Clinical effects of a selective urate reabsorption inhibitor dotinurad in patients with hyperuricemia and treated hypertension: a multicenter, prospective, exploratory study (DIANA)
Authors: Tanaka Atsushi , Taguchi Isao , Hisauchi Itaru , Yoshida Hisako , Shimabukuro Michio , Hongo Hiroshi , Ishikawa Tetsuya , Kadokami Toshiaki , Yagi Shusuke , Sata Masataka , Node Koichi ,   the DIANA study investigators, Asaka Machiko , Kamishita Kohei , Kaneko Tetsuya , Kaneta Kohei , Natsuaki Masahiro , Shiraki Aya , Sonoda Shinjo , Tago Motoko , Yajima Ayumu , Yokoi Kensuke , Yoshioka Goro , Nakamura Ryo , Nishi Junichiro , Onizuka Ken , Ise Takayuki , Kadota Muneyuki , Kawabata Yutaka , Kusunose Kenya , Matsumoto Kazuhisa , Matsuura Tomomi , Okushi Yuichiro , Seno Hiromitsu , Soeki Takeshi , Suto Kumiko , Takahashi Tomonori , Tobiume Takeshi , Wakatsuki Tetsuzo , Yamada Hirotsugu , Yamaguchi Koji , Hotta Yuki , Iwasaki Mariko , Kazama Junichiro , Saito Yu , Sato Masahiro , Takiguchi Yoshinori , Tanabe Hayato , Watanabe Kiriko , Yamaguchi Mizuki , Tomita Sachiko , Kagiyama Mikiko , Onodera Keiko 
Published: July 2023

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