Evaluating Bladder Cancer Risk Associated with Thiazolidinedione Use in Type 2 Diabetes

Evaluating Bladder Cancer Risk Associated with Thiazolidinedione Use in Type 2 Diabetes The daily special, controlled diabetes with a side of bladder cancer. Raelene Showery, Pharm.D. PGY2 Ambulatory Care Resident Blackstock Family Practice/CommUnityCare University of Texas College of Pharmacy October 18, 2013 Learning Objectives 1. Discuss epidemiology, pathophysiology, diagnosis and treatment options for type 2 diabetes 2. Discuss pathophysiology, diagnosis and treatment options for bladder cancer 3. Evaluate literature on thiazolidinedione use and risk of bladder cancer 4. Provide recommendations for thiazolidinedione use in the treatment of diabetes I. Introduction Showery 1

A. Epidemiology 1,2 1. Diabetes (DM) affects 25.8 million people in the United States (US) 2. Diabetes is the 7 th leading cause of death in the US 3. The prevalence of diabetes from 2007-2009 among US adults 20 years old according to race/ethnicity: a. African Americans 12.6% b. Hispanics 11.8% c. Asian Americans 8.4% d. Non- Hispanic whites 7.1% See Figure 1 for prevalence of diabetes from 2008-2010 among adults in Texas 18 years old Figure 1. Prevalence of diabetes among adults in Texas from 2008-2010 Source: Burden of Diabetes in Texas report, updated April 2013 B. Economic Costs of Diabetes in the US in 2012 3 1. Total cost of diagnosed diabetes - $245 billion a. Direct medical costs - $176 billion (hospital, emergency care, office visits and medications) b. Indirect medical costs - $69 billion (absenteeism, reduced productivity, unemployment caused by diabetes- related disability, and lost productivity due to early mortality) 2. Medical expenditures for people with diabetes is 2 to 3 times higher than for those without diabetes 3. More than 1 in 10 health care dollars in the US are spent directly on diabetes and its complications II. Type 2 Diabetes A. Pathophysiology 4,5 1. Normal insulin production and action (See Figure 2) a. Fasting state: 1. Majority of glucose production is derived from the liver 2. Glucagon produced by pancreatic alpha cells oppose the action of insulin to prevent hypoglycemia Showery 2

b. Fed state: 1. Carbohydrate ingestion increases plasma glucose concentration, stimulating insulin release from pancreatic beta cells 2. Insulin release leads to decreased hepatic glucose production and stimulation of glucose uptake by peripheral tissues Figure 2. Normal insulin production and action Source: http://da3.diabetesatlas.org/index15e4.html 2. Impaired insulin secretion and insulin resistance (See Figure 3) a. Insulin resistance: decreased glucose uptake in liver, muscle and adipose tissue b. Insulin deficiency: a consequence of progressive beta cell dysfunction c. Hepatic glucose overproduction: a consequence of impaired insulin release from beta cells Figure 3. Pathophysiology of type 2 diabetes Source: http://emedicine.medscape.com/article/117853- overview! Showery 3

B. Risk Factors 6 1. Overweight defined as a body mass index (BMI) 25kg/m 2 2. Physical inactivity 3. First- degree relative with DM 4. High- risk race/ethnicity (e.g. African American, Latino, Native American, Asian American, Pacific Islander) 5. Women delivering a baby weighing 9 pounds or gestational diabetes (GDM) diagnosis 6. Hypertension ( 140/90mmHG or on therapy to treat hypertension) 7. HDL < 35mg/dL and/or triglycerides > 250mg/dL 8. Women with polycystic ovary syndrome (PCOS) 9. A1c 5.7%, impaired glucose tolerance (IGT), impaired fasting glucose (IFG) on previous test 10. Other clinical conditions associated with insulin resistance (e.g. acanthosis nigricans) 11. History of cardiovascular disease (CVD) C. Complications 1 1. Heart disease and Stroke a. In 2004, heart disease was noted in 68% of diabetes- related death certificates people aged 65 years or older b. In 2004, stroke was noted in 16% of diabetes- related death certificates people aged 65 years or older c. Risk of stroke is 2 to 4 times higher in patients with diabetes 2. Visual impairment a. Leading cause of new cases of blindness among adults aged 20-74 years b. In 2005-2008, 4.2 million people with diabetes aged 40 years or older had diabetic retinopathy, and of these 655,000 had advanced diabetic retinopathy that could lead to severe vision loss 3. Kidney disease a. Diabetes is the leading cause of kidney failure (44% of new cases in 2008) b. In 2008, 48,374 people with diabetes began treatment for end- stage kidney disease c. In 2008, 202,290 people with end- stage kidney disease due to diabetes were on chronic dialysis or had a kidney transplant 4. Neuropathy a. Approximately 60-70% of people with diabetes have mild to severe forms of nervous system damage b. Amputations i. Approximately 60% of non- traumatic lower- limb amputations occur in people with diabetes ii. In 2006, approximately 65,700 non- traumatic lower- limb amputations were performed in people with diabetes D. Diagnosis 6 1. Hemoglobin A1c 6.5% 2. Fasting Plasma Glucose (FPG) 126 mg/dl 3. 2- hr plasma glucose after a 75g oral glucose tolerance test (OGTT) 200mg/dL 4. Symptomatic hyperglycemia + random plasma glucose 200mg/dL 5. A1c, FPG and OGTT should be repeated to confirm diagnosis E. Treatment 7,8 1. Goals of therapy a. Control hyperglycemia improve and reduce symptoms b. Prevent or delay complications without adversely affecting quality of life c. Prevent or decrease adverse effects associated with diabetes medications d. Glycemic targets and glucose- lowering therapies must be individualized 2. Glycemic Recommendations (See Table 1) Showery 4

