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REVIEW ARTICLE
Ahead of print publication  

A narrative review of clinical evidence validating the efficacy of topiroxostat in managing hyperuricemia


1 Chanre Rheumatology and Immunology Center and Research, Bengaluru, Karnataka, India
2 Medicine and Rheumatology, KMCT Medical College, Kozhikode, Kerala, India

Date of Submission22-Mar-2022
Date of Acceptance18-May-2022
Date of Web Publication13-Jul-2022

Correspondence Address:
S Chandrashekara,
Chanre Rheumatology and Immunology Center and Research, Bengaluru, Karnataka
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/injr.injr_59_22

  Abstract 


The current study conducted a critical review on available clinical evidence for topiroxostat, indicated for managing hyperuricemia in patients with or without gout. Relevant observational studies related to hyperuricemia and topiroxostat published between 2014 and 2022 were retrieved from various electronic databases based on the inclusion and exclusion criteria and using different combinations of MeSH terms. The systematic search yielded 2094 articles from various databases. Based on the inclusion and exclusion criteria, 16 articles were selected for systematic review. The review considered 16 studies on serum urate-lowering efficacy of topiroxostat and 6 studies that had evaluated the efficacy of the drug in hyperuricemia patients with chronic kidney disease. Four studies that evaluated hyperuricemia patients with cardiovascular risk and 10 studies that had evaluated adverse drug reactions linked to topiroxostat use were also considered. The literature findings validated the safety, efficacy, renoprotective effects, and reduced adverse events conferred by topiroxostat. The most common adverse event noted was gouty arthritis of mild to moderate in severity. The advantages of the drug when compared to the currently available xanthine oxidoreductase inhibitors include unique dual mechanism of action, cardiac safety, and renal protection.

Keywords: Hyperuricemia, renoprotective, serum uric acid, topiroxostat, uric acid, xanthine oxidoreductase



How to cite this URL:
Chandrashekara S, Paul BJ. A narrative review of clinical evidence validating the efficacy of topiroxostat in managing hyperuricemia. Indian J Rheumatol [Epub ahead of print] [cited 2022 Dec 5]. Available from: https://www.indianjrheumatol.com/preprintarticle.asp?id=350878




  Introduction Top


Hyperuricemia, characterized by abnormally elevated levels of serum uric acid (SUA, concentration of ≥416.4 μmol/L or ≥7.0 mg/dL), causes monosodium urate crystal deposition in tissues and is an independent precursor of gout. It is also associated with elevated risk for urolithiasis, and elevated cardiovascular mortality in patients with chronic kidney disease (CKD), diabetes mellitus, and nonalcoholic fatty liver disease. The pro-inflammatory and oxidative changes and the systemic endothelial dysfunction may also be involved in the etiopathogenesis of insulin resistance mediated by hyperuricemia.[1]

Understanding the plausible independent causal relationship between hyperuricemia and the pathogenesis of vascular damage has significant relevance, as the currently available hyperuricemia drugs are found to be very effective in reducing the circulatory levels of uric acid.[2] Xanthine oxidoreductase (XOR) has been identified as a critical drug target for the management of hyperuricemia, as it serves as a catalytic enzyme for the oxidative hydroxylation of hypoxanthine to xanthine and xanthine to uric acid, and the associated production of reactive oxygen species.[3]

Topiroxostat, a nonpurine selective hybrid inhibitor, inhibits the XOR activity via covalent binding with molybdenum and the interaction with amino acid residues in the substrate-binding pocket.[4] Several studies have validated the safety and efficacy of the drug, and its role in reducing SUA levels and its renoprotective effects.[4] Topiroxostat, approved for clinical use in Japan since 2013, has demonstrated good oral bioavailability with a biological half-life of 4.5–7.5 h. Moreover, several studies have suggested the superiority of the drug over other XOR inhibitors. Topiroxostat has also been found to be safe in reducing SUA levels in hyperuricemia patients undergoing hemodialysis, as opposed to allopurinol. In addition, the dose reduction is not needed for the drug, even in subjects with compromised renal function as the drug is not dialyzable.[5]

The present review is intended to provide a critical review on topiroxostat based on the available clinical evidence on its use in managing hyperuricemia in patients with or without gout. Because there is no study summarizing the clinical effects and safety of topiroxostat in the treatment of hyperuricemia, the present narrative review has attempted to draw a conclusion based on the existing clinical evidence.


