 Cases) PUNLMP b 2 (1%) 11 (1%) In situ 93 (50%) 521 (49%) Local 74 (40%) 409 (38%) Regional 8 (4%) 65 (6%) Distant 3 (2%) 34 (3%) Undetemined 6 (3%) 35 (3%) a Eve use is defined as two pesciptions fo pioglitazone within 6 and was teated as time updating b Papillay uethal neoplasm of low malignant potential

etable 2. Hazad Ratios and Confide Intevals fo All Vaiables Included in the Analysis of Eve Exposue to Pioglitazone and the Risk of Bladde Ca a : Kaise Pemanente Nothen Califonia Diabetes Registy All Covaiates Numbe with Chaactei stic Bladde Ca Fully Adjusted HR Diabetes Medications Neve use of Pioglitazone 158,918 1,075 Refee Eve use of Pioglitazone 34,181 186 1.06 (0.891.26) Neve use of Othe TZDs 187,856 1,223 Refee Eve use of Othe TZDs 5,243 38 1.09 (0.781.53) Neve use of Metfomin 91,134 697 Refee Eve use of Metfomin 101,965 564 1.02 (0.891.18) Neve use of Insulin 128,443 933 Refee Eve use of Insulin 64,656 328 1.03 (0.881.20) Neve use of Sulfonylueas 65,092 455 Refee Eve use of Sulfonylueas 128,7 806 1.03 (0.871.23) Neve use of Othe oal hypoglycemic agents 188,711 1,240 Refee Eve use of Othe oal hypoglycemic agents 4,388 21 0.91 (0.591.40) Teated with any diabetes medications 170,426 1,047 Refee Neve teated with any diabetes medications 22,673 214 1.09 (0.871.37) Teated with any diabetes medications o neve eceived even a single pesciption fo any diabetes medications Received at least one pesciption fo a diabetes medication but neve met the definition of exposue 185,914 1,217 Refee 7,185 44 0.98 (0.701.39) Sex Female 89,851 211 Refee Male 103,248 1,050 4.47 (3.855.20) Age at Cohot Enty Age 4049 45,064 39 Refee Age 5059 51,907 203 4.04 (2.865.70) Age 6069 50,489 514 9.98 (7.1813.9) Age >=70 45,639 505 14.8 (10.620.7) Cohot Enty Enteed cohot in 1997 90,379 701 Refee Enteed cohot in 1998 16,112 99 0.86 (0.641.14) Enteed cohot in 1999 18,920 124 1.02 (0.781.34) Enteed cohot in 20 18,818 103 0.92 (0.691.22) Enteed cohot in 21 25,827 130 0.76 (0.581.01) Enteed cohot in 22 23,043 104 0.75 (0.561.01)

etable 2. Hazad Ratios and Confide Intevals fo All Vaiables Included in the Analysis of Eve Exposue to Pioglitazone and the Risk of Bladde Ca a : Kaise Pemanente Nothen Califonia Diabetes Registy (continued) All Covaiates Numbe with Chaacteistic Bladde Ca Fully Adjusted HR Race Caucasian 1,628 954 Refee Black 20,696 88 0.54 (0.430.68) Asian 25,337 78 0.38 (0.3.48) Hispanic 21,479 73 0.42 (0.330.53) Othe ace 11,034 68 0.72 (0.560.92) Smoking Befoe Censo Date 34,597 305 1.46 (1.281.66) Any Bladde Conditions on o Pio to 29,267 164 0.92 (0.781.09) Cohot Enty Median Household Income Below aveage (<$59K) 96,683 622 Refee Above aveage (>$59K) 78,958 575 0.99 (0.881.11) Income census data missing 17,458 64 0.80 (0.611.04) Histoy of Congestive Heat Failue Absent 181,092 1,176 Refee Pesent 12,7 85 1.09 (0.871.37) Pio Diagnosis of Ca Othe Than Bladde Ca Absent 183,583 1,168 Refee Pesent 9,516 93 1.18 (0.951.46) Seum Ceatinine at Cohot Enty Nomal 149,053 987 Refee Abnomal 15,241 117 1.03 (0.841.26) Missing 28,805 157 1.03 (0.861.23) HbA1c at Cohot Enty <7 51,280 460 Refee 77.9 36,972 242 0.79 (0.630.99) 88.9 20,981 146 0.97 (0.751.25) 99.9 14,503 79 0.74 (0.541.02) >=10 35,347 172 0.91 (0.701.18) Missing 34,016 162 0.72 (0.540.94) Newly Diagnosed Diabetic 109,426 643 1.26 (0.951.67) Inteaction Tem HbA1c 77.9 and newly osed diabetic 20,794 121 1.04 (0.761.43) HbA1c 88.9 and newly osed diabetic 9,842 53 0.87 (0.591.28) HbA1c 99.9 and newly osed diabetic 6,645 31 1.01 (0.621.65) HbA1c >=10 and newly osed diabetic 20,890 81 0.75 (0.521.08) HbA1C missing and newly osed 20,505 90 0.88 (0.611.28) diabetic Newly Diagnosed Diabetic 109,426 643 1.26 (0.951.67)

