Intensive Urate Lowering in Diabetic Kidney Disease

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An intensive urate-lowering strategy consisting of verinurad and febuxostat reduces albuminuria in patients with type 2 diabetes and hyperuricemia, reports a phase 2 trial in the American Journal of Kidney Diseases.

The multicenter trial enrolled 60 adult patients with type 2 diabetes; albuminuria, urine albumin-to-creatinine ratio (UACR) 30 to 3500 mg/g; and hyperuricemia, serum urate (sUA) concentration 6.0 mg/dL or greater. Mean age was 61.5 years, 70% of patients were men, and about one-half had an estimated glomerular filtration rate (eGFR) of less than 60 mL/min/1.73 m2. The study excluded patients with stage 4 or 5 chronic kidney disease (CKD).

Patients were randomly assigned to intensive urate-lowering therapy with the specific urate reabsorption inhibitor verinurad (9 mg) plus the xanthine oxidase inhibitor febuxostat (80 mg) or placebo. Treatment lasted for 24 weeks. The primary outcome was change in UACR from baseline to 12 weeks.

Intensive urate lowering was associated with significant reductions in UACR compared to placebo: by 38.6% at 1 week, 39.4% at 12 weeks, and 49.3% at 24 weeks. The verinurad/febuxostat combination also lowered sUA levels: by 59.6% at 12 weeks and 63.7% at 24 weeks.

There were no significant differences in eGFR, serum creatinine, or cystatin C. The urate-lowering combination was well tolerated, with safety outcomes similar to those of placebo.

Hyperuricemia is associated with the presence and development of CKD and is an independent predictor of the development of microalbuminuria. Experimental and clinical evidence suggests that treatment to lower sUA may slow CKD progression, while reducing kidney and cardiovascular events.

This proof-of-concept study shows that the combination of verinurad and febuxostat, which reduces uric acid via different mechanisms, can lower albuminuria in patients with type 2 diabetes and hyperuricemia. Although noting that their study shows a “true pharmacologic effect,” the authors emphasize the need for larger clinical trials to determine whether intensive urate lowering can help to preserve kidney function [Stack AG, et al. Effect of intensive urate lowering with combined verinurad and febuxostat on albuminuria in patients with type 2 diabetes: A randomized trial. Am J Kidney Dis, published online ahead of print Oct. 29, 2020. doi: 10.1053/j.ajkd.2020.09.009;].