Febuxostat More Hepatotoxic than Benzbromarone in Gout, Study Finds

A recent propensity score-matched cohort study associated febuxostat use with significantly greater risk of mild to moderate perturbation of liver function, particularly when compared to benzbromarone, in patients with gout.

Benzbromarone has typically been considered a dangerous medication due to extreme cases of hepatotoxicity. Previous evidence has linked benzbromarone use to several mortalities due to comorbidities such as liver damage from alcohol drinking.2

“There is currently a lack of comparative data on hepatic safety of relatively long-term febuxostat or benzbromarone use,” wrote Wenyan Sun, PhD, Affiliated Hospital of Qingdao University, and colleagues. “Understanding the risk of hepatotoxicity and urate-lowering therapy (ULT) use may help guide decisions about specific ULT agents.”1

The study cohort was collated from the Biobank Information Management System (BIMS) at the Affiliated Hospital of Qingdao University. Records came from people seen at the Shandong Gout Clinical Medical Center with a diagnosis of gout since 2016.1

Patients who started either benzbromarone or febuxostat and had ≥3 tests of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) in a year after first taking the drugs were included for analysis. Those who were <18 years, had no follow-up data, were allopurinol starters, or had a baseline ALT or AST above 120 U/L were excluded from the study.1

Sun and colleagues paired febuxostat and benzbromarone users 1:1 according to age, sex, and ALT and AST value at the baseline, which was the prescription date of either drug. Covariates included age, sex, body mass index (BMI), drinking and smoking status, duration of gout, serum biochemical variables (AST, ALT, fasting blood glucose, etc.) and comorbidities (self-reported hypertension, diabetes, hepatosteatosis, cardiovascular disease, etc.).1

The team reported that 1844 and 494 of the 8952 included patients had started febuxostat or benzbromarone, respectively, with ≥3 AST/ALT measurements per year.1

The study's primary outcome defined hepatotoxicity as the first event of either ALT or AST above three times the upper limit of normal (ULN). The team also graded the severity of liver function test (LFT) abnormality, including AST and ALT increases.

• Grade 1: Above ULN to 3.0 x ULN if baseline was normal; 1.5-3.0 x baseline if abnormal
• Grade 2: >3.0-5.0 x ULN if baseline was normal; >3.0-5.0 x baseline if abnormal
• Grade 3: >5.0-20.0 x ULN if baseline was normal; >5.0-20.0 x baseline if abnormal
• Grade 4: >20.0 x ULN if baseline was normal; >20.0 x baseline if abnormal1

During follow-up, Sun and colleagues discovered that 864 participants had experienced an ALT/AST increase, including Grade 1 (38%), Grade 2 (1.3%), and Grade 3 (0.4%) in the febuxostat group and Grade 1 (22.1%), Grade 2 (0.6%), and Grade 3 (0.2%) in the benzbromarone group. . Investigators noted all Grade 2-3 participants experienced hepatotoxicity, most Grade 1 participants experienced mild liver abnormalities, and no Grade 4 elevations were observed during follow-up.1

Incidence of hepatotoxicity was lower among benzbromarone users (16.8/1000 person-years) than febuxostat users (39.6/1000 person-years). After age and sex adjustment, febuxostat use was still associated with a greater risk of hepatotoxicity (adjusted hazard ratio (HR), 2.75; 95% CI, 1.28-5.91) compared to benzbromarone.1

Subgroup analysis indicated that febuxostat users shared a similar risk of hepatotoxicity across many subgroups, including baseline liver disease (all P for interaction >.05). Investigators also performed subgroup analysis for those stratified by ALT or AST, indicating hepatotoxicity appeared to occur with increasing levels of transaminases, particularly above 40 U/L.1

Sun and colleagues noted that the results of this study seem to conflict with general practice. Benzbromarone is heavily restricted due to rare episodes of extreme hepatotoxicity in the past. This study indicates, however, that benzbromarone has markedly less hepatoxicity than febuxostat.1

“Hepatic safety, particularly in those with pre-existing liver disease, is an important consideration in prescribing either febuxostat or benzbromarone,” wrote Sun and colleagues. “Despite the widespread limitation of benzbromarone due to concerns about severe hepatotoxicity, these events are rare, and benzbromarone has lower risk of hepatotoxicity than febuxostat.”1

References

1. Sun W, Cui L, Terkeltaub R, et al. Risk of hepatotoxicity in patients with gout treated with FEBUXOSTAT or benzbromarone: A propensity score‐matched cohort study. Arthritis Care &amp; Research. Published online April 7, 2025. doi:10.1002/acr.25547

2. Zhang MY, Niu JQ, Wen XY, Jin QL. Liver failure associated with benzbromarone: A case report and review of the literature. World J Clin Cases. 2019;7(13):1717-1725. doi:10.12998/wjcc.v7.i13.1717