etable 3. Hazad Ratios a Assessing the Association between Pioglitazone Teatment and Bladde Ca Risk by Sex and Smoking Status: Kaise Pemanente Nothen Califonia Diabetes Registy Peson of followup time unexposed to pioglitazone Peson of followup time eve exposed to pioglitazone Cases of bladde ca among pioglitazone unexposed Cases of bladde ca among pioglitazone exposed Bladde ca incide ate among pioglitazone unexposed (pe peson) Bladde ca incide ate among pioglitazone exposed (pe peson) Men Women Smokes Nonsmokes 740,801 676,395 270,848 1,146,348 108,632 98,480 42,277 164,835 899 176 257 818 151 35 48 138 139.0 (116.8 161.2) 121.4 (113.4 129.3) 35.5 (23.8 47.3) 26.0 (22.2 29.9) 113.5 (81.4 145.7) 94.9 (83.3 106.5) 83.7 (69.8 97.7) 71.4 (66.5 76.2)

etable 3. Hazad Ratios a Assessing the Association between Pioglitazone Teatment and Bladde Ca Risk by Sex and Smoking Status: Kaise Pemanente Nothen Califonia Diabetes Registy (continued) Eve Exposed to Pioglitazone Inteaction p value Time si stating pioglitazone b <4.5 4.58.0 >8 Bladde ca (n) Men HR, 95% CI 151 1.03 (0.85 1.24) 0.12 75 0.94 (0.74 1.20) 50 1.20 (0.89 1.61) 26 1.23 (0.81 1.85) Bladde ca (n) Wome n HR, 95% CI 35 1.43 (0.96 2.15) 13 15 7 0.88 (0.50 1.56) 1.77 (1.02 3.07) 1.60 (0.72 3.56) Bladde ca (n) Smoke s HR, 95% CI 48 1.01 (0.72 1.41) 0.93 23 16 9 0.89 (0.58 1.37) 1.14 (0.68 1.93) 1.21 (0.60 2.43) Bladde ca (n) Nonsmoke s HR, 95% CI 138 1.12 (0.92 1.37) 65 49 24 0.95 (0.73 1.23) 1.35 (1. 1.82) 1.33 (0.86 2.03) Test fo tend p values 0.25 0.08 0.65 0.07 Inteaction p c values 0.13 0.82 Duation of Theapy b <1.5 1.54.0 >4 42 0.81 (0.59 1.11) 61 1.15 (0.88 1.50) 48 1.21 (0.89 1.64) 18 8 9 1.58 (0.97 2.59) 0.78 (0.38 1.61) 1.29 (0.65 2.58) 15 18 15 0.87 (0.52 1.48) 0.99 (0.61 1.62) 1.17 (0.68 2.02) 45 51 42 0.97 (0.72 1.32) 1.13 (0.84 1.50) 1.24 (0.90 1.72) Test fo tend p values 0.23 0.55 0.76 0.17 Inteaction p c values 0.58 0.78 Cumulative

