Article Figures & Data
Tables
- Table 1
- Effects of different antidiabetic drugs on the serum uric acid level in patients with type-2 diabetes mellitus.
Drugs class Serum UA levels Mechanisms Metformin ↓ Ameliorates insulin resistance and hyperinsulinemia, which increases urinary clearance of UA and reduces UA production. Sulfonylureas Glibenclamide NS NA Gliclazide NS Glimepiride NS Dipeptidyl peptidase 4 inhibitors Sitagliptin ↑ Unknown Alogliptin ↑ Decreases UA production by suppressing Linagliptin ↓ xanthine oxidase activity Vildagliptin ↓ Unknown Alpha-glucosidase inhibitors Acarbose No data NA Voglibose NS NA Thiazolidinediones Troglitazone ↓ Ameliorates insulin resistance and Rosiglitazone ↓ hyperinsulinemia; increases urine pH, which Pioglitazone ↓ enhances urinary excretion of UA Insulin ↑ Increases urate reabsorption via URAT1 or sodium-dependent anion cotransporter in renal proximal tubules Glucagon-like peptide-1 receptor agonists Exenatide NS NA Liraglutide NS Lixisenatide NS Dulaglutide NS Sodium-glucose cotransporter 2 inhibitors Empagliflozin ↓ Increases renal excretion of urate by altering renal tubular UA transporters (GLUT9 and URAT1); decreases flux through the pentose phosphate pathway via indirect activation of sirtuin-1, which can inhibit xanthine oxidase Dapagliflozin ↓ Canagliflozin ↓ Luseogliflozin ↓ Tofogliflozin ↓ Ipragliflozin ↓ GLUT9: glucose transporter 9, NA: not applicable, NS: not significant, UA: uric acid, URAT1: urate transporter 1
- Table 2
- Studies that evaluated the effects of different antidiabetic drugs on the serum level of uric acid in patients with type-2 diabetes.
Drug classification References Study location Study design Patients (N) Age (years) Gender (M/F) Metformin* (-) Gregorio et al20 Italy Before-after study 76 76.44±1.03 31/45 Gliclazide (sulfonylurea) Kilo et al30 USA Before-after study 29 56.1 19/10 Suijk et al32 Netherlands Randomized, double-blind, comparator-controlled, intervention trial 44 (gliclazide, n=20; dapagliflozin, n=24) 65 (8) 17/3 Glimepiride (suilfonylurea) Kitazawa et al33 Japan Multicenter, randomized, open-label, parallel-group trial 64 (glimepiride, n=31; tofogliflozin, n=33) 57.6±9.3 19/12 Sitagliptin (DDP4i) Matsushima et al34 Japan Multicenter, randomized, open-label, parallel-group trial 241 (sitagliptin, n=120; voglibose, n=121) 63.2±13.8 72/48 Kutoh et al35 Japan Prospective, nonrandomized, observational study 64 56.0±12.3 50/14 Tojikubo et al36 Japan Before-after study 73 66±13 41/32 Fuchigami et al37 Japan Prospective, randomized, open-label, blinded-endpoint, parallel-group trial 331 (sitagliptin, n=163; dapagliflozin, n=168) 57.9±12.1 95/68 Alogliptin (DDP4i) Kutoh et al35 Japan Prospective, nonrandomized, observational study 55 52.4±13.2 46/9 Linagliptin* (DDP4i) Tojikubo et al36 Japan