Table 3.
Concentrations of Urine metabolites in patients with type 2 diabetes mellitus before and 3 months after administration of dapagliflozin and insulin degludec
| Metabolite concentration (μmol/mmol creatinine) |
Baseline | Posttreatment | 2-way analysisa | ||||||
|---|---|---|---|---|---|---|---|---|---|
| Dapagliflozin | Insulin | ||||||||
| Controls | Dapagliflozin | Insulin | % change | P | % change | P | F | P | |
| 1-methylnicotinamide | 1.97 ± 0.70 | 2.72 ± 1.70* | 1.60 ± 0.49+ | −6.6 | NS | +15 | NS | 0.91 | NS |
| 1-methylhistidine | 9.44 ± 8.24 | 26.54 ± 14.14** | 13.18 ± 10.11* | +2.4 | NS | +17.7 | NS | 0.14 | NS |
| 2-aminobutyrate | 4.08 ± 2.02 | 6.46 ± 2.83** | 5.85 ± 4.34** | +14.4 | <0.0005 | +6.6 | NS | 8.92 | <0.05 |
| 2-hydroxy-3-methylvalerate | 3.87 ± 1.67 | 11.46 ± 6.34** | 5.56 ± 2.91*+ | +17.3 | <0.0005 | +10.2 | NS | 4.12 | <0.05 |
| 2-hydroxybutyrate | 1.91 ± 1.12 | 1.20 ± 1.00 | 3.61 ± 1.64*+ | +30 | <0.0005 | +22.2 | NS | 3.71 | <0.05 |
| 2-hydroxyisobutyrate | 5.66 ± 1.50 | 8.80 ± 3.08** | 4.31 ± 2.56+ | −7.6 | NS | +5.8 | NS | 1.61 | NS |
| 2-hydroxyisovalerate | 1.43 ± 0.59 | 4.72 ± 1.62** | 1.79 ± 1.22++ | +14.5 | <0.0005 | −1.1 | NS | 4.37 | <0.05 |
| 2-hydroxyvalerate | 2.36 ± 1.33 | 7.54 ± 6.29** | 3.33 ± 2.28+ | +2.9 | NS | +16.7 | NS | 0.06 | NS |
| 2-oxocaproate | 3.58 ± 1.66 | 2.7 ± 2.03 | 4.45 ± 3.72 | +0.2 | NS | −13.1 | NS | 0.71 | NS |
| 3-chlorotyrosine | 9.10 ± 12.40 | 24.17 ± 17.02** | 20.25 ± 19.27** | −30.5 | <0.0001 | +4.9 | NS | 3.90 | <0.05 |
| 3-hydroxybutyrate | 12.93 ± 13.10 | 46.00 ± 41.78** | 30.46 ± 20.02**+ | +21.2 | <0.0005 | −43.1 | <0.0005 | 7.25 | <0.05 |
| 3-hydroxyisobutyrate | 11.12 ± 10.21 | 12.34 ± 10.96 | 13.50 ± 12.91 | +15.2 | NS | −11.1 | NS | 2.28 | NS |
| 3-hydroxyisovalerate | 5.16 ± 1.73 | 4.78 ± 2.83 | 3.40 ± 2.53* | +18 | <0.0005 | +5.3 | NS | 3.44 | <0.05 |
| 3-indoxylsulfate | 13.85 ± 8.41 | 30.6 ± 17.61** | 21.17 ± 10.35**+ | −4.4 | NS | +11.3 | NS | 0.69 | NS |
| 3-methyl-2-oxovalerate | 3.98 ± 2.05 | 12.23 ± 7.54** | 9.33 ± 4.88**+ | −18.4 | NS | −10.6 | NS | 4.32 | <0.05 |
| 3-methyladipate | 2.96 ± 1.85 | 7.32 ± 6.45** | 6.65 ± 4.34** | +19.1 | NS | +8.5 | NS | 0.92 | NS |
| 3-methylhistidine | 15.70 ± 8.37 | 27.16 ± 17.85** | 22.15 ± 19.22** | −1.8 | NS | +5.7 | NS | 0.54 | NS |
| 4-hydroxybenzoate | 3.14 ± 2.51 | 5.90 ± 5.76* | 5.50 ± 3.97* | +7.9 | NS | +40.1 | NS | 2.64 | NS |
| Acetate | 15.20 ± 11.22 | 28.07 ± 9.25* | 20.86 ± 11.68 | −1.3 | NS | +23.5 | NS | 1.06 | NS |
| Acetoacetate | 14.08 ± 13.53 | 43.68 ± 16.68** | 36.05 ± 18.06** | +18.5 | <0.0005 | −45.2 | <0.0005 | 36.68 | <0.01 |
