A Phase IIb Randomized Controlled Trial Investigating the Effects of Tocotrienol-Rich Vitamin E on Diabetic Kidney Disease
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Design and Participants
2.2. Inclusion and Exclusion Criteria
2.3. Ethics
2.4. Screening Visit
2.5. Randomization and Blinding
2.6. Sample Size
2.7. Follow-Up Visits
2.8. Assessment of Outcomes
2.9. Serum Creatinine, eGFR, Liver Function Test and Lipid Profile, HbA1c
2.10. TGF- β1, VEGF-A, Tocotrienol, Tocopherol Levels
2.11. Urine Albumin Creatinine Ratio UACR
2.12. Statistical Analysis
3. Results
3.1. Baseline Characteristics
3.2. Six Months Post-Tocotrienol-Rich Vitamin E Supplementation
3.3. Twelve Months Post-Tocotrienol-Rich Vitamin E Supplementation
3.4. Correlation of Renal Parameters with TGF-β1 and VEGF-A
3.5. Subgroup Analysis
3.6. Post Washout Analysis
4. Discussion
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Baseline Characteristic | Tocovid (n = 31) | Placebo (n = 28) | p-Value | Total (n = 59) |
---|---|---|---|---|
Age (years) | 66 (13) | 70 (13) | 0.403 a | 67 (14) |
Gender | 0.985 b | |||
Male (%) | 20 (52.6 %) | 18 (47.4 %) | 38 (64.6 %) | |
Female (%) | 11 (52.4 %) | 10 (47.6 %) | 21 (35.6 %) | |
Race | 0.216 c | |||
Malay (%) | 21 (67.7 %) | 13 (46.4 %) | 34 (57.6 %) | |
Chinese (%) | 6 (19.4 %) | 9 (32.1 %) | 15 (25.4 %) | |
Indian (%) | 4 (12.9 %) | 4 (14.3 %) | 8 (13.6 %) | |
Others (%) | 0 (0 %) | 2 (7.2 %) | 2 (3.4 %) | |
BMI (kg/m2) | 28.1 ± 4.4 | 29.1 ± 5.0 | 0.403 d | 28.5 ± 4.7 |
SBP (mmHg) | 134 ± 14 | 129 ± 12 | 0.149 d | 132 ± 13 |
DBP (mmHg) | 76.7 ± 8.9 | 75.3 ± 9.7 | 0.557 d | 76 ± 9 |
Duration of diabetes (year) | 15.3 ± 7.6 | 17.9 ± 8.9 | 0.231 d | 16.5 ± 8.3 |
HbA1c (%) | 7.59 ± 0.95 | 7.56 ± 1.10 | 0.903 d | 7.57 ± 1.02 |
eGFR (mL/min/1.73 m2) | 54.9 ± 18.4 | 56.0 ± 20.4 | 0.829 d | 55.9 ± 19.2 |
Serum creatinine (µmol/L) | 122 ± 48 | 118 ± 34 | 0.829 d | 121 ± 42 |
UACR (mg/mmol) | 20.9 (45.6) | 18.8 (43.9) | 0.988 a | 19 (44.3) |
Urea (mmol/L) | 6.95 ± 2.56 | 6.82 ± 2.07 | 0.832 d | 6.89 ± 2.32 |
Uric acid (mmol/L) | 383 ± 102 | 427 ± 99 | 0.097 †,d | 404 ± 13 |