Table 1. Glycemic recommendations based on the American Diabetes Association and the American Association of Clinical Endocrinologists American Diabetes Association A1c < 6.5% If can be achieved without significant hypoglycemia Short duration of diabetes Long life expectancy No significant cardiovascular disease (CVD) < 7% Most non- pregnant adults < 8% History of severe hypoglycemia Limited life expectancy Advanced cardiovascular disease (CVD) Pre- prandial capillary plasma glucose 70-120mg/dL 2- hour post- prandial capillary plasma glucose < 180mg/dL American Association of Clinical Endocrinologists A1c 6.5% Healthy patients: Without current illness Low hypoglycemic risk > 6.5% Individualize for patients: Concurrent illness High hypoglycemic risk Repeating an A1c Quarterly for patients not at goal Twice a year for patients at goal F. Glycemic Control Algorithm 6,7,8 1. See Appendix A for characteristics of drugs listed in Table 2 Table 2. Therapeutic Drug Options for the Treatment of Type 2 Diabetes Therapeutic Drug Options Based on A1c A1c < 7.5% metformin, GLP- 1, DPP- IV inhibitor, AG- I, SGLT- 2, TZD, SU, GLN Monotherapy A1c 7.5% metformin or other 1 st line agent + Dual therapy GLP- 1, DPP- IV inhibitor, AG- I, colesevelam, bromocriptine, TZD, SGLT- 2, SU, GLN, basal insulin A1c >9.0% Add 3 rd agent if not at goal in 3 months Asymptomatic: Dual or Triple therapy Symptomatic: Insulin ± other agent(s) GLP- 1: glucagon- like peptide 1; DDP- IV: dipeptidyl peptidase IV inhibitor; AG- I: alpha- glucosidase inhibitor; SGLT- 2: sodium glucose transporter 2; TZD: thiazolidinediones; SU: sulfonylurea; GLN: meglitindes III. Thiazolidinediones (TZDs) A. Mechanism of action 9,10 1. Agonist of peroxisome proliferator- activated receptor- gamma (PPARγ) a. Nuclear receptors involved in regulating lipids and the effects of insulin b. Three major receptors: alpha, gamma and delta 2. PPARγ are present in adipose tissues, endothelial cells and several epithelial tissues Showery 5

3. Activation influences the production of a number of gene products involved in glucose and lipid metabolism 4. Lower blood glucose by improving target cell response to insulin, without increasing pancreatic insulin secretion 5. Dependent on presence of insulin for its activity 6. See Figure 4 for mechanism of action of TZDs Figure 4. Mechanism of action of thiazolidinediones Adapted from: http://www.medscape.com/viewarticle/579822_2 B. Indication 9,10 1. Indicated as an adjunct to diet and exercise in adults with type 2 DM 2. Used as monotherapy or in combination with other glucose lowering drugs 3. A1c reduction: 0.4-1.5% (monotherapy and combination therapy) C. Dosing 9 1. Pioglitazone a. 15-30 mg once daily, max 45 mg once daily b. No renal dose adjustments c. ALT > 3 times ULN do not use 2. Rosiglitazone a. 4 mg once daily or in divided doses twice daily doses, max 8 mg daily b. No renal dose adjustments c. ALT > 3 times ULN do not use Showery 6

