Effectiveness of benzbromarone versus febuxostat in gouty patients: a retrospective study

Benzbromarone and febuxostat use different mechanisms to reduce serum urate. However, the effectiveness of benzbromarone versus febuxostat in reducing serum urate in gouty patients classified with different types of hyperuricaemia remains unclear. In this retrospective study from January 1, 2018, to September 30, 2020, subjects were identified if they were newly treated with benzbromarone 25 mg daily or febuxostat 20 mg daily. The subjects were classified into four types according to their 24-h urinary uric acid and fractional excretion of uric acid. The baseline data and follow-up information after 28 ± 3 days of treatment were collected. Seventy-three subjects with gout were finally enrolled. Among them, 50 were treated with benzbromarone. The percent changes in serum urate from the baseline were − 33.71 ± 13.59% and − 29.45 ± 10.62% in the benzbromarone and febuxostat group, respectively, without a significant difference between the groups (P = 0.188). No differences were found between the groups in subjects classified as the renal underexcretion type, combined type, or “normal” type. In patients with eGFR ≥ 70 mL/min/1.73 m2, the rate of serum urate lowering was higher in those treated with benzbromarone than in those treated with febuxostat. Febuxostat treatment significantly lowered serum creatinine from the baseline (P = 0.001). Benzbromarone 25 mg daily and febuxostat 20 mg daily may have comparable effectiveness in lowering the serum urate among different types of hyperuricaemia. Benzbromarone was more effective than febuxostat in lowering serum urate in subjects with eGFR ≥ 70 mL/min/1.73 m2, while febuxostat had a renal protective effect. Key Points • Benzbromarone 25 mg daily and febuxostat 20 mg daily may have comparable effectiveness in lowering the serum urate in patients with different types of hyperuricaemia. • Benzbromarone 25 mg daily was more effective than febuxostat 20 mg daily in lowering serum urate in subjects with eGFR ≥ 70 mL/min/1.73 m2. • Febuxostat had a renal protective effect after about 1 month treatment.


Introduction
Gout is the most common inflammatory arthritis caused by elevated serum urate and subsequent deposition of monosodium urate crystals. Hyperuricaemia is a disease with genetic predisposition caused by the decreased excretion of urate by the kidneys or the gut and/or overproduction of uric acid in the liver [1,2]. Maintaining serum urate levels < 6 mg/dL could reduce gouty tophus and decrease the frequency of gout flares [3].
Based on the findings that ATP-binding cassette transporter, subfamily G, member 2 (ABCG2) plays an important role in intestinal urate excretion [4,5], hyperuricaemia is now classified into four types-the renal underexcretion type, renal overload type, combined type, and "normal" type-according to the 24-h urinary uric acid excretion and fraction excretion of uric acid (FE UA ) [5].
Benzbromarone, a uricosuric agent, is a first-line uratelowering drug according to the Chinese gout management guideline and the most prescribed urate-lowering drug in China [6]. Benzbromarone is primarily used in subjects with renal underexcretion of urate. Its urate-lowering effect is maintained even in gouty patients with mild to moderate renal dysfunction [7,8]. Benzbromarone was not approved by the Food and Drug Administration and has been withdrawn from the European market because of its hepatotoxicity [9]. However, in Asian and some European countries, it has been prescribed without evident safe concern for many years [8,10].
Febuxostat, a xanthine oxidoreductase inhibitor, is another first-line urate-lowering drug in China [6]. Febuxostat is primarily metabolized in the liver, and no dose reduction is required in subjects with renal dysfunction [11]. Its urate-lowering effect is not reduced with renal impairment, and even the renal function can be improved after febuxostat treatment [12]. Thus, clinically, febuxostat is preferably used in patients with renal dysfunction and/or uric acid overproduction.
However, the urate-lowering effect of xanthine oxidoreductase inhibitors and uricosuric drugs in gouty patients with different types of hyperuricaemia is unknown. In this retrospective study, we aimed to investigate the effectiveness of benzbromarone versus febuxostat in lowering serum urate in subjects with different types of hyperuricaemia.

