Effects of Tocotrienol-Rich Fraction Supplementation in Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

There are a large number of studies that have reported benefits of tocotrienol-rich fraction (TRF) in various populations with different health status. To date, no systematic reviews have examined randomized controlled trials (RCTs) on the effect of TRF supplementations specifically in patients with type 2 diabetes mellitus (T2DM). This systematic review and meta-analysis aim to examine the changes in HbA1c (glycated hemoglobin), blood pressure, and serum Hs-CRP (C-reactive protein high sensitivity) levels at post-TRF supplementation. Online databases including PubMed, Scopus, OVID Medline, and Cochrane Central Register of Controlled Trials were searched from inception until March 2023 for RCTs supplementing TRF in patients with T2DM. A total of 10 studies were included in the meta-analysis to estimate the pooled effect size. The Cochrane Risk-of-Bias (RoB) Assessment Tool was utilized to evaluate the RoB in individual studies. The meta-analysis revealed that TRF supplementation at a dosage of 250-400 mg significantly decreased HbA1c (-0.23, 95% CI: -0.44, -0.02, P < 0.05, n = 754), particularly where the intervention duration is less than 6 mo (-0.47%, 95% CI: -0.90, -0.05, P < 0.05, n = 126) and where duration of diabetes is less than 10 y (-0.37, 95% CI: -0.68, -0.07, P < 0.05, n = 83). There was no significant reduction in systolic and diastolic blood pressure and serum Hs-CRP (P > 0.05). The present meta-analysis demonstrated that supplementing with TRF in patients with T2DM decreased HbA1c but does not decrease systolic and diastolic blood pressure and serum Hs-CRP.

Tocotrienol-Rich Vitamin E (Tocovid) Improved Nerve Conduction Velocity in Type 2 Diabetes Mellitus Patients in a Phase II Double-Blind, Randomized Controlled Clinical Trial.

Diabetic peripheral neuropathy (DPN) is the most common microvascular complication of diabetes that affects approximately half of the diabetic population. Up to 53% of DPN patients experience neuropathic pain, which leads to a reduction in the quality of life and work productivity. Tocotrienols have been shown to possess antioxidant, anti-inflammatory, and neuroprotective properties in preclinical and clinical studies. This study aimed to investigate the effects of tocotrienol-rich vitamin E (Tocovid SuprabioTM) on nerve conduction parameters and serum biomarkers among patients with type 2 diabetes mellitus (T2DM). A total of 88 patients were randomized to receive 200 mg of Tocovid twice daily, or a matching placebo for 12 months. Fasting blood samples were collected for measurements of HbA1c, renal profile, lipid profile, and biomarkers. A nerve conduction study (NCS) was performed on all patients at baseline and subsequently at 2, 6, 12 months. Patients were reassessed after 6 months of washout. After 12 months of supplementation, patients in the Tocovid group exhibited highly significant improvements in conduction velocity (CV) of both median and sural sensory nerves as compared to those in the placebo group. The between-intervention-group differences (treatment effects) in CV were 1.60 m/s (95% CI: 0.70, 2.40) for the median nerve and 2.10 m/s (95% CI: 1.50, 2.90) for the sural nerve. A significant difference in peak velocity (PV) was also observed in the sural nerve (2.10 m/s; 95% CI: 1.00, 3.20) after 12 months. Significant improvements in CV were only observed up to 6 months in the tibial motor nerve, 1.30 m/s (95% CI: 0.60, 2.20). There were no significant changes in serum biomarkers, transforming growth factor beta-1 (TGFß-1), or vascular endothelial growth factor A (VEGF-A). After 6 months of washout, there were no significant differences from baseline between groups in nerve conduction parameters of all three nerves. Tocovid at 400 mg/day significantly improve tibial motor nerve CV up to 6 months, but median and sural sensory nerve CV in up to 12 months of supplementation. All improvements diminished after 6 months of washout.

A Phase IIb Randomized Controlled Trial Investigating the Effects of Tocotrienol-Rich Vitamin E on Diabetic Kidney Disease.