Parameters | 2 Months Post-Supplementation | 4 Months Post-Supplementation | 6 Months Post-Supplementation | |||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Intervention (31) | Placebo (28) | Mean Difference Mean (95%CI) | p-Value | Intervention (31) | Placebo (28) | Mean Difference Mean (95%CI) | p-Value | Intervention (31) | Placebo (28) | Mean Difference Mean (95%CI) | p-Value | |
General | ||||||||||||
HbA1c (%) | 7.74 ± 1.16 | 7.87 ± 1.36 | −0.16 (−0.62, 0.29) | 0.480 a | - | - | - | - | 7.43 ± 1.26 | 7.31 ± 1.06 | 0.082 (−0.47, 0.64) | 0.769 a |
Systolic BP—mmHg | 132 ± 15 | 129 ± 14 | −1.95 (−9.87, 5.98) | 0.624 a | 136 ± 15 | 130 ± 13 | 1.39 (−6.62, 9.41) | 0.729 a | 136 ± 14 | 133 ± 13 | −1.78 (−9.99, 6.43) | 0.666 a |
Diastolic BP—mmHg | 74.4 ± 8.90 | 75.0 ± 9.32 | −2.01 (−6.09, 2.08) | 0.329 a | 77.3 ± 9.30 | 72.9 ± 9.30 | 2.98 (−1.26, 7.24) | 0.165 a | 77.8 ± 8.66 | 77.7 ± 9.26 | −1.27 (−5.16, 2.61) | 0.516 a |
Renal Parameters | ||||||||||||
Serum creatinine—µmol/L | 118 ± 42.1 | 127 ± 39.3 | −13.4 (−22.1, −4.7) | 0.003 a,* | 117 ± 43.4 | 122 ± 41.1 | −10.4 (−19.9, −0.87) | 0.033 *,a | 117 ± 44 | 122 ± 38 | −9.66 (−18.49, −0.83) | 0.033 *,a |
eGFR—mL/min/1.73 m2 | 56.3 ± 18.7 | 51.4 ± 19.3 | 6.02 (2.18, 9.87) | 0.003 a,* | 57.2 ± 18.1 | 54.1 ± 20.8 | 4.2 (−0.01, 8.5) | 0.051 a | 58.1 ± 18.9 | 53.4 ± 19.7 | 5.69 (−0.96, 10.43) | 0.019 *,a |
UACR—mg/mmol | 13.8 (45) | 13.4 (27) | - | 0.264 b | - | - | - | - | 23.2 (46.7) | 9.55 (49.9) | 0.574 b | |
Urea – mmol/L | 7.69 ± 2.46 | 7.90 ± 2.48 | −0.33 (−1.31, 0.64) | 0.498 a | 7.43 ± 2.37 | 7.30 ± 2.10 | −0.01 (−0.79, 0.78) | 0.984 a | 7.26 ± 2.31 | 7.35 ± 2.65 | −0.22 (−1.19, 0.74) | 0.644 a |
Uric acid – mmol/L | 358 ± 121 | 418 ± 89.6 | −16.7 (46.4, 13.0) | 0.265 a | 387 ± 113 | 414 ± 91 | 17.0 (−10.0, 44.3) | 0.216 a | 395 ± 130 | 431 ± 105 | 7.89 (−28.6, 44.4) | 0.667 a |
Biomarkers | ||||||||||||
TGF-β1 – ng/mL | 23.3 (19.0) | 23.0 (11.4) | - | 0.933 b | - | - | - | - | 21.72 (7.5) | 17.4 (8.4) | - | 0.534 b |
VEGF-A—pg/mL | 862 ± 473 | 763 ± 472 | - | 0.127 a | - | - | - | - | 796 ± 488 | 551 ± 356 | - | 0.794 a |
Parameters | 8 Months Post-Supplementation | 10 Months Post-Supplementation | 12 Months Post-Supplementation | |||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Intervention (31) | Placebo (28) | Mean Difference Mean (95%CI) | p-value | Intervention (31) | Placebo (28) | Mean Difference Mean (95%CI) | p-Value | Intervention (31) | Placebo (28) | Mean Difference Mean (95%CI) | p-Value | |
