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1.  Febuxostat: the evidence for its use in the treatment of hyperuricemia and gout 
Core evidence  2010;4:25-36.
Introduction:
Gout is a common and disabling cause of arthritis in middle-aged and elderly populations, with its main predisposing factor being hyperuricemia (serum urate > 6.8 mg/dL). Options for treatment of chronic gout until 2008 were allopurinol, a xanthine oxidase inhibitor, and the group of drugs known as uricosurics that stimulate the renal excretion of uric acid. A proportion of patients, including some with chronic kidney disease and solid organ transplantations, could not be treated with the those therapies because of intolerance, drug interactions, or adverse events. Febuxostat is a nonpurine xanthine oxidase inhibitor, recently approved in Europe and the United States for the treatment of chronic gout.
Aim:
To review the clinical evidence (phase II and III studies) of the effectiveness and safety of febuxostat for treatment of hyperuricemia and gout.
Evidence review:
Febuxostat, at doses ranging from 40 to 240 mg/day, is efficacious in reducing serum urate in patients with hyperuricemia and gout, comparing favorably with fixed doses of allopurinol in that respect. Early safety signals with respect to liver test abnormalities and cardiovascular outcomes have not been confirmed in recent large prospective trials but need to be further monitored.
Clinical potential:
Given its low cost and extensive clinical experience, allopurinol will likely remain the first-line drug for management of hyperuricemia and gout. Febuxostat may provide an important option in patients unable to use allopurinol, those with very high serum urate levels, or in the presence of refractory tophi.
PMCID: PMC2899777  PMID: 20694062
febuxostat; gout; hyperuricemia; evidence
2.  Febuxostat for treating chronic gout 
Background
Gout is the most common inflammatory arthritis in men over 40 years and has an increasing prevalence among postmenopausal women. Lowering serum uric acid levels remains one of the primary goals in the treatment of chronic gout. In clinical trials, febuxostat has been shown to be effective in lowering serum uric acid levels to < 6.0 mg/dL.
Objectives
To evaluate the benefits and harms of febuxostat for chronic gout.
Search methods
We searched The Cochrane Library, MEDLINE, EMBASE, and International Pharmaceutical Abstracts from inception to July 2011. The ClinicalTrials.gov website was searched for references to trials of febuxostat. Our search did not include any restrictions.
Selection criteria
Two authors independently reviewed the search results and disagreements were resolved by discussion. We included any controlled clinical trial or open label trial (OLT) using febuxostat at any dose.
Data collection and analysis
Data and risk of bias were independently extracted by two authors and summarised in a meta-analysis. Continuous data were expressed as mean difference and dichotomous data as risk ratio (RR).
Main results
Four randomised trials and two OLTs with 3978 patients were included. Risk of bias differed by outcome, ranging from low to high risk of bias. Included studies failed to report on five to six of the nine outcome measures recommended by OMERACT. Patients taking febuxostat 120 mg and 240 mg reported more frequent gout flares than in the placebo group at 4 to 28 weeks (RR 1.7; 95% CI 1.3 to 2.3, and RR 2.6; 95% CI 1.8 to 3.7 respectively). No statistically significant differences were observed at 40 mg and 80 mg. Compared to placebo, patients on febuxostat 40 mg were 40.1 times more likely to achieve serum uric acid levels < 6.0 mg/dL at 4 weeks (95% CI 2.5 to 639), with an absolute treatment benefit of 56% (95% CI 37% to 71%). For febuxostat 80 mg and 120 mg, patients were 68.9 and 80.7 times more likely to achieve serum uric acid levels < 6.0 mg/dL at their final visit compared to placebo (95% CI 13.8 to 343.9, 95% CI 16.0 to 405.5), respectively; with an absolute treatment benefit of 75% and 87% (95% CI 68 to 80% and 81 to 91%), respectively. Total discontinuation rates were significantly higher in the febuxostat 80 mg group compared to placebo (RR 1.4; 95% CI 1.0 to 2.0, absolute risk increase 11%; 95% CI 3 to 19%). No other differences were observed.
When comparing allopurinol to febuxostat at 24 to 52 weeks, the number of gout flares was not significantly different between the two groups, except for febuxostat 240 mg (RR 2.3; 95% CI 1.7 to 3.0). Patients on febuxostat 40 mg showed no statistically significant differences in benefits or harms. Patients on febuxostat 80 mg and 120 mg were 1.8 and 2.2 times more likely to achieve serum uric acid levels < 6.0 mg/dL at their final visit (95% CI 1.6 to 2.2, 95% CI 1.9 to 2.5) with an absolute treatment benefit of 29% and 44% (95% CI 25% to 33%, 95% CI 38% to 50%), respectively, at 24 to 52 weeks. Total discontinuation rates were higher for febuxostat 80 mg and 120 mg compared to allopurinol (RR 1.5; 95% CI 1.2 to 1.8, absolute risk increase 11%; 95% CI 6% to 16%; and RR 2.6; 95% CI 2.0 to 3.3, absolute risk increase 20%; 95% CI 3% to 14%, respectively). Discontinuations due to adverse events were similar across groups. Total adverse events were lower for febuxostat 80 mg and 120 mg compared with allopurinol (RR 0.93; 95% CI 0.87 to 0.99, absolute risk increase 6%; 95% CI 0.7% to 11%; and RR 0.90; 95% CI 0.84 to 0.96, absolute risk increase 8%; 95% CI 3% to 13%, respectively). No other relevant differences were noted.
After 3 years of follow-up there were no statistically significant differences regarding effectiveness and harms between febuxostat 80 mg or 120 mg and allopurinol groups (adverse event rate per 100 patient-years 227, 216, and 246, respectively).
Authors’ conclusions
Although the incidence of gout flares requiring treatment may be increased in patients taking febuxostat compared to placebo or allopurinol during early treatment, no such increase in gout flares was observed in the long-term follow-up study when compared to allopurinol. Febuxostat at any dose was shown to be beneficial in achieving serum uric acid levels < 6.0 mg/dL and reducing serum uric acid levels in the period from baseline to final visit when compared to placebo and to allopurinol. However, the grade of evidence ranged from low to high, which indicates that further research is needed.
doi:10.1002/14651858.CD008653.pub2
PMCID: PMC4058893  PMID: 23152264
Allopurinol [adverse effects, therapeutic use]; Chronic Disease; Gout [blood*drug therapy]; Gout Suppressants [adverse effects*therapeutic use]; Hyperuricemia [drug therapy]; Randomized Controlled Trials as Topic; Thiazoles [adverse effects*therapeutic use]; Female; Humans; Male
3.  Hypouricemic effect and safety of febuxostat used for prevention of tumor lysis syndrome 
SpringerPlus  2014;3:501.
Purpose
We evaluated the efficacy and safety of febuxostat, a non-purine xanthine oxidase inhibitor, used for prevention of hyperuricemia associated with tumor lysis syndrome (TLS).
