Renoprotective effects of febuxostat compared with allopurinol in patients with hyperuricemia: A systematic review and meta-analysis.
ABSTRACT: Hyperuricemia is reported to be related to rapid progression of renal function in patients with chronic kidney disease (CKD). Allopurinol, a uric acid lowering agent, protects renal progression. However, it is not widely used in patients with CKD because of its serious adverse event. Febuxostat can be alternatively used for patients who are intolerable to allopurinol. We aimed to determine renoprotective effect and urate-lowering effect between the two drugs.We performed a systematic review and meta-analysis of randomized controlled trials to assess the effects of febuxostat compared to allopurinol in patients with hyperuricemia. MEDLINE, Embase, and Cochrane Library databases were searched to identify research publications.Four relevant publications were selected from among 3,815 studies. No significant differences were found in the changes in serum creatinine from baseline between the febuxostat and allopurinol groups. Changes in estimated glomerular filtration rate (eGFR) were observed between the two groups at 1 month (mean difference 1.65 mL/min/1.73 m2, 95% confidence interval [CI] 0.38, 2.91 mL/min/1.73 m2; heterogeneity ?2 = 1.25, I2 = 0%, P = 0.01); however, the changes in eGFR were not significantly different at 3 months. A significant difference did exist in the changes in albuminuria levels from baseline between the febuxostat and allopurinol groups (mean difference -80.47 mg/gCr, 95% CI -149.29, -11.64 mg/gCr; heterogeneity ?2 = 0.81, I2 = 0%, P = 0.02). A significant difference was also observed in the changes in serum uric acid from baseline between the febuxostat and allopurinol groups (mean difference -0.92 mg/dL, 95% CI -1.29, -0.56 mg/dL; heterogeneity ?2 = 6.24, I2 = 52%, P < 0.001).Febuxostat might be more renoprotective than allopurinol.
Project description:Whether the clinical trial treatment effect of urate-lowering therapy (ULT) in patient with chronic kidney disease (CKD) is generalizable to real-word settings is unclear. This study aimed to compare febuxostat with allopurinol for uric acid reduction and renal protection in patients with CKD. Adult CKD patients newly treated with ULT were identified using electronic health records from 2010 to 2015 from a large healthcare delivery system in Taiwan. Patients with renal replacement therapy or undergoing ULT for <3 months were excluded. Propensity score-matched cohort study design was conducted to compare outcomes between patients initiated with febuxostat or allopurinol therapy. Cox regression analyses were employed to compare the adjusted hazards ratio (aHR) of incident event of estimated glomerular filtration rate (eGFR) ? 30% decrease, and the difference in longitudinal changes in serum uric acid (SUA) and eGFR between groups was analyzed using linear mixed model. Overall, 1050 CKD patients who initiated febuxostat (n?=?525) or allopurinol (n?=?525) treatment were observed for 2.5 years. Compared with allopurinol, febuxostat use was associated with higher rate of patients maintaining SUA target <6?mg/dL in >80% of follow-up time with a reduction in mean SUA change. There were no significant differences in the mean eGFR changes over time between the febuxostat and allopurinol groups or in the risk of eGFR decline ?30% of baseline. Febuxostat was associated with greater reduction in SUA level than allopurinol in patients with CKD. However, febuxostat and allopurinol showed no difference in renal function changes during study follow-up. These findings require further investigation with long-term follow up in CKD patients with hyperuricemia.
Project description:INTRODUCTION:This 24-week randomized, double-blind, non-inferiority study compared the efficacy and safety of febuxostat, a xanthine oxidase inhibitor, with allopurinol using an up-titration method in hyperuricemic Chinese subjects with or without gout. METHODS:Eligible adults (serum uric acid [SUA]?>?7.0 mg/dl with a history of gout, SUA???8.0 mg/dl with complications or SUA???9.0 mg/dl without complications) were randomized (1:1:1) to febuxostat 40 mg/day, 80 mg/day, or allopurinol 300 mg/day. Starting doses of febuxostat 20 mg/day and allopurinol 100 mg/day were up-titrated, up to 16 weeks, to the randomized doses and maintained to week 24. Primary endpoint was non-inferiority of febuxostat 40 mg/day versus allopurinol 300 mg/day based on the percentage of subjects with SUA???6.0 mg/dl at week 24. The same comparison was made between febuxostat 60 mg/day or 80 mg/day versus allopurinol 300 mg/day. Safety assessments included measurement of treatment-emergent adverse events (TEAEs). RESULTS:The per-protocol population comprised 472 subjects. Non-inferiority of febuxostat 40 mg/day versus allopurinol 300 mg/day was not demonstrated based on the protocol-defined margin of -?10% (44.7 vs. 50.0%; -?5.3% difference; 95% confidence interval [CI]: -?16.4%, 5.8%); however, superiority over allopurinol 300 mg/day was demonstrated for febuxostat 60 mg/day at week 16 (66.3 vs. 51.2%; a 15.0% difference; 95% CI: 4.2%, 25.9%) and febuxostat 80 mg/day at week 24 (70.0 vs. 50.0%; a 20.0% difference; 95% CI: 9.3%, 30.7%). The frequency of TEAEs was similar across groups, with gout flares occurring frequently. CONCLUSIONS:Using a novel dose-titration method, although the primary endpoint of non-inferiority of febuxostat 40 mg/day versus allopurinol 300 mg/day was not reached, non-inferiority and superiority of febuxostat 60 mg/day and 80 mg/day versus allopurinol 300 mg/day was demonstrated at weeks 16 and 24, respectively. Febuxostat demonstrated an acceptable tolerability profile in the treatment of hyperuricemia in Chinese subjects with or without gout. TRIAL REGISTRATION:JapicCTI-132106. FUNDING:Astellas Pharma Global Development, Inc.