  Methodology Top


A systematic search of the literature was carried out (period of search: February 2022) to identify relevant observational studies related to hyperuricemia and topiroxostat published between 2014 and 2022. The articles were retrieved from the various electronic databases namely PubMed, Embase, Web of Science, Scopus, Google Scholar, Europe PubMed Central, Science Direct, and Cochrane library based on the inclusion and exclusion criteria and using different combinations of searchable terms encompassing key MeSH terms. The different combinations of the following MeSH terms were considered for literature search: Topiroxostat, hyperuricemia, xanthine oxidoreductase inhibitors, gout, and uric acid-lowering therapy [details provided as [Supplementary File 1], [Supplementary File 2], [Supplementary File 3]]. The study included hyperuricemic adult (age >18 years) patients with or without gout and study assessing the clinical evidence of decreased SUA level by topiroxostat. Abstracts, reviews, animal studies, editorial, case reports, duplicated or nonrelevant studies, studies not in English language, and studies with lack of data on decreased SUA level by topiroxostat were excluded.




  Results Top


Literature search conducted using various MeSH terms in combination yielded 2094 articles from various databases and one through cross reference. Seven hundred and three articles were removed before screening due to duplication of records. Out of 1392 articles screened, the records excluded due to various reasons were as follows: 1247 not in the field of interest, 41 articles not in English and 10 animal studies. Out of 94 articles selected for a full-text review based on the details in the title and abstract, 78 were excluded due to the following reasons: Review articles (n = 23,) editorial articles (n = 3), and lack of topiroxostat clinical data, and studies based on other drugs (n = 52). The study finally selected 16 articles, comprising of 10 randomized controlled trials, 2 cohort studies, and 1 each of multicentre postmarketing surveillance study, multicenter open-label study, cross-over trial, and retrospective study. Therefore, 16 studies included 5357 patients administered with topiroxostat, 157 patients with placebo, and 240 and 171 patients administered with allopurinol and febuxostat respectively. The descriptive and demographic characteristics of the included studies are listed in supplementary information. The PRISMA flow chart depicting the screening and selection of studies is provided in [Figure 1].
Figure 1: Identification of studies via databases and registers

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Efficacy and renoprotective effect

Sixteen studies that have evaluated the serum urate lowering efficacy of topiroxostat were considered for the review.[4],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20] Five articles that had investigated the efficacy of topiroxostat in hyperuricemia patients with or without gout have corroborated the serum urate-lowering effect of topiroxostat [Table 1]. All the studies were carried out in Japanese population. An 8-week, phase 2a, multicentre, randomized controlled study by Hosoya et al. considered the study arms administered with 40, 60, 80, 120 mg/day of topiroxostat and placebo. Significant dose-dependent serum urate level reduction was exhibited by topiroxostat compared to placebo.[6] A randomized, double-blinded, controlled phase 2b study by Hosoya et al. considered 157 Japanese hyperuricemia patients who received placebo, allopurinol at 200 mg/day or topiroxostat at 120 or 160 mg/day. The researchers noted a dose-response relationship for the serum urate-lowering effect of topiroxostat. The lowering rate of serum urate levels noted in the topiroxostat 160-mg/day group at the end of administration was-44.8%.[7]
Table 1: Characteristics of studies which included hyperuricemia patients with or without gout

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Another double-blind, active-controlled, parallel-group study by Hosoya et al., demonstrated that topiroxostat 120 mg/day had conferred non-inferior serum urate reduction when compared to allopurinol 200 mg/day (95% confidence interval [CI], −5.3 to 1.3%). The patients achieving the target SUA level was comparable for topiroxostat (72.4% [95% CI: 62.5–81.0]) and allopurinol (73.3% [95% CI: 63.8–81.5]).[8] A 54-week open-label, multicenter, postmarketing observational study by Ishikawa et al. reported significant uric acid reduction rate at 54 weeks and on the final visit compared to the baseline with 43.80% and 48.28% patients achieving the target SUA levels at 18 and 54 weeks respectively after administration of topiroxostat. The study has suggested that the treatment is not associated with any particular concern regarding the adverse drug reactions or the efficacy of topiroxostat in hyperuricemia patients with or without gout.[4] A similar open-label study by Hosoya et al. has concluded on the safety and efficacy of 58-week oral topiroxostat following step-wise increase in maintenance dosage to 240 mg/day.[9]