Subjects
This retrospective study was performed at the Rheumatology Department of Zhongshan Hospital, Shanghai, China. Outpatients diagnosed with gout were identified electronically from January 1, 2018, to September 30, 2020 if they were newly prescribed benzbromarone 25 mg daily or febuxostat 20 mg daily with 24-h urinary uric acid and 24-h urinary creatinine measured. Initially, 138 patients were identified. Among them, 50 subjects were excluded without follow-up information of 28 ± 3 days of treatment. Next, another 15 individuals were further excluded because their follow-up data were measured with drug cessation 1 week before the measurement. Finally, 73 subjects were included for analysis. The baseline data were not statistically significant between the 73 subjects included and other 65 subjects excluded (Supplementary Table 1). All the subjects included had no malignancy or acute renal dysfunction. Besides, all the patients took no medications influencing renal handling of uric acid, such as diuretics, aspirin, cyclosporine, and pyrazinamide, or renal function, namely, piperazine ferulate, bailing capsule, huangkui capsule, and shenshuai granule. This study was approved by the Ethics Committee of Zhongshan Hospital in Shanghai and complied with the ethical principles of the 1975 Declaration of Helsinki. Because of the retrospective nature of the study, patient informed consent was waived.

Measurement of serum parameters
Blood samples were collected after an overnight fasting. Patients were informed to avoid purine-rich food, proteinrich diet, and vigorous exercise before blood test. The levels of serum urate, creatinine, alanine aminotransferase, and aspartate aminotransferase were immediately determined using an automatic biochemical analyzer at the Department of Clinical Laboratory of Zhongshan Hospital, Fudan University (Cobas c702; Roche Diagnostics, Basel, Switzerland). The estimated glomerular filtration rate (eGFR, mL/min/1.73 m 2 ) was calculated according to the Chronic Kidney Disease-Epidemiology Collaboration formula [13].
Serum urate and creatinine were originally measured in μmol/L and were converted to mg/dL by dividing 59.5 and 88.4, respectively. Urinary uric acid and creatinine were transformed to mg/24 h from their original µmol/24 h by dividing 5.95 and 8.84, respectively.
All the patients were stratified into four types according to their 24-h urinary uric acid and FE UA . The renal underexcretion type was defined as 24-h urinary uric acid ≤ 600 mg/ day and FE UA < 5.5%; the renal overload type was classified as 24-h urinary uric acid > 600 mg/day and FE UA ≥ 5.5%; the combined type was specified as 24-h urinary uric acid > 600 mg/day and FE UA < 5.5%; and the "normal" type was characterized by 24-h urinary uric acid ≤ 600 mg/day and FE UA ≥ 5.5%.

Statistics
The Kolmogorov-Smirnov test was used to assess a normal distribution of the variables. Normally distributed variables were presented as means ± SD, while skewed distributed data were shown as medians (interquartile range), as otherwise indicated. Categorical data were expressed as cases (proportions). The difference between groups was calculated by independent-sample t test for normally distributed data and the Mann-Whitney U test for skewed distributed data. Pairedsamples t test and Wilcoxon test were used to calculate the difference between before and after treatment for normally distributed data and skewed data, respectively. The chi-square test was performed for categorical data. Because of inherent heterogeneity in the baseline characteristics between the groups, a multivariate linear regression model was explored to adjust the influence of baseline eGFR on the urate-lowering effect of the two drugs. All the above statistical analyses were performed using SPSS 25.0 (SPSS Inc., Chicago, Illinois, USA).

Baseline characteristics of the study population
Of the 73 subjects enrolled, 69 (94.52%) were men. The mean age of the subjects was 47.88 ± 15.73 years, without a significant difference between the benzbromarone and febuxostat groups (P = 0.876). The baseline serum urate concentrations were also comparable between the groups (P = 0.076). All the subjects involved had eGFR > 40 mL/ min/1.73 m 2 . Serum creatinine was significantly higher in the febuxostat group than in the benzbromarone group (P < 0.001); correspondingly, serum eGFR was significantly lower in the febuxostat group than in the benzbromarone group (P = 0.001). Twenty-four-hour urinary uric acid, FE UA , alanine transaminase, and aspartate aminotransferase were similar between the groups. Most of the patients were classified as the renal underexcretion type (Table 1).

Urate-lowering effect
For both drugs, after urate-lowering treatment, serum urate decreased significantly from baseline (P < 0.001 for both groups), while no significant difference in serum urate was observed between the febuxostat group and benzbromarone group after urate-lowering treatment (P = 0.054) ( Table 2). The percent changes (mean ± SD) in serum urate from baseline were − 33.71 ± 13.59% and − 29.45 ± 10.62% for benzbromarone and febuxostat, respectively, showing no significant differences between the groups (P = 0.188) (Fig. 1a).
In the multivariate linear regression model, after adjusting for baseline eGFR, the percent change in serum urate from baseline remained comparable between the groups (unstandardized B = 5.56; P = 0.108).