Methods
Records of adult patients with newly diagnosed or relapsed hematologic malignancies who received febuxostat within 7 days before initiation of chemotherapy were retrieved retrospectively at a single institute. The changes in serum uric acid levels from before and 7 days after initiation of febuxostat were evaluated and compared with the historical control group of patients who received allopurinol. We also evaluated non-hematological adverse events during the study period.
Results
A total of 78 patients’ records were analyzed, 38 in the febuxostat group and 39 in the allopurinol group. There were no significant differences in the incidence of treatment failure, defined as development of clinical TLS or receiving rasburicase, between the febuxostat and allopurinol group (5.2% vs 5.1%, P>0.99). The mean serum uric acid levels were significantly decreased, compared to the baseline (5.6 ± 2.1 mg/dL), at 7 days after initiation of febuxostat (3.1 ± 1.5 mg/dL, last observation carried forward, P<0.001). There were no statistically significant differences in the percent change in the serum uric acid levels between the 40 mg/day febuxostat and the 300 mg/day allopurinol groups (P = 0.57). Grade 3–4 liver dysfunctions were observed in both the febuxostat and allopurinol groups, without significant differences in incidence between the two groups (2.6% vs 5.1%, P>0.99). Neither gout flare nor skin rash occurred in any patients.
Conclusions
Febuxostat is feasible for prevention of hyperuricemia associated with TLS.
doi:10.1186/2193-1801-3-501
PMCID: PMC4164671  PMID: 25279293
Febuxostat; Allopurinol; Hyperuricemia; Tumor lysis syndrome; Cancer chemotherapy
4.  The urate-lowering efficacy and safety of febuxostat in the treatment of the hyperuricemia of gout: the CONFIRMS trial 
Introduction
The purpose of this study was to compare urate-lowering (UL) efficacy and safety of daily febuxostat and allopurinol in subjects with gout and serum urate (sUA) ≥ 8.0 mg/dL in a six-month trial.
Methods
Subjects (n = 2,269) were randomized to febuxostat 40 mg or 80 mg, or allopurinol 300 mg (200 mg in moderate renal impairment). Endpoints included the proportion of all subjects with sUA <6.0 mg/dL and the proportion of subjects with mild/moderate renal impairment and sUA <6.0 mg/dL. Safety assessments included blinded adjudication of each cardiovascular (CV) adverse event (AE) and death.
Results
Comorbidities included: renal impairment (65%); obesity (64%); hyperlipidemia (42%); and hypertension (53%). In febuxostat 40 mg, febuxostat 80 mg, and allopurinol groups, primary endpoint was achieved in 45%, 67%, and 42%, respectively. Febuxostat 40 mg UL was statistically non-inferior to allopurinol, but febuxostat 80 mg was superior to both (P < 0.001). Achievement of target sUA in subjects with renal impairment was also superior with febuxostat 80 mg (72%; P < 0.001) compared with febuxostat 40 mg (50%) or allopurinol (42%), but febuxostat 40 mg showed greater efficacy than allopurinol (P = 0.021). Rates of AEs did not differ across treatment groups. Adjudicated (APTC) CV event rates were 0.0% for febuxostat 40 mg and 0.4% for both febuxostat 80 mg and allopurinol. One death occurred in each febuxostat group and three in the allopurinol group.
Conclusions
Urate-lowering efficacy of febuxostat 80 mg exceeded that of febuxostat 40 mg and allopurinol (300/200 mg), which were comparable. In subjects with mild/moderate renal impairment, both febuxostat doses were more efficacious than allopurinol and equally safe. At the doses tested, safety of febuxostat and allopurinol was comparable.
Clinical Trial Registration
NCT00430248
doi:10.1186/ar2978
PMCID: PMC2888216  PMID: 20370912
5.  The efficacy and safety of febuxostat for urate lowering in gout patients ≥65 years of age 
BMC Geriatrics  2012;12:11.
Background
The incidence of gout rises with increasing age. Management of elderly (≥65 years) gout patients can be challenging due to high rates of comorbidities, such as renal impairment and cardiovascular disease, and concomitant medication use. However, there is little data specifically addressing the efficacy and safety of available urate-lowering therapies (ULT) in the elderly. The objective of this post hoc analysis was to examine the efficacy and safety of ULT with febuxostat or allopurinol in a subset of elderly subjects enrolled in the CONFIRMS trial.
Methods
Hyperuricemic (serum urate [sUA] levels ≥ 8.0 mg/dL) gout subjects were enrolled in the 6-month, double-blind, randomized, comparative CONFIRMS trial and randomized, 1:1:1, to receive febuxostat, 40 mg or 80 mg, or allopurinol (200 mg or 300 mg based on renal function) once daily. Flare prophylaxis was provided throughout the study duration.
Study endpoints were the percent of elderly subjects with sUA <6.0 mg/dL at the final visit, overall and by renal function status, percent change in sUA from baseline to final visit, flare rates, and rates of adverse events (AEs).
Results
Of 2,269 subjects enrolled, 374 were elderly. Febuxostat 80 mg was significantly more efficacious (82.0%) than febuxostat 40 mg (61.7%; p < 0.001) or allopurinol (47.3%; p < 0.001) for achieving the primary efficacy endpoint. Febuxostat 40 mg was also superior to allopurinol in this population (p = 0.029). In subjects with mild-to-moderate renal impairment, significantly greater ULT efficacy was observed with febuxostat 40 mg (61.6%; p = 0.028) and febuxostat 80 mg (82.5%; p < 0.001) compared to allopurinol 200/300 mg (46.9%). Compared to allopurinol 200/300 mg, the mean percent change in sUA from baseline was significantly greater for both febuxostat 80 mg (p < 0.001) and febuxostat 40 mg (p = 0.011) groups. Flare rates declined steadily in all treatment groups. Rates of AEs were low and comparable across treatments.
Conclusions
These data suggest that either dose of febuxostat is superior to commonly prescribed fixed doses of allopurinol (200/300 mg) in subjects ≥65 years of age with high rates of renal dysfunction. In addition, in this high-risk population, ULT with either drug was well tolerated.
Trial registration
clinicaltrials.gov NCT#00430248
doi:10.1186/1471-2318-12-11
PMCID: PMC3368715  PMID: 22436129
6.  African American patients with gout: efficacy and safety of febuxostat vs allopurinol 
Background
African Americans are twice as likely as Caucasians to develop gout, but they are less likely to be treated with urate-lowering therapy (ULT). Furthermore, African Americans typically present with more comorbidities associated with gout, such as hypertension, obesity, and renal impairment. We determined the efficacy and safety of ULT with febuxostat or allopurinol in African American subjects with gout and associated comorbidities and in comparison to Caucasian gout subjects.
Methods
This is a secondary analysis of the 6-month Phase 3 CONFIRMS trial. Eligible gouty subjects with baseline serum urate (sUA) ≥ 8.0 mg/dL were randomized 1:1:1 to receive febuxostat 40 mg, febuxostat 80 mg, or allopurinol (300 mg or 200 mg depending on renal function) daily. All subjects received gout flare prophylaxis. Primary efficacy endpoint was the proportion of subjects in each treatment group with sUA < 6.0 mg/dL at the final visit. Additional endpoints included the proportion of subjects with mild or with moderate renal impairment who achieved a target sUA < 6.0 mg/dL at final visit. Adverse events (AEs) were recorded throughout the study.