Diabetic kidney disease (DKD) is a debilitating complication of diabetes, which develops in 40% of the diabetic population and is responsible for up to 50% of end-stage renal disease (ESRD). Tocotrienols have shown to be a potent antioxidant, anti-inflammatory, and antifibrotic agent in animal and clinical studies. This study evaluated the effects of 400 mg tocotrienol-rich vitamin E supplementation daily on 59 DKD patients over a 12-month period. Patients with stage 3 chronic kidney disease (CKD) or positive urine microalbuminuria (urine to albumin creatinine ratio; UACR > 20-200 mg/mmol) were recruited into a randomized, double-blind, placebo-controlled trial. Patients were randomized into either intervention group (n = 31) which received tocotrienol-rich vitamin E (Tocovid SupraBioTM; Hovid Berhad, Ipoh, Malaysia) 400 mg daily or a placebo group which received placebo capsules (n = 28) for 12 months. HbA1c, renal parameters (i.e., serum creatinine, eGFR, and UACR), and serum biomarkers were collected at intervals of two months. Tocovid supplementation significantly reduced serum creatinine levels (MD: -4.28 ± 14.92 vs. 9.18 ± 24.96), p = 0.029, and significantly improved eGFR (MD: 1.90 ± 5.76 vs. -3.29 ± 9.24), p = 0.011 after eight months. Subgroup analysis of 37 patients with stage 3 CKD demonstrated persistent renoprotective effects over 12 months; Tocovid improved eGFR (MD: 4.83 ± 6.78 vs. -1.45 ± 9.18), p = 0.022 and serum creatinine (MD: -7.85(20.75) vs. 0.84(26.03), p = 0.042) but not UACR. After six months post washout, there was no improvement in serum creatinine and eGFR. There were no significant changes in the serum biomarkers, TGF-ß1 and VEGF-A. Our findings verified the results from the pilot phase study where tocotrienol-rich vitamin E supplementation at two and three months improved kidney function as assessed by serum creatinine and eGFR but not UACR.

The Effects of Tocotrienol-Rich Vitamin E (Tocovid) on Diabetic Neuropathy: A Phase II Randomized Controlled Trial.

Chronic hyperglycemia increases oxidative stress, activates inflammatory pathways and reduces nerve growth factor (NGF) among diabetic patients, which contribute to development of diabetic peripheral neuropathy (DPN). Tocotrienol-Rich Vitamin E (Tocovid) possesses potent antioxidant and anti-inflammatory properties which are postulated to target these pathogeneses in order to ameliorate DPN. This study aims to evaluate the effects of Tocovid on nerve conduction parameters and serum biomarkers among diabetic patients. This multicenter, prospective, randomized, double-blind, placebo-controlled clinical trial was conducted on 80 eligible participants. The intervention group (n = 39) was randomly allocated to receive 200 mg of Tocovid twice a day, and the control group (n = 41) received placebo twice a day. At the end of eight weeks, the nerve conduction parameters, as assessed by nerve conduction study, as well as serum biomarkers (NGF, malondialdehyde, vascular cell adhesion molecule 1, tumor necrosis factor receptor 1 and thromboxane B2) were compared between the two groups. Compared to placebo, Tocovid significantly improves the nerve conduction velocities of all nerves (+1.25 m/s, interquartile range [IQR] 3.35, p < 0.001, median nerve; +1.60 m/s, IQR 1.80, p < 0.001, sural nerve; +0.75 m/s, IQR 2.25, p < 0.001, tibial nerve). Meanwhile, the levels of serum NGF were significantly higher in the Tocovid group as compared to placebo at eight weeks post-intervention. Participants receiving Tocovid illustrated highly significant improvement in terms of nerve conduction velocities for all nerves tested after eight weeks of supplementation. In addition, Tocovid supplementation elevated the levels of serum NGF, in which its increase is postulated to reflect enhanced neuronal functions. This novel finding suggests that Tocovid could be a disease-modifying agent targeting serum NGF to improve nerve conduction velocities.

Tocotrienol-rich vitamin E improves diabetic nephropathy and persists 6-9 months after washout: a phase IIa randomized controlled trial.

Chronic hyperglycemia in type 2 diabetes mellitus increases oxidative stress and inflammation which contributes to long-term diabetic kidney disease. Tocotrienol-rich vitamin E, as Tocovid, has been shown to reduce oxidative stress and inflammation to ameliorate diabetes in rat models and human subjects. In this prospective, multicenter, double-blinded, placebo-controlled clinical trial, 54 patients (duration = 18.4 years, HbA1c = 8.8%) with diabetic nephropathy were randomized to receive Tocovid 200 mg or placebo for 12 weeks. Fasting blood samples were taken to measure HbA1c, serum creatinine, estimate glomerular filtration rate (eGFR), urine albumin:creatinine ratio, malondialdehyde, tumor necrosis factor receptor-1, vascular cell adhesion molecule-1 (VCAM-1), and thromboxane-B2. Patients were reassessed 6-9 months post-washout. After 12 weeks of supplementation, Tocovid significantly decreased serum creatinine levels (mean difference: -3.3 ± 12.6 versus 5.4 ± 14.2, p = 0.027) and significantly increase eGFR (mean difference: 1.5 ± 7.6 versus -2.9 ± 8.0, p = 0.045) compared with placebo. There were no significant changes in HbA1c, blood pressure, and other parameters. Subgroup analysis revealed that in patients with low serum vitamin E concentrations at baseline, Tocovid reduced serum creatinine, eGFR, and VCAM-1 significantly. After 6-9 months of washout, persistent difference in serum creatinine remained between groups (mean difference: 0.82 ± 8.33 versus 11.26 ± 15.47, p = 0.031), but not eGFR. Tocovid at 400 mg/day significantly improved renal function in 12 weeks of supplementation, as assessed by serum creatinine and eGFR, which remained significant 6-9 months post-washout.