The review considered 6 studies that had evaluated the efficacy of hyperuricemia patients with CKD [Table 2]. Matsuo et al. reported a significant decrease in SUA level from 8.6 ± 1.1 at baseline to 6.0 ± 1.1 mg/dl at 24 weeks of administration of topiroxostat; whereas, the corresponding values noted for febuxostat were 8.4 ± 1.1 mg/dl and 5.9 ± 1.3 mg/dl.[10] Similarly, Hosoya et al.(2014) reported significant reduction in serum urate levels (−45.38 vs. −0.08%, P < 0.0001) and the percent change in urinary albumin-to-creatinine ratio (−33.0 vs. −6.0%, P = 0.0092) by the administration of topiroxostat 160 mg when compared to placebo after 22 weeks.[11] In concurrence with these findings, the UPWARD study by Wada et al., 2018, has concluded that the topiroxostat treatment (stepwise dosing from 40 to 160 mg/day) helps in achieving strict SUA level control by preventing the reduction of estimated glomerular filtration rate (eGFR) in these patients.[12] Horino et al. have noted that the topiroxostat treatment (40 mg/day twice daily) contributed to significant reduction in systolic blood pressure (BP) (−8.9 mmHg), diastolic BP (−5.0 mmHg), SUA (−1.53 mg/dL), and urinary protein excretion (−795.5 mg/gCr) compared to baseline. However, no significant difference in serum creatinine, urinary N-acetyl-β-D-glucosaminidase levels and eGFR rate were noted. The study has suggested the renoprotective effect of the drug in hyperuricemia patients with CKD and highlighted the need for further studies to evaluate the effect of topiroxostat in preventing the progression of renal disease.[13]
Table 2: Characteristics of studies which included hyperuricemia patients with kidney disease

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ETUDE study by Mizukoshi et al. has found that topiroxostat 160 mg daily helped in achieving reduction in albuminuria in patients with diabetic nephropathy upon 24 weeks of treatment. The changes in urine albumin-to-creatinine ratio noted following 24 weeks of treatment with respect to the baseline were-122 mg/gCr (95% CI: −5.1 to − 240.1, P = 0.041).[14] The 3 months, cross-over clinical trial study on hemodialysis patients conducted by Nagaoka et al. have demonstrated that the low-dose topiroxostat (40 mg) helped to attain a reduced SUA level <7.0 mg/dL in subjects who received hemodialysis. Moreover, the mean SUA levels in the topiroxostat-treated group were significantly lesser than the allopurinol-treated arm (P < 0.0001).[15]

The multicenter, open-label study by Hosoya et al. has shown a significant reduction in urinary albumin levels and cystatin C levels following stepwise increase in oral topiroxostat up to 240 mg/day. The corresponding cystatin C levels noted at final visit for 120 mg, 160 mg, and ≥ 200 mg were 0.089 ± 0.081 mg/L, 0.062 ± 0.055 mg/L, and 0.091 ± 0.094 mg/L. The changes in baseline and after treatment in urinary albumin levels in geometric mean after 30 weeks, 58 weeks, and at the final visit were 0.997 (n = 107), 0.753 (n = 103), and 0.794 (n = 118) respectively.[9]

Vascular effects of topiroxostat

Four studies that evaluated hyperuricemia patients with cardiovascular risk and hypertension are considered for the review [Table 3]. The retrospective cohort study by Higa et al. has investigated the effects of topiroxostat on vascular function measured through flow-mediated dilation (FMD) using ultrasonography. The study significantly noted reduction in SUA level from 7.31 ± 1.43 baseline to 5.44 ± 1.11 mg/dL after 8 weeks and a significant increase in the peak percentage change in diameter delta flow-mediated dilatation (△FMD) from 4.53% ± 2.09% to 5.54% ± 3.08% after administration of topiroxostat.[16]
Table 3: Characteristics of studies that considered hyperuricemia patients with cardiovascular risk and hypertension