Results
Of the 2,269 subjects enrolled, 10.0% were African American and 82.1% were Caucasian. African American subjects were mostly male (89.5%), obese (BMI ≥ 30 kg/m2; 67.1%), with mean baseline sUA of 9.8 mg/dL and mean duration of gout of 10.4 years. The proportions of African American subjects with a baseline history of diabetes, renal impairment, or cardiovascular disease were significantly higher compared to Caucasians (p < 0.001). ULT with febuxostat 80 mg was superior to both febuxostat 40 mg (p < 0.001) and allopurinol (p = 0.004). Febuxostat 40 mg was comparable in efficacy to allopurinol. Significantly more African American subjects with mild or moderate renal impairment achieved sUA < 6.0 mg/dL in the febuxostat 80 group than in either the febuxostat 40 mg or allopurinol group (p < 0.05). Efficacy rates in all treatment groups regardless of renal function were comparable between African American and Caucasian subjects, as were AE rates.
Conclusions
In African American subjects with significant comorbidities, febuxostat 80 mg is significantly more efficacious than either febuxostat 40 mg or allopurinol 200/300 mg. Febuxostat was well tolerated in this African American population.
Please see related article: http://www.biomedcentral.com/1741-7015/10/15
doi:10.1186/1471-2474-13-15
PMCID: PMC3317813  PMID: 22316106
7.  Gout 
BMJ Clinical Evidence  2011;2011:1120.
Introduction
Gout affects about 5% of men and 1% of women, with up to 80% of people experiencing a recurrent attack within 3 years.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for acute gout? What are the effects of treatments to prevent gout in people with prior acute episodes? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2010 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 16 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review, we present information relating to the effectiveness and safety of the following interventions: colchicine, corticosteroids, corticotropin (ACTH), non-steroidal anti-inflammatory drugs (NSAIDs), sulfinpyrazone, xanthine oxidase inhibitors, advice to lose weight, advice to reduce alcohol intake, and advice to reduce dietary intake of purines.
Key Points
Gout is characterised by deposition of urate crystals, causing acute monoarthritis and crystal deposits (tophi) in the skin. Gout affects about 5% of men and 1% of women, with up to 80% of people experiencing a recurrent attack within 3 years.Diagnosis is usually clinical, supported by presence of hyperuricaemia.Risk factors are those associated with hyperuricaemia, including: older age; non-white ethnicity; obesity; consumption of alcohol, meat, and fish; and use of diuretics.Hyperuricaemia may be associated with an increased risk of cardiovascular events; we don't know whether it is an independent risk factor.
We don't know whether NSAIDs reduce pain and tenderness in an acute attack of gout, although they are commonly used in clinical practice. They are associated with increased risks of gastrointestinal, and possible cardiovascular, adverse effects. Indometacin is widely used to treat acute gout despite the absence of RCT evidence of benefit. Etoricoxib is as effective as indometacin with reduced risks of gastrointestinal adverse effects.
Colchicine may be more effective than placebo at improving symptoms in acute gout. Its use is limited by the high incidence of adverse effects; although these may be reduced with low-dose colchicine regimens. Low-dose colchicine may be as effective at reducing pain in gout and may produce fewer adverse effects than high-dose colchicine.
We don't know whether intra-articular or parenteral corticosteroids, or corticotropin (ACTH), improve symptoms in acute gout. Oral corticosteroids seem as effective as NSAIDs and may have fewer short-term adverse events.
We don't know whether colchicine prevents attacks of gout in people with prior episodes, but it may reduce the risk of an attack in a person starting allopurinol treatment.
We don't know whether advice to lose weight or reduce alcohol or dietary purine intake prevents further attacks of gout.
We don't know whether sulfinpyrazone reduces the risk of recurrent attacks compared with placebo or other treatments.
We don't know whether xanthine oxidase inhibitors reduce the risk of recurrent attacks in the long term when compared with placebo or other treatments. Higher doses of febuxostat may increase the risks of gout attacks within the first 8 weeks of treatment compared with placebo, and compared with allopurinol.
PMCID: PMC3275296  PMID: 21575286
8.  Management of hyperuricemia in gout: focus on febuxostat 
Gout is the most common inflammatory arthritis in an elderly population, and can be diagnosed with absolute certainty by polarization microscopy. However, diagnosis may be challenging because atypical presentations are more common in the elderly. Management of hyperuricemia in the elderly with gout requires special consideration because of co-medication, contra-indications, and risk of adverse reactions. Urate-lowering agents include allopurinol and uricosuric agents. These also must be used sensibly in the elderly, especially when renal function impairment is present. However, if used at the lowest dose that maintains the serum urate level below 5.0 to 6.0 mg/dL (0.30 to 0.36 mmol/L), the excess urate in the body will eventually be eliminated, acute flares will no longer occur, and tophi will resolve. Febuxostat, a new xanthine oxidase inhibitor, is welcomed, as few alternatives for allopurinol are available. Its pharmacokinetics and pharmacodynamics are not significantly altered in patients with moderate renal function or hepatic impairment. Its antihyperuricemic efficacy at 80 to 120 mg/day is better than “standard dosage” allopurinol (300 mg/day). Long-term safety data and efficacy data on tophus diminishment and reduction of gout flares have recently become available. Febuxostat may provide an important option in patients unable to use allopurinol, or refractory to allopurinol.
PMCID: PMC2817937  PMID: 20169038
aging; febuxostat; hyperuricemia; gout; pharmacotherapy; xanthine oxidase
9.  Urate Lowering Therapy with Febuxostat in Daily Practice—A Multicentre, Open-Label, Prospective Observational Study 
Introduction. Febuxostat, a novel xanthine oxidase inhibitor for the treatment of symptomatic hyperuricemia, showed superiority over allopurinol in the reduction of serum uric acid levels in pivotal studies. Whether this holds true the FORTE (febuxostat in the oral urate lowering treatment: effectiveness and safety) study was conducted to evaluate treatment with febuxostat under daily practice conditions. Materials/Methods. The multicentre, open-label, and prospective observational study was conducted in 1,690 German medical practices from 9/2010 to 5/2011. Safety and efficacy data were assessed at baseline and week 4. Results. Data from 5,592 gout patients (72.6% male, mean age 63.7 years) were collected. Under urate lowering treatment with febuxostat mean serum uric acid levels decreased significantly from 8.9 ± 1.9 mg/dL (534.0 ± 114.6 μmol/L) at baseline to 6.2 ± 2.5 mg/dL (372.0 ± 150.0 μmol/L) at week 4. 67% which reached the mean uric acid target (6.1 ± 1.0 mg/dL [366.0 ± 59.4 μmol/L]). Only 43.1% of patients received concomitant flare prophylaxis. A total of 178 adverse events (mostly gout flares) were reported in 152 patients (2.6%). Conclusion. Febuxostat lowers serum uric acid levels effectively in routine clinical practice. Overall, treatment with febuxostat in both available dosages (80 mg/120 mg) was safe and well tolerated.
doi:10.1155/2014/123105
PMCID: PMC4167949  PMID: 25276138
10.  Clinical and health care use characteristics of patients newly prescribed allopurinol, febuxostat and colchicine for gout 
Arthritis care & research  2013;65(12):2008-2014.
