Efficacy of Xanthine Oxidase Inhibitors in Lowering Serum Uric Acid in Chronic Kidney Disease: A Systematic Review and Meta-Analysis

Objective: Current guidelines for gout recommend a treat-to-target approach with serum uric acid (SUA). However, there is little evidence for the dose-dependent effects of urate-lowering therapy (ULT). Herein, we analyzed the reported SUA-lowering effect and SUA target achievement differences for various doses of xanthine oxidase inhibitors. Methods: Approved ULT drugs were selected from the FDA Drug Database. We included prospective randomized controlled trials of ULT drugs from ClinicalTrials.gov, articles published in the journal “Drugs”, and Embase, a literature database. A meta-analysis was performed to determine the ability of different ULT drugs and doses to lower and maintain a target SUA < 6 mg/dL. Results: We identified 35 trials including 8172 patients with a baseline SUA of 8.92 mg/dL. The allopurinol, febuxostat, and topiroxostat showed dose-proportional SUA-lowering responses. Compared with allopurinol 300 mg daily, febuxostat 80 mg daily and 120 mg daily more effectively maintained SUA < 6 mg/dL. Conclusion: Allopurinol, febuxostat, and topiroxostat showed dose-proportional ability to lower and achieve a target SUA < 6 mg/dL. Significance and Innovations. We showed dose-dependent SUA lowering effects of allopurinol, febuxostat, and topiroxostat. Febuxostat is effective at ULT compared to allopurinol and could be potentially offered as an alternative agent when patients (1) have CKD, (2) have the human leukocyte antigen HLA-B*5801 allele, and (3) become refractory to allopurinol. Gradual allopurinol dose increase with a lower starting dose is needed in CKD.

Gout occurs when highly immunogenic monosodium urate crystals [15] form in joints and soft tissue and is promoted when the SUA concentrations exceed solubility limits. These crystals produce painful attacks and debilitating bone erosion [16]. According to the 2015-2016 National Health and Nutrition Examination Survey, the prevalence of hyperuricemia and gout in the United States was 20.1% and 3.9%, respectively, and both increased in prevalence since the previous survey in 1988-1994 [17,18]. An increasing prevalence of gout has also been reported in other developed countries [19].
Urate-lowering therapy (ULT) is the mainstay of chronic gout management. Both the 2020 American College of Rheumatology (ACR) and 2016 European Alliance of Associations for Rheumatology (EULAR) guidelines recommend a treat-to-target management strategy in the absence of tophi (aggregates of monosodium urate crystals), aiming to reduce SUA to <6 mg/dL. EULAR further recommends a target of SUA of <5 mg/dL when tophi are present [20,21]. As treatment success is inversely related to baseline SUA [22], researchers should account for baseline SUA when examining the effectiveness of ULT, as variations in baseline SUA can result in different efficacies of ULT.
ULTs comprise xanthine oxidase inhibitors (XOIs), uricosuric agents, and recombinant uricase. The XOIs inhibit the enzyme xanthine oxidase that metabolizes hypoxanthine to uric acid and thereby reduces uric acid generation. The most commonly used XOI, allopurinol, is an analog of hypoxanthine and xanthine; it competes with these molecules in binding xanthine oxidase and inhibits the formation of uric acid [23]. Febuxostat non-selectively inhibits oxidized and reduced forms of xanthine oxidase [23]. It is a competitive inhibitor of the enzyme. Topiroxostat, a selective non-purine molecule, competitively inhibits xanthine oxidase [24]. Allopurinol and febuxostat are approved for use in the United States, whereas topiroxostat is only approved in Japan. The 2020 ACR and 2016 EULAR guidelines recommend low-dose allopurinol as a first-line treatment for gout [20,21]. Although febuxostat has better SUA-lowering efficacy than allopurinol, there are ongoing concerns regarding cardiovascular safety arising from the Cardiovascular Safety of Febuxostat and Allopurinol in Patients With Gout study [25]. However, more recent studies show no increased cardiovascular risk after febuxostat initiation compared with allopurinol [26,27].
Recombinant uricases convert uric acid into a more water-soluble compound, allantoin, for excretion in the urine. Pegloticase and rasburicase are recombinant uricases. Both are pegylated to increase plasma half-life by reducing renal excretion, and pegylation may also provide resistance to proteolysis and reduce antigenicity. Both agents are recommended for treatment-refractory gout based on their efficacy in lowering SUA and promoting the resolution of tophi [28].
Understanding the ability of ULT drugs to lower and maintain a target SUA is critical for clinicians to manage and treat hyperuricemia and gout appropriately. Several studies have demonstrated the efficacy of different ULT drugs across class and dose. Here we performed a systematic review and meta-analysis to determine the SUA-lowering effect and achievement difference (AD) in maintaining the target SUA for different ULT drugs at various doses, considering baseline SUA in hyperuricemic patients.
We included randomized prospective clinical trials (phase 1 to 4) of ULT drugs for the treatment of gout, hyperuricemia, or tumor lysis syndrome, regardless of the study masking method. Trials that involved dose titration intervals in step-up protocols were included by recording the extent of SUA-lowering after participants reached the maintenance dose for the time defined by each study protocol.

