Randomized, Open-Label, Cross-Over Comparison of the Effects of Benzbromarone and Febuxostat on Endothelial Function in Patients with Hyperuricemia

Abstract

Uric acid is generated with reactive oxygen species via xanthine oxidase (XO), and hyperuricemia, which is identified as the excess of uric acid in the blood, has been associated with vascular endothelial dysfunction. However, the effects of urate-lowering medicines on endothelial function have not been fully elucidated. Thus this study determined and compared the effects of benzbromarone (urate transporter 1 inhibitor) and febuxostat (XO inhibitor) on endothelial function. This randomized, cross-over, open-label study initially recruited 30 patients with hyperuricemia. They were divided into two groups, treated initially with benzbromarone or febuxostat for three months and then were switched for the next three months. Endothelial function was defined as reactive hyperemia indexes (RHI) determined using Endo-PAT 2000 before and at three and six months after medication using the two agents. Blood levels of asymmetric dimethylarginine (ADMA) and high-molecular-weight (HMW) adiponectin were also compared. We finally analyzed data from 24 patients whose endothelial function was assessed as described above. Our findings show that levels of uric acid significantly decreased, whereas those of HMW adiponectin and the RHI have significantly increased after treatment with benzbromarone. Meanwhile, in patients administered with febuxostat, uric acid levels tended to decrease and RHI significantly decreased. Neither of the two agents altered ADMA levels. The changes in RHI (P = 0.026) and HMW adiponectin levels (P = 0.001) were found to be significantly greater in patients treated with benzbromarone than febuxostat. Changes in the levels of HMW adiponectin and of uric acid were significantly correlated (r = −0.424, P = 0.039). Benzbromarone has increased adiponectin besides reducing uric acid levels, and thus, this might confer more benefits on endothelial function than febuxostat.

Assessing the Causal Effects of Adipokines on Uric Acid and Gout: A Two-Sample Mendelian Randomization Study

“…In the course of treatment, the concentration of ADP was elevated, possibly due to the involvement of reactive oxygen species [ 30 ]. Similar results were seen in patients tread with benzbromarone for gout [ 31 ]. Benzbromarone is a potent UA excretion drug that works by inhibiting urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) [ 29 ].…”

High remnant cholesterol level is relevant to diabetic retinopathy in type 2 diabetes mellitus

“…Other studies suggested that UA can protect vascular endothelium, which may be caused by the antioxidant effect of UA concentrations in a particular range [ 30 ]. However, inflammatory responses can be stimulated [ 31 ]. Notably, a sizeable cross-sectional study of a rural Chinese populace reported that high uric acid levels might be associated with various blood lipids [ 32 ].…”

Uric Acid in Inflammation and the Pathogenesis of Atherosclerosis

“…Febuxostat had a modest systolic blood pressure-lowering effect, but flow-mediated dilation (FMD) and production of NO were not altered [113]. In a smallscale study comparing febuxostat and benzbromarone, vascular endothelial function was not improved by febuxostat but was improved by benzbromarone [114]. In Japanese patients with asymptomatic hyperuricemia, the development of atherosclerosis was assessed by carotid intima-media thickness.…”