Clinical effects of a selective urate reabsorption inhibitor dotinurad in patients with hyperuricemia and treated hypertension: a multicenter, prospective, exploratory study (DIANA)

Abstract

Introduction Dotinurad is a newer urate-lowering agent that selectively inhibits urate transporter 1 in the renal proximal tubule and increases urinary urate excretion. Currently, little is known about the clinical efficacies of dotinurad in patients with hyperuricemia and hypertension. The aim of this study was to assess the clinical effects of a selective urate reabsorption inhibitor dotinurad on serum uric acid (SUA) levels and relevant vascular markers in patients with hyperuricemia and treated hypertension. Methods This investigator-initiated, multicenter, prospective, single-arm, open-label, exploratory clinical trial in Japan enrolled patients with hyperuricemia and treated hypertension who received a 24-week dotinurad therapy (a starting dose at 0.5 mg once daily and up-titrated to 2 mg once daily). The primary endpoint was a percentage change in the SUA level from baseline to week 24. The secondary endpoints were cardiovascular and metabolic measurements, including changes in the cardio-ankle vascular index (CAVI) and derivatives of reactive oxygen metabolites (d-ROMs) concentration at week 24. Results Fifty patients (mean age 70.5 ± 11.0 years, with 76.0% being men, and mean SUA level 8.5 ± 1.2 mg/dL) were included in the analysis. The percentage change from baseline in the SUA level at week 24 was − 35.8% (95% confidence interval [CI] − 39.7% to − 32.0%, P < 0.001), with approximately three quarters of patients achieving an SUA level of ≤ 6.0 mg/dL at week 24. The proportional changes from baseline in the geometric mean of CAVI and d-ROMs at week 24 were 0.96 (95% CI 0.92 to 1.00, P = 0.044) and 0.96 (95% CI 0.92 to 1.00, P = 0.044), respectively. Conclusion In addition to meaningful SUA-lowering effects, 24 weeks of dotinurad therapy may favorably affect arterial stiffness and oxidative stress markers, suggesting off-target vascular protection of dotinurad. Further research is expected to verify our findings and elucidate the entire off-target effects of dotinurad. Trial registration jRCTs021210013, registration date June 24, 2021

Relationship of Serum Uric Acid with Kidney Function Decline Mediated by Systemic Arterial Stiffness: A Retrospective Cohort Study in Japan

“…However, a sub-analysis of the above study found that topiroxostat reduced CAVI in a sub-population with liver dysfunction [26]. On the other hand, dotinurad, a urate reabsorption inhibitor, also reduced CAVI despite not inhibiting xanthine oxidase [27]. Considering these previous reports indicating that the inhibition of xanthine oxidase is not necessarily required to improve CAVI, it seems less relevant to consider SUA as just an atherogenic marker.…”

A Possible Therapeutic Application of the Selective Inhibitor of Urate Transporter 1, Dotinurad, for Metabolic Syndrome, Chronic Kidney Disease, and Cardiovascular Disease

“…When the CAVI was incorporated into a model with known CVD risks for predicting CV events, the global χ2 value increased, suggesting that the CAVI predicted CV events. The 24-week treatment with dotinurad significantly reduced the CAVI from 9.29 to 8.92 ( p = 0.044), suggesting that dotinurad may favorably affect arterial stiffness [ 15 ]. The derivatives of the reactive oxygen metabolite concentration at week 24 were significantly lower than those at the baseline [ 15 ].…”

“…The 24-week treatment with dotinurad significantly reduced the CAVI from 9.29 to 8.92 ( p = 0.044), suggesting that dotinurad may favorably affect arterial stiffness [ 15 ]. The derivatives of the reactive oxygen metabolite concentration at week 24 were significantly lower than those at the baseline [ 15 ]. URAT1 inhibition by dotinurad at the urate entry site on the vascular walls and the resultant attenuation of ROS production might have caused such beneficial vascular effects [ 103 , 104 ].…”

“…Unexpectedly, we found that dotinurad improved serum lipids, blood pressure, body weight, albuminuria, and the estimated glomerular filtration rate (eGFR); in addition, it reduced serum UA in patients with hyperuricemia complicated by CKD and diabetic kidney disease (DKD) [ 14 ]. Furthermore, the 24 week-dotinurad treatment favorably affected arterial stiffness and oxidative stress, suggesting that dotinurad provides off-target vascular protection [ 15 ].…”