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Tohyo have evaluated the effect of topiroxostat on circulating lipid concentrations in hyperuricemia patients. The researchers noted significant reduction in SUA, total cholesterol, and low-density lipoprotein cholesterol (LDL-c) between baseline and 24 weeks.[17] Similarly, the prospective, randomized, open-label, blinded-end-point clinical trial by Sakuma et al. has suggested the potential advantages of topiroxostat in decreasing left ventricular end-diastolic pressure, and conferring renoprotection as opposed to allopurinol in patients with heart failure with reduced ejection fraction (HFrEF).[18]

Kario et al. have compared the effects of topiroxostat and febuxostat on arterial properties in hypertensive subjects' with hyperuricemia. The researchers have noted significant reduction in SUA (−2.9 and − 2.5 mg/dl; both P < 0.001) and morning home systolic BP (−3.6 and − 5.1 mm Hg; both P < 0.01) following 24 weeks of treatment with febuxostat and topiroxostat. There was a significant decrease in urinary albumin-creatinine ratio (UACR) from baseline to 24 weeks with topiroxostat (−20.8%; P = 0.021). However, the same renoprotective effect has not been observed for febuxostat (−8.8%; P = 0.362). However, neither topiroxostat nor febuxostat had any significant effects on arterial stiffness over 24 weeks of treatment.[19] The TROFEO trial by Sezai et al. has concluded on the comparable renal protective and anti-inflammatory effects of febuxostat and topiroxostat after 6 months of treatment. The researchers also underscored the potential of both the drugs in managing hyperuricemia in patients with cardiovascular disease.[20]

Safety

Ten studies included in this review have evaluated the adverse events and adverse drug reactions linked to topiroxostat use. The prevalence and type of adverse events and drug reactions noted by various studies are listed in supplementary file. No serious adverse event was observed in any of the studies and most of the adverse events observed were of mild to moderate in severity. The overall incidence rates of adverse events noted for various doses of topiroxostat namely 40 mg, 60 mg, 80 mg, and 120 mg were comparable. However, in the 120 mg group, the incidence of adverse events was significantly lower than the placebo group.[6] Hosoya et al. have noted that the incidence of overall adverse events in the topiroxostat was similar to that of placebo. Moreover, the researchers have noted that the incidence of adverse event in the 120 mg was significantly lower than the placebo group.[6] Comparison of adverse effects of topiroxostat and allopurinol in the phase 3, multicentre, randomized study by Hosoya and researchers has demonstrated that the drugs were well tolerated and the overall adverse drug reaction and incidence rates were comparable between the groups.[8] The corresponding percentage of adverse effects including gouty arthritis noted in the allopurinol, placebo, 120mg topiroxostat, and 160 mg topiroxostat groups were 25.6%, 38.5%, 20.5%, and 17.5%. The adverse events and drug reactions were mild to moderate in severity in topiroxostat group.[7] In the UPWARD study, the occurrence of diabetic retinopathy and colon cancer led to the study withdrawal in 2 patients and 1 patient each.[12] The postmarketing observational study conducted by Ishikawa et al. in Japan has concluded that that there is no particular concern with regard to the efficacy or adverse effect of topiroxostat in hyperuricemia patients with or without gout. The study has noted a lower rate of incidence of adverse drug reactions with topiroxostat of 6.95% when compared to 35.35% reported for aggregated results in the preapproval trials.[4] In a long-term study of topiroxostat by Hosoya et al., dosage of 40–80 mg and at a maintenance dosage of 120 mg/day for up to 58 weeks was considered safe for step-wise increments. Three adverse events noted in two patients, which could be attributed to topiroxostat were aortic aneurysm, coronary artery stenosis, and cardiac failure congestive.[9] Kario et al. has reported that the treatment with topiroxostat and febuxostat was well tolerated and the adverse events noted in the topiroxostat group were gout (three subjects), nausea, cholelithiasis arthralgia, and malaise (one patient each).[19]

The 2014 study by Hosoya et al. reported that the adverse events were mild to moderate in severity and the overall incidence of adverse events were similar in both topiroxostat and placebo groups. The adverse events that resulted in treatment withdrawal in the topiroxostat group (one patient each) were increased liver enzymes, eczema and polyarthritis, and acute hepatitis in the placebo group (one patient).[11] The blinded-end-point clinical trial carried out by Sakuma et al. has noted no significant difference in the safety between topiroxostat and allopurinol, whereas one patient in topiroxostat and two patients in the allopurinol group withdrew from the study due to serious adverse events.[18]

The most common adverse event noted in the selected studies was gouty arthritis of mild to moderate in severity. Nasopharyngitis, elevated liver enzymes and urinary beta 2 microglobulin were other commonly noted adverse events in included studies. Almost all the studies had reported topiroxostat to be safe and well tolerated with very minimal incidence of serious adverse events.