General | ||||||||||||
HbA1c (%) | 7.88 ± 1.44 | 7.97 ± 1.27 | −0.13 (−0.78, 0.53) | 0.698 a | 7.68 ± 1.36 | 8.86 ± 5.87 | −1.02 (−3.26, 0.83) | 0.239 a | 7.75 ± 1.41 | 7.98 ± 1.22 | −0.26 (−0.32, 0.38) | 0.424 a |
Systolic BP—mmHg | 135 ± 13 | 129 ± 11 | 1.39 (−6.17, 8.94) | 0.715 a | 132 ± 15 | 132 ± 12 | −4.76 (−13.0, 3.48) | 0.252 a | 135 ± 13 | 131 ± 10 | −0.68 (3.79, −6.91) | 0.858 a |
Diastolic BP—mmHg | 74.2 ± 8.26 | 74.6 ± 10.5 | −1.86 (−5.87, 2.14) | 0.355 a | 72.9 ± 10.5 | 75.9 ± 10.9 | −4.40 (−8.94, 0.15) | 0.058 a | 74.2 ± 9.16 | 76.0 ± 10.4 | 2.01 (−7.22, 0.82) | 0.117 a |
Renal Parameters | ||||||||||||
Serum creatinine—µmol/L | 118 ± 41.3 | 127 ± 45.0 | −13.4 (−23.9, −2.95) | 0.029 *,† | 116 ± 41 | 120 ± 37 | −8.75 (−18.1, 0.59) | 0.066 a | 114 (38.8) | 107 (40.2) | - | 0.076 b |
eGFR—mL/min/1.73 m2 | 56.7 ± 18.4 | 52.6 ± 21.0 | 5.19 (1.22, 9.16) | 0.011* | 56.8 ± 16.1 | 54.2 ± 19.3 | 3.69 (−0.93, 8.32) | 0.115 a | 56.8 ± 16.7 | 53.8 ± 20.2 | 4.07 (−0.522, 8.66) | 0.081 a |
UACR—mg/mmol | - | - | - | - | - | - | - | - | 28.6 (56.4) | 15.3 (45.8) | 0.125 b | |
Urea – mmol/L | 6.40 ± 2.55 | 7.54 ± 2.85 | 5.19 (1.22, 9.16) | 0.014 * | 6.83 ± 2.02 | 7.07 ± 1.90 | −0.37 (−1.24, 0.49) | 0.394 a | 6.68 (2.18) | 7.43 (4.02) | 0.021 *,b | |
Uric acid – mmol/L | 401 ± 118 | 426 ± 101 | 19.2 (−18.7, 57.2) | 0.314 a | 385 ± 110 | 399 ± 80.5 | 30.1 (−1.94, 62.3) | 0.065 a | 372 ± 83 | 416 ± 106 | 0.049 (−37.8, 37.9) | 0.998 a |
Biomarkers | ||||||||||||
TGF-β1 – ng/mL | - | - | - | - | - | - | - | - | 19.0 (8.7) | 14.6 (7.3) | - | 0.638 b |
VEGF-A pg/mL | - | - | - | - | - | - | - | - | 653(429) | 497 (511) | - | 0.940 a |
Baseline Parameters | TGF-β1 – ng/mL | VEGF-A pg/mL | ||
---|---|---|---|---|
Correlation, r | p-Value a | Correlation, r | p-Value a | |
Serum creatinine—µmol/L | −0.036 | 0.785 | −0.062 a | 0.638 |
eGFR—mL/min/1.73 m2 | 0.054 | 0.687 | 0.119 a | 0.370 * |
Parameters (Subgroup) | 2 Months Post-Supplementation | 4 Months Post-Supplementation | 6 Months Post-Supplementation | ||||||
---|---|---|---|---|---|---|---|---|---|
Intervention (31) | Placebo (28) | p-Value | Intervention (31) | Placebo (28) | p-Value a | Intervention (31) | Placebo (28) | p-Value | |
General | |||||||||
