Background & Objectives
In patients with gout, increased serum urate, (i.e., hyperuricemia), promotes crystal deposition of monosodium urate monohydrate crystals in articular and periarticular structures, which can trigger acute episodes of very painful inflammatory arthritis. The predominant mechanism driving hyperuricemia in gout is the underexcretion of renal uric acid; however, uric acid overproduction and intestinal uric acid underexcretion with renal uric acid overload can also drive hyperuricemia, alone or in combination with renal uric acid underexcretion.
Based on available evidence to date, both the ACR and EULAR guidelines for the first-line management of gout recommend urate-lowering therapy with a xanthine oxidase inhibitor (e.g., allopurinol or febuxostat), irrespective of the cause of the hyperuricemia. Whereas the 2016 EULAR guidelines recommend uricosuric therapy with an agent that inhibits renal urate transporter 1 (URAT1) (e.g., benzbromarone or probenecid) as a second-line urate-lowering therapy option, the 2020 ACR guideline only provides a conditional recommendation for probenecid use as a second-line agent after treatment failure with allopurinol. Because benzbromarone is not approved for use in the U.S., it is not included in the ACR recommendation.
In this comparative effectiveness clinical trial, Yan et al. set out to compare nontitrated, low-dose benzbromarone with low-dose febuxostat as the first-line therapy in gout patients with renal uric acid underexcretion.
Yan et al. conducted a prospective, randomized, single-center, open-label trial in men with gout and renal uric acid underexcretion (defined as fractional excretion of urate <5.5% and uric acid excretion ≤600 mg/day/1.73 m2). A total of 196 participants were randomly assigned to receive low-dose benzbromarone 25 mg daily or low-dose febuxostat 20 mg daily for 12 weeks. All participants received daily urine alkalization with oral sodium bicarbonate. The primary end point was the rate of achieving the serum urate target of <6 mg/dL.
More participants in the low-dose benzbromarone group achieved the serum urate target than those in the low-dose febuxostat group (61% compared with 32%, P<0.001). Rates of adverse events, including gout flares and urolithiasis, did not differ between groups, with the exception of greater transaminase elevation in the low-dose febuxostat group (4% for low-dose benzbromarone compared with 15% for low-dose febuxostat, P=0.008).
Compared with low-dose febuxostat, low-dose benzbromarone has superior urate-lowering and similar safety in relatively young and healthy patients with renal uric acid underexcretion-type gout.
Further investigation is warranted to test precision in the model for use of a URAT1 inhibitor in selecting a first-line urate-lowering therapy according to primary renal uric acid underexcretion, as opposed to decreased renal function. However, the results suggest that low-dose benzbromarone may warrant consideration as a safe and effective therapy to achieve serum urate target in gout patients without moderate chronic kidney disease.