  Discussion Top


The present critical review summarizes the available clinical evidence on the use of topiroxostat for managing hyperuricemia. The literature findings validate the safety, efficacy and renoprotective effects conferred by topiroxostat, thereby corroborating its clinical use for reducing SUA level in patients with hyperuricemia. Almost all the studies considered in the present narrative review have validated the positive effects of the topiroxostat on renal function and reducing SUA in hyperuricemia patients. Some of these major studies are ETUDE study, UPWARD study, TROFEO Trial, long-term multicenter, open-label study of topiroxostat by Hosoya et al., the study by Horino et al. in hyperuricemic patients with CKD and the study comparing the effects of topiroxostat and febuxostat in patients with CKD.[9],[12],[13],[14],19],[20]

Literature findings have also concluded on the low rate of serious adverse events with majority of the effects being mild to moderate.[6],[12],[14] The incidence of adverse events was comparable to that of allopurinol.[7],[8]

The study by Nakamura et al. has noted that the topiroxostat treatment promoted a dose-dependent reduction in urinary albumin excretion and plasma XOR activity.[21] Similarly, a randomized, multicenter, double-blind study by Hosoya et al. noted that the therapeutic use of topiroxostat 160 mg in patients with hyperuricemia stage 3 CKD, irrespective of their gout status, helped in reducing urinary albumin excretion and SUA level.[11] The study has also concluded on the dose-dependent relationship between the serum urate-lowering efficacy and the safety of the drug. However, the low target SUA achievement rate (<50%) noted in the study may be due to a relatively increased serum urate level or lack of doses of topiroxostat.[6] In a study by Katsuyama et al., topiroxostat reduced urinary protein and eGFR conferring renoprotective effects and reduced SUA level.[22]

Majority of the studies have reported comparable efficacy of topiroxostat, allopurinol and febuxostat.[7],[8],[10],[19],[20] Hosoya et al. reported that topiroxostat and allopurinol had equivalent efficacy and no statistically significant difference in the occurrence of adverse events.[7] Another study by Hosoya et al. noted that the serum urate-lowering efficacy of topiroxostat is noninferior to serum allopurinol and both the drugs had comparable adverse events and drug reactions.[8] According to Sakuma et al., the topiroxostat group had significant reduction in uric acid levels at 24 week than allopurinol group. Moreover, the study also suggested that the topiroxostat bestows certain potential advantages over allopurinol in patients with HFrEF such as reduced left ventricular end-diastolic pressure, nonimpairment of oxidative stress in proximal renal tubule, and renoprotection.[18] In the cross-over clinical trial by Nagaoka et al., topiroxostat exhibited significant reduction in SUA levels and safety at the minimum dose compared to allopurinol.[15] In all the studies that used allopurinol, the dose was not escalated to the maximum to attain the target uric acid level. Sezai et al. reported that febuxostat therapy reduces serum urate level more dramatically and quickly than topiroxostat. However, there was no difference in serum urate levels between the two medications after 6 months and the efficacy was comparable. In terms of antioxidant activity, febuxostat outperformed topiroxostat after 3 months, but not after 6 months.[20] Matsuo et al. reported comparable reduction in SUA level between topiroxostat and febuxostat.[10] A study by Kario et al. found that there was no significant difference between the topiroxostat and febuxostat in terms of decrease in SUA level and both the treatments were well tolerated.[19]

Apart from the renoprotective and serum urate reduction benefits, the drug has been reported to confer cardiac safety and the studies by Higa et al., Kario et al., Sakuma et al., and Tohyo have corroborated the same.[16],[17],[18],[19] The single-center, double-blind, four-period cross-over study by Sugiyama et al. has suggested that topiroxostat treatment is not associated with any concern on QT-interval prolongation in both the genders.[23] Some studies have also reported that the pleiotropic pharmacological actions of topiroxostat, especially plasma brain natriuretic peptide reduction would be beneficial in patients with chronic heart failure.[24] Kuki et al. have demonstrated the anti-atherogenic effects of topiroxostat in patients with hyperuricemia at high-risk cardiovascular disease, apart from the hypouricemic and the renoprotective effects.[24],[15] In line with these findings, the retrospective study by Tohoyo et al. has concluded on the beneficial effects of topiroxostat in reducing total cholesterol, low-density lipoprotein cholesterol and SUA levels.[17]