HbA1c (%) | 0.05 ± 1.08 | 0.44 ± 0.85 | 0.295 †,a | - | - | - | −0.090 ± 1.27 | −0.34 ± 0.86 | 0.505 a |
Systolic BP—mmHg | 0.05 ± 15.77 | −0.82 ± 13.41 | 0.858 a | 2.13 ± 15.23 | 1.88 ± 14.88 | 0.962 | 4.56 ± 16.58 | 6.08 ± 15.82 | 0.778 a |
Diastolic BP—mmHg | −2.00 ± 9.84 | −1.77 ± 6.17 | 0.933 a | 0.57 ± 8.35 | −2.41 ± 5.15 | 0.210 | 1.54 ± 8.54 | 3.51 ± 7.12 | 0.455 a |
Renal Parameters | |||||||||
Serum creatinine—µmol/L | −5.88 ± 18.66 | 12.45 ± 16.58 | 0.004 a,* | −9.55 ± 8.92 | −7.23 ± 17.68 | 0.046 a,*,† | −7.23 ± 17.68 | 5.82 ± 21.38 | 0.050 a,* |
eGFR—mL/min/1.73 m2 | 1.65 ± 6.70 | −4.18 ± 6.30 | 0.010 a,* | 4.36 ± 9.38 | −3.41 ± 4.27 | 0.003 a,* | 4.55 ± 11.06 | −1.11 ± 7.09 | 0.078 a |
UACR—mg/mmol | 0.10 (8.83) | −0.70 (10.65) | 0.177 b | - | - | - | 0.60 (27.08) | 0.50(7.60) | 0.497 b |
Urea – mmol/L | 0.84 ± 2.06 | 0.68 ± 1.82 | 0.808 a | 0.45 ± 1.82 | 0.30 ± 1.27 | 0.777 | −0.40 (1.03) | 0.00(2.40) | 0.729 b |
Uric acid – mmol/L | −17.9 ± 44.7 | −11.8 ± 65.5 | 0.744 a | −5.95 ± 43.9 | −1.19 ± 40.0 | 0.734 | 17.5 ± 77.6 | 16.7± 72.1 | 0.973 a |
Parameters (Subgroup) | 8 Months Post-Supplementation | 10 Months Post-Supplementation | 12 Months Post-Supplementation | ||||||
---|---|---|---|---|---|---|---|---|---|
Intervention (31) | Placebo (28) | p-Value | Intervention (31) | Placebo (28) | p-Value | Intervention (31) | Placebo (28) | p-Value | |
General | |||||||||
HbA1c (%) | 0.32 ± 1.38 | 0.30 ± 0.98 | 0.969 †,a,* | - | - | - | 0.42 ± 1.65 | 0.49 ± 6.78 | 0.879 a |
Systolic BP—mmHg | 1.77 ± 16.40 | −0.88 ± 10.75 | 0.573 a | 1.57 ± 17.79 | 0.65 ± 10.89 | 0.854 | 3.79 ± 19.59 | 2.12 ± 8.23 | 0.746 a |
Diastolic BP—mmHg | −3.38 ± 6.64 | −1.47 ± 9.84 | 0.489 a | −3.58 ± 9.75 | −1.71 ± 7.25 | 0.518 | −2.45 ± 8.44 | 0.88 ± 7.48 | 0.558 a |
Renal Parameters | |||||||||
Serum creatinine—µmol/L | −7.29 ± 14.31 | 13.8 ± 27.4 | 0.008 a,* | −11.15 ± 17.66 | 1.91. ± 19.50 | 0.040 * | −7.85 (20.75) | 0.84 (26.03) | 0.042 b |
eGFR—mL/min/1.73 m2 | 2.35 ± 5.43 | −3.29 ± 9.10 | 0.026 a,* | 5.09 ± 6.34 | −0.13 ± 6.85 | 0.021 * | 4.83 ± 6.78 | −1.45 ± 9.18 | 0.022 a,* |
UACR—mg/mmol | - | - | - | - | - | - | 1.78 (45.7) | 0.56 (17.04) | 0.141 b |
Urea – mmol/L | −0.72 ± 2.13 | 0.79 ± 1.59 | 0.021 a,* | −0.58 ± 1.45 | −0.17 ± 1.59 | 0.421 | −0.87 ± 1.69 | 0.81 ± 2.39 | 0.017 a,* |