| Acetone | 4.21 ± 2.07 | 3.35 ± 2.10 | 5.49 ± 4.72 | +14 | NS | −10.7 | NS | 1.05 | NS |
| Alanine | 21.25 ± 9.36 | 44.63 ± 30.47** | 40.45 ± 24.93** | +26.5 | <0.0001 | +13.1 | NS | 3.42 | <0.05 |
| Allantoin | 10.38 ± 6.83 | 8.55 ± 5.18 | 6.64 ± 5.58 | +7.2 | NS | +7.3 | NS | 0.25 | NS |
| Anserine | 6.57 ± 3.79 | 9.76 ± 4.51* | 8.64 ± 6.32 | −19.4 | <0.0005 | −8.3 | NS | 4.58 | <0.05 |
| Betaine | 12.96 ± 7.74 | 72.87 ± 48.04** | 76.92 ± 42.12** | +54.9 | <0.0001 | −58.3 | <0.0005 | 9.22 | <0.01 |
| Butyrate | 3.35 ± 1.71 | 1.69 ± 0.98* | 1.05 ± 0.84* | +15.4 | NS | +2.6 | NS | 1.20 | NS |
| Carnitine | 8.12 ± 6.57 | 6.75 ± 5.85 | 6.73 ± 7.33 | −15.9 | NS | −10.4 | NS | 0.02 | NS |
| Choline | 5.68 ± 4.18 | 6.69 ± 4.78 | 5.35 ± 4.08 | +13.5 | NS | +11.2 | NS | 0.07 | NS |
| cis-Aconitate | 22.11 ± 14.96 | 16.56 ± 8.73 | 15.27 ± 7.84 | −10.9 | NS | +9.2 | NS | 3.02 | NS |
| Citrate | 347.10 ± 181.68 | 357.30 ± 233.27 | 373.18 ± 273.63 | +18.4 | <0.0005 | −10.5 | NS | 3.85 | <0.05 |
| Creatine | 12.62 ± 12.69 | 49.65 ± 31.64** | 50.69 ± 37.23** | +40.3 | <0.0001 | +2.3 | NS | 4.22 | <0.05 |
| Creatine phosphate | 26.61 ± 18.70 | 155.92 ± 188.61** | 143 ± 127.89** | +1.6 | NS | −6.1 | NS | 0.04 | NS |
| Cytosine | 5.16 ± 3.64 | 3.35 ± 2.59 | 6.34 ± 5.58 | +1.2 | NS | −9.6 | NS | 0.95 | NS |
| Dimethylamine | 35.05 ± 12.24 | 24.67 ± 10.92* | 27.23 ± 14.85 | +0.1 | NS | +18.5 | NS | 0.68 | NS |
| Ethylmalonate | 4.02 ± 1.89 | 1.64 ± 0.97** | 1.92 ± 1.34** | +33.5 | <0.0001 | +4.6 | NS | 6.52 | <0.01 |
| Formate | 27.89 ± 16.14 | 22.92 ± 11.72 | 21.45 ± 21.31 | −4.8 | NS | +24.2 | NS | 0.56 | NS |
| Fumarate | 0.80 ± 0.56 | 1.00 ± 0.72 | 1.23 ± 1.12 | −2.0 | NS | −14.6 | NS | 0.66 | NS |
| Gluconate | 44.28 ± 18.37 | 45.55 ± 25.23 | 37.58 ± 26.88 | +33.26 | <0.0005 | +7.2 | NS | 5.42 | <0.05 |
| Glucose | 39.55 ± 14.13 | 2273 ± 5551** | 1175 ± 2174* | +723.6 | <0.0001 | −68.1 | <0.0005 | 31.18 | <0.01 |
| Glycine | 124.18 ± 78.18 | 121.35 ± 78.74 | 86.65 ± 76.54 | −7.7 | NS | +5.8 | NS | 0.05 | NS |
| Hippurate | 325.72 ± 255.79 | 327.06 ± 259.02 | 300.01 ± 349.25 | +33.3 | <0.0005 | +7.7 | NS | 6.33 | <0.05 |
| Hypoxanthine | 7.59 ± 8.02 | 5.55 ± 5.05 | 4.41 ± 4.76 | −18.9 | NS | +19.5 | NS | 5.88 | <0.05 |
| Indole-3-acetate | 6.32 ± 5.03 | 6.01 ± 4.11 | 9.35 ± 7.18 | −3.3 | NS | +8.2 | NS | 0.65 | NS |
| Indole-3-lactate | 7.76 ± 8.11 | 13.03 ± 6.27* | 9.35 ± 8.42 | −8.5 | NS | +5.6 | NS | 0.58 | NS |
| Isoleucine | 2.25 ± 1.01 | 6.46 ± 3.62* | 9.88 ± 6.43** | +13.3 | NS | −9.2 | NS | 2.85 | NS |
| Kynurenate | 2.29 ± 1.66 | 2.86 ± 2.13 | 4.17 ± 2.84* | +32.1 | NS | +28.2 | NS | 0.74 | NS |
| Lactate | 7.94 ± 4.74 | 12.93 ± 8.43** | 11.16 ± 7.02** | +116 | <0.0001 | −25.2 | <0.0005 | 9.82 | <0.01 |