D. Advantages 10,11,12 1. Once daily dosing 2. Increase in HDL (pioglitazone ~19%) 3. Decrease in triglycerides (pioglitazone ~12%) E. Disadvantages 10,11,12 1. Worsening heart failure (rosiglitazone) 2. Increase in LDL (rosiglitazone - up to 21%) F. Side effects 9 1. Edema (monotherapy up to 6.5%) 2. Upper respiratory tract infections (monotherapy up to 13%) 3. Fractures - nonvertebral including lower limb and distal upper limb ~5% (women>men) G. Contraindications 9 : New York Heart Association heart failure III and IV (initiation of therapy) IV. Bladder Cancer A. Bladder has four main layers 13 1. Urothelium or transitional epithelium: innermost lining 2. Lamina propria: beneath thin layer of connective tissue, blood vessels and nerves 3. Muscularis propria: next thick layer of muscle 4. Outside layer of fatty connective tissue: separates bladder from other nearby organs Figure 5. Bladder wall layers Source: http://www.cancerresearchuk.org/cancer- help/type/bladder- cancer/about/the- bladder B. Staging is based on cell appearance 13 1. Transitional cell (urothelial) carcinoma a. Most common type b. Accounts for 95% of all bladder cancers Figure 6. Staging of bladder cancer Source: http://www.urologyatkumed.com/main/clinicalconditions/bladdercancer.aspx Showery 7

2. Incidence rate based on cases diagnosed from 2006-2010 as reported by the National Cancer Institute 14 Table 3. Bladder cancer incidence rate based on sex and race/ethnicity Race Male Female White 39.8 per 100,000 9.5 per 100,000 Hispanic 20.2 per 100,000 5.2 per 100,000 Black 21.0 per 100,000 7.1 per 100,000 Asian/Pacific Islander 16.1 per 100,000 3.9 per 100,000 American Indian/Alaska Native 13.7 per 100,000 3.0 per 100,000 All races 36.6 per 100,000 8.9 per 100,000 C. Risk factors 13 1. Smoking (3 times more likely than non- smokers) 2. Workplace exposures (aromatic amines found in dye) 3. Race and ethnicity 4. Age (9 out 10 > 55 years) 5. Gender (men > women) 6. Chronic bladder irritation and infections 7. Family history D. Diagnosis 16 1. Routine screening of the general public not recommended no test shown to improve survival 2. Based on signs and symptoms a. Hematuria typically first warning sign b. Polyuria c. Dysuria d. Flank pain 3. Tests a. Cystoscopy gold standard b. Biopsy E. Treatment 13,16 1. Transurethral resection of the bladder tumor (TURBT) 2. Cystectomy (partial or radical) 3. Intravesical therapy (immunotherapy or chemotherapy) 4. Chemotherapy 5. Radiation therapy F. Survival rates based on staging as reported by the National Cancer Institute 13 Table 4. Survival Based on Bladder Cancer Stage Stage Relative 5- year survival rate 0 98% I 88% II 63% III 46% IV 15% Showery 8

V. Relationship between bladder cancer risk associated with TZD use 17, 18,19 A. Hypothesized pathophysiology 1. Exact mechanism in humans is unknown 2. PPARγ are present in adipose tissues, endothelial cells and several epithelial tissues such as urothelium 3. PPARγ agonist were once thought to inhibit cell proliferation and/or induce apoptosis in a variety of malignancies 4. Now data to suggest PPARγ activation promotes carcinogenesis and cancer progression a. Produce urothelial tumors in rats b. Male rats more so than female rats 5. These effects are thought to be due to one of the following: a. A direct effect on PPARγ in the urothelium b. Indirect mechanism involving toxic changes in urine composition 6. In- vitro studies have shown that when TZD s are added to human urothelial carcinoma of the bladder cell lines, promoted cell migration and invasion VI. Background literature A. Dormandy, et al. PROactive trial Lancet 2005 20 1. Purpose: determine whether pioglitazone reduces macrovascular mobidity and mortality in high- risk patients with type 2 diabetes 2. Design: prospective, randomized controlled trial 3. Patients: a. Type 2 diabetes aged 35-74 b. A1c >6.5% c. Current use of other anti- diabetic agent +/- insulin d. History of macrovascular disease: MI or stroke >6months before inclusion, percutaneous coronary intervention or coronary bypass artery graft >6months, acute coronary syndrome >3months before inclusion 4. Outcomes: a. Primary outcome (composite) time from randomization to: all cause mortality, non- fatal MI, stroke, acute coronary syndrome, endovascular or surgical intervention the coronary or leg arteries, or amputation b. Secondary outcome (composite): death from any cause, non- fatal MI, stroke 5. Results: a. Primary outcome: HR 0.90 (95% CI 0.80, 1.02) p=0.095 b. Secondary outcome: HR 0.84 (95% CI 0.72, 0.98) p=0.027 c. No difference in the overall incidence of malignant neoplasms d. There were some imbalances in the incidence of individual tumors e. More bladder tumors (14 vs 6) in the pioglitazone group when compared to placebo 6. Authors Conclusions: Pioglitazone reduces composite all- cause mortality, non- fatal MI, and stroke in patients with type 2 diabetes who have a high risk of macrovascular events. Further review of bladder cancer, six of the fourteen patients treated with pioglitazone and three of the six in the placebo group developed bladder cancer during the second year of exposure. 7. Comments: First cardiovascular outcomes study with a TZD. First study to show a potential relationship between TZD use and increased risk of bladder cancer in humans. VII. Clinical Question: Should thiazolidinediones still be used in the treatment of type 2 diabetes? Showery 9