Dose b 1 140 mg 141 4 mg >4 mg 45 0.79 (0.59 1.07) 63 1.27 (0.98 1.66) 43 1.12 (0.81 1.54) 21 6 8 1.66 (1.05 2.63) 0.62 (0.27 1.41) 1.28 (0.62 2.65) 16 21 11 0.84 (0.51 1.40) 1.29 (0.82 2.03) 0.85 (0.46 1.58) Test fo tend p values 0.26 0.67 0.96 Inteaction p c values 0.17 0.97 a Adjusted fo age, sex, and calenda yea of cohot enty b Refee goup is unexposed to pioglitazone c Inteaction p values ae fo the inteaction between the exposue and sex o smoking in the test fo tend analysis 50 48 40 0.99 (0.74 1.32) 1.12 (0.83 1.51) 1.25 (0.90 1.74) 0.17

etable 4. Analysis of Bladde Ca Risk and Duation of Exposue to Pioglitazone with Altenative Categoies of Exposue Including the Categoies Used in the Pio Repot of this Cohot among 193,099 Patients: Kaise Pemanente Nothen Califonia Diabetes Registy Peson Yeas Cases of Bladde Ca Model 1 (HR, 95% Model 2 (HR, 95% Unexposed to Pioglitazone 1,417,196 1,075 Refee Refee Time si Stating Pioglitazone < 1.5 49,135 34 1.04 (0.731.47) 0.98 (0.691.38) 1.5 to 3 43,246 27 0.84 (0.571.24) 0.81 (0.551.20) > 3 121,190 125 1.17 (0.951.44) 1.12 (0.911.38) 3.1 to 4.4 36,709 27 0.92 (0.621.36) 0.88 (0.601.31) 4.5 to 8 58,247 65 1.26 (0.971.65) 1.21 (0.931.59) > 8 26,234 33 1.22 (0.841.78) 1.20 (0.831.75) Duation of Theapy < 1 yea 62,577 39 0.88 (0.631.22) 0.83 (0.601.15) 1.02.0 47,568 40 1.10 (0.801.52) 1.06 (0.771.46) > 2 107,011 107 1.14 (0.911.41) 1.09 (0.881.36) 2.14.0 56,866 50 1.05 (0.781.41) 1.01 (0.751.35) 4.16.0 29,558 36 1.32 (0.941.87) 1.29 (0.911.82) > 6 20,587 21 1. (0.641.56) 0.99 (0.631.55) Cumulative dose 1 10,5 mg 78,693 55 0.97 (0.731.28) 0.92 (0.701.22) 10,501 28,0 mg 63,919 47 0.92 (0.681.24) 0.87 (0.641.18) >28,0 mg 74,431 84 1.27 (1.1.62) a 1.23 (0.961.56) 28,1 40,0 mg 24,121 33 1.59 (1.122.27) 1.53 (1.072.18) >40,0 mg 50,310 51 1.09 (0.811.47) 1.07 (0.791.44) Model 1 is adjusted fo: age, sex, ace/ethnicity, othe diabetes medications, smoking, othe bladde conditions, median household income, congestive heat failue, ca othe than bladde ca, enal insufficiency, HbA1c and the inteaction with new osis of diabetes, duation of diabetes, and yea of cohot enty Model 2 is adjusted fo all vaiables in model 1 plus the 3level time updated poteinuia testing vaiable (no testing, negative and positive testing fo poteinuia) a Lowe bound of 95% CI is 0.998.

