Comparative efficacy and safety of urate-lowering therapy for the treatment. of hyperuricemia: a systematic review and network meta-analysis
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1 Comparative efficacy and safety of urate-lowering therapy for the treatment of hyperuricemia: a systematic review and network meta-analysis Shu Li 1,2*, Hongxi Yang 1,2*, Fengjiang Wei 3, Xilin Yang 4, Daiqing Li 2, Mingzhen Li 2, Weili Xu 4,5, Weidong Li 3, Li Sun 1, Yanan Guo 1, Ying Gao 1 & Yaogang Wang 1+ Appendix Supplementary Figure 1A. Risk of bias graph of included studies on overall level.
2 Supplementary Figure 1B. Risk of bias summary of included studies. 2
3 Supplementary Figure 2. Predictive interval plot for urate-lowering drugs on a logarithmic scale. (ALLO=allopurinol, FEBU1=febuxostat 20 mg/day, FEBU2=febuxostat 40 mg/day, FEBU3=febuxostat 60 mg/day, FEBU4=febuxostat 80 mg/day, FEBU5=febuxostat 120 mg/day, FEBU6=febuxostat 240 mg/day, BENZ=benzbromarone, PROB=probenecid, PEGL1=pegloticase 8 mg every 2 weeks, PEGL2=pegloticase 8 mg every 4 weeks, PLA=placebo.) 3
4 Intervention Direct comparisons/ participants (n/n) Pairwise meta-analysis Odds ratio (95% CI) Network meta-analysis Efficacy allopurinol vs. benzbromarone 29/ (0.21, 24.64) 1.36 (0.49,3.81) febuxostat 20 mg QD 0.27 (0.13,0.59) febuxostat 40 mg QD 1364/ (1.05, 1.59) 1.52 (1.15,1.99) febuxostat 60 mg QD 5/ (0.39, ) 2.01 (0.71,5.69) febuxostat 80 mg QD 100/ (2.69, 4.89) 3.54 (2.80,4.47) febuxostat 120 mg QD 420/ (4.79, 8.40) 5.95 (4.15,8.52) febuxostat 240 mg QD 171/ (9.17, 36.58) (8.22,36.89) pegloticase 8 mg 2W 0.45 (0.02,9.85) pegloticase 8 mg 4W 0.62 (0.03,13.63) probenecid 0.86 (0.06,12.72) placebo 287/ (0.00, 0.09) 0.01 (0.00,0.03) benzbromarone vs. febuxostat 20 mg QD 0.20 (0.06,0.73) febuxostat 40 mg QD 1.11 (0.39,3.21) febuxostat 60 mg QD 1.47 (0.34,6.35) febuxostat 80 mg QD 2.60 (0.91,7.43) febuxostat 120 mg QD 4.37 (1.47,12.93) febuxostat 240 mg QD (3.58,45.60) pegloticase 8 mg 2W 0.33 (0.01,8.54) pegloticase 8 mg 4W 0.46 (0.02,11.81) probenecid 3/ (0.05, 7.39) 0.63 (0.05,7.62) placebo 0.01 (0.00,0.03) febuxostat 20 mg QD vs. febuxostat 40 mg QD 52/ (3.29, 16.63) 5.52 (2.62,11.64) febuxostat 60 mg QD 29/ (1.99, 16.63) 7.32 (2.54,21.06) febuxostat 80 mg QD 28/ (2.73, 25.15) (6.01,27.60) febuxostat 120 mg QD (9.49,49.42) febuxostat 240 mg QD (22.00,182.68) pegloticase 8 mg 2W 1.63 (0.07,37.18) pegloticase 8 mg 4W 2.26 (0.10,51.45) probenecid 3.13 (0.19,51.56) placebo 112/ (0.00, 0.14) 0.04 (0.01,0.13) febuxostat 40 mg QD vs. febuxostat 60 mg QD 14/ (0.38, 3.58) 1.32 (0.48,3.69) febuxostat 80 mg QD 1073/ (1.92, 2.70) 2.33 (1.79,3.03) febuxostat 120 mg QD 17/ (2.60, 61.38) 3.92 (2.62,5.88) febuxostat 240 mg QD (5.27,25.01) pegloticase 8 mg 2W 0.30 (0.01,6.49) pegloticase 8 mg 4W 0.41 (0.02,8.97) 4
