Benzbromarone Tops Febuxostat for Gout?

Results from a randomized controlled trial conducted in China found low-dose benzbromarone to be more effective in lowering serum urate levels than low-dose febuxostat (Uloric), with a similar safety profile, in gout with renal uric acid underexcretion.

Benzbromarone is not approved in the United States because of concerns of acute liver injury but is approved in several other countries, including China, Brazil, and New Zealand.

“The results suggest that low dosing of benzbromarone may warrant stronger consideration as a safe and effective therapy to achieve serum urate target in gout without moderate chronic kidney disease,” the study team writes.

“Benzbromarone is severely hepatotoxic in some individuals and unlikely to ever gain approval in the United States,” one of the study’s investigators, Robert Terkeltaub, MD, professor of medicine, University of California San Diego, told Medscape Medical News.

However, this study “illustrates the value and impact of uricosuric therapy in general in gout, including potentially as an initial urate-lowering monotherapy strategy, and the sheer number of subjects reaching urate target with low-dose uricosuric monotherapy was impressive,” Terkeltaub said.

The study was published online July 7 in Arthritis & Rheumatology.

“Renal uric acid underexcretion is the chief mechanism driving hyperuricemia in gout, yet the standard urate-lowering therapy recommendation is first-line xanthine oxidase inhibition irrespective of the cause of hyperuricemia,” the study team explains in their article.

Their prospective, randomized, single-center, open-labeled trial was conducted at the Gout Clinic of the Affiliated Hospital of Qingdao University in China.

A total of 196 relatively young healthy men with gout and uric acid underexcretion were randomly assigned to receive low-dose benzbromarone (25 mg/d) or low-dose febuxostat (20 mg/d) for 12 weeks.

Renal uric acid underexcretion was defined as fractional excretion of urate < 5.5% and uric acid excretion ≤ 600 mg/d/1.73 m².

A “major aspect” of this comparative effectiveness trial was its specific focus on gout-associated renal uric acid underexcretion, where the uricosuric targeted the dominant abnormality promoting the hyperuricemia, Terkeltaub told Medscape Medical News.

In addition, all participants received daily urine alkalinization with oral sodium bicarbonate. “This is not always done in clinical practice, nor in clinical trials of uricosuric agents,” Terkeltaub said.

The results showed that more participants in the benzbromarone group achieved the serum urate target of < 6 mg/dL compared to those in the febuxostat group (primary endpoint, 61% vs. 32%, P < .001).

Adverse events, including gout flares and urolithiasis, did not differ significantly between the two groups, with the exception of more transaminase elevation in the febuxostat group (15% vs 4%; P = .008).

“We did not find severe hepatotoxicity with low-dose benzbromarone, but ethnic background may affect drug responses, and severe hepatotoxicity of benzbromarone has rarely been reported in Asia,” the authors write.

The incidence of urolithiasis was numerically, but not significantly, higher in the benzbromarone group (5% vs 2%).

This study found no significant changes in participants’ triglyceride levels, though a previous study suggested febuxostat could increase serum triglycerides.

The investigators caution that the study only included patients with who had baseline serum urate levels ranging from 8.0 to 10 mg/dL, who were relatively young, and with few comorbidities.

The authors further noted the “…results may not be generalizable to patients with higher serum urate levels or impaired kidney function, as well [as] patients from other geographical regions, age, and ethnicity groups. The study only included men, and the findings may not be generalizable to women with gout.”

“Very Useful” in Select Cases

Weighing in on the results, Valderilio Feijó Azevedo, MD, PhD, adjunct professor of rheumatology, Federal University of Paraná, Brazil, noted that in some specific clinical circumstances, benzbromarone has been “a very useful medication alone or combined to treat gout patients.”

“We have great experience with the drug in Brazil. However, it is not used to treat all patients. Patients must be very well-selected in our clinical practice,” Azevedo told Medscape Medical News.

“For most patients, benzbromarone is effective for those who have failed to achieve serum uric acid goals with allopurinol treatment. We do not use it to treat patients with asymptomatic hyperuricemia. In general, we avoid patients with hepatic dysfunction due to previous hepatotoxicity reports. In every patient, we do active monitoring of enzymes,” Azevedo explained.

“We also avoid using it in patients with severe kidney disease. However, we have used it in some patients with estimated glomerular filtration rate less than 30. We also avoid dosage over 200 mg per day. On average, we use 100 mg per day combined with allopurinol or alone,” said Azevedo, who was not involved with the study.

Also weighing in for Medscape Medical News, Michael Pillinger, MD, rheumatologist at NYU Langone Health, New York City, noted that while benzbromarone is not used in the United States, “in many parts of the world, it is used and is felt to be effective.” Pillinger was not associated with this current research.

This study, Pillinger said, “does underline the fact that an alternative drug that lowers urate by promoting urate excretion, if it could gain [US FDA] approval and if it were safe, could present a viable new option for therapy.”

He added, “If one conclusion to the study is that determining the basis of hyperuricemia is helpful in guiding benzbromarone use, that implies an additional layer of effort for physicians and patients in a disease that is already notoriously known for patient noncompliance — and in a case where febuxostat and allopurinol will work for both overproducers and underexcreters and would not need this additional assessment.”

The study was sponsored by Shandong Provincial Key Research and Development Plan, the National Natural Science Foundation of China and Shandong Provincial Science Foundation for Outstanding Youth Scholarship. Terkeltaub was supported by the National Institutes of Health (NIH ) and the VA Research Service. Terkeltaub has received research funding from AstraZeneca, and has consulted with Horizon, Selecta, SOBI, Dyve BioSciences, Fortress, AstraZeneca, Allena, Fortress Biotech, and LG Life Sciences. Azevedo and Pillinger have no reported no relevant financial relationships.

Arthritis Rheum. Published online July 7, 2022. Abstract

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