Background
Gout is a common inflammatory arthritis with the increasing prevalence in the developed countries. It is well-known that many patients with gout have significant comorbidities and high health care utilization.
Methods
Using US insurance claims data (2009–2011), a population-based cohort study was conducted to describe clinical characteristics and health care utilization patterns in patients with gout newly prescribed allopurinol, febuxostat or colchicine.
Results
There were 25,051 allopurinol, 4,288 febuxostat and 6,238 colchicine initiators. Mean age was 53 years and 83%–87% were male. More than half of patients had hypertension and hyperlipidemia, 20% had diabetes and 10% cardiovascular disease. The mean uric acid level (mg/dl) was similar at baseline ranging from 8.1 to 8.5 across the groups. Compared to allopurinol or colchicine initiators, febuxostat initiators had more comorbidities and greater health care uses including outpatient, inpatient or emergency room visits, both at baseline and during the follow-up. Use of gout related drugs, such as opioids, steroids and non-steroidal anti-inflammatory drugs, was most common in febuxostat and least common in colchicine initiators. The median daily dose at both start and end of treatment was 300mg for allopurinol, 40mg for febuxostat, and 1.2mg for colchicine. The dosage of allopurinol and febuxostat was rarely increased during the follow-up.
Conclusion
Patients who started allopurinol, febuxostat or colchicine for gout generally had hyperuricemia and multiple comorbidities. Febuxostat initiators had more comorbidities and greater use of health care resources and gout-related drugs than other groups. Overall, the dosages of allopurinol or febuxostat remained unchanged over time.
doi:10.1002/acr.22067
PMCID: PMC4096791  PMID: 23861232
gout; allopurinol; febuxostat; colchicine
11.  Gout  
BMJ Clinical Evidence  2008;2008:1120.
Introduction
Gout affects about 5% of men and 1% of women, with up to 80% of people experiencing a recurrent attack within 3 years.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for acute gout? What are the effects of treatments to prevent gout in people with prior acute episodes? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2008 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 21 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: colchicine, corticosteroids, corticotrophin (ACTH), non-steroidal anti-inflammatory drugs (NSAIDs), sulfinpyrazone, xanthine oxidase inhibitors, advice to lose weight, advice to reduce alcohol intake, advice to reduce dietary intake of purines.
Key Points
Gout is characterised by deposition of urate crystals, causing acute monoarthritis and crystal deposits (tophi) in the skin. Gout affects about 5% of men and 1% of women, with up to 80% of people experiencing a recurrent attack within 3 years.Diagnosis is usually clinical, supported by signs of hyperuricaemia.Risk factors are those associated with increased serum urate concentrations, including: older age; non-white ethnicity; obesity; consumption of alcohol, meat, and fish; and use of diuretics.Hyperuricaemia may be associated with an increased risk of cardiovascular events; we don't know whether it is an independent risk factor.
We don't know whether NSAIDs reduce pain and tenderness in an acute attack of gout, although they are commonly used in clinical practice. They are associated with increased risks of gastrointestinal, and possible cardiovascular, adverse effects. Indometacin is widely used to treat acute gout despite the absence of RCT evidence of benefit. Etoricoxib is as effective as indometacin with reduced risks of gastrointestinal adverse effects.
Although it has been widely used for many years, we don't know whether oral colchicine improves symptoms in acute gout. Its use is limited by the high incidence of adverse effects.
We don't know whether intra-articular, parenteral or oral corticosteroids, or corticotropin (ACTH), improve symptoms in acute gout.
We don't know whether colchicine prevents attacks of gout in people with prior episodes, but it may reduce the risk of an attack in a person starting allopurinol treatment. We don't know whether advice to lose weight or reduce alcohol or dietary purine intake prevents further attacks of gout.We don't know whether allopurinol or febuxostat, orsulfinpyrazone reduce the risk of recurrent attacks compared with placebo or other treatments.
PMCID: PMC2907998  PMID: 19445790
12.  Diabetes and gout: efficacy and safety of febuxostat and allopurinol 
Diabetes, Obesity & Metabolism  2013;15(11):1049-1055.
Aim Assess influences of demographics and co-morbidities of gout patients with or without diabetes on safety and efficacy of urate-lowering agents.
Methods Post-hoc analysis of 312 diabetic and 1957 non-diabetic gout patients [baseline serum urate levels (sUA) ≥8.0 mg/dl] enrolled in a 6-month randomized controlled trial comparing urate-lowering efficacy (ULE) and safety of daily xanthine oxidase inhibitors (XOIs) febuxostat (40 mg or 80 mg) and allopurinol (200 mg or 300 mg). We compared baseline demographic, gout and co-morbid characteristics, ULE, and safety of XOI treatment in diabetic and non-diabetic gout patients. ULE was measured by the proportion of diabetic and non-diabetic patients in each treatment group achieving final visit sUA < 6.0 mg/dl. Safety was monitored throughout the trial.
Results Diabetic gout patients were older, more frequently female, and had longer gout duration. Co-morbidities were more frequent among diabetic patients: cardiovascular disease; impaired renal function; hyperlipidemia; and obesity (body mass index >30 kg/m2) (p < 0.001 for all comparisons). Febuxostat 80 mg ULE exceeded that of febuxostat 40 mg or allopurinol (p < 0.050) at all levels of renal function, achieving sUA goal range in the majority of diabetic and non-diabetic patients. Diabetics and non-diabetics reported self-limiting diarrhoea and URIs as the most common adverse events.
Conclusions Despite higher co-morbidity rates in diabetic patients, febuxostat and allopurinol were safe in both groups at the doses tested. Febuxostat 80 mg achieved sUA <6.0 mg/dl more often than febuxostat 40 mg or allopurinol at commonly prescribed doses.
doi:10.1111/dom.12135
PMCID: PMC3902994  PMID: 23683134
clinical trial; diabetes mellitus; drug utilisation
13.  Switching from allopurinol to febuxostat for the treatment of hyperuricemia and renal function in patients with chronic kidney disease 
Clinical Rheumatology  2014;33(11):1643-1648.