etable 5. Analysis of Bladde Ca Risk and Duation of Diabetes Theapies among the 59,070 Patients Who Wee Newly Diagnosed with Diabetes at Cohot Enty: a Kaise Pemanente Nothen Califonia Diabetes Registy Pioglitazone HR Metfomin HR Sulfonylueas HR Insulin HR N Unexposed 50,024 25,144 19,234 47,346 N Unexposed Cases 368 235 176 364 N Exposed 9,046 33,926 39,836 11,724 N Exposed Cases 34 167 226 38 N Exposed Cases/ N Exposed by End of FollowUp Duation of Theapy <1.5 13/2,589 37/5,760 57/7,448 14/4,857 1.54.0 12/3,198 58/8,229 68/9,564 13/3,730 > 4 9/3,259 72/19,937 101/22,824 11/3,137 Model 1 Eve/Neve Ex posed 0.84 (0.58 1.21) 0.93 (0.75 1.16) 0.90 (0.73 1.11) 0.95 (0.67 1.34) Duation of Theapy Neve exposed Refee Refee Refee Refee <1.5 0.82 (0.47 1.44) 0.81 (0.57 1.15) 1.01 (0.75 1.36) 0.67 (0.39 1.14) 1.54.0 0.75 (0.42 1.34) 0.94 (0.70 1.27) 0.90 (0.68 1.20) 0.99 (0.56 1.73) > 4 0.89 (0.45 1.76) 0.90 (0.67 1.22) 0.73 (0.56 0.97) 1.49 (0.81 2.77) Model 2 Duation of Theapy Neve exposed Refee Refee Refee Refee <1.5 0.85 (0.49 1.50) 0.82 (0.58 1.17) 1.01 (0.75 1.37) 0.70 (0.41 1.20) 1.54.0 0.77 (0.43 1.39) 0.96 (0.71 1.30) 0.91 (0.68 1.21) 1.03 (0.59 1.82) >4 0.92 (0.46 1.81) 0.93 (0.68 1.26) 0.75 (0.56 0.99) 1.53 (0.83 2.84) a The definition of newly osed with diabetes equied that the peson was a membe of KPNC fo a minimum of 2 befoe the fist diabetes osis. Model 1 Results of age, sex, ace, smoking and calenda yea of cohot enty adjusted models. Model 2 Adjusted fo model 1 vaiables plus each of the othe thee diabetes theapies whee the othe theapy is teated as a time updating vaiable fo neve vesus eve exposed.

etable 6. Sensitivity Analysis of Bladde Ca Risk and Pioglitazone Exposue Censoing FollowUp If Pioglitazone Was Discontinued fo at Least 1 Yea: Kaise Pemanente Nothen Califonia Diabetes Registy N Cases of Bladde Ca Fully Adjusted Adding the Poteinuia Testing Vaiable (HR, 95% Unexposed to Pioglitazone Eve Exposed to Pioglitazone 158,918 1,075 Refee 34,181 117 1.07 (0.881.32) Time si stating pioglitazone <4.5 21,257 79 0.98 (0.771.24) 4.58.0 8,795 32 1.28 (0.891.84) >8 4,129 6 0.73 (0.321.65) Duation of theapy <1.5 11,477 36 0.90 (0.641.27) 1.54.0 11,245 44 1.07 (0.781.45) >4 11,459 37 1.05 (0.741.48) Cumulative Dose 1 140 mg 12,657 39 0.90 (0.651.25) 141 4 mg 10,957 45 1.16 (0.851.57) >4 mg 10,567 33 0.96 (0.671.38)