VIII. Literature Review 21,22,23,24 Lewis JD, Ferrara A, Peng T, et al. Risk of bladder cancer among diabetic patients treated with pioglitazone; interim report of a longitudinal cohort study. Diabetes Care. 2011 Apr;34(4):916-22. 21 Purpose Examine the association between pioglitazone therapy and the risk bladder cancer in patients with diabetes Design 10- year, observational cohort study, midpoint interim analysis Nested case- control study: assess for missing data on confounding variables Methods Patient were identified through the Kaiser Permanente Northern California (KPNC) diabetes registry Ever use: 2 prescriptions filled within a 6- month period Inclusion Starting 1/01/1997: DM diagnosis, 40 years old, members of KPNC From 1/01/1997 12/31/2002: DM, 40 years old when joined KPNC Exclusion History of bladder cancer 6 months from inclusion No prescription benefits Gap coverage > 4 months within 4 months of inclusion Outcomes Bladder cancer Statistics Continuous and categorical variables compared with Wilcoxon rank sum test, X 2 test or Fisher s exact test Confounders adjusted for*: Age and sex Full model (e.g. other diabetes medications, other cancer, etc.) Results N= 193,099 o Pioglitazone use: 30,173 o Never used: 162,926 Median follow- up 3.3 years Bladder cancer: o Pioglitazone use: 90 o Never used: 791 Mean incidence rate per 100,000 HR (95% CI) Adjusted for age and sex Fully adjusted* HR (95% CI) Never use pioglitazone 68.8 Ever use pioglitazone 81.5 1.2 (0.9, 1.5) 1.2 (0.9, 1.5) Duration of therapy (months) <12 48.4 0.8 (0.5, 1.2) 0.8 (0.6, 1.3) 12-24 86.7 1.3 (0.9, 2.0) 1.4 (0.9, 2.1) > 24 102.8 1.5 (1.1, 2.0) 1.4 (1.03, 2.0) >48 Not reported 1.7 (1.1, 2.9) Cumulative dose (mg) 1-10,500 59.7 1.0 (0.7, 1.4) 1.0 (0.7, 1.5) 10,501-28,000 76.8 1.1 (0.8, 1.6) 1.2 (0.8, 1.8) >28,000 105.9 1.5 (1.1, 2.2) 1.4 (0.96, 2.1) Pioglitazone and bladder cancer in men: o > 24 months: HR 1.6 (95% CI 1.2, 1.3) o Cumulative dose > 28,000 mg: HR 1.8 (95% CI 1.2, 2.6) Use >2 years was associated with a statistically significant increase in risk of bladder cancer Risk also appears to be associated with increasing cumulative doses and sex (men > women) Analyses from case- control revealed the absence of confounding due to variables incomplete or not measured Ninety- five percent of cancers diagnosed in pioglitazone users were detected in early stage Authors In this cohort of patients with diabetes, short- term (<2 years) use of pioglitazone was not associated with an increased Conclusions incidence of bladder cancer, but use for more than 2 years was weakly associated with increased risk. Comments Included a large sample size A long follow- up period Adjusted for potential confounders (e.g. use of other diabetes medications, race/ethnicity etc.) Smoking status missing for some patients Incomplete information on race/ethnicity Occupational exposures unknown See appendix B for list of fully adjusted model Showery 10