Hyperuricemia is a frequent complication of chronic kidney disease (CKD). Febuxostat is a novel xanthine oxidase inhibitor that is metabolized by many metabolic pathways in the kidney and the liver. We performed a 1-year cohort study of 73 hyperuricemic patients who had an estimated glomerular filtration rate (eGFR) below 45 ml/min and were being treated with urate-lowering therapy. In 51 patients, treatment was changed from allopurinol to febuxostat, and the other 22 patients were continued on allopurinol. The serum levels of uric acid (UA) level, creatinine, and other biochemical parameters were measured at baseline and after 3, 6, 9, and 12 months of treatment. The serum UA levels significantly decreased from 6.1 ± 1.0 to 5.7 ± 1.2 mg/dl in the febuxostat group and significantly increased from 6.2 ± 1.1 to 6.6 ± 1.1 mg/dl in the allopurinol group. The eGFR decreased 27.3 to 25.7 ml/min in the febuxostat group and from 26.1 to 19.9 ml/min in the allopurinol group. The switch from allopurinol to febuxostat was significantly associated with the changes in eGFR according to a multiple regression analysis (β = −0.22145, P < 0.05). Febuxostat reduced the serum UA levels and slowed the progression of renal disease in our CKD cohort in comparison with allopurinol.
doi:10.1007/s10067-014-2745-5
PMCID: PMC4192559  PMID: 25048744
Allopurinol; Chronic kidney disease; eGFR; Febuxostat; Hyperuricemia; Uric acid
14.  Efficacy and safety of febuxostat in elderly female patients 
Background
Maintenance of low serum urate levels is important for the management of gout. Achieving the recommended serum urate levels of less than 6.0 mg/dL is difficult in elderly (65 years of age or older) patients with renal impairment. Xanthine oxidase inhibitors allopurinol and febuxostat are used for this purpose. Although febuxostat had been shown to be efficacious in elderly patients, its safety and efficacy in elderly female patients with hyperuricemia remain unclear.
Objective
The aim of this study was to assess the efficacy and safety of febuxostat in elderly female patients.
Methods
We studied a retrospective cohort study. The study included elderly Japanese patients (65 years of age or older) who were treated with febuxostat at Fujita Health University Hospital from January 2012 to December 2013. The treatment goal was defined as achievement of serum urate levels of 6.0 mg/dL or lower within 16 weeks; this was the primary endpoint in the present study. Adverse events of febuxostat were defined as more than twofold increases in Common Terminology Criteria for adverse events scores from baseline.
Results
We evaluated 82 patients treated with febuxostat during the observation period and classified them into male (n=53) and female (n=29) groups. The mean time to achievement of the treatment goal was significantly shorter in the female group (53 days) than in the male group (71 days). There were no significant differences in adverse events between the 2 groups.
Conclusion
Our findings suggest that the efficacy of febuxostat in elderly female patients is superior to that in elderly male patients and that the safety is equivalent.
doi:10.2147/CIA.S70855
PMCID: PMC4158997  PMID: 25214776
febuxostat; elderly female patients; hyperuricemia
15.  Comparative effectiveness of urate lowering with febuxostat versus allopurinol in gout: analyses from large U.S. managed care cohort 
Introduction
To assess the comparative effectiveness of febuxostat and allopurinol in reducing serum urate (sUA) levels in a real-world U.S. managed care setting.
Methods
This retrospective study utilized 2009 to 2012 medical and pharmacy claims and laboratory data from a large U.S. commercial and Medicare Advantage health plan. Study patients had at least one medical claim with a diagnosis of gout, at least one filled prescription for febuxostat or allopurinol and at least one sUA measurement post-index prescription. Reduction in sUA was examined using propensity score-matched cohorts, matched on patient demographics (gender, age), baseline sUA, comorbidities, geographic region and insurance type.
Results
The study sample included 2,015 patients taking febuxostat and 14,025 taking allopurinol. At baseline, febuxostat users had a higher Quan-Charlson comorbidity score (0.78 vs. 0.53; P <0.001), but similar age and gender distribution. Mean (standard deviation (SD)) sUA level following propensity score matching among treatment-naïve febuxostat vs. allopurinol users (n = 873 each) were: pre-index sUA, 8.86 (SD, 1.79) vs. 8.72 (SD, 1.63; P = 0.20); and post-index sUA, 6.53 (SD, 2.01) vs. 6.71 (SD, 1.70; P = 0.04), respectively. A higher proportion of febuxostat users attained sUA goals of <6.0 mg/dl (56.9% vs. 44.8%; P <0.001) and <5.0 mg/dl (35.5% vs. 19.2%; P <0.001), respectively. Time to achieve sUA goals of <6.0 mg/dl (346 vs. 397 days; P <0.001) and <5.0 mg/dl was shorter in febuxostat vs. allopurinol users (431 vs. 478 days; P <0.001), respectively. Similar observations were made for overall propensity score-matched cohorts that included both treatment-naïve and current users (n = 1,932 each).
Conclusions
Febuxostat was more effective than allopurinol at the currently used doses (40 mg/day for febuxostat in 83% users and 300 mg/day or lower for allopurinol in 97% users) in lowering sUA in gout patients as demonstrated by post-index mean sUA level, the likelihood of and the time to achieving sUA goals.
Electronic supplementary material
The online version of this article (doi:10.1186/s13075-015-0624-3) contains supplementary material, which is available to authorized users.
doi:10.1186/s13075-015-0624-3
PMCID: PMC4427980  PMID: 25963969
Gout; Comparative effectiveness; Serum urate; Febuxostat; Allopurinol
16.  Protocol of the Febuxostat versus Allopurinol Streamlined Trial (FAST): a large prospective, randomised, open, blinded endpoint study comparing the cardiovascular safety of allopurinol and febuxostat in the management of symptomatic hyperuricaemia 
BMJ Open  2014;4(7):e005354.
Introduction
Gout affects 2.5% of the UK's adult population and is now the most common type of inflammatory arthritis. The long-term management of gout requires reduction of serum urate levels and this is most often achieved with use of xanthine oxidase inhibitors, such as allopurinol. Febuxostat is the first new xanthine oxidase inhibitor since allopurinol and was licensed for use in 2008. The European Medicines Agency requested a postlicensing cardiovascular safety study of febuxostat versus allopurinol, which has been named the Febuxostat versus Allopurinol Streamlined trial (FAST).
Methods and analysis
FAST is a cardiovascular safety study using the prospective, randomised, open, blinded endpoint design. FAST is recruiting in the UK and Denmark. Recruited patients are aged over 60 years, prescribed allopurinol for symptomatic hyperuricaemia and have at least one additional cardiovascular risk factor. After an allopurinol lead-in phase where the dose of allopurinol is optimised to achieve European League against Rheumatism (EULAR) urate targets (serum urate <357 µmol/L), patients are randomised to either continue optimal dose allopurinol or to use febuxostat. Patients are followed-up for an average of 3 years. The primary endpoint is first occurrence of the Anti-Platelet Trialists’ Collaboration (APTC) cardiovascular endpoint of non-fatal myocardial infarction, non-fatal stroke or cardiovascular death. Secondary endpoints are all cause mortality and hospitalisations for heart failure, unstable, new or worsening angina, coronary or cerebral revascularisation, transient ischaemic attack, non-fatal cardiac arrest, venous and peripheral arterial vascular thrombotic event and arrhythmia with no evidence of ischaemia. The primary analysis is a non-inferiority analysis with a non-inferiority upper limit for the HR for the primary outcome of 1.3.