Uric acid – mmol/L | −12.0 (103) | 6.00 (104) | 0.916 b | −12.36 ± 70.75 | −25.71 ± 57.89 | 0.545 | −22.07 ± 63.88 | 1.45 ± 82.73 | 0.336 a |
Renal Parameters | Intervention Group (n = 29) | Placebo (n = 27) | p-Value | ||||
---|---|---|---|---|---|---|---|
At 12 Months | 6-Months Washout | Change | At 12 Months | 6-Months Washout | Change | ||
HbA1c (%) | 7.50 ± 1.20 | 7.50 ± 1.30 | −0.40 ± 1.00 | 8.00 ± 1.20 | 7.70 ± 1.20 | −0.30 ± 0.80 | 0.426 |
UACR (mg/mmol) | 28.60 (56.40) | 15.80 (34.20) | −19.30 ± 25.70 | 15.30 (45.80) | 18.50 (56.20) | 4.60 ± 17.90 | 0.006 * |
Serum creatinine (umol/L) | 107.00 (37.10) | 116.70 (42.40) | 9.70 ± 1.60 | 102.6 (47.20) | 108.70 (63.90) | 6.10 ± 3.00 | 0.657 |
eGFR (ml/min/1.73 m2) | 61.70 ± 18.20 | 50.90 ± 15.50 | −10.80 ± 22.20 | 59.00 ± 21.40 | 54.70 ± 19.20 | −4.30 ± 12.80 | 0.212 |
Urea (mmol/L) | 6.20 ± 1.60 | 7.70 ± 2.50 | 1.50 ± 2.40 | 7.20 ± 2.30 | 7.20 ± 2.40 | 0.10 ± 2.20 | 0.026 * |
Uric acid (mmol/L) | 370.30 ± 87.60 | 355.90 ± 73.20 | −5.60 ± 24.40 | 382.30 ± 78.70 | 392.30 ± 92.90 | 10.00 ± 63.20 | 0.250 |
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Koay, Y.Y.; Tan, G.C.J.; Phang, S.C.W.; Ho, J.-I.; Chuar, P.F.; Ho, L.S.; Ahmad, B.; Abdul Kadir, K. A Phase IIb Randomized Controlled Trial Investigating the Effects of Tocotrienol-Rich Vitamin E on Diabetic Kidney Disease. Nutrients 2021, 13, 258. https://doi.org/10.3390/nu13010258
Koay YY, Tan GCJ, Phang SCW, Ho J-I, Chuar PF, Ho LS, Ahmad B, Abdul Kadir K. A Phase IIb Randomized Controlled Trial Investigating the Effects of Tocotrienol-Rich Vitamin E on Diabetic Kidney Disease. Nutrients. 2021; 13(1):258. https://doi.org/10.3390/nu13010258
Chicago/Turabian StyleKoay, Yan Yi, Gerald Chen Jie Tan, Sonia Chew Wen Phang, J-Ian Ho, Pei Fen Chuar, Loon Shin Ho, Badariah Ahmad, and Khalid Abdul Kadir. 2021. "A Phase IIb Randomized Controlled Trial Investigating the Effects of Tocotrienol-Rich Vitamin E on Diabetic Kidney Disease" Nutrients 13, no. 1: 258. https://doi.org/10.3390/nu13010258
APA StyleKoay, Y. Y., Tan, G. C. J., Phang, S. C. W., Ho, J.-I., Chuar, P. F., Ho, L. S., Ahmad, B., & Abdul Kadir, K. (2021). A Phase IIb Randomized Controlled Trial Investigating the Effects of Tocotrienol-Rich Vitamin E on Diabetic Kidney Disease. Nutrients, 13(1), 258. https://doi.org/10.3390/nu13010258