Tseng CH. Pioglitazone and bladder cancer: a population- based study of Taiwanese. Diabetes Care. 2012 Feb;35(2):278-80. 22 Purpose Investigate the association between pioglitazone and bladder cancer in the Asian population. Design Retrospective, cohort study Inclusion Ever users: prescribed pioglitazone Never users: never used pioglitazone Exclusion Death prior to inclusion Bladder cancer before inclusion Not on oral anti- diabetes medications or insulin Outcomes Bladder cancer Methods Randomly sampled from the National Health Insurance database in Taiwan Reimbursement records from 1996-2009 Ever used: prescribed pioglitazone Never used: no prescription for pioglitazone Statistics Bladder cancer incidence and 95% CI Cox regression to calculate HR Confounders adjusted for*: Age and sex Variables predictive of bladder cancer (e.g. urinary tract disease, etc.) Full model (e.g. other diabetes medications, occupation, other cancer, etc.) Results N=54,928 o Ever used = 2,545 o Never used = 52,383 Bladder cancer: o Ever used: 10 o Never used: 155 Pioglitazone use Incidence rate per 100,000 (95% CI) Never use 78.93 (66.99-92.38) Ever use 104.47 (50.10, 192.13) Duration of therapy (months) < 12 124.05 (53.56, 244.43) > 12 64.05 (7.76, 231.36) Cumulative dose (mg) 1-10,500 116.82 (50.43, 230.18) > 10,500 73.44 (8.89, 265.28) Age and sex HR (95%CI) 1.261 (0.665, 2.392) 1.525 (0.749, 3.106) 0.745 (0.185, 3.006) 1.429 (0.702, 2.910) 0.858 (0.213, 3.462) Previously identified risks* HR (95%CI) 1.148 (0.601, 2.192) 1.360 (0.664, 2.785) 0.706 (0.174, 2.860) 1.281 (0.625, 2.623) 0.809 (0.200, 3.281) Fully adjusted* HR (95%CI) 1.305 (0.66, 2.576) 1.540 (0.727, 3.262) 0.816 (0.199, 3.347) 1.450 (0.686, 3.064) 0.935 (0.227, 3.844) Authors Conclusions No statistically significant difference in the risk of bladder cancer between groups All bladder cancer occurred within 2 years and in patient who had a cumulative dose < 28,000mg Bladder cancer is potentially an early effect of pioglitazone use Insignificant overall increase in bladder cancer risk among pioglitazone users. All bladder cancer occurred within 2 years of the start of therapy and no patients with a cumulative dose >28,00mg developed bladder cancer, which suggests an early effect of pioglitazone use. Comments Relatively large sample size Adjusted for confounding variables Data on smoking status and occupational exposures missing Unknown stage bladder cancers were found Contrary to earlier studies, shows a potential early risk of bladder cancer with pioglitazone use Difficult to generalize results as based on specific patient population Please see Appendix C for detailed list Showery 11

Neumann A, Weill A, Ricordeau P, et al. Pioglitazone and risk of bladder cancer among diabetic patients in France: a population- based cohort study. Diabetologia. 2012 Jul;55(7):1953-62. 23 Purpose Investigate the association between pioglitazone exposure and bladder cancer in France Design Cohort study Inclusion Aged 40-79 on 12/31/2006 Registered in the French National Health Insurance system Filled at least one prescription for a glucose- lowering drug in 2006 Pioglitazone Rosiglitazone Metformin Sulfonylurea Other oral hypoglycemic agent Insulin Exclusion Bladder cancer diagnosed within the first 6 months after inclusion Outcomes Incidence of bladder cancer Methods Patients identified from: French National Health Insurance information system Exposure: 2 prescriptions for pioglitazone over 6 consecutive months Statistics Categorical and continuous variables using the X 2 and Wilcoxon test Mantel- Haenszel method for age and sex adjusted comparisons HR using a Cox proportional hazard model Results N=1,491,060 o Pioglitazone use: 155,535 Mean duration of follow- up: 39.9 months Bladder cancer: o Exposed: 175 o Non- exposed: 1,841 Incidence rate per 100,000 HR (95% CI) Adjusted for age, sex, other diabetes medications Men HR (95% CI) Women HR (95% CI) Non- exposed 42.8 Exposed 49.4 1.22 (1.05, 1.43) 1.28 (1.09, 1.51) 0.78 (0.44, 1.37) Duration of therapy (months) < 12 1.05 (0.82, 1.36) 1.10 (0.84, 1.43) 0.76 (0.34, 1.72) 12-23 1.34 (1.02, 1.75) 1.39 (1.06, 1.84) 0.87 (0.32, 2.35) 24 1.36 (1.04, 1.79) 1.44 (1.09, 1.91) 0.71 (0.22, 2.23) Cumulative dose (mg) < 10,500 1.12 (0.89, 1.40) 1.17 (0.92, 1.48) 0.77 (0.36, 1.65) 10,500 27,999 1.20 (0.93, 1.53) 1.24 (0.96, 1.60) 0.84 (0.35, 2.06) 28,000 1.75 (1.22, 2.50) 1.88 (1.30, 2.71) 0.57 (0.08, 4.11) Pioglitazone use was significantly associated with increased risk of bladder cancer No evidence of association with other glucose- lowering drugs, including rosiglitazone Rosiglitazone use: o Adjusted for age, sex, other antidiabetic medications: HR 1.08 (95% CI 0.92, 1.26) Authors In this cohort of diabetic patients from France, pioglitazone exposure was significantly associated with increased risk of bladder Conclusions cancer. Comments Largest sample size compared to studies previously reported First to report findings with rosiglitazone use Smoking status unknown Occupational exposure unknown No data on the stage of bladder cancer found Showery 12