Before-after study 73 66±13 41/32 Yamagishi et al38 Japan Prospective trial 26 69.4±12.4 18/8 Vildagliptin* (DDP4i) Shimodaira et al39 Japan Retrospective study 62 67.2±12.2 42/20 Voglibose (alpha-glucosidase inhibitor) Matsushima et al34 Japan Multicenter, randomized, open-label, parallel-group trial 241 (voglibose, n=121; sitagliptin, n=120) 63.2±11.6 71/50 Troglitazone* (thiazolidinedione) Iwatani et al42 Japan Before-after study 95 61.1±10.3 61/34 Rosiglitazone* (thiazolidinedione) Seber et al43 Turkey Prospective trial 40 NR NR Macić-Dzanković et al44 Sarajevo Before-after study 21 NR NR Pioglitazone* (thiazolidinedione) Kutoh et al45 Japan Cohort study 19 53.6±12.6 NR Insulin (-) MacFarlane et al47 USA Matched cohort study 23 57 (47,64) 11/12 Exenatide (GLP-1 RA) Dutour et al51 France Prospective randomized clinical trial 44 (exenatide, n=22; reference, n=22) 51±2 13/9 Muskiet et al52 Sweden, Finland, Netherlands Post-hoc analysis of a randomized, open-label, active-comparator, parallel-group trial 54 (exenatide, n=26; insulin glargine, n=28) 59.7±8.1 16/10 Liraglutide (GLP-1 RA) Tonneijck et al53 Netherlands Randomized, double-blind, placebo-controlled trial 36 (liraglutide, n=19; placebo, n=17) 63.0±7.0 27/9 Nakaguchi et al54 Japan Open-label, parallel-group, randomized controlled trial 61 (liraglutide, n=30; empagliflozin, n=31) 67.2±9.0 21/9 Kurir et al55 Croatia Non-randomized, controlled, interventional study 15 60 (55,68) all male Liakos et al56 Greece Randomized, double blind, placebo-controlled trial 62 (liraglutide, n=31; placebo, n=31) 60.5±12.0 19/12 Lixisenatide (GLP-1 RA) Tonneijck et al53 Netherlands Randomized, open-label, comparator-controlled trial 35 (lixisenatide, n=17; insulin glulisine, n=18) 61.7±6.6 23/12 Dulaglutide (GLP-1 RA) Kuchay et al57 India Open-label, parallel-group, randomized controlled trial 64 (dulaglutide,n=32; control,n=32) 46.6±9.1 23/9 Hirai et al58 Japan Retrospective comparative study 20 (dulaglutide, n=10; liraglutide, n=10) 67.6±9.9 6/4 Iwasaki et al59 Japan Single–center, open–label, single–arm, pilot study 36 66.7±11.1 15/21 Empagliflozin* (SGLT2i) You Y et al61 NA Meta-analysis 7801 51–78.4 NR Dapagliflozin* (SGLT2i) Hao Z et al62 China Randomized controlled trial 59 (dapagliflozin, n=29; control,n=30) 57.77±12.29 20/9 Fuchigami et al37 Japan Prospective, randomized, open-label, blinded-endpoint, parallel-group trial 331 (dapagliflozin, n=168; sitagliptin, n=163) 58.3±12.4 104/64 Suijk et al32 Netherlands Randomized, double-blind, comparator-controlled intervention trial 44 (dapagliflozin, n=24; gliclazide, n=20) 63±7 17/7 Canagliflozin* (SGLT2i) Davies et al63 NR Post-hoc analysis of pooled data from four randomized placebo-controlled phase III multinational studies 2313 (canagliflozin, n=1667; placebo, n=646) 59.1±9.6 