To Treat or Not to Treat? Effect of Urate-Lowering Therapy on Renal Function, Blood Pressure and Safety in Patients with Asymptomatic Hyperuricemia: A Systematic Review and Network Meta-Analysis

Yu-Yu Tien; Ming-Chieh Shih; Chiao-Pang Tien; Huei-Kai Huang; Yu-Kang Tu

doi:10.3122/jabfm.2022.01.210273

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Figure 1.
Flowchart of the process to identify eligible studies with reasons for inclusion or exclusion.
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Appendix 1.
Literature search strategy
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Appendix 2.
Data extraction from included trials: Details of secondary outcomes
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Appendix 3.
Summary of the risks of bias in every included trial
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Appendix 4.
Network plot for effect of urate-lowering therapy. Each node represents a treatment group, and an edge indicates at least 1 trial comparing the 2 treatments on the ends of the edge. The node size in the network plot is proportional to the number of patients randomized to the treatment group, and the width of an edge is proportional to the number of studies making the pairwise comparison
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Appendix 5.
League table of the network meta-analysis comparing the events of secondary outcomes of all drugs, including odds ratios and 95% confidence intervals
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Result of pairwise meta-analyses of all directly compared interventions Appendix 6.1 Results of pairwise meta-analyses of all directly compared interventions of short-term results. P value is obtained from the Cochrane Q test for heterogeneity.
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Appendix 6.2
Results of pairwise meta-analyses of all directly compared interventions of long-term results. P value is obtained from the Cochrane Q test for heterogeneity.

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Table 1.