etable 7. Sensitivity Analysis of Bladde Ca Risk and Pioglitazone Exposue Using Fine Gadation of the Oldest Age Categoy: a Kaise Pemanente Nothen Califonia Diabetes Registy Adjusted fo Age, Sex and Yea of Cohot Enty (HR, 95% Fully Adjusted b (HR, 95% Fully Adjusted Adding the Poteinuia Testing Vaiable c (HR, 95% Unexposed to Pioglitazone Refee Refee Refee Eve Exposed to Pioglitazone 1.09 (0.921.29) d 1.10 (0.931.31) 1.06 (0.891.26) Time si Stating Pioglitazone <4.5 0.94 (0.751.17) 0.94 (0.751.18) 0.89 (0.711.12) 4.58.0 1.30 (1.1.68) 1.27 (0.971.66) 1.22 (0.931.59) >8 1.29 (0.901.86) 1.24 (0.851.80) 1.20 (0.831.75) Test fo tend p values 0.06 0.13 0.28 Duation of Theapy <1.5 0.95 (0.731.24) 0.94 (0.721.23) 0.89 (0.681.16) 1.54.0 1.09 (0.851.40) 1.09 (0.841.40) 1.03 (0.801.34) >4 1.22 (0.921.61) 1.19 (0.901.59) 1.16 (0.871.54) Test fo tend p values 0.16 0.26 0.47 Cumulative Dose 1 140 mg 0.95 (0.741.23) 0.95 (0.731.22) 0.90 (0.691.16) 141 4 mg 1.17 (0.911.50) 1.16 (0.901.50) 1.10 (0.861.42) >4 mg 1.14 (0.851.52) 1.09 (0.811.48) 1.06 (0.791.44) Test fo tend p values 0.20 0.35 0.59 a Age categoies wee 4049, 5059, 6069, 7079, 8089, 90 and olde. b Fully adjusted efes to: age, sex, ace/ethnicity, othe diabetes medications, smoking, othe bladde conditions, median household income, congestive heat failue, ca othe than bladde ca, enal insufficiency, HbA1c and the inteaction with new osis of diabetes, duation of diabetes, and yea of cohot enty c Fully adjusted model adding the 3level time updated poteinuia testing vaiable (no testing, negative and positive testing fo poteinuia), excluding same day test fo hematuia d Also adjusted fo use of othe diabetes medication

etable 8. Sensitivity Analysis of Bladde Ca Risk and Pioglitazone Exposue Using Altenative FollowUp Peiods and Altenative Methods to Calculate Cumulative Dose and Duation: Kaise Pemanente Nothen Califonia Diabetes Registy Unexposed to Pioglitazone Eve exposed to Pioglitazone Model 1 a (HR, 95% Model 2 a (HR, 95% Model 3 a (HR, 95% Model 4 a (HR, 95% Refee Refee Refee Refee 1.10 (0.921.31) N/A 1.11 (0.931.33) 0.93 (0.631.35) Time si Stating Pioglitazone < 4.5 0.93 (0.741.17) 4.58.0 1.26 (0.971.65) >8 1.22 (0.841.78) Duation of Theapy <1.5 0.93 (0.711.22) 1.54.0 1.08 (0.831.39) >4 1.19 (0.891.58) 0.98 (0.781.22) 1.28 (0.971.68) 1.27 (0.871.86) 1.02 (0.791.32) 1.13 (0.871.46) 1.19 (0.891.61) 0.95 (0.761.20) 1.26 (0.951.66) 1.24 (0.841.84) 0.92 (0.701.22) 1.09 (0.841.42) 1.22 (0.911.64) 0.92 (0.591.44) 0.55 (0.241.25) 1.85 (0.804.32) 0.88 (0.501.55) 0.81 (0.451.46) 0.98 (0.501.95) Cumulative Dose 1 140 mg 0.94 (0.731.22) 1. (0.781.29) 0.95 (0.731.24) 0.94 (0.561.57) 141 4 mg 1.15 (0.891.49) 1.27 (0.991.64) 1.15 (0.881.49) 0.96 (0.541.70) >4 mg 1.09 (0.811.47) 1.04 (0.761.42) 1.12 (0.821.52) 0.60 (0.241.47) Model 1 pimay analysis model (i.e. Model 3 in Table 2) Model 2 calculating dose and duation of exposue stating with the second of two pesciptions fo pioglitazone equied to meet the definition of exposue Model 3 stating followup 6 afte cohot enty Model 4 stating followup 6 afte cohot enty among those newly osed with diabetes a Adjusted fo: age, sex, ace/ethnicity, othe diabetes medications, smoking, othe bladde conditions, median household income, congestive heat failue, ca othe than bladde ca, enal insufficiency, HbA1c and the inteaction with new osis of diabetes, duation of diabetes, and yea of cohot enty N/A not applicable