Ethics and dissemination
FAST (ISRCTN72443728) has ethical approval in the UK and Denmark, and results will be published in a peer reviewed journal.
Trial Registration number
FAST is registered in the EU Clinical Trials Register (EUDRACT No: 2011-001883-23) and International Standard Randomised Controlled Trial Number Register (ISRCTN No: ISRCTN72443728).
doi:10.1136/bmjopen-2014-005354
PMCID: PMC4120410  PMID: 25011991
Cardiovascular Safety; Clinical Trial; Allopurinol; Febuxostat
17.  Efficacy and safety of febuxostat in the treatment of hyperuricemia in stable kidney transplant recipients 
Background
Post-transplant hyperuricemia (PTHU), defined as serum uric acid concentration ≥7.0 mg/dL or need for treatment with allopurinol or benzbromarone, reduces long-term allograft survival in kidney transplant recipients. Febuxostat, a new nonpurine selective xanthine oxidase inhibitor, is well tolerated in patients with moderate renal impairment. However, its efficacy and safety in kidney recipients with PTHU is unclear. We therefore assessed the efficacy and safety of febuxostat in stable kidney transplant recipients with PTHU.
Methods
Of 93 stable adult kidney transplant recipients, 51 were diagnosed with PTHU (PTHU group) and 42 were not (NPTHU group). Of the 51 patients with PTHU, 26 were treated with febuxostat (FX group) and 25 were not (NFX group), at the discretion of each attending physician. One-year changes in serum uric acid concentrations, rates of achievement of target uric acid (<6.0 mg/dL), estimated glomerular filtration rates in allografts, and adverse events were retrospectively analyzed in the FX, NFX, and NPTHU groups.
Results
The FX group showed significantly greater decreases in serum uric acid (−2.0±1.1 mg/dL versus 0.0±0.8 mg/dL per year, P<0.01) and tended to show a higher rate of achieving target uric acid levels (50% versus 24%; odds ratio 3.17 [95% confidence interval 0.96–10.5], P=0.08) than the NFX group. Although baseline allograft estimated glomerular filtration rates tended to be lower in the FX group than in the NFX group (40±14 mL/min/1.73 m2 versus 47±19 mL/min/1.73 m2), changes in allograft estimated glomerular filtration rate were similar (+1.0±4.9 mL/min/1.73 m2 versus −0.2±6.9 mL/min/1.73 m2 per year, P=0.50). None of the patients in the FX group experienced any severe adverse effects, such as pancytopenia or attacks of gout, throughout the entire study period. Nephrologists were more likely than urologists to start febuxostat in kidney transplant recipients with PTHU (69% versus 8%).
Conclusion
Treatment with febuxostat sufficiently lowered uric acid levels without severe adverse effects in stable kidney transplant recipients with PTHU.
doi:10.2147/DDDT.S56597
PMCID: PMC3933431  PMID: 24600205
post-transplant hyperuricemia; febuxostat; uric acid; chronic kidney disease
18.  Febuxostat: A Novel Agent for Management of Hyperuricemia in Gout 
Gout is a metabolic disorder characterized by elevated uric acid levels in the body, associated with painful arthritis, tophi and nephropathy. The most frequently used pharmacologic urate lowering strategies involve reducing urate production with a xanthine oxidase inhibitor and enhancing urinary excretion of uric acid with a uricosuric agent. Urate lowering agents are limited in number, availability and effectiveness. The emergence of a new medication, febuxostat, to lower serum urate levels is welcome as no new drug have been approved since the introduction of allopurinol, in 1964, and the drugs that are available have limitations owing to inefficacy or toxicity. Febuxostat is a novel, nonpurine selective inhibitor of xanthine oxidase, is a potential alternative to allopurinol for patients with hyperuricemia and gout.
doi:10.4103/0250-474X.100231
PMCID: PMC3480742  PMID: 23112391
Gout; hyperuricemia; xanthine oxidase inhibitor
19.  A Real-World Study of Switching From Allopurinol to Febuxostat in a Health Plan Database 
Journal of Clinical Rheumatology  2015;21(8):411-418.
Supplemental digital content is available in the text.
Objective
The objective of this study was to assess the real-world comparative effectiveness of continuing on allopurinol versus switching to febuxostat.
Methods
In a retrospective claims data study of enrollees in health plans affiliated with Optum, we evaluated patients from February 1, 2009, to May 31, 2012, with a gout diagnosis, a pharmacy claim for allopurinol or febuxostat, and at least 1 serum uric acid (SUA) result available during the follow-up period. Univariate and multivariable-adjusted analyses (controlling for patient demographics and clinical factors) assessed the likelihood of SUA lowering and achievement of target SUA of less than 6.0 mg/dL or less than 5.0 mg/dL in allopurinol continuers versus febuxostat switchers.
Results
The final study population included 748 subjects who switched to febuxostat from allopurinol and 4795 continuing users of allopurinol. The most common doses of allopurinol were 300 mg/d or less in 95% of allopurinol continuers and 93% of febuxostat switchers (prior to switching); the most common dose of febuxostat was 40 mg/d, in 77% of febuxostat switchers (after switching). Compared with allopurinol continuers, febuxostat switchers had greater (1) mean preindex SUA, 8.0 mg/dL versus 6.6 mg/dL (P < 0.001); (2) likelihood of postindex SUA of less than 6.0 mg/dL, 62.2% versus 58.7% (P = 0.072); (3) likelihood of postindex SUA of less than 5.0 mg/dL, 38.9% versus 29.6% (P < 0.001); and (4) decrease in SUA, 1.8 (SD, 2.2) mg/dL versus 0.4 (SD, 1.7) mg/dL (P < 0.001). In multivariable-adjusted analyses, compared with allopurinol continuers, febuxostat switchers had significantly higher likelihood of achieving SUA of less than 6.0 mg/dL (40% higher) and SUA of less than 5.0 mg/dL (83% higher).
Conclusions
In this “real-world” setting, many patients with gout not surprisingly were not treated with maximum permitted doses of allopurinol. Patients switched to febuxostat were more likely to achieve target SUA levels than those who continued on generally stable doses of allopurinol.
doi:10.1097/RHU.0000000000000322
PMCID: PMC4654265  PMID: 26580304
comparative effectiveness; gout; medication switching; serum urate; urate-lowering therapy
20.  Efficacy and Safety of Febuxostat in Patients with Hyperuricemia and Gout 
The past decade has witnessed an exponential increase of novel therapeutic modalities for a variety of rheumatic disorders, including gout. During the past few years two novel therapeutic agents have been approved by the US Food and Drug Administration for the treatment of hyperuricemia in patients with gout, one of them being febuxostat, a nonpurine selective inhibitor of xanthine oxidase. Review of its pharmacokinetics and pharmacodynamics, efficacy and safety profile, and use in gout patients with comorbid conditions reveals that age and gender have no clinically significant effect and dose adjustments based on age or gender are not required. In addition, febuxostat can be used in patients with mild-to-moderate renal or hepatic involvement. Its overall efficacy and safety profile is comparable and, in certain subsets such as gout patients with mild and moderate renal insufficiency, is superior to allopurinol.