Subgroup analysis
Because only 1 patient with renal overload was treated with febuxostat 20 mg daily, subgroup analysis was not performed in this subgroup. In subjects of the combined type, the rate of serum urate lowering from baseline was numerically higher in the benzbromarone group than in the febuxostat group, but the difference was not significant (P = 0.105). The rate of serum urate lowering was also comparable between the groups in subjects stratified by the renal underexcretion or "normal" type (renal underexcretion, P = 0.440; "normal" type, P = 0.636) ( Table 3). A similar trend remained after adjusting for baseline eGFR (Supplementary Table 2).  Subjects were further analyzed according to their baseline eGFR. In subjects with eGFR ≥ 70 mL/min/1.73 m 2 , the rate of serum urate lowering was significantly higher in the benzbromarone group than in the febuxostat group (− 34.55 ± 13.03% versus − 23.60 ± 7.71%; P = 0.027). No significant difference in the rate of serum urate lowering was observed between the groups in patients with eGFR < 70 mL/ min/1.73 m 2 (− 29.90 ± 16.19% versus − 32.57 ± 10.85%; P = 0.632) ( Table 3).
The overall rate of serum creatinine lowering from baseline were 1.55 ± 1.22% and 7.61 ± 1.83% in the benzbromarone group and febuxostat group, respectively, indicating a significant decrease in serum creatinine from baseline in the febuxostat group (P = 0.001) but not in the benzbromarone group (P = 0.174). Accordingly, the rate of eGFR increase from baseline was significant in the febuxostat group (P = 0.001), but not in the benzbromarone group (P = 0.142) ( Table 2).
When comparing changes in serum creatinine and eGFR between the benzbromarone group and febuxostat group after urate-lowering treatment, it was found that subjects in the febuxostat group experienced higher decline in serum creatinine and enhanced increase in eGFR than those in the benzbromarone group (serum creatinine, P = 0.005; eGFR, P = 0.003) (Fig. 2).

Safety
After urate-lowering treatment, one patient in the benzbromarone group (1/50) and 1 in the febuxostat group (1/23) showed increases in both serum alanine transaminase and aspartate transaminase. The other 3 patients in the benzbromarone group (3/50) showed a mild increase only in alanine transaminase. These increases were all within 2 upper limits of normal.