etable 9. Compaison of Suvey Respondents and NonRespondents by CaseContol Status in Nested CaseContol Study of Bladde Ca and Pioglitazone Exposue: Kaise Pemanente Nothen Califonia Diabetes Registy Case Paticipant (n=464) Case Refuse (n=119) Age at Refee Date 4059 6069 118 18 (25.4%) (15.1%) 7079 210 54 (45.3%) (45.4%) >80 118 41 (25.4%) (34.5%) Sex 70 (15.1%) 20 Case Non Paticipant fo Othe Reason (n=117) Contol Paticipant (n=464) Contol Refuse (n=209) Contol Non Paticipant fo Othe Reason (n=360) 18 (3.9%) 6 (5%) 7 (6%) 19 (4.1%) 4 (1.9%) 9 (2.5%) 28 (23.9%) 126 (27.2%) 58 (27.8%) 71 (19.7%) 38 (32.5%) 210 78 139 (38.6%) (45.3%) (37.3%) 44 (37.6%) 109 69 141 (39.2%) (23.5%) (33%) 31 (26.5%) 70 (15.1%) 35 63 (17.5%) (Female) (16.8%) (16.7%) Congestive 21 (4.5%) 12 7 (6%) 13 (2.8%) 8 (3.8%) 16 (4.4%) Heat Failue (10.1%) Elevated 23 (5%) 9 (7.6%) 17 (14.5%) 28 (6%) 13 30 (8.3%) Ceatinine a (6.2%) Pevalent 109 35 15 (12.8%) 110 64 91 (25.3%) Case (23.5%) (29.4%) (23.7%) (30.6%) Pioglitazone 91 (19.6%) 12 26 (22.2%) 81 (17.5%) 42 49 (13.6%) (10.1%) (20.1%) Othe TZDs 14 (3%) 3 (2.5%) 4 (3.4%) 10 (2.2%) 7 (3.3%) 9 (2.5%) Metfomin 258 58 56 (47.9%) 252 105 162 (45%) (55.6%) (48.7%) (54.3%) (50.2%) Sulfonyluea 313 69 77 (65.8%) 296 122 229 (63.6%) (67.5%) (58%) (63.8%) (58.4%) Insulin 107 31 36 (30.8%) 123 50 68 (18.9%) (23.1%) (26.1%) (26.5%) (23.9%) No Diabetes 71 (15.3%) 22 18 (15.4%) 66 (14.2%) 43 67 (18.6%) Medications (18.5%) (20.6%) Cuent 116 (25%) 34 30 (25.6%) 77 (16.6%) 44 60 (16.7%) Smoke b (28.6%) (21.1%) a Ceatinine >1.4 fo women and >1.5 fo men b As defined in the cohot study data TZD = Thiazolidinedione

etables fo Association of Pioglitazone Exposue and Risk of Risk of Ca of the Postate, Female Beast, Lung/Bonchus and Colon, nonhodgkin Lymphoma, Copus Utei, Paas, Kidney/Renal Pelvis, and Rectum and Melanoma