812/855 Luseogliflozin* (SGLT2i) Seino et al64 Japan Phase II, randomized, placebo-controlled, double-blind, parallel-group study 236 (luseogliflozin,n=182; placebo,n=54) 58.3±9.4 35/26 Chino et al65 Japan Retrospective study 480 (luseogliflozin, n=297; placebo, n=183) 58±10 207/90 Tofogliflozin* (SGLT2i) Terauchi et al66 Japan Randomized, double-blind, placebo-controlled multicentre trial 211 (tofogliflozin, n=141; placebo, n=70) 59.1±10.8 90/51 Ipragliflozin* (SGLT2i) Tanaka et al67 Japan Randomized, open-label, active-controlled, blinded-endpoint trial 30 (ipragliflozin,n=15; control,n=15) 59.1±11.2 8/7 Tsukagoshi-Yamaguchi et al68 Japan Prospective, multicenter, open-label, blinded-end point, randomized, controlled study 30 (ipragliflozin,n=15; metformin,n=15) 57.8±13.3 9/6 Nagao et al69 Japan Multicenter, open-label, randomized controlled trial 160 (ipragliflozin,n=77; sitagliptin,n=83) 62(53–67) 44/33 Drug classification References Study location BMI (kg/m2) eGFR (mL/min/1.73 m2) Baseline Serum UA (mg/dL) HbA1c (%) Duration of diabetes (years) Metformin* (-) Gregorio et al20 Italy NR NR 5.88±0.25 >9 15.08±1.27 Gliclazide (Sulfonylurea) Kilo et al30 USA 42.8% overweight NR NR 10.1±0.44 8.03 Suijk et al32 Netherlands 32±4 89 (22) 5.2±0.9 7.4±0.6 NR Glimepiride (Suilfonylurea) Kitazawa et al33 Japan 25.4±3.8 88.5±16.2 5.5±1.6 7.5±0.4 7.7±6.7 Sitagliptin (DDP4i) Matsushima et al34 Japan 25.0±4.5 88.0±23.3 5.08±1.14 7.9±1.0 NR Kutoh et al35 Japan 24.58±4.35 NR 4.91±1.28 10.14±2.19 NR Tojikubo et al36 Japan 24.6±5.0 78.0±24.4 5.10±1.13 8.19±1.07 15.3±7.8 Fuchigami et al37 Japan 27.9±4.2 78.9±16.9 5.4±1.4 7.8±0.8 5.6±5.8 Alogliptin (DDP4i) Kutoh et al35 Japan 25.69±5.21 NR 4.69±1.60 10.60±2.24 NR Linagliptin* (DDP4i) Tojikubo et al36 Japan 24.6±4.1 71.8±23.3 5.63±1.24 7.32±1.05 15.3±7.8 Yamagishi et al38 Japan 24.7±3.6 NR 5.5±1.2 7.4±1.4 NR Vildagliptin* (DDP4i) Shimodaira et al39 Japan 24.7±3.8 71.7±26.8 6.0±1.6 7.7±1.0 NR Voglibose (alpha-glucosidase inhibitor) Matsushima et al34 Japan 25.1±4.5 83.7±22.2 5.13±1.40 7.8±0.8 NR Troglitazone* (Thiazolidinedione) Iwatani et al42 Japan 25.4±3.0 NR 5.5±1.2 8.4±1.3 NR Rosiglitazone* (Thiazolidinedione) Seber et al43 Turkey 30.31±5.3 NR 4.78±1.1 9.95±9.7 NR Macić-Dzanković et al44 Sarajevo NR NR 6.22±1.31 8.55±1.9 NR Pioglitazone* (Thiazolidinedione) Kutoh et al45 Japan 27.82±6.32 NR 6.87±0.73 8.63±1.74 Newly Diagnosed Insulin (-) MacFarlane et al47 USA 38.1 (32.8,39.1) NR 6.4 (4.6, 8.2) 8.9 (7.5, 10.9) NR Exenatide (GLP-1 RA) Dutour et al51 France 37.2±1.8 NR 6.3±1.5 NR 4 (2, 8) Muskiet et al52 Sweden, Finland, Netherlands 30.4±4.1 84.7±17.0 NR 7.53±0.98 NR Liraglutide (GLP-1 RA) Tonneijck et al53 Netherlands 31.2 (29.2,33.3) 79±3 5.39±1.07 7.4±0.7 8 (4–12) Nakaguchi et al54 Japan 26.4±4.6 63.3±18.9 5.3±1.3 8.04±0.75 18.8±9.9 Kurir