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Disproportionality Analysis of Bladder Cancer Risk with Pioglitazone Use in VigiBase: Implications for Bladder Cancer Monitoring and Treatment
Jonathan J. Song, BA1, Nancy Donohoo, BA1, Mark A. Preston, MD2, Daniel A. Wollin, MD2.
1Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA, 2Brigham and Women's Hospital, Boston, MA, USA.
BACKGROUND: Pioglitazone, a thiazolidinedione (TZD) medication indicated for diabetes, is discouraged for use with active or prior bladder cancer by the FDA despite conflicting evidence, although it remains an important combination therapy option. We studied the association of bladder cancer with TZDs and comparator medications in a global, real-world database.
METHODS: We conducted a pharmacovigilance study of bladder cancer adverse events reported with TZDs (pioglitazone, rosiglitazone) in VigiBase, a WHO global database of individual case-safety reports. Adverse events from 1999 to 2022 were included; only internally identified duplicates were excluded. Disproportionality analysis was conducted with a significance threshold of lower bound 95% Empiric Bayes Estimator >1, from which we describe the reporting odds ratio (ROR) and 95% confidence interval.
RESULTS: Of 61,299,050 total adverse events, 3573 cases of bladder cancer included TZDs, of which 3291 (92%) were pioglitazone. Bladder cancer was significantly associated with TZDs overall (ROR 71.3; 95% CI 68.9-73.9), pioglitazone (ROR 132.8; 95% CI 128.0-137.9), and rosiglitazone (ROR 9.7; 95% CI 8.6-10.9). Significant disproportionality signals were observed by reported age and sex. ROR increased with dose for pioglitazone (ROR 10-25mg: 212.3, ROR 25-40mg: 298.0, ROR 40-50mg: 371.3) but not rosiglitazone. Comparator diabetes medications of metformin (ROR 9.5; 95% CI 9.0-9.9), SGLT-2 inhibitors (ROR 2.5; 95% CI 2.0-3.2), and insulin (ROR 1.6; 95% CI 1.5-1.7 were similarly significant, although no dose-dependent relationships existed.
CONCLUSIONS:TZDs, particularly pioglitazone, were significantly associated with dose-dependent reporting of bladder cancer, while comparator diabetes medications were not. Our results support continued safety monitoring of TZDs, especially during bladder cancer surveillance, and counseling vulnerable patients on the risk of developing bladder cancer with TZDs.
Disproportionality analysis of bladder cancer associated with TZD and comparators by dose| Group | Count | Expected Count | EBE | ROR (95% CI) |
| Pioglitazone 10-25 mg | 301 | 1.57 | 189.63* | 212.33 (188.54-239.11) |
| Pioglitazone 25-40 mg | 481 | 1.86 | 256.43* | 298.04 (270.80-328.01) |
| Pioglitazone 40-50 mg | 368 | 1.17 | 310.42* | 371.32 (332.33-414.89) |
| Rosiglitazone 1-4 mg | 11 | 0.45 | 34.20* | 24.60 (13.58-44.57) |
| Rosiglitazone 4-7 mg | 67 | 4.06 | 11.12* | 16.66 (13.10-21.19) |
| Rosiglitazone 7-10 mg | 52 | 2.36 | 14.55* | 22.28 (16.95-29.29) |
| Metformin 250-750 mg | 352 | 21.36 | 16.25* | 16.80 (15.12-18.67) |
| Metformin 750-1500 mg | 322 | 22.50 | 13.72* | 14.56 (13.04-16.25) |
| Metformin 1500-2500 mg | 108 | 5.04 | 16.85* | 21.69 (17.94-26.23) |
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