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

This investigator-initiated, multicenter, prospective, open-label, single-arm, exploratory clinical trial (effect of dotinurad in hyperuricemia with hypertension [DIANA]; jRCTs021210013) was conducted to assess the net clinical effects of dotinurad therapy on SUA levels and vascular function in Japanese patients with hyperuricemia (SUA > 7.0 mg/dL) without active gouty arthritis and had treated hypertension. Detailed inclusion and exclusion criteria are provided in Additional file 1: Table S1.

After written informed consent acquisition and eligibility assessment, eligible patients received dotinurad (starting dose at 0.5 mg once daily and up-titrated to a maintenance 2 mg once daily) for 24 weeks. The dose of dotinurad was requested to be up-titrated, in principle, to 1.0 mg once daily at week 4 and 2 mg once daily at week 8. If the SUA level exceeds 6.0 mg/dL in spite of maintenance dose of dotinurad, a further escalation of dotinurad to a maximum of 4 mg once daily was allowed. If a patient had been receiving any uric acid-lowering drug at the time of consent, dotinurad therapy was initiated after at least a 27-day break in the prior drug. The follow-up visits were made at weeks 4, 8, 12, and 24 after the initiation of dotinurad therapy. The background therapy of each patient remained unchanged during the study interval, and the use of any urate-lowering agent other than dotinurad was prohibited.

This study was approved by the Fukushima Medical University Certified Review Board (No. F2021002 on June 10, 2021) and conducted in accordance with the Declaration of Helsinki and the Clinical Trial Act in Japan.

The primary endpoint was a percentage change in the SUA level from baseline to week 24 of dotinurad therapy. The secondary endpoints included relevant clinical measurements, such as changes in the SUA level at weeks 4, 8, 12, and 24, proportions of patients who achieved an SUA level of ≤ 6.0 mg/dL at corresponding weeks, change in blood pressure (BP) over 24 weeks, and changes in the cardio-ankle vascular index (CAVI) and several biomarkers including C-reactive protein (CRP, mg/dL), interleukin-6 (IL-6, pg/mL), growth differentiation factor 15 (GDF-15, pg/mL), N-terminal pro-brain natriuretic peptide (NT-proBNP, pg/mL), high-sensitivity troponin T (hs-TnT, pg/mL), derivatives of reactive oxygen metabolites (d-ROMs, U.CARR), and urinary albumin creatinine ratio (UACR) at week 24. CRP, IL-6, GFF-15, NT-proBNP, and hs-TnT levels were measured at a central commercial-based laboratory (SRL, Inc., Tokyo, Japan). The evaluation of d-ROMs concentrations was centrally conducted at an academic laboratory (Department of Cardiology, Dokkyo Medical University Saitama Medical Center, Saitama, Japan) by measuring hydroperoxide serum levels (Diacron, Grosseto, Italy) and quantified by a photometer (FREE, Diacron) at a wavelength of 505 nm [10]. UACR was measured from the urine sample obtained at the time of the office visit. The estimated glomerular filtration rate (eGFR), estimated by a revised equations from serum creatinine for Japanese [11], and Fib-4 index were also measured at baseline and weeks 12 and 24.

Detailed methods for measuring CAVI were described previously [12]. Briefly, using a VeSera device (Fukuda Denshi, Tokyo, Japan), the CAVI was automatically measured based on the standard protocol on the right and left sides of the body, and the mean value of each one was used in the analysis.

The target sample size of the DIANA study was initially based on the percent change in the SUA level (effect size) at 14 weeks in the phase 3 study of dotinurad and at 34 weeks in the long-term study, which ranged from 41.82% to 46.73% [13‐15]. Then, in this study, the percent change in the SUA level at 24 weeks was assumed to be 42% (standard deviation 12%). If the lower limit of its 95% confidence interval (CI) was > 30%, we considered it an effective urate-lowering effect. As regards the primary endpoint, the number of cases required would be < 10 when calculated with α = 0.05 and 1 − β (power) = 0.80. However, this exploratory study also sought to explore the effects of dotinurad therapy on other clinical measurements, including BP and vascular function, and the relationships between changes in the SUA level and those parameters in the planned sub-analyses. In this context, assuming that the correlation was approximately r = 0.40, the number of cases required would be 47 when calculated with α = 0.05 and 1 − β (power) = 0.80. Taking dropouts into account, the required sample size was set at 50.

SUA levels were evaluated at each visit (weeks 4, 8, 12, and 24) using a mixed model for repeated measures and compared with the baseline. According to several background characteristics stratified by gender, age, body mass index level, eGFR level, SUA level, histories of diabetes, dyslipidemia, and CVD, pre-specified subgroup analyses were also performed to explore the robustness of the primary endpoint. The prevalence of patients whose SUA levels reached ≤ 6 mg/dL was calculated, and the relationship between the SUA level at baseline and the prevalence of achieving an SUA level of ≤ 6 mg/dL at week 24 was examined using a logistic model as a post hoc analysis. To account for non-linear associations, a restricted cubic spline with three knots was included in the model. Other secondary endpoints were evaluated generally in the same manner as the primary endpoint. For variables for which the measured values were non-normally distributed, the proportional changes in the pre- and post-geometric means were calculated. Unless otherwise stated, the significance level was set at 5% two sided. No adjustments for multiple comparisons were considered. All statistical analyses were performed using R software version 4.2.0 (R Foundation for Statistical Computing, Vienna, Austria).