Discussion
In this retrospective cohort study, no significant difference was observed in the effectiveness of serum urate lowering between the benzbromarone and febuxostat groups. Comparable effectiveness remained among subjects with the renal Fig. 2 Renal function. Percent changes in serum creatinine (a) and eGFR (b) from the baseline. The data are shown as means ± SE. Abbreviation: eGFR estimated glomerular filtration rate underexcretion type, combined type, or "normal type." In gouty patients with eGFR ≥ 70 mL/min/1.73 m 2 , benzbromarone was more effective in lowering the serum urate than febuxostat. Renal function improved significantly in the febuxostat group but not in the benzbromarone group.
In our study, 25 mg of benzbromarone daily showed comparable effectiveness in lowering serum urate to 20 mg of febuxostat daily. Their comparable effectiveness in Chinese gouty patients was also described in another prospective study [12]. In our cohort, the two groups had inherent heterogeneity in the baseline characteristics. Clinically, subjects with lower eGFR were likely prescribed febuxostat. Thus, as a real-world study, it is reasonable that the baseline eGFR was significantly lower in the febuxostat group than in the benzbromarone group. To minimize the influence of baseline renal function on the effectiveness of the two drugs, multivariate linear regression was conducted. However, benzbromarone and febuxostat still showed similar uratelowering effects.
Subgroup analysis was performed with individuals stratified by different types of hyperuricaemia. The uratelowering effect of the two drugs remained comparable in subjects stratified into the renal underexcretion, combined type, or "normal" type. Benzbromarone is a urate anion transporter 1 (URAT1) inhibitor and functions in inhibiting the reabsorption of urate in the proximal tubule, thus increasing urate excretion in the kidneys [14]. Febuxostat binds to xanthine oxidoreductase, a rate-limiting enzyme in purine metabolism, thus obstructing substrate binding to this enzyme and inhibiting the generation of uric acid [15]. Because of the different mechanisms of reducing serum urate, clinically, benzbromarone and febuxostat are preferably prescribed to subjects for renal underexcretion and overproduction, respectively. In our analysis, we found that, even in patients with renal underexcretion of uric acid, febuxostat 20 mg daily was as effective as benzbromarone 25 mg daily in reducing serum urate. The effectiveness of febuxostat in lowering serum urate in underexcretors has also been described previously [16]. Thus, febuxostat may be another consideration for subjects with renal underexcretion.
In patients of the combined type, the urate-lowering effect of benzbromarone was numerically higher than that of febuxostat but without a significant difference. In this type of subject, hyperuricaemia resulted from the overproduction of uric acid in the liver or decreased excretion of urate in the intestine, combined with renal underexcretion of urate [5]. Because of the small number of patients included in our study, the effectiveness of benzbromarone 25 mg daily versus febuxostat 20 mg daily in subjects of the combined type should be further investigated with a larger population.
As the baseline renal function was better in subjects treated with benzbromarone than in those treated with febuxostat, subjects were further analyzed according to their eGFR. In subjects with eGFR ≥ 70 mL/min/1.73 m 2 , the urate-lowering effect of benzbromarone 25 mg daily was significantly better than that of febuxostat 20 mg daily. The two drugs had comparable effectiveness in lowering serum urate in subjects with eGFR < 70 mL/min/1.73 m 2 . Previously, benzbromarone was reported to be as effective as febuxostat in reducing serum urate in hyperuricaemia patients with eGFR 20-60 mL/min/1.73 m 2 [7]. In this study, we found that, in gouty patients with eGFR ≥ 70 mL/ min/1.73 m 2 , benzbromarone 25 mg daily was more effective in reducing serum urate than febuxostat 20 mg daily. Studies with prospective designs are required to further confirm this effect of benzbromarone with long-term observation.
In our study, we found that febuxostat had a favorable effect on renal function. The renoprotective effect of febuxostat has also been found in a prospective study with 12-week treatment of febuxostat and in hyperuricaemia patients without end-stage renal disease [12,17]. However, this renofavorable effect of febuxostat could not always be proven. In a meta-analysis including subjects with CKD stages 1-5, compared with either placebo or urate-lowering agents (allopurinol or benzbromarone), febuxostat showed no renal protective effect [18]. In subgroup analysis, the renoprotective effect of febuxostat was found only in subjects with CKD stages 3 and 4, or with treatment duration ≥ 6 months compared with controls [17]. In our study, the subjects had CKD stages 1-3; after a relatively short treatment duration of 28 ± 3 days, renal improvement was observed with febuxostat 20 mg daily treatment. Our results support the viewpoint that febuxostat was more favorable in patients with renal dysfunction. Nevertheless, the exact effect and mechanism of febuxostat on renal function need more in-depth investigation both clinically and basically.
The increase in serum transaminase was mild without drug cessation. Because the data were collected through medical records electronically rather than through selfreport, information about gout flares was not known. However, in another prospective cohort study, benzbromarone 25 mg daily had a similar occurrence rate of gout flares as febuxostat 20 mg daily during 12 weeks of treatment [12].
The first limitation of the study was the limited sample size. The non-significant difference between the benzbromarone and febuxostat groups may due to the small sample size. Nevertheless, in another prospective study conducted in China involving 214 gouty patients (105 in the febuxostat 20 mg daily group and 109 in the benzbromarone 25 mg daily group), febuxostat 20 mg daily also achieved comparative effectiveness with benzbromarone 25 mg daily during 12-week follow-up [12]. Second, the retrospective design of the study made the baseline renal function was not balanced between the benzbromarone and febuxostat groups. Nevertheless, when baseline eGFR was adjusted, the percent change in serum urate from baseline remained comparable between the groups. Whatever, large prospective studies with enough sample size are needed to validate this result, especially in subjects with different types of hyperuricaemia. Third, the relatively short experimental period was another limitation. A dose-escalation study with a longer period will provide more information to guide prescriptions in choosing urate-lowering drugs and evaluating the renal function changes.
In conclusion, benzbromarone 25 mg daily and febuxostat 20 mg daily may have comparable effectiveness in reducing serum urate regardless of the type of hyperuricaemia. A stronger effect of benzbromarone in reducing serum urate in subjects with eGFR ≥ 70 mL/min/1.73 m 2 was observed. Febuxostat treatment improved renal function. Further investigations with prospective designs are needed.