Thiazolidinediones and the risk of bladder cancer: A cohort study. R Mamtani, K Haynes, WB Bilker, DJ Vaughn, BL Strom, K Glanz, JD Lewis

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1 Thiazolidinediones and the risk of bladder cancer: A cohort study R Mamtani, K Haynes, WB Bilker, DJ Vaughn, BL Strom, K Glanz, JD Lewis

2 Study objective To investigate the risk of bladder cancer associated with thiazolidinedione (TZD) therapy in patients with type II diabetes

3 Diabetes and risk of bladder cancer Larsson SC Diabetologia 2006

4 Potential underlying mechanisms Diabetes Tobacco Age Obesity Hyperglycemia Hyperinsulinemia Chronic inflammation Diabetes treatment Bladder Cancer

5 TZDs Rosiglitazone (ROSI), pioglitazone (PIO) 2 nd line treatment of type II diabetes Promote insulin sensitivity through PPARγ Regulate cancer cell growth and differentiation TZD Yki-Jarvinen H NEJM 2004

6 Pioglitazone and bladder cancer

7 Dormandy et al Lancet 2005 Lewis et al Diabetes Care 2011 Neumann et al Diabetologia 2012 Limited clinical data PROactive study 14 (PIO) vs 6 (placebo) bladder cancers, P =.07 Kaiser Permanente (KPNC) cohort study >24 months of PIO therapy, HR = 1.5 [ ] French SNIIRAM cohort study >24 months of PIO therapy, HR = 1.4 [ ]

8 Unanswered questions Bladder cancer risk of TZDs relative to the common alternative therapy (sulfonylureas)? Unique to pioglitazone or TZD class effect?

9 Specific Aim To compare bladder cancer risk over time with use of TZDs relative to sulfonylureas (SUs), and between pioglitazone (PIO) and rosiglitazone (ROSI)

10 Hypothesis Compared to SUs, long-term TZD therapy is associated with a greater risk of bladder cancer in patients with type II diabetes

11 Design Cohort study of patients with type II diabetes who initiated treatment with either a TZD or SU ( ) The Health Improvement Network (THIN) U.K. general practitioner database Electronic medical records of 9.5 million patients

12 Population Source population Subjects in THIN after July 2000 Diagnostic code for diabetes (n=403,707) Study cohort New user* of a TZD (n=41,396) Comparator cohort New user* of a SU (n=18,459) * New user = 6 mos of enrollment in THIN without prior Rx for either drug Exclude Prior bladder cancer (n=391)

13 Exposure Exposure definition = two prescriptions for a TZD within 6 months Index date = date of 2 nd prescription Comparator = SUs, also indicated as 2 nd line treatment for type II diabetes

14 Outcome Incident diagnosis with bladder cancer occurring after the index date

15 Potential confounders Other diabetes medications Risk factors for bladder cancer age, sex, smoking, recurrent urinary infection Variables associated with the likelihood of being prescribed a TZD diabetes duration, hemoglobin A1C, congestive heart failure, renal impairment

16 Data analysis Incidence rates of bladder cancer calculated Hazard ratios (HRs) for bladder cancer by Cox regression: TZD vs SU, PIO vs ROSI Cox regression to assess whether cancer risk increased with: Duration of therapy (time on drug) Time since initiation of therapy

17 Cohort demographics New TZD New SU N 18,459 41,396 Age, median (IQR), y 60 [51-69] 65 [55-74] Sex (% M) 10,502 (56 9) 23,228 (56 1) Smoking ( % Ever) 12,220 (66 2) 27,163 (65 6) A1C level, median, % 8 5 [ ] 8 4 [ ] DM duration, median, y 3 8 [ ] 2 3 [ ] Other diabetes drugs (%) Metformin 16,410 (88 9) 26,030 (62 9) Insulin 708 (3 8) 1,060 (2 6) Other 801 (4 3) 803 (1 9)

18 Cohort demographics Congestive heart failure (%) New TZD New SU 321 (1 7) 1,782 (4 3) Renal impairment (%) 1,174 (6 4) 3,639 (8 8) Recurrent urinary infection (%) 1,135 (6 1) 2,663 (6 4) Myocardial infarction (%) 1,028 (5 6) 3,316 (8 0) BMI, median, kg/m [ ] 29 2 [ ] Time since initiation, median, y Duration of therapy, median, y 3 7 [ ] 2 4 [ ] 2 1 [ ] 2 1 [ ]

19 HRs of bladder cancer TZD vs SU New use of SU New use of TZD IR* HR, unadjusted HR, adjusted [ ] 1 00 (referent) 1 00 (referent) 87 1 [ ] 0 81 [ ] 0 93 [ ] Incidence rate of bladder cancer in UK = 73/100,000 PYS ( * Incidence rate per 100,000 PYS Adjusted for age, sex, A1C level, and smoking

20 HRs of bladder cancer over time TZD vs SU (referent) Time since Initiation, y HR, adjusted Duration of therapy, y HR, adjusted <1 year 0 52 [ ] <1 year 0 95 [ ] 1-< [ ] 1-< [ ] 2-< [ ] 2-< [ ] 3-< [ ] 3-< [ ] 4-< [ ] 4-< [ ] [ ] [ ] P trend 0 03 P trend 0 20 Adjusted for age, sex, A1C level, and smoking

21 HRs of bladder cancer pioglitazone vs rosiglitazone New use of ROSI New use of PIO IR* HR, unadjusted HR, adjusted [ ] 1 00 (referent) 1 00 (referent) [ ] 1 16 [ ] 1 14 [ ] * Incidence rate per 100,000 PYS Adjusted for age, sex, smoking, history of myocardial infarction, and past SU use

22 HRs of bladder cancer over time pioglitazone vs rosiglitazone (referent) Duration of therapy, y HR, adjusted <1 year 1 07 [ ] 1-< [ ] 2-< [ ] 3-< [ ] 4-< [ ] [ ] P trend 0 75 Adjusted for age, sex, smoking, history of myocardial infarction, and past SU use

23 Summary 5 years of exposure to TZDs may be associated with an increased risk of bladder cancer, which may be a class effect

24 Strengths Accurate prescription and diagnostic information on which exposure and outcome was based Study period stopped prior to public warnings minimizing risk of detection bias Comparable reference group and ability to adjust for baseline A1C level

25 Limitations No clear dose response in duration analyses Threshold effect Low number of events in duration subcategories Chance

26 Conclusion Long-term TZD use may increase the risk of bladder cancer in patients with type II diabetes Results should be placed in context of other potential benefits and harms of TZDs & SUs Our data help regulators, prescribers, and patients to assess the risk-benefit relationship when choosing between these drugs

27 Acknowledgements National Institutes of Health (T32-CA009679,RM; K24-DK078228,JL) Data access provided by ACARD (UL1 RR024134) through an agreement with Cegedim Strategic Data Follow-up study evaluating cancer stage supported by ASCO YIA