Project description:Hyperuricemia has been associated with chronic kidney disease (CKD) progression. The antihyperuricemic febuxostat's potential renoprotective effect has been demonstrated in stage 1-3 CKD. Large-scale studies comparing the renoprotective potential of febuxostat and allopurinol in advanced CKD are lacking. We exclusively selected 6,057 eligible patients with predialysis stage 5 CKD prescribed either febuxostat or allopurinol using the National Health Insurance Research Database in Taiwan during 2012-2015. There were 69.57% of allopurinol users and 42.01% febuxostat users who required long-term dialysis (P < 0.0001). The adjusted hazard ratio (HR) of 0.65 (95% confidence interval (CI) 0.60-0.70) indicated near 35% lower hazards of long-term dialysis with febuxostat use. The renal benefit of febuxostat was consistent across most patient subgroups and/or using the propensity score-matched cohort. The adjusted HR was 0.66 (95% CI, 0.61-0.70) for long-term dialysis or death. In conclusion, lower risk of progression to dialysis was observed in predialysis stage 5 CKD febuxostat users without compromising survival.
Project description:Gout is a common form of inflammatory arthritis with an increasing prevalence in developed countries. It is well known that many patients with gout have significant comorbidities and high health care utilization. We aimed to describe the clinical characteristics and health care utilization patterns in patients with gout who were newly prescribed allopurinol, febuxostat, or colchicine.We used US insurance claims data (2009-2011) to conduct a population-based cohort study.There were 25,051 allopurinol, 4,288 febuxostat, and 6,238 colchicine initiators. The mean age was 53 years and 83-87% were men. More than one-half of the patients had hypertension and hyperlipidemia, 20% had diabetes mellitus, and 10% had cardiovascular disease. The mean uric acid level was similar across the groups at baseline, ranging from 8.1-8.5 mg/dl. Compared with allopurinol or colchicine initiators, febuxostat initiators had more comorbidities and greater health care utilization, including outpatient, inpatient, or emergency room visits, both at baseline and during followup. Use of gout-related drugs such as opioids, steroids, and nonsteroidal antiinflammatory drugs was most common in febuxostat initiators and least common in colchicine initiators. The median daily doses at both the start and end of treatment were 300 mg for allopurinol, 40 mg for febuxostat, and 1.2 mg for colchicine. The doses of allopurinol and febuxostat were rarely increased during followup.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 the other groups. Overall, the doses of allopurinol or febuxostat remained unchanged over time.
Project description:The ability of antihyperuricemic therapy to exert renoprotective effects in patients with chronic kidney disease (CKD) is controversial. In the present study, we studied patient characteristics that may mask favorable impact of antihyperuricemic therapy on the progression of CKD.This was a single-center, retrospective, follow-up study. One-hundred and seventy-eight CKD patients with hyperuricemia who received febuxostat therapy were included in this study. Mean serum uric acid (mUA) level after treatment and changes in estimated glomerular filtration rate (?eGFR) over 6 months were measured and their correlation was examined. Patients were divided into two groups based on mUA, and their ?eGFR were compared. These analyses were evaluated in various subgroups.Febuxostat therapy markedly decreased UA level in any CKD stage patients without resulting in serious adverse events. eGFRs of CKD patients in the mUA < 6.0 mg/dl group were maintained, whereas those in the mUA ? 6.0 mg/dl group decreased. A significant inverse correlation was observed between mUA and ?eGFR (r = -0.16, p = 0.019). The renoprotective effects of febuxostat were significant in the following subgroups: male patients, age < 70 years, systolic blood pressure < 130 mmHg, normal cholesterol levels, and absence of diabetes. Coexisting vascular risk factors appear to exert additive masking effects against febuxostat renoprotection.The results of this study suggest that various vascular risk factors markedly attenuate the renoprotective effects of febuxostat.