Colmers IN, Bowker SL, Majumdar SR, et al. Use of thiazolidinediones and the risk of bladder cancer among people with type 2 diabetes: a meta- analysis. CAMJ 2012 Sep 4;184(12):E675-83. 24 Purpose Evaluate the risk of bladder cancer among adults with type 2 diabetes taking thiazolidinediones Design Systematic review and meta- analysis Inclusion Adults with type 2 diabetes Exposure (ever used a thiazolidinedione) Comparison group (never used a thiazolidinedione) Outcome (incident bladder cancer, even if not main outcome) Study design (RCT, cohort study, case- control study) Exclusion Duplicate reports from the same study Patients with type 1 diabetes Descriptive observational studies Outcomes Evaluate the risk of bladder cancer among patients with type 2 diabetes taking thiazolidinediones Methods Searched key biomedical databases (including MEDLINE, Embase, Scopus) from inception to March 2012 for published and unpublished studies Statistics Statistical heterogeneity using I 2 Results 4 RCT, 5 cohort studies, 1 case- control study N= 2,657,365 Bladder cancer: 3,643 Study Medication Studied No. of patients Exposed Comparison Exposed Comparison RCT Dormandy et al. 2005 Pioglitazone No TZD use 2,605 2,633 Kahn et al., 2006 Rosiglitazone No TZD use 1,456 2,895 (monotherapy) Home et al., 2009 Rosiglitazone No TZD use 2,220 2,227 (+ sulfonylurea or metformin) Sanofi- Aventis 2009 TZD (unspecified) No TZD use 256 130 Cohort Oliveria et al., 2008 TZD (unspecified) No TZD use Not reported Not reported Lewis et al., 2011 Pioglitazone No pioglitazone 30,173 162,926 Tseng, 2011 Pioglitazone No TZD use 1,028 112,520 and/or rosiglitazone Tseng, 2012 Pioglitazone No pioglitazone 2,545 52,383 Neumann el at., 2012 Pioglitazone No pioglitazone 155,535 1,335,525 Rosiglitazone No rosiglitazone 153,334 1,337,726 Case- control Piccinni et al., 2011 Pioglitazone No pioglitazone 37,841 561,244 Meta- analysis of the risk of bladder cancer associated with pioglitazone Study Exposed Comparison Risk ratio (95%CI) n/n n/n Lewis et al., 2011 90/30,173 791/162,926 1.2 (0.9-1.5) Neumann et al., 2012 175/155,535 1,841/1,335,525 1.2 (1.05-1.43) Tseng, 2012 10/2,545 155/52,383 1.30 (0.66, 2.58) Overall 1.22 (1.07-1.39) Heterogeneity: I 2 = 0% Showery 13

Meta- analysis of the risk of bladder cancer associated with rosiglitazone Study Intervention Control Risk ratio (95%CI) n/n n/n Kahn et al., 2006 2/1,456 2/2,895 0.50 (0.11-2.34) Home et al., 2009 6/2,220 5/2,227 1.20 (0.37-3.94) Overall 0.87 (0.34-2.23) Heterogeneity: I 2 = 0% Pioglitazone use was associated with increased risk of bladder cancer Limited evidence among rosiglitazone use Authors Results suggest an association between pioglitazone use and bladder cancer in adults with type 2 diabetes. Given the limited Conclusions evidence among rosiglitazone users, it remains unclear if the association is a class effect of all thiazolidinediones. Comments Large sample size Extensive search criteria as to not miss any potential studies Included published and unpublished studies Includes the three largest cohort studies Some data not available (e.g. smoking status) Showery 14

IX. Summary A. Long- term follow- up from the cohort study conducted per the FDA s request is still ongoing 1. Interim results reported increased risk with longer duration of therapy and higher cumulative doses. 2. Similar results were seen in studies with different patient populations. 3. Unclear at this point whether risk of bladder cancer is a class effect of all thiazolidinediones. 4. Based on combined available literature, longer duration of therapy and higher cumulative doses are associated with a higher risk of bladder cancer. a. Long- term use of pioglitazone ( 2 years) b. Cumulative doses 28,000mg (30 mg/day for 2.5 years) 5. It appears that men are also at a greater risk when compared to women. 6. Unclear what stage of bladder cancer. 7. No data on additive risk of bladder cancer in patients who are being treated with TZDs and have risk factors for bladder cancer. B. Recommendations 1. In patients with a history of bladder cancer pioglitazone should be avoided. 2. In patients who have multiple risk factors for developing bladder cancer pioglitazone should be avoided. 3. In patients currently being treated with pioglitazone who have multiple risk factors for developing bladder cancer, consideration should be made for discontinuation if: a. Duration of therapy 2years b. Cumulative dose 28,000mg (30 mg/day for 2.5 years) 4. Pioglitazone may still to be appropriate therapy in patients who have contraindications, cannot tolerate, or have failed other therapies, are not at goal and have minimal risks for bladder cancer. C. Future topics for research 1. Observational cohort studies to determine class effect 2. Studies to determine the mechanism of thiazolidinedione induced bladder cancer 3. Explore the differences in incidence between men and women Showery 15