5 probenecid 0.57 (0.04,8.49) placebo 130/ (0.00, 0.02) 0.01 (0.00,0.02) febuxostat 60 mg QD vs. febuxostat 80 mg QD 11/ (0.40, 5.19) 1.76 (0.63,4.94) febuxostat 120 mg QD 2.96 (1.01,8.72) febuxostat 240 mg QD 8.67 (2.44,30.78) pegloticase 8 mg 2W 0.22 (0.01,5.53) pegloticase 8 mg 4W 0.31 (0.01,7.66) probenecid 0.43 (0.02,7.67) placebo 43/ (0.00, 0.05) 0.00 (0.00,0.02) febuxostat 80 mg QD vs. febuxostat 120 mg QD 250/ (1.05, 2.08) 1.68 (1.18,2.40) febuxostat 240 mg QD 80/ (2.20, 8.96) 4.92 (2.32,10.43) pegloticase 8 mg 2W 0.13 (0.01,2.78) pegloticase 8 mg 4W 0.18 (0.01,3.85) probenecid 0.24 (0.02,3.63) placebo 282/ (0.00, 0.01) 0.00 (0.00,0.01) febuxostat 120 mg QD vs. febuxostat 240 mg QD 66/ (1.53, 6.32) 2.93 (1.35,6.33) pegloticase 8 mg 2W 0.08 (0.00,1.67) pegloticase 8 mg 4W 0.10 (0.00,2.31) probenecid 0.14 (0.01,2.19) placebo 219/ (0.00, 0.01) 0.00 (0.00,0.01) febuxostat 240 mg QD vs. pegloticase 8 mg 2W 0.03 (0.00,0.61) pegloticase 8 mg 4W 0.04 (0.00,0.85) probenecid 0.05 (0.00,0.81) placebo 136/ (0.00, 0.01) 0.00 (0.00,0.00) pegloticase 8 mg 2W vs. pegloticase 8 mg 4W 104/ (0.75, 2.60) 1.39 (0.67,2.87) probenecid 1.92 (0.03,115.82) placebo 98/ (0.00, 0.36) 0.02 (0.00,0.37) pegloticase 8 mg 4W vs. probenecid 1.38 (0.02,83.32) placebo 92/ (0.00, 0.26) 0.02 (0.00,0.27) probenecid vs. placebo 0.01 (0.00,0.22) Safety allopurinol vs. benzbromarone 7/ (0.05, 1.62) 0.29 (0.05,1.62) febuxostat 20 mg QD 0.91 (0.50,1.65) febuxostat 40 mg QD 1345/ (0.84, 1.16) 1.02 (0.87,1.19) febuxostat 60 mg QD 0.80 (0.36,1.76) febuxostat 80 mg QD 2024/ (0.99, 1.38) 1.15 (0.99,1.32) febuxostat 120 mg QD 787/ (1.17, 2.08) 1.39 (1.10,1.78) febuxostat 240 mg QD 298/ (0.67, 1.73) 1.02 (0.66,1.55) 5
6 pegloticase 8 mg 2W 0.11 (0.00,2.30) pegloticase 8 mg 4W 1.22 (0.25,5.92) probenecid 0.12 (0.01,1.00) placebo 297/ (0.70, 1.79) 1.08 (0.78,1.50) benzbromarone vs. febuxostat 20 mg QD 3.18 (0.51,19.98) febuxostat 40 mg QD 3.57 (0.62,20.41) febuxostat 60 mg QD 2.79 (0.41,18.85) febuxostat 80 mg QD 4.01 (0.70,22.92) febuxostat 120 mg QD 4.88 (0.84,28.20) febuxostat 240 mg QD 3.55 (0.59,21.24) pegloticase 8 mg 2W 0.37 (0.01,12.69) Pegloticase 8 mg 4W 4.28 (0.41,44.68) probenecid 17/ (0.12, 1.41) 0.42 (0.12,1.41) placebo 3.77 (0.64,22.11) febuxostat 20 mg QD vs. febuxostat 40 mg QD 102/ (0.64, 2.51) 1.12 (0.62,2.02) febuxostat 60 mg QD 51/ (0.33, 2.14) 0.88 (0.37,2.10) febuxostat 80 mg QD 52/ (0.45, 2.61) 1.26 (0.70,2.28) febuxostat 120 mg QD 1.53 (0.82,2.86) febuxostat 240 mg QD 1.12 (0.55,2.28) pegloticase 8 mg 2W 0.12 (0.01,2.64) Pegloticase 8 mg 4W 1.34 (0.26,7.06) probenecid 0.13 (0.01,1.19) placebo 102/ (0.54, 2.22) 1.19 (0.64,2.18) febuxostat 40 mg QD vs. febuxostat 60 mg QD 49/ (0.31, 1.99) 0.78 (0.36,1.72) febuxostat 80 mg QD 1241/ (0.93, 1.29) 1.12 (0.96,1.31) febuxostat 120 mg QD 39/ (0.48, 2.91) 1.37 (1.05,1.78) febuxostat 240 mg QD 1.00 (0.64,1.54) pegloticase 8 mg 2W 0.10 (0.00,2.25) pegloticase 8 mg 4W 1.20 (0.25,5.81) probenecid 0.12 (0.01,0.98) placebo 135/ (0.56, 1.68) 1.06 (0.76,1.48) febuxostat 60 mg QD vs. febuxostat 80 mg QD 49/ (0.50, 3.26) 1.43 (0.65,3.15) febuxostat 120 mg QD 1.75 (0.78,3.93) febuxostat 240 mg QD 1.27 (0.53,3.07) pegloticase 8 mg 2W 0.13 (0.01,3.14) pegloticase 8 mg 4W 1.53 (0.27,8.71) probenecid 0.15 (0.02,1.44) placebo 46/ (0.56, 3.75) 1.35 (0.60,3.02) febuxostat 80 mg QD vs. febuxostat 120 mg QD 800/ (0.87, 1.48) 1.22 (0.96,1.54) febuxostat 240 mg QD 279/ (0.49, 1.22) 0.89 (0.58,1.35) 6
7 pegloticase 8 mg 2W 0.09 (0.00,2.00) Pegloticase 8 mg 4W 1.07 (0.22,5.15) probenecid 0.10 (0.01,0.87) placebo 367/ (0.64, 1.35) 0.94 (0.68,1.30) febuxostat 120 mg QD vs. febuxostat 240 mg QD 281/ (0.49, 1.24) 0.73 (0.47,1.13) pegloticase 8 mg 2W 0.08 (0.00,1.65) pegloticase 8 mg 4W 0.88 (0.18,4.26) probenecid 0.09 (0.01,0.72) placebo 318/ (0.56, 1.27) 0.77 (0.54,1.10) febuxostat 240 mg QD vs. pegloticase 8 mg 2W 0.10 (0.00,2.31) pegloticase 8 mg 4W 1.20 (0.24,6.07) probenecid 0.12 (0.01,1.02) placebo 195/ (0.61, 1.78) 1.06 (0.65,1.73) pegloticase 8 mg 2W vs. pegloticase 8 mg 4W 164/ (0.63, ) (0.63,212.19) probenecid 1.12 (0.03,47.26) placebo 125/ (0.48, ) (0.48,216.91) pegloticase 8 mg 4W vs. probenecid 0.10 (0.01,1.37) placebo 121/ (0.15, 4.20) 0.88 (0.19,4.12) probenecid vs. placebo 9.06 (1.06,77.67) Supplementary Table 1. Pairwise and network estimates of the effects of different drugs. 7
8 Intervention Efficacy Safety SUCRA Rank SUCRA Rank allopurinol benzbromarone febuxostat 20 mg QD febuxostat 40 mg QD febuxostat 60 mg QD febuxostat 80 mg QD febuxostat 120 mg QD febuxostat 240 mg QD pegloticase 8 mg 2W pegloticase 8 mg 4W probenecid placebo Supplementary Table 2. Ranking of drugs according to efficacy and safety. 8
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