Overview of Included Studies

Author/Country	Population	Study Design	No. of Patients(Treatment/Control)	Baseline Characteristic^* (Treatment/Control)	Treatment	Comparison	Period(weeks)	Primary Outcome
Siu, 2005 China²⁸	patients with chronic kidney disease	randomized controlled trial	25/26	uric acid (mg/dL): 9.75/5.88 Cr (mg/dL): 1.62/1.86 SBP (mm Hg): 138/135 DBP (mm Hg): 79/71	allopurinol, 100 to 300 mg/day	no urate-lowering medical therapy	48	– stable kidney function with less than 40% increase in serum creatinine level – impaired renal function with creatinine level increase greater than 40% of baseline value
Ogino, 2010 Japan²⁹	patients with stable compensated CHF	double-blind, placebo-controlled, randomized crossover study	14/14	uric acid (mg/dL): 10.2/10.2	Benzbromarone 50 mg/day	placebo	8	– the change of BNP levels – change in echocardiographic parameters of left ventricle dimensions and LVEF
Kanbay, 2011 Turkey³⁰	patients with normal renal function	randomized, controlled trial	30/37	uric acid (mg/dL): 8.3/7.9^{^†,^‡} eGFR: 86.3/84.3 SBP (mm Hg):127.6/123.2 DBP (mm Hg): 75.1/75.6	allopurinol 300 mg/day	no urate-lowering medical therapy	16	– endothelial dysfunction – BP – eGFR
Liu, 2015 China³¹	patients with type 2 diabetes	randomized open parallel-controlled study	88/88	uric acid (μmol/L) : 433/432 eGFR: 90.1/90.1SBP (mm Hg): 121/121 DBP (mm Hg): 74/74	allopurinol starting from 100 mg/day	no urate-lowering medical therapy	144	changes in the carotid IMT
Sircar, 2015 India³²	eastern India aged 18 to 65 years with CKD stages 3 and 4	double-blind, randomized, parallel-group, placebo-controlled study	45/48	uric acid (mg/dL): 9.0/8.2 eGFR: 31.5/32.6	febuxostat 40 mg/day	placebo	24	≥10% decline in eGFR from baseline
Takir, 2015 Turkey³³	patients without a history of diabetes mellitus, kidney and liver disease	randomized, controlled trial	40/33	uric acid (mg/dL): 7.86/7.45 Cr (mg/dL): 0.9/1.07	allopurinol 300 mg/day	no urate-lowering medical therapy	12	improvement in insulin resistance defined by homeostatic model assessment of insulin resistance
Beddhu, 2016 USA³⁴	overweight or obese adults with type 2 diabetic nephropathy	double-blinded randomized controlled trial	37/39	uric acid (μmol/L): 426/422 eGFR: 52.2/54.8SBP (mm Hg): 125.2/128.3DBP (mm Hg): 68.1/72.0	febuxostat 80 mg/day	placebo	24	– adipose tissue TBARS and adiponectin concentrations – urinary transforming growth factor–β
Jalal, 2017 USA³⁵	≥ 18 years of age with stage 3 CKD	double-blind, randomized, controlled trial	39/41	uric acid (mg/dL): 8.3/8.7 eGFR: 41.3/42.4 SBP (mm Hg): 127/130 DBP (mm Hg): 77.4/77.7	allopurinol 300 mg/day (200 mg, 100 mg)	placebo	12	change in brachial artery flow-mediated Dilation
Kimura, 2018 Japan³⁶	patients with CKD stage 3	randomizeddouble-blind, parallel-group, placebo-controlled trial	219/222	uric acid (mg/dL): 7.8/7.8eGFR: 45.2/44.9 SBP (mm Hg): 132.5/129.6 DBP (mm Hg): 77.9/77.3	febuxostat (10 mg, 20 mg, 40 mg)	placebo	108	eGFR slope
Mukri, 2018 Malaysia³⁷	CKD stage 3 and 4 patients with diabetic nephropathy	open-label, randomized study	47/46	uric acid (μmol/L): 539.5/537.3 eGFR: 26.2/28.2 SBP (mm Hg): 141/146 DBP (mm Hg): 73.7/71.7	febuxostat 40 mg/day	no urate-lowering medical therapy	24	slowing the eGFR decline
Kojima, 2019 Japan³⁸	elderly patients who had one or more risks for cerebral, cardiovascular, or renal disease	randomized open-label, blinded endpoint study	537/533	uric acid (mg/dL): 7.54/7.50 eGFR: 54.62/55.35 SBP (mm Hg): 132.9/132.3 DBP (mm Hg): 73.5/73.6	febuxostat (10-40 mg/day)	non-febuxostat groupno treatment or allopurinol 100 mg (27.2% patients)	144	– fatal and non-fatal cerebral, cardiovascular and renal – death other than cerebral or cardiorenal vascular disease
Perrenoud, 2020 USA³⁹	patients with CKD stage 3	double-blind randomized placebo-controlled study	39/41	eGFR: 41.4/41.7 SBP (mm Hg): 127/129 DBP (mm Hg): 77/77	allopurinol 300 mg/day	placebo	12	– change of albumin-creatinine ratio – neutrophil gelatinase-associated lipocalin – kidney injury molecule 1 transforming growth factor β1
Tanaka, 2020 Japan⁴⁰	adults with maximum IMT of the CCA ≥ 1.1 mm at screening	randomized, open-label, blinded-endpoint clinical trial	257/257	uric acid (mg/dL): 7.76/7.73 eGFR: 56.26/57.12 SBP (mm Hg): 128.9/127.3 DBP (mm Hg): 73.3/74.18	febuxostat (10-60 mg/day)	no urate-lowering medical therapy	96	– percentage change from baseline to 24 months in mean IMT of the CCA

Abbreviations: BNP, brain natriuretic peptide; BP, blood pressure; CCA, common carotid artery; CHF, chronic heart failure; CKD, chronic kidney disease; CRP, C-reactive protein; CV, cardiovascular; DBP, diastolic blood pressure; DN, diabetic nephropathy; eGFR, estimated Glomerular filtration rate; FMD, Flow-mediated dilation; IMT, intima-media thickness; IL-6, interleukin-6; LVEF, left ventricular ejection fraction; MCP-1, monocyte chemotactic protein-1; Ox-LDL, oxidized low-density lipoprotein; NF-kB, nuclear factor-kappa B; SBP, systemic blood pressure; TBARS, thiobarbituric acid-reducing substances; UAER, urinary albumin excretion rate.
↵* Values are expressed as mean.
↵† The unit of eGFR is mL/min/1.73 m².
↵‡ Values are expressed as median.

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Table 2.

