Effect of Intensive Urate Lowering With Combined Verinurad and Febuxostat on Albuminuria in Patients With Type 2 Diabetes: A Randomized Trial

Abstract

Rationale & objective: Hyperuricemia 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 design: Phase 2, multicenter, prospective, randomized, double-blind, parallel-group, placebo-controlled trial.

Setting & participants: Patients 18 years or older with hyperuricemia, albuminuria, and T2DM.

Intervention: Patients randomly assigned 1:1 to verinurad (9mg) plus febuxostat (80mg) or matched placebo once daily for 24 weeks.

Outcomes: The 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.

Results: 60 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.

Limitations: Sample 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.

Conclusions: Verinurad 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.

Funding: This study was supported by AstraZeneca.

Trial registration: Registered at ClinicalTrials.gov with study number NCT03118739.

Keywords: Albuminuria; cardiovascular outcomes; chronic kidney disease (CKD); febuxostat; hyperuricemia; randomized controlled trial (RCT); renal function; safety; type 2 diabetes; urate lowering; urinary albumin-creatinine ratio (UACR); verinurad.

Figure 1.

Patient disposition

Figure 2.

Estimated mean ratio of UACR with 95% confidence intervals by treatment visit. Error bars are 95% confidence intervals. Mixed-effects model for repeated measures with changes from baseline in ln(UACR) as the response variable, randomized treatment, visit, interaction of treatment group and visit as fixed effects, baseline ln(UACR) as a covariate and subject as a random effect. LSM change in ln(UACR) from baseline and the 95% CI of ln(UACR) were exponentiated to yield the least square estimated mean ratio of UACR. Abbreviations: LSM, least squares mean; UACR, urine albumin-to-creatinine ratio

Figure 3.

Estimated mean ratio of sUA with 95% confidence intervals by treatment visit. Mixed-effects model for repeated measures with changes from baseline in sUA as the response variable, randomized treatment, visit, interaction of treatment group, visit and baseline sUA as fixed effects, and subject as a random effect. LSM change in ln(sUA) from baseline and the 95% CI of ln(sUA) were exponentiated to yield the least square estimated mean ratio of sUA. Abbreviations: LSM, least squares mean; sUA, serum urate.

Figure 4.

Estimated mean ratio of eGFR with 95% confidence intervals by treatment visit. Mixed-effects model for repeated measures with changes from baseline in eGFR as the response variable, randomized treatment, visit, interaction of treatment group, visit and baseline eGFR as fixed effects, and subject as a random effect. LSM change in ln(eGFR) from baseline and the 95% CI of ln(eGFR) were exponentiated to yield the least square estimated mean ratio of sUA. Abbreviations: eGFR, estimated glomerular filtration rate; LSM, least squares mean.