Dotinurad Treatment for Patients With Hyperuricemia Complicating CKD

Abstract

Introduction: The management of hyperuricemia is important to reduce cardiovascular risk and the progression of renal injury in chronic kidney disease (CKD). This study aimed to assess the efficacy and safety of dotinurad, a novel urate transporter-1 inhibitor, in patients with hyperuricemia and CKD.

Methods: In a nonrandomized, parallel interventional study, patients were grouped based on their estimated glomerular filtration rate (eGFR) at baseline. The starting dotinurad dose was 0.5 mg/d and titrated to a final dose of 2 mg/d to 4 mg/d. The primary end point was the noninferiority of the change in serum uric acid (UA) levels between the G1/G2 and G3/G4 groups at week 24. The main secondary end points were changes in eGFR and UA clearance-to-creatinine clearance ratio (C_UA/C_Cr). Reported adverse events were also investigated.

Results: Ninety-eight patients continued the dose titration. The mean percentage reduction in serum UA level at week 24 were 47.2% and 42.8% for the G1/G2 and G3/G4 groups, respectively; the between-group difference was -4.3% (95% confidence interval [CI], -9.5% to 0.9%, noninferiority P = 0.0321), validating the noninferiority of treatment in the G3/G4 group to the G1/G2 group. eGFR tended to increase slightly through to week 24, suggesting that spontaneous eGFR decline was counteracted. Mean C_UA/C_Cr generally increased over time from week 4 to week 24. No new safety issues of particular concern were identified; and there were no marked changes in urinary pH.

Conclusion: Dotinurad therapy may be well-tolerated in patients with hyperuricemia and may have efficacy comparable with existing standard treatment in patients with CKD stages G3/G4. Randomized controlled trials in larger patient groups are needed.

Keywords: chronic kidney disease; dotinurad; efficacy; hyperuricemia; safety; serum uric acid.

Graphical abstract

Figure 1

Participant flow diagram.

Figure 2

Dotinurad final dosages. Some percentage values do not total 100% because of rounding of numbers. PPS, per protocol set.

Figure 3

Serum uric acid level. (a) Percentage decrease in serum uric acid level from baseline and (b) percentage of patients achieving target UA level at week 24 in the G1/G2 and G3/G4 groups. (c) Percentage decrease in serum uric acid level from baseline and (d) percentage of patients achieving the target UA level at week 24 in the G1, G2, G3a, G3b, and G4 groups. UA, uric acid; W, week.

Figure 4

Indicators related to renal function. Changes in the G1, G2, G3a, G3b, and G4 groups in (a and b) eGFR, (c and d) urine protein-to-creatinine ratio, and (e and f) urine albumin-to-creatinine ratio. Cr, creatinine; eGFR, estimated glomerular filtration rate; W, week.

Figure 5

Relationship between changes in serum uric acid levels and changes in eGFR at week 24 from baseline. (a) Correlation between percentage changes; (b) correlation between values of changes. CI, confidence interval; eGFR, estimated glomerular filtration rate; UA, uric acid.

Figure 6

Change (increase) in C_UA/C_Cr (W24 − W0) in the G1, G2, G3a, G3b, and G4 groups. C_UA/C_Cr, uric acid clearance-to-creatinine clearance ratio; W, week.