Data Extraction and Imputation of Missing Values
Data were extracted from the journal article associated with each clinical trial or the ClinicalTrials.gov entry when a journal article was unavailable. Data were entered into a standardized data extraction form.

SUA-Lowering Analysis
In the SUA-lowering analysis, we excluded trial arms for any of the following six reasons: (1) SD or SE for percent SUA lowering were not reported, which are required for meta-regression; (2) we excluded placebo arms; (3) baseline SUA was within normal range (<6.8 mg/dL); (4) a dosing frequency other than once daily was used; (5) a dose titration scheme was used; or (6) the study did not define CKD.
After excluding 152 trial arms (64.68%; Figure 1 and Supplemental Table S1), 35 studies encompassing the following 83 trial arms were included: 29 arms for allopurinol, 4 arms for benzbromarone, 28 arms for febuxostat, 1 arm for lesinurad, 1 arm for probenecid, 16 arms for topiroxostat, and 4 arms for a combination of two ULT drugs (Supplemental Table S1). Only allopurinol, febuxostat, and topiroxostat were included in the final meta-analysis due to insufficient data for other ULT drugs.

Achievement Difference Analysis
In the AD analysis, we selected trial arms based on 2020 ACR and 2016 EULAR guidelines [20,21]. As the 2020 ACR guidelines strongly recommend allopurinol as a firstline ULT, we included all trials using allopurinol 300 mg daily (the standard dose) as a control group [20]. To analyze studies targeting maintenance of SUA <6 mg/dL, we included the following 7 trial arms for febuxostat: 2 arms at 40 mg daily, 4 arms at 80 mg daily, and 1 arm at 120 mg daily.

Statistical Analysis
Previous studies of ULT drugs used the following different dosing frequencies: daily, twice daily, three times daily, or every four days. We chose to focus on daily doses, the most commonly used regimen, to harmonize the SUA-lowering effect of different ULT drugs. Thus, we excluded all other dosing frequencies.
In estimation of the dose-dependent SUA-lowering effect, we conducted a meta-analysis using the metareg command of Stata, version 16 (StataCorp; 2019, College Station, TX: StataCorp LLC.). To account for the effect of baseline SUA on dose-dependent SUA-lowering outcomes, we selected only trials including subjects with an elevated baseline SUA of >6 mg/dL. We adjusted the analysis for covariates, including CKD diagnosis, sample size, length of follow-up, collection site, and proportion of male participants in each arm, as all studies included a preponderance of males. The proportion of male participants was transformed into a binary variable based on the following median values for trial arms (0.82 for allopurinol arms, 0.95 for febuxostat arms, and 0.91 for topiroxostat arms): 1 for more male-dominant arms and 0 for less male-dominant arms. This transformation was performed because the proportion of male participants was highly skewed, and this degraded model fit when it was introduced as a covariate. The meta-regression was performed only for allopurinol, febuxostat, and topiroxostat after excluding unqualified trial arms.

Achievement Difference Analysis
In the AD analysis, we selected trial arms based on 2020 ACR and 2016 EULAR guidelines [20,21]. As the 2020 ACR guidelines strongly recommend allopurinol as a first-line ULT, we included all trials using allopurinol 300 mg daily (the standard dose) as a control group [20]. To analyze studies targeting maintenance of SUA <6 mg/dL, we included the following 7 trial arms for febuxostat: 2 arms at 40 mg daily, 4 arms at 80 mg daily, and 1 arm at 120 mg daily.

