Featured contentReview articleEfficacy and Tolerability of Febuxostat in Hyperuricemic Patients With or Without Gout: A Systematic Review and Meta-Analysis
Introduction
Gout is a common disease characterized by hyperuricemia and urate crystal deposition.1, 2 Hyperuricemia is typically defined as a serum concentration of uric acid at or above the limit of its solubility (∼6.8 mg/dL).2, 3 Individuals with hyperuricemia are usually asymptomatic and do not always have gout symptoms.2, 4 Gout is associated with insulin resistance, diabetes, obesity, dyslipidemia, and hypertension.2, 4, 5 Therefore, gout patients not only suffer potentially disabling arthritis but are also at high risk for cardiovascular diseases.6, 7, 8
The management of chronic gout is aimed at maintaining serum urate (sUA) concentrations below the level of saturation (<∼6.0 mg/dL).9, 10, 11 Achieving this goal usually requires urate-lowering therapy (ULT), which, if maintained over time, may result in a reduction in the frequency of acute gout flares and tophi resolution.12, 13, 14 The most commonly employed approaches to ULT involve reducing urate production with a xanthine oxidase (XO) inhibitor and enhancing urinary excretion of uric acid with a uricosuric agent. With regard to uric acid synthesis inhibitors, the purinelike XO inhibitor allopurinol has been widely used. Although a maximum dosage of 800 mg/d is recommended by the US Food and Drug Administration (FDA) and the European League Against Rheumatism, allopurinol is commonly administered at 100 to 300 mg/d in clinical practice.11, 13, 15 However, some patients fail to achieve target sUA levels at the commonly utilized doses. The prolonged half-life of the primary metabolite of allopurinol, oxypurinol, in patients with decreased creatinine clearance has prompted dose reductions in patients with impaired renal function.16, 17 Allopurinol may occasionally induce severe or life-threatening skin reactions (eg, exfoliative dermatitis) or allopurinol-hypersensitivity syndrome.11, 18, 19
Febuxostat, a non-purinelike XO inhibitor,20 was approved by the FDA for the treatment of hyperuricemia in patients with gout. In contrast to allopurinol, febuxostat inhibits both oxidized and reduced forms of XO and has little effect on other purine- and pyrimidine-metabolizing enzymes,20, 21 which indicates a potential for achieving a better urate-lowering effect. Febuxostat is mainly metabolized in the liver, with ∼45% excreted in the stool, and the remaining 49% (<3% unchanged) found in the urine,22 which allows febuxostat to be prescribed without dose adjustment in patients with mild to moderate renal or hepatic impairment.2 Evidence on treatment outcomes and tolerability with febuxostat therapy have accumulated in randomized controlled trials (RCTs) over the past decade. The present meta-analysis and systematic review were conducted to assess the efficacy and tolerability of febuxostat in hyperuricemic patients with/without gout.
Section snippets
Search Strategy
Literature searches of all publication years (up to February 2012) were conducted using PubMed, EMBASE, the Science Citation Index, the Cochrane library, the Chinese Biological Medical Database, the Chinese National Knowledge Infrastructure, and the VIP Database for Chinese Technical Periodicals, using the following search terms: febuxostat, Uloric, TMX-67, and TEI-6720 in English and fei bu si ta in Chinese. The Web sites of the American College of Rheumatology, the European League Against
Studies Included in the Meta-analysis and Systematic Review
We identified 271 citations, from which 237 were excluded based on the title and abstract. Therefore, 34 studies were selected for a full-text review, of which 6 were excluded for not meeting the inclusion criteria, 16 for containing duplicate data, 1 for letters, and 1 for data insufficiency for meta-analysis. In summary, 10 RCTs21, 26, 27, 28, 29, 30, 31, 32, 33 were included in the meta-analysis (Figure 1).
The characteristics of these studies are summarized in Table I.21, 26, 27, 28, 29, 30,
Discussion
Allopurinol is a widely used urate-lowering agent in the treatment of chronic gout. However, some patients with gout, especially those with impaired renal function, fail to achieve target sUA levels with allopurinol because of the dose reduction in these patients. Moreover, allopurinol can occasionally induce exfoliative dermatitis or allopurinol hypersensitivity syndrome, which also limits the usage of allopurinol. As a novel urate-lowering agent, febuxostat may offer gout patients another
Conclusions
Febuxostat was effective in reducing serum urate in hyperuricemic patients with/without gout. The efficacy of 40 mg/d was superior to that of allopurinol 100 to 300 mg/d, and with dosage increases, the efficacy of febuxostat 80 and 120 mg/d was enhanced. The doses of allopurinol to which febuxostat has been compared, though commonly prescribed, are low in the range of approved doses of allopurinol. The tolerability of febuxostat for treatment of hyperuricemia with/without gout was similar to
Conflicts of Interest
This research and its publication were supported by National Natural Science Foundation of China grant nos. 81170751 and 81200589. The authors have indicated that they have no other conflicts of interest with regard to the content of this article.
Acknowledgments
Drs. Ye and Yang are co-first authors. Drs. Lv, Cheng and Mei made the search strategy and searched major electronic databases. Drs. Luo and Liu searched the websites and reviewed the references for unpublished studies. Drs. Ye, Yang and Zhang selected studies, assessed the methodological quality of each trial and extracted data. Drs. Li and Chen reviewed/edited the manuscript.
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