Abstract A27: Association between diabetes pharmacotherapies and bladder cancer: A Medicare epidemiologic study
Authors: Smith Jeremy , Zaha Rebecca , Mackenzie Todd A. , Karagas Margaret R. , Morden Nancy E. 
Published: October 2015

Abstract
Background: Patients with type two diabetes mellitus (T2DM) have an increased risk of bladder cancer; they are also commonly treated with pioglitizone and angiotensin receptor blockers (ARBs), medications associated with an increased cancer risk in some studies. This study aimed to further explore the relationship between these medications and bladder cancer in an older population with higher baseline risk of this cancer and common exposure to these drugs. We examine the risk associated with exposure to the individual drug/drug class, and risk associated with exposure to both to assess for a potential cancer promoting interaction.
Methods: Using a 40% Medicare random sample denominator and corresponding inpatient, outpatient (2004-2012) and prescription (2006-2012) claims, we studied fee-for-service beneficiaries age 67 and older. We identified pharmacotherapeutically treated diabetics (2006 to 2011) defined as patients filling one or more prescription for an oral hypoglycemic drug. Individual-level, time varying exposure to all oral and injectable hyopglycemics as well as ARBs and ACE-Is was calculated as count of drug-specific daily doses; daily doses were derived empirically as the median daily dose (MDDs) for this population. Cox proportional hazards models, adjusted for patient characteristics, comorbidities and diabetes complications, were used to examine the risk of incident bladder cancer associated with cumulative observed exposure to pioglitazone and ARBs. To address possible indication bias for the exposures of interest, we also estimated risk associated ACE-I exposure and non-pioglitazone TZD exposure, substitutes for the exposures of interest not suspected of increasing cancer risk. Interaction terms estimated the effect of exposure to ARBs with pioglitazone and ARBs with non-pioglitazone TZD. Secondary models repeated main models stratified on gender due to the higher baseline risk of bladder cancer in men.
Results: Overall, we identified 1,161,443 diabetics, 62.5% female, 10.7% black, 9.8% Hispanic. Mean age at the beginning of follow-up was 75.1 years (SD 7.5); 18.9% had evidence of current or past tobacco use. Mean follow time was 42.2 months (SD 26.4). Overall, 20.2% of the cohort used some pioglitazone (mean exposure 642 MDDs); 31.7% used some ARB (Mean exposure 745 MDDs); 10.4% used some non-pioglitazone TZD (mean exposure 503 MDDs); 59.1% used some ACE-I (mean exposure 855 MDDs). 8.0% used both pioglitazone and ARBs; 13.2% used both pioglitazone and ACE-I; 4.1% used non-pioglitazone TZD and ARB; and 6.8% used non-pioglitazone TZD and ACE-I. In total, 5,874 bladder cancers were identified, 69% amongst men, an incidence of 0.28/1000 PY in men and 0.07/1000 PY in women. Compared to no observed exposure, the risk of bladder cancer associated with each additional year of exposure at median daily dose was: 0.97 (95% CI 0.89, 1.06) for pioglitazone, 1.04 (95% CI 0.97, 1.12) for ARBs; 0.99 (95% CI 0.95, 1.03) for ACE-Is and 0.98 (95% CI 0.86, 1.12) for non- pioglitizone TZDs. The risk of bladder cancer associated with each additional year of exposure to both pioglitizone and ARB was 0.97 (95% CI 0.91, 1.04); for pioglitazone and ACE-I, 1.01 (95% CI 0.98, 1.03); for non-pioglitazone TZD and ARB, 0.99 (95% CI 0.91, 1.08); and for non-pioglitazone TZD and ACE-I, 0.99 (95% CI 0.93, 1.04). Results did not differ when stratified by sex.
Conclusions: We found no increased risk of bladder cancer associated with pioglitizone use, ARB use or exposure to both over an average observation time of 3.5 years. While the findings of this observational study should be confirmed in a prospective trial of longer duration, overall the results should reassure diabetics and their clinicians using these products to minimize the substantial health risks associated with diabetes.
Citation Format: Jeremy Smith, Rebecca Zaha, Todd A. Mackenzie, Margaret R. Karagas, Nancy E. Morden. Association between diabetes pharmacotherapies and bladder cancer: A Medicare epidemiologic study. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr A27.