Statistical Analysis
Previous studies of ULT drugs used the following different dosing frequencies: daily, twice daily, three times daily, or every four days. We chose to focus on daily doses, the most commonly used regimen, to harmonize the SUA-lowering effect of different ULT drugs. Thus, we excluded all other dosing frequencies.
In estimation of the dose-dependent SUA-lowering effect, we conducted a metaanalysis using the metareg command of Stata, version 16 (StataCorp; 2019, College Station, TX, USA: StataCorp LLC.). To account for the effect of baseline SUA on dose-dependent SUA-lowering outcomes, we selected only trials including subjects with an elevated baseline SUA of >6 mg/dL. We adjusted the analysis for covariates, including CKD diagnosis, sample size, length of follow-up, collection site, and proportion of male participants in each arm, as all studies included a preponderance of males. The proportion of male participants was transformed into a binary variable based on the following median values for trial arms (0.82 for allopurinol arms, 0.95 for febuxostat arms, and 0.91 for topiroxostat arms): 1 for more male-dominant arms and 0 for less male-dominant arms. This transformation was performed because the proportion of male participants was highly skewed, and this degraded model fit when it was introduced as a covariate. The meta-regression was performed only for allopurinol, febuxostat, and topiroxostat after excluding unqualified trial arms.
To compare AD among ULT drugs, we conducted a meta-analysis using the meta command of Stata, version 16 (StataCorp; 2019, College Station, TX, USA: StataCorp LLC.) model. For the analysis, we selected only arms, including subjects with a baseline SUA >6.8 mg/dL, which we defined as the upper limit of normal. In the model, we entered the numbers of participants who achieved and did not achieve the intended therapeutic outcome, which yielded the efficacy of the intended therapeutic effect. Systematic bias and heterogeneity among studies are shown as a funnel plot (Supplemental Figure S4).

Trial Characteristics
We used achievement difference (AD) meta-analysis to examine which study arms achieved the target serum uric acid level, as defined in each study. This analysis included 1849 patients with a baseline SUA of 9.79 ± 0.18 mg/dL (mean ± SD; range, 9.43-9.98 mg/dL). There were 632 patients on allopurinol with a baseline SUA of 9.83 ± 0.13 mg/dL and 1217 patients on febuxostat with a baseline SUA of 9.76 ± 0.21 mg/dL.