et al55 Croatia 40.9±7.3 NR 6.69±1.21 7.98±0.70 NR Liakos et al56 Greece 33.6 (7.9) 82.3 (30.3) NR 7.8 (1.7) 8.0 (6.0) Lixisenatide (GLP-1 RA) Tonneijck et al53 Netherlands 31.5±4.0 93±3 5.68±1.19 8.0±0.9 13±7 Dulaglutide (GLP-1 RA) Kuchay et al57 India 29.6±3.6 NR 5.0±1.7 8.4±1.0 4.9±3.1 Hirai et al58 Japan 25.7±3.2 20.3±10.4 6.3±0.8 7.2±0.8 NR Iwasaki et al59 Japan 28.7±5.3 NR 4.93±1.35 7.80±0.99 17.9±9.1 Empagliflozin* (SGLT2i) You Y et al61 NA NR NR NR NR NR Dapagliflozin* (SGLT2i) Hao Z et al62 China 27.34±3.88 NR 5.86±1.72 9.89±1.24 12.20±6.59 Fuchigami et al37 Japan 27.8±4.0 79.0±18.5 5.4±1.3 7.8±0.8 6.0±6.4 Suijk et al32 Netherlands 31±4 84 (24) 5.5±1.2 7.3 (0.8) NR Canagliflozin* (SGLT2i) Davies et al63 NR 32.0±6.5 88.8±18.9 5.3–5.4 8.0±0.9 NR Luseogliflozin* (SGLT2i) Seino et al64 Japan 24.8±3.56 NR 5.09±1.49 8.07±0.90 6.15±6.50 Chino et al65 Japan NR 85±18 5.1±1.3 8.1±0.9 NR Tofogliflozin* (SGLT2i) Terauchi et al66 Japan 25.8±3.5 79.7±19.8 5.05±1.25 8.53±0.75 15.02±9.36 Ipragliflozin* (SGLT2i) Tanaka et al67 Japan 30.5±7.0 67.3±18.2 5.7±1.4 7.0±0.5 NR Tsukagoshi-Yamaguchi et al68 Japan 29.0±5.7 NR 5.1±1.4 8.1±0.7 4.4±4.9 Nagao et al69 Japan NR NR 5.5 (4.5–6.2) 7.5 (7.1–7.9) NR Drug classification Reference, year Study location Drug dose Drug duration Serum urate change (mg/dL) P-value Metformin* (-) Gregorio et al20 Italy 1000 mg/day progressively increased to 1500 mg/day 1 year From 5.88±0.25 to 5.02±0.28 p<0.05 vs. baseline Gliclazide (Sulfonylurea) Kilo et al30 USA 80-320 mg/day 1 year No significant change p>0.05 vs. baseline Suijk et al32 Netherlands 30 mg/day 12 weeks No significant change during hyperglycemic conditions p=0.07 vs. baseline Glimepiride (Suilfonylurea) Kitazawa et al33 Japan 0.5 mg/day 24 weeks No significant change p=0.773 vs. baseline Sitagliptin (DDP4i) Matsushima et al34 Japan 50 mg/day 12 weeks From 5.08±1.14 to 5.30±1.24 p=0.001 vs. baseline Kutoh et al35 Japan 25 mg/day for females (n=14), 50 mg/day for males (n=50) 3 months From 4.91±1.28 to 5.42±1.43 p<0.00001 vs. baseline Tojikubo et al36 Japan 50 mg/day at least 1 year From 5.10±1.13 to 5.63±1.24 p<0.001 vs. baseline Fuchigami et al37 Japan 50–100 mg/day 24 weeks From 5.4±1.4 to 5.6±1.3 p=0.004 vs. baseline Alogliptin (DDP4i) Kutoh et al35 Japan 12.5 mg/day for females (n=9), 5 mg/day for males (n=46) 3 months From 4.69±1.60 to 5.24±1.61 p<0.00001 vs. baseline Linagliptin* (DDP4i) Tojikubo et al36 Japan 5 mg/day 1 year From 5.63±1.24 to 5.24±1.10 p<0.001 vs. baseline Yamagishi et al38 Japan 5 mg/day 24 weeks From 5.5±1.2 to 5.1±1.2 p<0.05 vs. baseline Vildagliptin* (DDP4i) Shimodaira et al39 Japan 100 mg/day 1 year From 6.0 ± 1.6 to 5.3±1.3 p<0.05 vs. baseline Voglibose (alpha-glucosidase inhibitor) Matsushima et al34 Japan 0.6 mg/day 12 weeks No significant change p=0.073 vs. baseline