Project description:BACKGROUND:Hyperuricemia is an independent risk factor in chronic kidney disease (CKD). Allopurinol and febuxostat are prescription medicines used to treat hyperuricemia but suffer side-effects. Earlier clinical study has shown that an aqueous extract of Terminalia bellerica (TBE), significantly reduced uric acid levels with no serious adverse effects in hyperuricemic subjects. The objective of this study is to determine the efficacy and tolerability of TB in reducing uric acid and creatinine levels in CKD subjects. METHODS:59-subjects were randomized to three groups-40?mg-once-daily febuxostat, 500?mg-twice-daily and 1000?mg-twice-daily of TBE. Serum uric acid, creatinine levels and estimated-glometular-filtration-rate were measured at baseline, 4, 8, 12, 16, 20, 24-weeks. Biomarkers of oxidative-stress, endothelial function, systemic inflammation, and platelet-aggregation were evaluated at baseline, 4, 8, 12, 24-weeks. Adverse drug reactions were recorded. Statistical analysis evaluated using GraphPadPrism4. RESULTS:55-subjects completed 24-week study. Starting at 4-weeks, all treatment groups showed a significant decrease in serum uric acid levels from baseline (p???0.0001). At 24-weeks, febuxostat, T.bellerica 500?mg-twice-daily, and T.bellerica 1000?mg-twice-daily doses decreased mean-percentage serum uric acid by 63.70?±?4.62, 19.84?±?6.43 and 33.88%?±?4.95% respectively (p???0.0001). Significant decrease in serum creatinine with all the groups starting at 16-weeks was seen (p???0.005-p???0.0001). At 24-weeks, the mean-percentage change in creatinine levels was 23.71?±?12.50, 11.70?±?9.0, and 24.42?±?8.14, respectively with febuxostat, T.bellerica 500?mg-twice-daily and T.bellerica 1000?mg-twice-daily. Statistically significant (p???0.05) increase in estimated glomerular filtration rate-(eGFR) was seen at 20 (p ??0.05) and 24-weeks (p???0.01) for both febuxostat vs T.bellerica 500?mg-twice-daily and T.bellerica 1000?mg-twice-daily vs T.bellerica 500?mg-twice-daily. There was no statistically significant difference between febuxostat and T.bellerica 1000?mg-twice-daily, with an increase of eGFR of 41.38 and 40.39?ml/min/1.73m2 respectively, with the inference that T.bellerica at 1000?mg-twice-daily dose is as good as febuxostat 40?mg-once-daily. Positive improvements were made by all the groups in endothelial function and the related biomarkers and high-sensitivity C-reactive protein. None of the products showed effect on platelet aggregation. CONCLUSION:In this 24-week study Febuxostat 40?mg, T. bellerica 500?mg-twice-daily and 1000?mg-twice-daily, significantly decreased the serum uric acid and creatinine levels, increased eGFR in CKD subjects. T. bellerica 500?mg-twice-daily and 1000?mg-twice-daily were one-third and more than half as effective at 24-weeks, respectively. T. bellerica extract may be considered a natural alternative for reducing serum uric acid levels. TRIAL REGISTRATION:This study was registered with the Clinical Trials Registry - India (CTRI) with the registration number: CTRI/2019/11/022093 [Registered on: 21/11/2019] Trial Registered Retrospectively.
Project description:Higher urinary uric acid excretion is a suspected risk factor for calcium oxalate stone formation. Febuxostat, a xanthine oxidoreductase inhibitor, is effective in lowering serum urate concentration and urinary uric acid excretion in healthy volunteers and people with gout. This work studied whether febuxostat, compared with allopurinol and placebo, would reduce 24-hour urinary uric acid excretion and prevent stone growth or new stone formation.In this 6-month, double-blind, multicenter, randomized controlled trial, hyperuricosuric participants with a recent history of calcium stones and one or more radio-opaque calcium stone ? 3 mm (as seen by multidetector computed tomography) received daily febuxostat at 80 mg, allopurinol at 300 mg, or placebo. The primary end point was percent change from baseline to month 6 in 24-hour urinary uric acid. Secondary end points included percent change from baseline to month 6 in size of index stone and change from baseline in the mean number of stones and 24-hour creatinine clearance.Of 99 enrolled participants, 86 participants completed the study. Febuxostat led to significantly greater reduction in 24-hour urinary uric acid (-58.6%) than either allopurinol (-36.4%; P=0.003) or placebo (-12.7%; P<0.001). Percent change from baseline in the size of the largest calcium stone was not different with febuxostat compared with allopurinol or placebo. There was no change in stone size, stone number, or renal function. No new safety concerns were noted for either drug.Febuxostat (80 mg) lowered 24-hour urinary uric acid significantly more than allopurinol (300 mg) in stone formers with higher urinary uric acid excretion after 6 months of treatment. There was no change in stone size or number over the 6-month period.