References 1. Centers for Disease Control and Prevention. National Diabetes Fact Sheet 2011. Available at http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf 2. Texas Diabetes Council. Burden of Diabetes in Texas. Updated April 2013. Available at http://www.dshs.state.tx.us/diabetes/tdcdata.shtm 3. American Diabetes Association. Economic costs of diabetes in the U.S. in 2013. Diabetes Care. 2013 Apr;36(4):1033-46. 4. Triplitt CL, Reasener CA II, Isley WL. Pharmacotherapy a pathophysiologic approach. 7 th ed. New York: McGraw Hill Medical; c2008. Chapter 77, Diabetes Mellitus; p.1205-1241. 5. Porth CM. Essentials of pathophysiology concepts of altered mental health. 2 nd ed. New York: Lippincott Willams & Wilkins; c2007. Chapter 32, Diabetes Mellitus and the Metabolic Syndrome; p. 699-723. 6. American Diabetes Association. Standards of medical care in diabetes- 2013. Diabetes Care. 2013 Jan;36 Suppl 1:S11-66. 7. Texas Diabetes Council. Glycemic Control Algorithm for Type 2 Diabetes Mellitus in Adults 2010. Available at http://www.tdctoolkit.org/ wpcontent/themes/tdc/algorithms/09_ Glycemic Control Algorithm.pdf. 8. Garber AJ, Abrahamson MJ, Barzilay, et al. AACE comprehensive diabetes management algorithm 2013. Endocr Pract. 2013 Mar- Apr;19(2):327-36. 9. Takeda. Actos (pioglitazone) package insert. Revised 07/2011. Available at http://www.takeda.us/products/ 10. Yki- Järvinen H. Thiazolidinediones. N Engl J Med. 2004 Sep 9;351(11):1106-18. 11. Deeg MA, Tan MH. Pioglitazone versus rosiglitazone: effects on lipids, lipoproteins, and apolipoproteins in head- to- head randomized clinical trials. PPAR Res. 2008;2008:520465. 12. Singh S, Bhat J, Wang PH. Cardiovascular effects of anti- diabetic medications in type 2 diabetes. Curr Cardiol Rep. 2013 Jan;15(1):327. 13. American Cancer Society. Bladder Cancer. Available at http://www.cancer.org/acs/groups/cid/documents/webcontent/003085- pdf.pdf 14. National Cancer Institute. SEER Stats Fact Sheets: Bladder. Available at http://seer.cancer.gov/statfacts/html/urinb.html#incidence- mortality. 15. National Cancer Institute. What you need to know about bladder cancer. Available at http://www.cancer.gov/cancertopics/wyntk/bladder/wyntk_bladder.pdf 16. Jacobs BL, Lee CT, Montie JE. Bladder cancer in 2010: how far have we come? CA Cancer J Clin. 2010 Jul- Aug;60(4):244-72. 17. Barbalat Y, Dombrovskiy VY, Weiss RE. Association between pioglitazone and urothelial cancer. Urology. 2012 Jul;80(1):1-4. 18. Yang DR, Lin SJ, Ding XF, et al. Higher expression of peroxisome proliferator- activated receptor γ or its activation by agonist thiazolidinedione- rosiglitazone promotes bladder cancer cell migration and invasion. Urology. 2013 May;81(5):1109.e1-6. 19. Cohen SM. Effects of PPARgamma and combined agonists on the urinary tract of rats and other species. Toxicol Sci. 2005 Oct;87(2):322-7. 20. Dormandy JA, Charbonnel B, Eckland DJ, 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 randomized controlled trial. Lancet. 2005 Oct 8;366(9493):1279-89. 21. Lewis JD, Ferrara A, Peng T, et al. Risk of bladder cancer among diabetic patients treated with pioglitazone; interim report of a longitudinal cohort study. Diabetes Care. 2011 Apr;34(4):916-22. 22. Tseng CH. Pioglitazone and bladder cancer: a population- based study of Taiwanese. Diabetes Care. 2012 Feb;35(2):278-80. 23. Neumann A, Weill A, Ricordeau P, et al. Pioglitazone and risk of bladder cancer among diabetic patients in France: a population- based cohort study. Diabetologia. 2012 Jul;55(7):1953-62. 24. Colmers IN, Bowker SL, Majumdar SR, et al. Use of thiazolidinediones and the risk of bladder cancer among people with type 2 diabetes: a meta- analysis. CAMJ 2012 Sep 4;184(12):E675-83. Showery 16

