Context: Combining a sodium-glucose cotransporter 2 (SGLT2) 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' 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-hour uUA excretion.
Results: Both regimens lowered mean peak uUA excretion (least squares mean changes from baseline: -12.9 mg/h [95% 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 versus 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.
Keywords: Dapagliflozin; febuxostat; hyperuricemia; uric acid; verinurad; xanthine oxidase.
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