etable 10 Cude of Ca at 10 Sites Accoding to Dose and Duation of Pioglitazone Exposue (n= 236,507)], Kaise Pemanente Nothen Califonia Diabetes Registy, 19972012. Neve Pioglitazo ne Post ate pe peso n be of ca 449.3 (3301) Femal e Beas t pe peso n be of ca 360.1 (2477) Lung/ Bonc hus pe peso n be of ca 158.2 (2,292 ) Colon NHL Cop us Utei pe peso n be of ca 128.1 (1841) pe peso n be of ca 57.6 (835) pe peso n be of ca 123.5 (798) Panc eas pe peso n be of ca 48.4 (647) Kidne y/ Renal Pelvi s pe peso n be of ca 47.3 (685) Rectu m pe peso n be of ca 39.5 (568) Melan oma pe peso n be of ca 40.9 (592) Eve Pioglitazo ne 453.3 (476) 333.3 (320) 137.9 (282) 114.8 (233) 58.7 (120) 133.0 (118) 81.1 (164) 53.8 (110) 29.1 (59) 49.9 (102) Time Si Initiation <12 360.8 (55) 318.9 (42) 103.1 (32) 68.2 (22) 59.7 (21) 126.6 (14) 104.6 (33) 35.3 (12) 24.6 (8) 38.0 (10) 1223 468.4 (82) 272.8 (42) 143.7 (48) 90.4 (30) 77.8 (26) 139.7 (20) 65.9 (22) 29.9 (10) 24.1 (8) 53.9 (18) 2435 493.0 (76) 343.3 (47) 152.1 (45) 160.0 (47) 54.1 (16) 94.6 (12) 60.8 (18) 60.8 (18) 37.4 (11) 40.6 (12) 3647 557.3 (75) 255.7 (31) 142.1 (37) 1.6 (26) 46.1 (12) 134.0 (15) 73.0 (19) 65.3 (17) 46.4 (12) 61.5 (16) 4883 421.3 (119) 349.0 (91) 135.5 (75) 129.4 (71) 43.4 (24) 150.1 (36) 74.1 (41) 63.3 (35) 21.9 (12) 43.4 (24) >84 476.2 (69) 453.6 (67) 150.4 (45) 124.8 (37) 70.2 (21) 155.1 (21) 103.6 (31) 60.1 (18) 27.0 (8) 73.5 (22)

etable 10 Cude of Ca at 10 Sites Accoding to Dose and Duation of Pioglitazone Exposue (n= 236,507)], Kaise Pemanente Nothen Califonia Diabetes Registy, 19972012. (continued) Post ate pe peso n be of ca Femal e Beas t pe peso n be of ca Lung/ Bonc hus pe peso n be of ca Colon NHL Cop us Utei pe peso n be of ca pe peso n be of ca pe peso n be of ca Panc eas pe peso n be of ca Kidne y/ Renal Pelvis pe peso n be of ca Rectu m pe peso n be of ca Melan oma pe peso n be of ca Duati on of use < 12 month s 397.2 (118) 281.3 (88) 123.1 (83) 104.7 (72) 52.0 (35) 147.1 (43) 83.7 (55) 47.9 (32) 31.7 (21) 41.0 (25) 12 23 month s 522.6 (121) 349.3 (75) 132.4 (60) 106.6 (48) 70.6 (32) 120.8 (24) 66.2 (30) 44.1 (20) 28.9 (13) 64.0 (29) 24 35 month s 430.0 (72) 333.0 (47) 130.7 (41) 128.3 (40) 63.8 (20) 145.0 (19) 57.4 (18) 54.2 (17) 28.9 (9) 44.6 (14) 36 59 month s 478.9 (99) 357.9 (61) 146.0 (56) 86.8 (33) 44.3 (17) 121.6 (19) 93.9 (36) 60.0 (23) 21.0 (8) 36.5 (14) >60 month s 453.0 (66) 419.8 (49) 156.6 (42) 150.4 (40) 59.6 (16) 121.2 (13) 93.2 (25) 67.1 (18) 30.1 (8) 74.6 (20)

Cumul ative Dose 1 90 mg 436.8 (129) 295.6 (92) 134.7 (90) 106.3 (72) 51.4 (34) 149.1 (43) 82.9 (54) 43.1 (28) 30.8 (20) 45.8 (28) 9,1 25,0 mg 503.4 (167) 315.2 (98) 124.1 (81) 107.9 (70) 67.4 (44) 132.1 (38) 61.8 (40) 56.7 (37) 27.8 (18) 52.1 (34) 25,1 50,0 mg 450.1 (109) 386.5 (77) 135.9 (61) 125.7 (56) 62.4 (28) 103.0 (19) 84.7 (38) 51.2 (23) 26.9 (12) 46.8 (21) 50, 1 mg 385.3 (71) 386.8 (53) 152.5 (50) 107.7 (35) 42.7 (14) 143.2 (18) 97.6 (32) 67.1 (22) 27.7 (9) 57.9 (19)