Another distinct feature of topiroxostat, when compared to other structure-based XOR inhibitors, is its dual mechanism of action. Topiroxostat acts by interacting with amino acid residues of the solvent channel and covalently binding to molybdenum, the reaction center of XOR. Moreover, the pharmacokinetic properties of topiroxostat and its metabolites are not affected by mild to moderate renal impairment.[11] Hosoya et al. have termed the drug as a hybrid-type inhibitor with significant potential in reducing serum urate levels.[9]

The key strength of the included studies is that majority of them are randomized controlled trials, multicenter based studies, and postmarketing studies. There are 7 studies evaluating the treatment of hyperuricemia with topiroxostat and with allopurinol or febuxostat.[7],[8],[10],[15],[18],[19],[20] Uniformity in the ethnicity of the cohort considered in all the included studies is another advantage. The drawbacks of the included studies are lack of diversity, consideration of only Japanese population and not escalating the doses of allopurinol and febuxostat to the maximal level for attaining a reduction in SUA.

In patients receiving allopurinol for hyperuricemia, Mercuro et al. found a clear link between the percentage increase in △FMD and the percentage reduction in serum urate levels.[25] Whereas, the study by Higa et al. did not to find a significant correlation between the percentage increase in FMD and the percentage decrease in serum urate levels. Subgroup analyses of urate level at week 8 revealed that lower serum urate levels were associated with greater improvements in vascular endothelial function. These findings suggest that decreased urate levels about 8 weeks after starting topiroxostat medication are linked to a higher FMD.[16] Sakuma et al. reported no correlation between urate level and left ventricular end-diastolic pressure.[18] Tohyo reported positive correlation between serum urate level, total cholesterol, and LDL-c concentrations.[17]

Miao et al. reported that the degree of reduction in serum urate level is linked to the long-term renal risk reduction.[26] Correlation between the decrease of SUA levels and the increase in eGFR at 3 and 6 months after starting topiroxostat was reported by Katsuyama et al.[22] There was no correlation reported between urate level and eGFR in the study by Wada et al.[12] The multicentre study by Hosoya et al. did not report any association between decrease in SUA level and improvement in urinary albumin level.[9],[11] According to Mizukoshi et al., the antialbuminuric action of topiroxostat may be independent of serum urate levels.[14] In the study by Kario et al., the urinary albumin-creatinine ratio decreased significantly from baseline to 24 weeks with topiroxostat, but not with febuxostat. Whereas, serum urate levels decreased significantly from baseline in both the topiroxostat and febuxostat groups, implying that the anti-albuminuric action may be independent of serum UA levels.[19] According to Horino et al., renoprotective effect of topiroxostat may be independent of its serum urate-lowering effect.[13]

The present narrative review holds significant relevance, as to the best of our knowledge, there is no review summarizing the clinical effects and safety of topiroxostat in managing hyperuricemia. Moreover, following a more rigorous and prospectively defined objective process for the data collection, extraction and compilation assisted in critically scrutinizing the study methodologies and excluding articles with vague study designs and protocols and those not in field of interest.

The current study could not perform a meta-analysis of the available literature due to the diversity of the studies. Since a meta-analysis could not be carried out, generalization of the study findings is not possible. Population examined in all studies in the review was limited to Japanese population, as a result, the study is less generalizable. The study has only included full text articles in English, studies with significant findings in other language could not be considered.


  Conclusion Top


Topiroxostat can be considered as a safe and effective therapeutic choice for the management of hyperuricemia. The unique dual mechanism of action, cardiac safety, and renal protection are additional advantages of the drug in comparison to other currently available XOR inhibitors. Long-term randomized trials and meta-analysis are required to further characterize the efficacy and safety in comparison to other antihyperuricemia drugs.

Acknowledgment

The authors are thankful to Research Assist (http://www.researchassist.com) for assisting in editing, formatting, and other secretarial work.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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