Background/Purpose: Gout is a chronic inflammatory arthritis that is undertreated and managed with the xanthine oxidase inhibitors febuxostat or allopurinol. Despite the United States Food and Drug Administration (FDA) mandating febuxostat carry its most prominent warning for serious side effects that include cardiovascular-related death, febuxostat is widely prescribed. A large, manufacturer-sponsored clinical trial (CARES) led to the febuxostat FDA warning label; however, a recent, large clinical trial (FAST) did not replicate these data in patients without pre-existing cardiovascular risk. Whether febuxostat increases cardiovascular risk remains an important question and to date there are few mechanistic studies designed to resolve this controversy.

Methods: We compared the transcriptomic signature of oral gout medications alongside 107 other clinical stage compounds, 33 of which are FDA labelled for increased cardiovascular risk, in an in vitro human primary cell-based cardiovascular disease model to clarify the potential risk of febuxostat.

Results: Febuxostat significantly modulated more signaling pathways associated with cell stress and cardiovascular risk than allopurinol or topiroxostat, gout medications not associated with increased cardiovascular risk. Moreover, these signaling pathways were commonly regulated by other drugs FDA labelled for cardiovascular risk. Lastly, these results were replicated with a febuxostat analog.

Conclusion: Together, these data support the FDA warning for febuxostat and suggest that cardiovascular risk associated with gout medications stems from chemical structure of the medication, itself, rather than the target, xanthine oxidase.

« Back to ACR Convergence 2023

ACR Meeting Abstracts - https://acrabstracts.org/abstract/human-cardiovascular-disease-model-provides-transcriptomic-evidence-of-cardiovascular-risk-associated-with-febuxostat/