Dataset Information

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

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.

SUBMITTER: Stack AG

PROVIDER: S-EPMC8063233 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Rationale & objectiveHyperuricemia has been implicated in the development and progression of chronic kidney disease. Verinurad is a novel, potent, specific urate reabsorption inhibitor. We evaluated the effects on albuminuria of intensive urate-lowering therapy with verinurad combined with the xanthine oxidase inhibitor febuxostat in patients with hyperuricemia and type 2 diabetes mellitus (T2DM).Study designPhase 2, multicenter, prospective, randomized, double-blind, parallel-group, placebo-controlled trial.Setting & participantsPatients 18 years or older with hyperuricemia, albuminuria, and T2DM.InterventionPatients randomly assigned 1:1 to verinurad (9mg) plus febuxostat (80mg) or matched placebo once daily for 24 weeks.OutcomesThe primary end point was change in urinary albumin-creatinine ratio (UACR) from baseline after 12 weeks' treatment. Secondary end points included safety and tolerability and effect on glomerular filtration.Results60 patients were enrolled (n=32, verinurad and febuxostat; n=28, placebo). UACRs after treatment with verinurad plus febuxostat were lower than after placebo at 1, 12, and 24 weeks: -38.6% (90% CI, -60.9% to-3.6%), -39.4% (90% CI, -61.8% to-3.8%), and-49.3% (90% CI, -68.2% to-19.0%), respectively. Serum urate levels after treatment with verinurad plus febuxostat were 59.6% and 63.7% lower than after placebo at 12 and 24 weeks, respectively. No clinically meaningful changes were observed in estimated glomerular filtration rate or serum creatinine or serum cystatin C concentrations. Verinurad plus febuxostat was well tolerated.LimitationsSample size and study duration were insufficient to evaluate definitive effects of verinurad plus febuxostat on UACR and glomerular filtration. Generalizability was limited by exclusion of patients with stages 4 and 5 chronic kidney disease.ConclusionsVerinurad plus febuxostat reduced albuminuria and lowered serum urate concentrations in patients with T2DM, albuminuria, and hyperuricemia. Definitive assessment of their combined impact on preservation of kidney function awaits larger clinical studies.FundingThis study was supported by AstraZeneca.Trial registrationRegistered at ClinicalTrials.gov with study number NCT03118739.

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