Dapagliflozin Added to Verinurad Plus Febuxostat Further Reduces Serum Uric Acid in Hyperuricemia: The QUARTZ Study

Austin G Stack, David Han, Ronald Goldwater, Susanne Johansson, Nalina Dronamraju, Jan Oscarsson, Eva Johnsson, Joanna Parkinson, Fredrik Erlandsson, Austin G Stack, David Han, Ronald Goldwater, Susanne Johansson, Nalina Dronamraju, Jan Oscarsson, Eva Johnsson, Joanna Parkinson, Fredrik Erlandsson

Abstract

Context: Combining a sodium-glucose cotransporter 2 inhibitor with a xanthine oxidase inhibitor (XOI) and a urate transporter 1 (URAT1) inhibitor may enhance serum uric acid (sUA) lowering. However, concerns exist regarding high urinary UA (uUA) excretion rates and subsequent crystallization in renal tubules.

Objective: To assess whether dapagliflozin added to verinurad, a selective URAT1 inhibitor, and febuxostat, an XOI, increases uUA excretion.

Design: Randomized, placebo-controlled, 2-way crossover study (NCT03316131).

Patients: Adults with asymptomatic hyperuricemia.

Interventions: Subjects (N = 36) were randomized to oral once-daily 9 mg verinurad plus 80 mg febuxostat plus 10 mg dapagliflozin for 7 days and 7 days of oral once-daily 9 mg verinurad plus 80 mg febuxostat plus placebo with an intervening 7- to 21-day washout period.

Main outcome measure: Difference in peak uUA excretion between groups from baseline to day 7. Secondary outcomes included changes in sUA levels and 24-h uUA excretion.

Results: Both regimens lowered mean peak uUA excretion (least squares mean changes from baseline: -12.9 mg/h [95% confidence interval (CI): -21.0 to -4.7], dapagliflozin; -13.2 mg/h [95% CI -21.3 to -5.0], placebo). sUA concentrations were lower with dapagliflozin (mean treatment difference -62.3 µmol/L [95% CI -82.8 to -41.8]). Dapagliflozin did not impact verinurad pharmacokinetics, its main metabolites, or febuxostat or fasting plasma glucose levels vs verinurad plus febuxostat. There were no clinically relevant changes in safety parameters.

Conclusions: Dapagliflozin further reduced sUA without influencing uUA excretion, suggesting that its combination with verinurad and febuxostat at the doses tested does not adversely affect kidney function.

Clinical trial registration number: NCT03316131.

Keywords: dapagliflozin; febuxostat; hyperuricemia; uric acid; verinurad; xanthine oxidase.

© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Figures

Figure 1.
Figure 1.
Study design. Abbreviations: 1o, primary; R, randomization.
Figure 2.
Figure 2.
uUA excretion rates and sUA concentrations. (A) Peak uUA excretion rates (mg/h) for each treatment showing differences between baseline and day 7. (B) Total uUA excretion in the 24 h following treatment administration (mean change from baseline at day 7). (C) sUA concentrations after treatment administration on day 7. (D) Fractional excretion of UA (%) for each treatment showing change from baseline at day 7. Mean peak UA excretion was determined as UA (mg) excreted within 1-h intervals for the first 8 h after dosing. Peak and total uUA excretion rates and fractional excretion of UA were assessed for 25 participants. Abbreviations: CI, confidence interval; sUA, serum uric acid; UA, uric acid; uUA, urinary uric acid. *P < 0.05.
Figure 3.
Figure 3.
Geometric mean (standard deviation) verinurad or febuxostat plasma concentrations over time with or without dapagliflozin. Error bars represent standard deviation.

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