The cardiovascular safety of xanthine oxidase inhibitors in complex patient populations has emerged as a critical clinical consideration following conflicting evidence from major trials. This review synthesizes current evidence on the cardiovascular safety of febuxostat versus allopurinol in patient populations characterized by comorbidities, including chronic kidney disease, diabetes mellitus, and Asian ethnicity. There are raised concerns about the increased cardiovascular and all-cause mortality with febuxostat in gout patients with cardiovascular disease, while the subsequent non-inferior cardiovascular safety in a moderate-risk population. Recent evidence revealed heterogeneous effects across subgroups: in Asian populations, febuxostat is associated with significantly increased risks of acute coronary syndrome and atrial fibrillation, with particularly elevated risks among Asian subgroups for cardiovascular death and all-cause mortality. In patients with chronic kidney disease, evidence suggests that febuxostat may decrease cardiovascular events. In contrast, association with concomitant diabetes mellitus and chronic kidney disease exhibited higher risks of heart failure hospitalization and cardiovascular interventions with febuxostat. Interestingly, achieving serum urate control below 5 mg/dL appears independently associated with reduced cardiovascular risk regardless of the agent used. These findings highlight that cardiovascular safety comparisons cannot be generalized across populations; rather, risk-benefit assessments must integrate ethnicity, renal function, diabetic status, and baseline cardiovascular disease. Future research should prioritize prospective studies in underrepresented populations and elucidate mechanisms underlying differential treatment effects.