| Leucine | 2.50 ± 1.28 | 11.27 ± 4.31** | 9.04 ± 9.03** | +22.2 | <0.0005 | −8.5 | NS | 4.88 | <0.05 |
| Lysine | 19.82 ± 15.37 | 57.45 ± 17.51** | 46.83 ± 47.27** | +7.2 | NS | −7.3 | NS | 1.30 | NS |
| Mannitol | 49.68 ± 20.93 | 72.21 ± 41.17 | 83.22 ± 117.08 | +7.7 | NS | −11.3 | NS | 0.23 | NS |
| Methanol | 47.61 ± 30.70 | 23.31 ± 12.45** | 16.09 ± 13.63** | −22.7 | <0.0005 | +18 | NS | 6.10 | <0.05 |
| Methylamine | 4.79 ± 5.02 | 5.52 ± 3.86 | 4.92 ± 4.42 | −4.3 | NS | −7.11 | NS | 0.10 | NS |
| Myo-inositol | 42.23 ± 26.31 | 87.61 ± 71.31** | 82.88 ± 68.71** | +77.1 | <0.0001 | −32.5 | <0.0005 | 14.49 | <0.01 |
| N,N-dimethylglycine | 2.73 ± 1.38 | 4.47 ± 3.60 | 3.54 ± 3.11 | +233.8 | <0.0001 | +1.4 | NS | 13.92 | <0.01 |
| N-isovaleroylglycine | 1.37 ± 0.66 | 3.39 ± 1.91** | 2.13 ± 1.54* | −17.7 | <0.0005 | +13.6 | NS | 4.89 | <0.05 |
| N-methylhydantoin | 10.33 ± 5.45 | 20.83 ± 9.15** | 22.44 ± 21.34** | +16 | <0.0005 | +2.9 | NS | 4.32 | <0.05 |
| N-phenylacetylglycine | 34.99 ± 13.70 | 49.64 ± 30.41* | 58.90 ± 43.36** | +13.1 | NS | −12.1 | NS | 4.81 | <0.05 |
| Phenylalanine | 11.40 ± 12.43 | 46.72 ± 39.10** | 30.19 ± 28.36**+ | −5.2 | NS | +38.1 | NS | 2.25 | NS |
| Pyruvate | 4.40 ± 2.52 | 5.56 ± 3.17 | 5.05 ± 3.20 | −3.9 | NS | −3.9 | NS | 0.06 | NS |
| Sarcosine | 6.07 ± 7.46 | 1.66 ± 0.88** | 1.98 ± 1.53** | +109 | <0.0005 | −14.1 | NS | 56.31 | <0.01 |
| Succinate | 5.29 ± 3.39 | 12.49 ± 5.89 | 13.99 ± 12.4* | +5.8 | NS | −2.3 | NS | 0.03 | NS |
| Threonine | 21.59 ± 10.92 | 36.61 ± 21.63* | 29.20 ± 22.91 | +10.4 | NS | +10.5 | NS | 0.01 | NS |
| trans-Aconitate | 5.26 ± 4.18 | 4.24 ± 3,81 | 2.94 ± 1.91 | −24.5 | NS | +0.7 | NS | 2.41 | NS |
| Trigonelline | 33.46 ± 35.39 | 35.69 ± 28.77 | 43.02 ± 19.15 | +96.1 | <0.0001 | +7.6 | NS | 22.37 | <0.01 |
| Trimethylamine | 2.08 ± 0.96 | 3.79 ± 1.91 | 4.34 ± 4.13 | −2.6 | NS | +3.7 | NS | 0.22 | NS |
| Trimethylamine N-oxide | 50.40 ± 41.32 | 36.38 ± 37.80 | 36.63 ± 28.06 | −16.8 | NS | +2.9 | NS | 0.47 | NS |
| Tyrosine | 6.78 ± 3.82 | 19.11 ± 7.38** | 15.81 ± 14.69** | +9.4 | NS | −2.1 | NS | 0.29 | NS |
| Valerate | 4.69 ± 3.20 | 20.96 ± 11.73** | 15.95 ± 13.00** | −28.72 | NS | +1.2 | NS | 1.99 | NS |
| Valine | 3.63 ± 1.28 | 8.56 ± 4.10** | 3.11 ± 1.91++ | +35.1 | <0.0001 | +19.2 | NS | 4.45 | <0.05 |
| Xanthurenate | 9.81 ± 10.26 | 18.17 ± 12.75* | 12.15 ± 28.24 | +11.8 | NS | +28.2 | NS | 1.23 | NS |
a F- and P-values for the treatment*time point interaction.
* P < 0.0005 and **P < 0.0001 compared to control group baseline values.
+ P < 0.0005 and ++P < 0.0001 compared to dapagliflozin group baseline values.