doi:10.1177/1759720X11416405
PMCID: PMC3383531  PMID: 22870483
hyperuricemia; febuxostat; gout; safety profile; efficacy profile
21.  New and improved strategies for the treatment of gout 
The Western world appears to be in the midst of the third great gout epidemic of all time. In this century, gout is increasing in prevalence despite an increased understanding of its risk factors and pathophysiology, and the availability of reasonably effective treatment. The main cultural factors responsible for this appear to be diet, obesity, ethanol use and medications. Excess fructose consumption is a newly recognized modifiable risk factor. The debate has been renewed concerning hyperuricemia as an independent risk factor for renal insufficiency and cardiovascular disease. Prevention is still rooted in lifestyle choices. Existing treatments have proven to be unsatisfactory in many patients with comorbidities. New treatments are available today and on the horizon for tomorrow, which offer a better quality of life for gout sufferers. These include febuxostat, a nonpurine inhibitor of xanthine oxidase with a potentially better combination of efficacy and safety than allopurinol, and investigational inhibitors of URAT-1, an anion exchanger in the proximal tubule that is critical for uric acid homeostasis. New abortive treatments include interleukin-1 antagonists that can cut short the acute attack in 1 to 2 days in persons who cannot take nonsteroidal anti-inflammatory drugs, colchicine or corticosteroids. Lastly, newer formulations of uricase have the ability to dissolve destructive tophi over weeks or months in patients who cannot use currently available hypouricemic agents. Diagnostically, ultrasound and magnetic resonance imaging offer advanced ways to diagnose gout noninvasively, and just as importantly, a way to follow the progress of tophus dissolution. The close association of hyperuricemia with metabolic syndrome, hypertension and renal insufficiency ensures that nephrologists will see increasing numbers of gout-afflicted patients.
doi:10.2147/IJNRD.S6048
PMCID: PMC3108771  PMID: 21694941
hyperuricemia; metabolic syndrome; tophi; colchicine; febuxostat; allopurinol
22.  EULAR evidence based recommendations for gout. Part II: Management. Report of a task force of the EULAR Standing Committee For International Clinical Studies Including Therapeutics (ESCISIT) 
Annals of the Rheumatic Diseases  2006;65(10):1312-1324.
Objective
To develop evidence based recommendations for the management of gout.
Methods
The multidisciplinary guideline development group comprised 19 rheumatologists and one evidence based medicine expert representing 13 European countries. Key propositions on management were generated using a Delphi consensus approach. Research evidence was searched systematically for each proposition. Where possible, effect size (ES), number needed to treat, relative risk, odds ratio, and incremental cost‐effectiveness ratio were calculated. The quality of evidence was categorised according to the level of evidence. The strength of recommendation (SOR) was assessed using the EULAR visual analogue and ordinal scales.
Results
12 key propositions were generated after three Delphi rounds. Propositions included both non‐pharmacological and pharmacological treatments and addressed symptomatic control of acute gout, urate lowering therapy (ULT), and prophylaxis of acute attacks. The importance of patient education, modification of adverse lifestyle (weight loss if obese; reduced alcohol consumption; low animal purine diet) and treatment of associated comorbidity and risk factors were emphasised. Recommended drugs for acute attacks were oral non‐steroidal anti‐inflammatory drugs (NSAIDs), oral colchicine (ES = 0.87 (95% confidence interval, 0.25 to 1.50)), or joint aspiration and injection of corticosteroid. ULT is indicated in patients with recurrent acute attacks, arthropathy, tophi, or radiographic changes of gout. Allopurinol was confirmed as effective long term ULT (ES = 1.39 (0.78 to 2.01)). If allopurinol toxicity occurs, options include other xanthine oxidase inhibitors, allopurinol desensitisation, or a uricosuric. The uricosuric benzbromarone is more effective than allopurinol (ES = 1.50 (0.76 to 2.24)) and can be used in patients with mild to moderate renal insufficiency but may be hepatotoxic. When gout is associated with the use of diuretics, the diuretic should be stopped if possible. For prophylaxis against acute attacks, either colchicine 0.5–1 mg daily or an NSAID (with gastroprotection if indicated) are recommended.
Conclusions
12 key recommendations for management of gout were developed, using a combination of research based evidence and expert consensus. The evidence was evaluated and the SOR provided for each proposition.
doi:10.1136/ard.2006.055269
PMCID: PMC1798308  PMID: 16707532
EULAR; gout; guidelines; treatment
23.  SLC2A9 Is a High-Capacity Urate Transporter in Humans 
PLoS Medicine  2008;5(10):e197.
Background
Serum uric acid levels in humans are influenced by diet, cellular breakdown, and renal elimination, and correlate with blood pressure, metabolic syndrome, diabetes, gout, and cardiovascular disease. Recent genome-wide association scans have found common genetic variants of SLC2A9 to be associated with increased serum urate level and gout. The SLC2A9 gene encodes a facilitative glucose transporter, and it has two splice variants that are highly expressed in the proximal nephron, a key site for urate handling in the kidney. We investigated whether SLC2A9 is a functional urate transporter that contributes to the longstanding association between urate and blood pressure in man.
Methods and Findings
We expressed both SLC2A9 splice variants in Xenopus laevis oocytes and found both isoforms mediate rapid urate fluxes at concentration ranges similar to physiological serum levels (200–500 μM). Because SLC2A9 is a known facilitative glucose transporter, we also tested whether glucose or fructose influenced urate transport. We found that urate is transported by SLC2A9 at rates 45- to 60-fold faster than glucose, and demonstrated that SLC2A9-mediated urate transport is facilitated by glucose and, to a lesser extent, fructose. In addition, transport is inhibited by the uricosuric benzbromarone in a dose-dependent manner (Ki = 27 μM). Furthermore, we found urate uptake was at least 2-fold greater in human embryonic kidney (HEK) cells overexpressing SLC2A9 splice variants than nontransfected kidney cells. To confirm that our findings were due to SLC2A9, and not another urate transporter, we showed that urate transport was diminished by SLC2A9-targeted siRNA in a second mammalian cell line. In a cohort of men we showed that genetic variants of SLC2A9 are associated with reduced urinary urate clearance, which fits with common variation at SLC2A9 leading to increased serum urate. We found no evidence of association with hypertension (odds ratio 0.98, 95% confidence interval [CI] 0.9 to 1.05, p > 0.33) by meta-analysis of an SLC2A9 variant in six case–control studies including 11,897 participants. In a separate meta-analysis of four population studies including 11,629 participants we found no association of SLC2A9 with systolic (effect size −0.12 mm Hg, 95% CI −0.68 to 0.43, p = 0.664) or diastolic blood pressure (effect size −0.03 mm Hg, 95% CI −0.39 to 0.31, p = 0.82).
Conclusions
This study provides evidence that SLC2A9 splice variants act as high-capacity urate transporters and is one of the first functional characterisations of findings from genome-wide association scans. We did not find an association of the SLC2A9 gene with blood pressure in this study. Our findings suggest potential pathogenic mechanisms that could offer a new drug target for gout.
