Study Design Choices for Evaluating Comparative Safety of Diabetic Medications: An Evaluation of Pioglitazone and Bladder Cancer Risk Among Older US Adults with Type-2 Diabetes.

AIM: Empirically demonstrates the effect of varying study design choices to evaluate the safety of pioglitazone on bladder cancer.

METHODS: We identified Medicare beneficiaries aged >65 with diabetes between 2008 and 2015 and classified exposure (≥2 claims within 180 days) to glucose-lowering drugs (GLD; pioglitazone or other). The effects of varying the following study design parameters on bladder cancer risk were assessed - new versus existing drug use, choice of referent (all non-users and users of GLDs, non-insulin GLDs, and DPP-4's), and whether or not censoring accounted for treatment change. We used Cox proportional hazards models to obtain adjusted HRs and 95% CI.

RESULTS: We included 1,510,212 patients classified as pioglitazone users (N=135,188) or non-users (N=1,375,024). Users had more diabetic complications than non-users, but less than insulin users. The HR ranged from 1.10(1.01-1.20) to 1.13(0.99-1.29) when censoring ignored treatment changes, suggesting weak or no association between pioglitazone and bladder cancer, likely under-estimating risk, but was 1.20(1.01-1.42) when cohorts restricted to new users, censored upon treatment change, and used DPP-4 as the referent, suggesting an increased risk of bladder cancer associated with pioglitazone.

CONCLUSIONS: The continued demand for new GLDs compels the need for more robust observational methods to improve the value of the RWE generation in order to equip clinicians to make informed prescribing decisions. Although there is no one-size-fits all approach, we recommend active comparator new user study designs that compare therapeutically equivalent drugs and account for treatment changes during follow-up to present the least biased comparative safety estimates. This article is protected by copyright. All rights reserved.