Discussion
Increased uric acid levels play a central role in the pathogenesis of particular diseases, including gout and tumor lysis syndrome, and are associated with a higher risk of cardiovascular disease [8,9], CKD [11], diabetes mellitus [10], and nonalcoholic fatty liver disease [10]. However, there have been few systematic reviews and meta-analyses of ULT. The present meta-analysis provides insight into the dose effects of different ULT drugs and may help guide clinicians in selecting the appropriate dosing to achieve a specific SUA-lowering effect.
We analyzed the following three different XOIs that showed dose-dependent SUAlowering effects: allopurinol, febuxostat, and topiroxostat. These agents showed meaningful SUA-lowering effects that persisted after controlling for the presence of CKD, sample size, length of follow-up, collection site, and proportion of male participants. With regards to CKD, concerns have arisen with regard to using allopurinol in CKD due to its potentially detrimental effect on renal function, and untreated hyperuricemia may promote poor outcomes of gout or hyperuricemia [65]. Stamp et al. [66,67] studies were supported by results showing allopurinol dose escalation in CKD can achieve effective SUA with comparable safety; a lower starting dosing was required to achieve target SUA in CrCl < 30 mL/min. The analysis presented here shows CKD has a marginal influence on the SUA-lowering effects of allopurinol and hence supports the current ACR 2020 practice guidelines, which recommend a lower allopurinol starting dose in CKD [20].
The present meta-analysis showed that febuxostat had better SUA-lowering ability than allopurinol or topiroxostat (Table 1). Based on the null model, the expected SUAlowering effect of allopurinol 300 mg was a 15% reduction from the baseline SUA level. Based on our SUA-lowering analysis, an equivalent outcome would be achieved by febuxostat 83.33 mg or topiroxostat 150 mg (Tables 2-4). Previous meta-analyses that examined the comparative efficacy of ULT drugs showed similar AD results as in the present study. Ye et al. [68] report that the efficacy of febuxostat 40 mg daily is higher than that of allopurinol 100-300 mg daily and is greater with higher doses (80-120 mg daily). Borghi et al. [69] showed that doses of febuxostat >40 mg daily are superior to allopurinol at 300 mg daily. Furthermore, Li et al. [70] suggested that febuxostat has greater efficacy at 120 mg daily compared to allopurinol at 300 mg daily. Based on our AD analysis results (Table 5), febuxostat 80 mg daily may be a better treatment option than allopurinol for patients with refractory SUA levels, consistent with 2016 EULAR and 2020 ACR recommendations [20,21].
The meta-analysis presented here suggests that febuxostat could be preferable to allopurinol for treating gout. Given the higher cost and black box warning associated with febuxostat, allopurinol is currently recommended as the first-line treatment for most gout patients. However, studies have shown the cost-effectiveness of febuxostat compared with allopurinol in chronic gout management [71,72]. Thus, it may be worthwhile to further examine the advantages of febuxostat from an economic perspective. Moreover, recent studies show no increased cardiovascular risk of febuxostat compared with allopurinol [26,27]. Apart from its overall greater efficacy, febuxostat may also be a better ULT option in specific instances. First, febuxostat may be more beneficial to patients with mild to moderate renal impairment (creatinine clearance of 30-80 mL/min/1.73 m 2 ), as it is not influenced by renal function [73]. Second, febuxostat may be better for treating patients with the human leukocyte antigen HLA-B*5801 allele [74,75]. Previous studies reveal that allopurinol can cause a spectrum of severe skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, in patients with the HLA-B*5801 allele [74,75]. Although rare, allopurinol hypersensitivity syndrome can cause serious mortality and morbidity. Therefore, according to ACR 2020 gout guidelines, testing for the HLA-B*5801 allele prior to starting allopurinol is recommended for patients of Southeast Asian descent and for African American patients [20]. Third, febuxostat may be a better choice for patients who are refractory to allopurinol. Individuals with a minor allele (rs2231142) of the ATP-binding cassette ABCG2 transporter show minimal response to allopurinol. Therefore, patients with a higher risk of treatment failure and a lack of biological sensitivity to allopurinol could consider initiating treatment with febuxostat [76].
Strengths of the present study include the analysis of SUA-lowering and AD efficacy of ULT drugs at different doses compared with allopurinol 300 mg daily, which is most commonly used in the United States [77]. We also included trials from various geographic regions, including the United States, Europe, China, Japan, Iran, and India. However, this analysis also has limitations, including (1) the specific details of the studies were not captured due to the nature of the meta-analysis technique; (2) heterogeneity among studies may have resulted from the inclusion of older studies between the 1970s and 1980s, which may have included patients with different lifestyles and employed different trial designs; (3) treatment duration and patient characteristics varied among trials; (4) we did not analyze the potential influence of renal function on treatment efficacy by accounting for patients' body mass index, sex, or ethnicity; (5) there was a lack of standardized reporting of SUA-lowering effects among included trials.
We recommend that future studies analyze sex differences in hyperuricemia. Although men, compared to women, have a higher risk of developing gout (5.2% vs. 2.7%) and hyperuricemia (20.2% vs. 4.2%) [18], there is evidence that during the late menopausal transition stage, SUA rises in women to levels comparable to those of men at a similar age [78]. In addition, although body mass index is typically considered in clinical trials, future trials involving agents that affect SUA should report detailed information on the body mass index of participants, so that clinicians can better understand appropriate doses of ULT. Furthermore, standardized approaches to reporting data should be considered in future studies to improve the feasibility of subsequent meta-analyses.
In summary, the meta-analysis presented here shows the dose-dependent SUA-lowering effects of allopurinol, febuxostat, and topiroxostat. Further, it suggests that febuxostat is a more effective ULT than allopurinol, especially at higher doses. These findings support the ULT recommendations in the 2016 EULAR and 2020 ACR guidelines.