Appendix A: Characteristics of available therapeutic options for type 2 diabetes Class Drug Mechanism Primary Advantages Disadvantages Biguanides Metformin Activates AMPkinase ê hepatic glucose Experience GI side effects production No weight gain Lactic acidosis Sulfonylureas Meglitinides (glinides) Thiazolidinediones α-glucosidase inhibitors DPP-4 inhibitors 2 nd generation: Glyburide Glipizide Glimepride Repaglinide Nateglinide Pioglitazone Rosiglitazone Acarbose Miglitol Sitagliptin Saxagliptin Linagliptin Closes K ATP channels on β-cell plasma membranes Closes K ATP channels on β-cell plasma membranes Activates nuclear transcription factor PPAR-γ Inhibits intestinal α-glucosidase Inhibits DPP-4 activity é postprandial active incretin concentrations Bile acid sequestrants Colesevelam Binds bile acids in intestinal tract, é hepatic bile acid production Dopamine-2 agonists Bromocriptine Acitivates dopaminergic receptors GLP-1 receptor agonists Exenatide Liraglutide Activates GLP-1 receptos é insulin secretion é insulin secretion é insulin sensitivity Slows intestinal carbohydrate digestion/ absorption é insulin secretion ê glucagon secretion Unknown Modulates hypothalamic regulation of metabolism é insulin sensitivity é insulin secretion ê glucagon secretion Slows gastric emptying é satiety No hypoglycemia Experience ê microvascular risk (UKPDS) ê postprandial glucose Dosing flexibility No hypoglycemia é HDL ê TG No hypoglycemia ê postprandial glucose No hypoglycemia Well tolerated No hypoglycemia ê LDL No hypoglycemia No hypoglycemia Weight loss CI: CKD, acidosis Hypoglycemia Weight gain Hypoglycemia Weight gain Frequent dosing schedule Weight gain Edema/HF é LDL Bladder cancer GI side effects Modest A1c efficacy Frequent dosing schedule Modest A1c efficacy Pancreatitis Modest A1c efficacy é TG Constipation Modest A1c efficacy Dizziness/syncope Nausea Fatigue Rhinitis GI side effects Acute pancreatitis Amylin mimetics Pamlintide Activates amylin receptors Sodium glucose cotransporter 2 (SGT-2) inhibitor Human NPH Human Regular Lispro Aspart Glulisine Glargine Detemir Premixed (several) Canagliflozin Activates insulin receptors Inhibits SLGT2 in kidneys ê glucose reabsorption é glucose disposal ê hepatic glucose production ê glucagon secretion Slows gastric emptying é satiety é glucose incretion in urine Universally effective Theroretically unlimited efficacy ê microvascular risk (UKPDS) ê postprandial glucose Weight loss Dosing flexibility Modest A1c efficacy GI side effects Hypoglycemia Frequent dosing Modest A1c efficacy Yeast infections Hypoglycemia Weight gain Showery 17

Appendix B: Lewis, et al. 2011 Statistical analysis Lewis JD, Ferrara A, Peng T, et al. Risk of bladder cancer among diabetic patients treated with pioglitazone; interim report of a longitudinal cohort study. Diabetes Care. 2011 Apr;34(4):916-22. 20 Fully adjusted model: Age Sex Race/ethnicity Current smoker Renal function Bladder condition o History of UTI o Urolithiasis o Incontinence o Other bladder or urethral conditions) Congestive heart failure Income Baseline A1c Newly diagnosed with diabetes Duration of diabetes Other cancer prior to baseline Other diabetes medications Duration of therapy Showery 18

Appendix C: Tseng, et al. 2012 Statistical analysis Tseng CH. Pioglitazone and bladder cancer: a population- based study of Taiwanese. Diabetes Care. 2012 Feb;35(2):278-80. 21 Statistical analysis: adjusted for the following confounding variables Age and sex Variables predictive of bladder cancer o Age o Sex o Diabetes duration o Urinary tract disease o Statin use o Nephropathy o COPD o Region of residence Full Model o Age o Sex o Diabetes duration o Urinary tract disease o Statin use o Nephropathy o COPD o Region of residence o Hypertension o Ischemic heart disease o Sulfonylurea o Metformin o Insulin o Fibrate o Rosiglitazone o Meglitinide o Acarbose o ACEI/ARB/CCB o Cerebrovascular disease o Peripheral arterial disease o Dyslipidemia o Other cancer before baseline Showery 19