Of the 54 patients screened and registered, 50 met the eligibility criteria and were included in the efficacy and safety analysis (Fig. 1), and 49 patients completed the study. The demographics and baseline characteristics of patients are shown in Table 1. The mean patient age was 70.5 ± 11.0 years, in which 76.0% were men, and the mean SUA level was 8.5 ± 1.2 mg/dL at registration. A total of 37 (74.0%) patients were naïve for urate-lowering agents, and the remaining had been taking urate-lowering agents by at least 27 days before the initiation of dotinurad therapy.

The prevalence of the doses of dotinurad at each visit is shown in Additional file 2: Fig. S1). At week 24, 38 (76.0%) patients received 2 mg of dotinurad once daily.

The raw SUA levels at baseline and weeks 4, 8, 12, and 24 are provided in Additional file 3: Table S2. The estimated mean values and 95% CIs of the SUA levels measured at each time point and changes from baseline using a mixed-effect model are shown in Table 2. As illustrated in Fig. 2, the percentage change in the SUA level from baseline was − 21.0% (95% CI − 24.8% to − 17.2%) at week 4, − 24.3% (95% CI − 28.1% to − 20.5%) at week 8, − 36.7% (95% CI − 40.6% to − 32.9%) at week 12, − 35.8% (95% CI − 39.7% to − 32.0%) at week 24 (primary endpoint of the study). In the pre-specified subgroup analyses for the primary endpoint, the treatment effect was almost consistent, except for subgroups by a history of diabetes or CVD (Fig. 3).

The proportion of patients who achieved an SUA level of ≤ 6.0 mg/dL was 43.8% (21/48) at week 4, 46.8% (22/47) at week 8, 72.9% (35/48) at week 12, 74.5% (35/47) at week 24 (Fig. 4A). The probability of achieving an SUA level of ≤ 6.0 mg/dL, based on baseline SUA levels, is shown in Fig. 4B. The odds ratios achieving it for each 0.5 mg/dL lower SUA level at baseline are also shown in Additional file 4: Table S3.

Systolic and diastolic BPs did not significantly change over 24 weeks (Additional file 5: Table S4). Meanwhile, the geometric mean of CAVI at baseline and week 24 were 9.29 (95% CI 8.83 to 9.78) and 8.92 (95% CI 8.47 to 9.40), respectively, and the proportional change in CAVI from baseline to week 24 was 0.96 (95% CI 0.92 to 1.00 P = 0.044). Dotinurad therapy did not affect the levels of the following biomarkers: eGFR, CRP, GDF-15, NT-proBNP, hs-TnT, and UACR, except for IL-6. The d-ROMs concentration at week 24 was significantly lower than that at baseline (a proportional change in the geometric mean of d-ROMs concentration, 0.96 [95% CI 0.92 to 1.00], P = 0.044), and the Fib-4 index at week 24 tended to be lower than that at baseline (a proportional change in the geometric mean of Fib-4 index, 0.96 [95% CI 0.91 to 1.00], P = 0.061) (Additional file 5: Table S4).

During the study, site investigators reported four adverse events, namely, mild elbow pain, stomach pain, eruption, and lateral abdominal pain. No new onset of a gout attack or nephrolithiasis was reported.

This study has some limitations. First, this is a non-randomized, single-arm, open-label, exploratory study with relatively small sample size and short-term intervention. This may limit the interpretation of whether dotinurad specifically influenced the endpoints. Therefore, our findings should be further verified in randomized studies with an appropriate sample size and an appropriate control group. Second, dose adjustment (up-titration) of dotinurad was not uniformly performed in all participants. The up-titration of dotinurad was based on the site investigators’ judgment in a clinically pragmatic fashion. Although the maintenance dose of 2 mg daily was used at week 24 in 76% of the patients, no one received its maximum dose of 4 mg daily during the study interval. Therefore, determining the dose-dependence property of dotinurad on the study endpoints is impossible. Third, the clinical subtype of hyperuricemia based on its etiology, such as overproduction or underexcretion of urate, was not identified in the study participants. Fourth, this study focused on clinically stable Japanese patients with hyperuricemia and treated hypertension; thus, the generalizability of our findings to patient populations with other comorbidities and clinical situations is still uncertain. Importantly, the indication to treat asymptomatic hyperuricemia is still highly debated, as many countries do not recommend treating it, unlike Japan. Given that dotinurad is currently approved only in Japan, further studies are needed to determine its clinical efficacy in other ethnicities or regions and symptomatic hyperuricemia. Finally, we had no measurement of carotid-femoral PWV, which has been widely recognized as a gold standard method to assess central arterial stiffness non-invasively [49, 50].