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

• Published in: The journal of clinical endocrinology and metabolism 2021-05, Vol.106 (5), p.e2347-e2356
• Main Authors: Stack, Austin G, Han, David, Goldwater, Ronald, Johansson, Susanne, Dronamraju, Nalina, Oscarsson, Jan, Johnsson, Eva, Parkinson, Joanna, Erlandsson, Fredrik
• Format: Article
• Language: English
• Subjects: Antidiabetics; Clinical s; Clinical trials; Crystallization; Dapagliflozin; Dextrose; Excretion; Glucose; Hyperuricemia; Iron compounds; Medical research; Medicine, Experimental; Metabolites; Oxidases; Pharmaceutical industry; Pharmacokinetics; Placebos; Renal tubules; Sodium-glucose cotransporter; Type 2 diabetes; Uric acid; Xanthine oxidase
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/clinem/dgaa748

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.