Troglitazone* (Thiazolidinedione) Iwatani et al42 Japan 400 mg/day 9.7±7.6 months From 5.5±1.2 to 5.0±1.2 p<0.0001 vs. baseline Rosiglitazone* (Thiazolidinedione) Seber et al43 Turkey 4 mg/day 12weeks From 4.78±1.1 to 4.41±1.1 p=0.001 vs. baseline Macić-Dzanković et al44 Sarajevo 4 mg/day 12 weeks From 6.22±1.31 to 6.02±1.27 p<0.015 vs. baseline Pioglitazone* (Thiazolidinedione) Kutoh et al45 Japan 7.5–30 mg/day 12 weeks From 6.87±0.73 to 5.90±0.77 p<0.00001 vs. baseline Insulin (-) MacFarlane et al47 USA NA Mean of 2.9 years +1.25 p=0.02 Exenatide (GLP-1 RA) Dutour et al51 France 10–20 µg/day 26 weeks No significant change p=0.79 vs. reference Muskiet et al52 Sweden, Finland, Netherlands 20 µg/day 52 weeks No significant change p>0.05 vs. baseline Liraglutide (GLP-1 RA) Tonneijck et al53 Netherlands 1.8 mg/day 12 weeks No significant change p=0.8 vs. placebo Nakaguchi et al54 Japan 0.9 mg/day 24 weeks No significant change NR Kurir et al55 Croatia 1.2 mg/day 3 months No significant change p=0.104 vs. baseline Liakos et al56 Greece 1.2 mg/day 5 weeks No significant change p=0.23 vs. placebo Lixisenatide (GLP-1 RA) Tonneijck et al53 Netherlands 20 µg/day 8 weeks No significant change p>0.1 vs. baseline Dulaglutide (GLP-1 RA) Kuchay et al57 India 1.5 mg/week 24 weeks No significant change p=0.11 vs. control Hirai et al58 Japan 0.75 mg/week 1 year No significant change p>0.05 vs. baseline Iwasaki et al59 Japan 0.75 mg/week 24 weeks No significant change p=0.0818 vs. baseline Empagliflozin* (SGLT2i) You Y et al61 NA 10 or 25 mg/day 5 days to 164 weeks SMD: -1.34 p<0.001 vs. placebo Dapagliflozin* (SGLT2i) Hao Z et al62 China 10 mg/day NR From 5.86±1.72 to 4.71±1.20 p<0.001 vs. baseline Fuchigami et al37 Japan 5-10 mg/day 24 weeks From 5.4±1.3 to 4.9 ± 1.1 p<0.001 vs. baseline Suijk et al32 Netherlands 10 mg/day 12 weeks From 5.5±1.1 to 4.6±1.0 p<0.001 vs. baseline Canagliflozin* (SGLT2i) Davies et al63 NR 100 or 300 mg/day 26 weeks −0.7 NR Luseogliflozin* (SGLT2i) Seino et al64 Japan 2.5 mg/day 12 weeks −0.63 p<0.05 vs. placebo Chino et al65 Japan 2.5 or 5 mg/day 12 weeks −0.6 p<0.05 vs. baseline Tofogliflozin* (SGLT2i) Terauchi et al66 Japan 20 mg/day 16 weeks −0.18 p=0.0062 vs. placebo Ipragliflozin* (SGLT2i) Tanaka et al67 Japan 50 mg/day 12 weeks From 5.7±1.4 to 5.0±1.3 p<0.05 vs. baseline Tsukagoshi-Yamaguchi et al68 Japan 50 mg/day 24 weeks −11.3 % p=0.012 vs. control Nagao et al69 Japan 50 mg/day 6 months −0.41 p<0.05 vs. baseline ↵* Drugs that decreased serum uric acid.
NA: not applicable, NR: not reported, SMD: standardized mean difference, F: female, M: male, N: number, SGLT2i: sodium-glucose cotransporter 2 inhibitors, GLP-RA: glucagon-like peptide-1 receptor agonists, DDP4i: dipeptidyl peptidase 4 inhibitor
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