League Table of Random-Effects Network Meta-Analysis for Effect of Urate-Lowering Therapy^*

Serum Uric Acid Level (Short-Term Follow-Up, mg/dL)
Allopurinol	.	.	−2.16 (−3.20 to −1.13)
0.89 (−1.49 to 3.26)	Benzbromarone	.	−3.05 (−5.19 to −0.91)
0.55 (−1.03 to 2.13)	−0.34 (−2.79 to 2.11)	Febuxostat	−2.71 (−3.90 to −1.52)
−2.16^{^†} (−3.20 to −1.13)	−3.05^* (−5.19 to −0.91)	−2.71^{^†} (−3.90 to −1.52)	Placebo

Serum Uric Acid Level (Long-Term Follow-Up, mg/dL)
Allopurinol	.	−3.17 (−5.19 to −1.15)
−0.55 (−3.97 to 2.88)	Febuxostat	−2.62 (−5.39 to 0.15)
−3.17^{^†} (−5.19 to −1.15)	−2.62 (−5.39 to 0.15)	Placebo

Renal Function (Short-Term Follow-Up, mL/min/1.73 m²)
Allopurinol	.	3.07 (0.18 to 5.95)
2.00 (−2.54 to 6.53)	Febuxostat	1.07 (−2.43 to 4.57)
3.07^{^†} (0.18 to 5.95)	1.07 (−2.43 to 4.57)	Placebo

Renal Function (Long-Term Follow-Up, mL/min/1.73 m²)
Allopurinol	.	4.10 (2.66 to 5.54)
3.70^{^†} (1.94 to 5.46)	Febuxostat	0.40 (−0.60 to 1.40)
4.10^{^†} (2.66 to 5.54)	0.40 (−0.60 to 1.40)	Placebo

Systolic Blood Pressure (Short-Term Follow-Up, mm Hg)
Allopurinol	.	0.04 (−4.22 to 4.30)
4.54 (−4.29 to 13.37)	Febuxostat	−4.50 (−12.23 to 3.23)
0.04 (−4.22 to 4.30)	−4.50 (−12.23 to 3.23)	Placebo

Systolic Blood Pressure (Long-Term Follow-Up, mm Hg)
Allopurinol	.	−4.74 (−11.12 to 1.63)
−3.96 (−10.58 to 2.66)	Febuxostat	−0.78 (−2.57 to 1.01)
−4.74 (−11.12 to 1.63)	−0.78 (−2.57 to 1.01)	Placebo

Diastolic Blood Pressure (Short-Term Follow-Up, mm Hg)
Allopurinol	.	1.58 (−2.31 to 5.48)
1.48 (−4.06 to 7.03)	Febuxostat	0.10 (−3.85 to 4.05)
1.58 (−2.31 to 5.48)	0.10 (−3.85 to 4.05)	Placebo

Diastolic Blood Pressure (Long-Term Follow-Up, mm Hg)
Allopurinol	.	0.86 (−3.88 to 5.61)
2.34 (−2.62 to 7.29)	Febuxostat	−1.47 (−2.90 to −0.04)
0.86 (−3.88 to 5.61)	−1.47^{^†} (−2.91 to −0.04)	Placebo

↵* Data are shown as mean difference (95% confidence interval).
↵† Difference in treatment effect is statistically significant.

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Table 3.

P-Score of Different Rankings of Each Treatment Strategy

SHORT-TERM		LONG-TERM
Serum Uric Acid		Serum Uric Acid
Benzbromarone	0.7908	Allopurinol	0.8108
Febuxostat	0.7146	Febuxostat	0.6728
Allopurinol	0.4937	Placebo	0.0164
Placebo	0.0009	Renal Function
Renal Function		Allopurinol	1.0000^*
Allopurinol	0.8937	Febuxostat	0.3912
Febuxostat	0.4598	Placebo	0.1088
Placebo	0.1465	Systolic Blood Pressure
Systolic Blood Pressure		Allopurinol	0.9035^*
Febuxostat	0.8581	Febuxostat	0.4626
Allopurinol	0.3246	Placebo	0.1340
Placebo	0.3173	Diastolic Blood Pressure
Diastolic Blood Pressure		Febuxostat	0.9000
Placebo	0.6534	Placebo	0.3307
Febuxostat	0.5900	Allopurinol	0.2693
Allopurinol	0.2567