Gout Therapies Allopurinol, Febuxostat Do Not Increase Retinal Microvascular Disorder Risk

There is no difference in the risk of retinal microvascular disorders between allopurinol and febuxostat initiators, according to a recent cohort study on patients initiating both medications to treat gout.

Recent studies comparing urate-lowering therapies (ULTs) – specifically the xanthine oxidase inhibitors (XOIs) febuxostat and allopurinol – have uncovered a higher risk of all-cause and cardiovascular (CV) mortality in febuxostat compared to allopurinol. However, the vast majority of this research has focused on macrovascular events at the expense of the microvascular.2

“Therefore, it would be necessary to generate more thorough information on the comparative CV effects of different XOIs by investigating the microvascular end-points,” wrote Min Jung Kim, division of rheumatology, department of internal medicine, Seoul Metropolitan Government-Seoul National University Hospital Boramae Medical Center, and colleagues. “To this end, we aim to compare the risk of retinal microvascular disorders between allopurinol initiators versus febuxostat in patients with gout.”1

Investigators utilized the 2011-2019 Korean National Health Insurance Service (KNHIS) database, which collects longitudinal patient data from birth to death from all citizens of Korea. The database includes demographics, International Classification of Diseases, 10th Revision (ICD10) diagnosis codes, procedures, pharmacy dispensing records, and type of medical utilization – i.e., outpatient, inpatient, or emergency department.1

Investigators selected patients aged ≥40 years with ICD10 diagnosis codes of gout who initiated febuxostat or allopurinol. For inclusion, patients had to be free of any ULT use for ≥12 months before the first dispensing date of either medication. Patients who had a diagnosis of choroid or retinal disorders, such as diabetic retinopathy, type 1 diabetes, cancer, or chronic kidney disease, were also excluded.1

Patients were stratified into diabetes mellitus (DM) and non-DM subgroups, which were based on baseline type 2 diabetes mellitus (T2DM), which was in turn defined based on the presence and absence of IDC10 codes for T2DM. Those without ICD10 codes for T2DM who used anti-diabetic drugs were excluded.1

Investigators defined the primary outcome as a composite of retinal disorders representing microvascular complications, such as retinal vascular occlusions, hemorrhage, and other changes in retinal vascular appearances. Secondary outcomes involved individual components of the primary outcome; however, given the likelihood of increased DM progression in the presence of gout, DM retinopathy was included as a secondary outcome only in the DM subgroup.1

A total of 405,445 new users of allopurinol (n = 321,365 without DM, n = 84.080 with DM) and 131,783 new users of febuxostat (n = 97,917 without DM, n = 33,866 with DM) were identified. After 1:1 propensity score matching, 118,376 pairs of allopurinol and febuxostat initiators were generated, with 89,642 pairs from the non-DM subgroup and 27,834 pairs from the DM subgroup. Baseline covariates were well-balanced, and mean age was 55.5 and 62.9 years in the non-DM and DM groups, respectively.1

The pooled analysis indicated a retinal microvascular disorder risk per 100 person-years of 0.88 among allopurinol users and 0.93 among febuxostat users over 223 days of mean follow-up. The propensity score-matched hazard ratio (HR) was 0.98 (95% CI, 0.83-1.15) comparing allopurinol to febuxostat. The non-DM subgroup showed a risk of 0.77 among allopurinol and 0.81 among febuxostat (HR, 0.94; 95% CI, 0.76-1.15), and the DM subgroup had a risk of 1.15 among allopurinol and 1.26 among febuxostat (HR, 1.05; 95% CI, 0.8-1.39).1

“Due to the concordance and similarities in risk factors of microvascular and macrovascular disorders, it is not surprising that the results are consistent between them,” Kim and colleagues wrote. “However, our findings provide more assuring CV safety data for different ULTs among gout patients.”1

References

1. Kim M.J., Pyo J.Y., Choi S.R., et al. Comparative risk of retinal microvascular disorders in patients with gout initiating febuxostat versus allopurinol: a population-based cohort study. Sci Rep 15, 28939 (2025). https://doi.org/10.1038/s41598-025-00551-z

2. Mackenzie IS, Ford I, Nuki G, et al. Long-term cardiovascular safety of febuxostat compared with allopurinol in patients with gout (FAST): a multicentre, prospective, randomised, open-label, non-inferiority trial. Lancet. 2020;396(10264):1745-1757. doi:10.1016/S0140-6736(20)32234-0