etable 11. Adjusted a Hazad Ratios fo Eve Use of Pioglitazone and othe diabetes medications and Risk of Ca of the Postate, Female Beast, Lung/Bonchus and Colon, nonhodgkin Lymphoma, Copus Utei, Paas, Kidney/Renal Pelvis, and Rectum and Melanoma: Kaise Pemanente Nothen Califonia Diabetes Registy, 19972012. Post ate Adjusted a Hazad Ratios Confide Intevals) Fem ale Bea st Lung/ Bonc hus Colo n NHL Cop us Utei Panc eas Kidn ey/ Rena l Pelvi s Rect um Melano ma Pesons with 3,777 2,574 2,074 955 916 811 795 627 694 Ca 2,797 Eve 1.13 1. 1. 0.91 1. 0.88 1.41 0.95 0.81 1.15 Pioglitazone b (1.02 1.26) (0.88 1.13) (0.87 1.15) (0.78 1.05) (0.81 1.23) (0.71 1.09) (1.16 1.71) (0.76 1.18) (0.60 1.08) (0.91 1.46) Eve Othe TZD 0.90 0.94 0.90 1.06 1.11 1.31 1.31 1.34 0.81 1.28 (0.71 (0.73 (0.68 (0.80 (0.75 (0.91 (0.92 (0.89 (0.44 (0.83 1.14) 1.19) 1.66) 1.89) 2.02) 1.49) 1.97) 1.21) 1.41) 1.88) Eve Metfomin 1.07 0.94 0.89 0.92 1.07 1.06 1.21 1.07 1. 0.95 (0.99 (0.86 (0.81 (0.83 (0.91 (0.90 (1.02 (0.90 (0.82 (0.79 1.16) 0.98) 1.26) 1.43) 1.28) 1.22) 1.15) 1.04) 1.03) 1.25) Eve Insulin 0.90 1.08 1.21 1.03 0.91 1. 2.34 1.11 0.95 0.99 (0.81 (0.97 (1.08 (0.90 (0.76 (0.84 (1.97 (0.91 (0.75 (0.80 0.99) 1.35) 1.10) 2.78) 1.35) 1.21) 1.23) 1.21) 1.16) 1.20) Eve 0.95 0.98 1.11 1.10 0.98 1.09 1.49 1.02 1.14 1.07 Sulfonylueas (0.86 (0.88 (0.99 (0.96 (0.82 (0.91 (1.22 (0.84 (0.90 (0.86 1.04) 1.24) 1.18) 1.81) 1.23) 1.44) 1.32) 1.08) 1.24) 1.30) Eve Othe OHA 0.83 0.60 1.08 0.82 1.67 0.76 1.11 0.97 0.83 1.10 (0.61 (0.41 (0.78 (0.55 (1.10 (0.44 (0.71 (0.56 (0.39 (0.62 1.12) 1.49) 2.52) 1.74) 1.70) 1.76) 1.96) 0.88) 1.21) 1.32) Neve diabetes 0.95 0.97 0.98 0.87 0.97 1. 0.74 1.08 1.11 1.03 dug pesciption (0.84 (0.84 (0.84 (0.73 (0.75 (0.76 (0.54 (0.82 (0.81 (0.76 1.08) 1.14) 1.25) 1.02) 1.42) 1.53) 1.38) 1.13) 1.03) 1.30) Neve 2 same 1.18 0.91 1.02 1.05 1.18 0.88 1.55 0.70 1.12 1.31 dug pesciptions (0.99 (0.72 (0.81 (0.81 (0.82 (0.58 (1.02 (0.43 (0.71 (0.87 1.41) 1.28) 1.69) 2.36) 1.14) 1.78) 1.98) 1.14) 1.35) 1.34) a Hazad Ratios ae adjusted fo age, eve use of othe diabetes medications, yea of cohot enty, sex, aceethnicity, income, cuent smoking, baseline HbA1c, diabetes duation, new diabetes osis, ceatinine and congestive heat failue. b Neve use of pioglitazone as efee goup. Identical method was used to detemine the HR of othe diabetes medications. NHL = NonHodgkin lymphoma TZD = Thiazolidinedione OHA = Oal hypoglycemic agent