Editors' Summary
Background.
Blood is continually pumped around the human body to deliver the chemicals needed to keep the body's cells alive and to take cellular waste products to the kidneys where they are filtered out of the blood and excreted in the urine. In healthy people, the levels of nutrients and waste products in serum (the liquid part of blood) fall within “normal” ranges but in ill people these levels can be very different. For example, serum uric acid (urate) levels are usually increased in people with gout. In this arthritic condition, uric acid crystallizes in the joints (often those in the big toe) and causes swelling and intense pain. Increased serum urate levels, which are also associated with high blood pressure, diabetes, and several other important conditions, can be caused by eating food that is rich in chemicals called purines (for example, liver, dried beans, and port). The body also converts its own purines into uric acid so genetic variations in the enzymes involved in purine breakdown can alter serum urate levels, as can variations in the rate of urate removal from the body by the kidneys. Urinary urate excretion is controlled by urate transporters, proteins that carry urate into and out of the kidney cells. Uricosuric drugs, which are used to treat gout, reduce serum urate levels by inhibiting a urate transporter that reabsorbs urate from urine.
Why Was This Study Done?
Several urate transporters have already been identified but recently, using an approach called genome-wide association scanning, scientists found that some genetic variants of a human gene called SLC2A9 are more common in people with high serum urate levels than in people with normal levels. SLC2A9 encodes a glucose transporter (a protein that helps to move the sugar glucose through cell membranes) and is highly expressed in the kidney's main urate handling site. Given these facts, could SLC2A9 (the protein made from SLC2A9) be a urate transporter as well as a glucose transporter? In this study, the researchers investigate this possibility and also ask whether genetic variations in SLC2A9 might be responsible for the association between serum urate levels and high blood pressure.
What Did the Researchers Do and Find?
The researchers first expressed SLC2A9 in frog eggs, a type of cell that does not have its own urate transporter. They found that urate rapidly moved into eggs expressing SLC2A9 but not into control eggs, that SLC2A9 transported urate about 50 times faster than glucose, and that glucose stimulated SLC2A9-mediated urate transport. Similarly, overexpression of SLC2A9 in human embryonic kidney cells more than doubled their urate uptake. Conversely, when the researchers used a technique called RNA interference to reduce the expression of mouse SLC2A9 in mouse cells that normally makes this protein, urate transport was reduced. Next, the researchers looked at two small parts of SLC2A9 that vary between individuals (so-called single polynucleotide polymorphisms) in nearly 900 men who had had their serum urate levels and urinary urate excretion rates measured. They found that certain genetic variations at these two sites were associated with increased serum urate levels and decreased urinary urate excretion. Finally, the researchers used a statistical technique called meta-analysis to look for an association between one of the SLC2A9 gene variants and blood pressure. In two separate meta-analyses that together involved more than 20, 000 participants in several studies, there was no association between this gene variant and blood pressure.
What Do These Findings Mean?
Overall, these findings indicate that SLCA9 is a high capacity urate transporter and suggest that this protein plays an important part in controlling serum urate levels. They provide confirmation that common genetic variants in SLC2A9 affect serum urate levels to a marked degree, although they do not show exactly which genetic variant is responsible for increasing serum urate levels. They also provide important new insights into how the kidneys normally handle urate and suggest ways in which this essential process may sometimes go wrong. Thus, these findings could eventually lead to new treatments for gout and possibly for other diseases that are associated with increased serum urate levels.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050197.
The UK National Health Service Direct health encyclopedia provides detailed information for patients about gout
MedlinePlus provides links to many sources of information about gout (in English and Spanish), including “What is gout?”, an easy-to-read guide from the US National Institutes of Arthritis and Musculoskeletal and Skin Diseases
Wikipedia also has pages on gout, uric acid, and SCL2A9 (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The Arthritis Research Campaign also has information on gout
Mark Caulfield and colleagues show that theSLC2A9 gene, which encodes a facilitative glucose transporter, is also a high-capacity urate transporter.
doi:10.1371/journal.pmed.0050197
PMCID: PMC2561076  PMID: 18842065
24.  Linking uric acid metabolism to diabetic complications 
World Journal of Diabetes  2014;5(6):787-795.
Hyperuricemia have been thought to be caused by the ingestion of large amounts of purines, and prevention or treatment of hyperuricemia has intended to prevent gout. Xanthine dehydrogenase/xanthine oxidase (XDH/XO) is rate-limiting enzyme of uric acid generation, and allopurinol was developed as a uric acid (UA) generation inhibitor in the 1950s and has been routinely used for gout prevention since then. Serum UA levels are an important risk factor of disease progression for various diseases, including those related to lifestyle. Recently, other UA generation inhibitors such as febuxostat and topiroxostat were launched. The emergence of these novel medications has promoted new research in the field. Lifestyle-related diseases, such as metabolic syndrome or type 2 diabetes mellitus, often have a common pathological foundation. As such, hyperuricemia is often present among these patients. Many in vitro and animal studies have implicated inflammation and oxidative stress in UA metabolism and vascular injury because XDH/XO act as one of the major source of reactive oxygen species Many studies on UA levels and associated diseases implicate involvement of UA generation in disease onset and/or progression. Interventional studies for UA generation, not UA excretion revealed XDH/XO can be the therapeutic target for vascular injury and renal dysfunction. In this review, the relationship between UA metabolism and diabetic complications is highlighted.
doi:10.4239/wjd.v5.i6.787
PMCID: PMC4265865  PMID: 25512781
Uric acid; Xanthine dehydrogenase/xanthine oxidase; Diabetes mellitus; Diabetic complications; Xanthine oxidase inhibitor; Metabolism
25.  Can racial disparities in optimal gout treatment be reduced? evidence from a randomized trial 
BMC Medicine  2012;10:15.
There is a disproportionate burden of gout in African-Americans in the U.S. due to a higher disease prevalence and lower likelihood of receiving urate-lowering therapy (ULT), compared to Caucasians. There is an absence of strong data as to whether the response to ULT differs by race/ethnicity. BMC Musculoskeletal Disorders recently published a secondary analyses of the CONFIRMS trial, a large randomized controlled, double-blind trial of 2,269 gout patients. The authors reported that the likelihood of achieving the primary study efficacy end-point of achieving serum urate < 6 mg/dl was similar between African-Americans and Caucasians, for all three treatment arms (Febuxostat 40 mg and 80 mg and allopurinol 300/200 mg). More importantly, rates were similar in subgroups of patients with mild or moderate renal insufficiency. Adverse event rates were similar, as were the rates of gout flares. These findings constitute a convincing evidence to pursue aggressive ULT in gout patients, regardless of race/ethnicity. This approach will likely help to narrow the documented racial disparities in gout care.
Please see related article: http://www.biomedcentral.com/1471-2474/13/15
doi:10.1186/1741-7015-10-15
PMCID: PMC3337326  PMID: 22316088
Gout; Disparity; Race; treatment; Febuxostat; Allopurinol; randomized; African-American

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