Project description:Hyperuricemia drives the development of nonalcoholic fatty liver disease (NAFLD). Pharmacological inhibition of xanthine oxidase (XO), a rate-limiting enzyme for uric acid (UA) production, has been demonstrated to improve hepatic steatosis in diet-induced obese mice. However, it remains unclear whether inhibition of XO improves nonalcoholic steatohepatitis (NASH), a more advanced form of NAFLD, in terms of both liver inflammation and fibrosis. Here, we investigated the effects of febuxostat and allopurinol, two XO inhibitors clinically used for gout, on a mouse model of NASH. Furthermore, we conducted a single-arm, open-label intervention study with febuxostat for NAFLD patients with hyperuricemia. Despite a similar hypouricemic effect of the XO inhibitors on blood UA level, febuxostat, but not allopurinol, significantly decreased hepatic XO activity and UA levels in the NASH model mice. These reductions in hepatic XO activity and UA levels were accompanied by attenuation of insulin resistance, lipid peroxidation, and classically activated M1-like macrophage accumulation in the liver. Furthermore, in NAFLD patients with hyperuricemia, treatment with febuxostat for 24 weeks decreased the serum UA level, accompanied by reductions in the serum levels of liver enzymes, alanine aminotransferase and aspartate aminotransferase. XO may represent a promising therapeutic target in NAFLD/NASH, especially in patients with hyperuricemia.
Project description:Hyperuricemia is associated with hypertension, with elevated serum uric acid levels postulated to have a causal role in the development of hypertension. Consequently, serum uric acid reduction may help lower blood pressure (BP). A Phase 2, double-blind, placebo-controlled trial was conducted to assess the potential BP-lowering effects of the xanthine oxidase inhibitor febuxostat in subjects with hypertension and hyperuricemia (serum uric acid ?0.42 mmol/L [?7.0 mg/dL]).Subjects (n=121) were randomized 1:1 to febuxostat 80 mg once daily or to placebo. The primary end point was change from baseline to Week 6 in 24-hour mean ambulatory systolic BP (SBP). Additional end points included the following: change from baseline to Week 3 in 24-hour mean SBP and changes from baseline to Weeks 3 and 6 in 24-hour mean ambulatory diastolic BP, serum uric acid, mean daytime and nighttime ambulatory SBP/diastolic BP, and clinic SBP/diastolic BP. For the overall study population, there were no significant differences between febuxostat and placebo for changes from baseline to Weeks 3 or 6 in ambulatory, daytime or nighttime, or clinic SBP or diastolic BP. However, in a preplanned subgroup analysis, there was a significant decrease in SBP from baseline to Week 6 in subjects with normal renal function (estimated glomerular filtration rate ?90 mL/min) treated with febuxostat versus placebo; least squares mean difference, -6.7; 95% confidence interval -13.3 to -0.0; P=0.049.This study suggests that febuxostat may lower BP in hyperuricemic patients with hypertension and normal renal function; further studies should be conducted to confirm this finding.URL: http://www.clinicaltrials.gov. Unique identifier: NCT01496469.
Project description:The prevalence of hyperuricemia and gout has been increasing, but the comparative effectiveness and safety of different treatments remain uncertain. We aimed to compare the effectiveness and safety of different treatments for hyperuricemia using network meta-analysis methodology. We systematically reviewed fifteen randomized controlled trials (involving 7,246 patients through January 2016) that compared the effects of different urate-lowering drugs (allopurinol, benzbromarone, febuxostat, pegloticase and probenecid) on hyperuricemia. Drug efficacy and safety, as outcomes, were measured by whether the target level of serum urate acid was achieved and whether any adverse events occurred, respectively. We derived pooled effect sizes expressed as odds ratios (ORs) and 95% confidence intervals (CIs). The efficacy and safety of the drugs were ranked by cumulative ranking probabilities. Our findings show that febuxostat, benzbromarone, probenecid, pegloticase, and allopurinol were all highly effective at reducing the risk of hyperuricemia compared to placebo. Febuxostat had the best efficacy and safety compared to the other drugs. Furthermore, febuxostat 120?mg QD was more effective at achieving urate-lowering targets (OR: 0.17, 95% CI: 0.12-0.24) and safer (OR: 0.72, 95% CI: 0.56-0.91) than allopurinol.