The effects of tocotrienol supplementation on lipid profile: A meta-analysis of randomized controlled trials

Shuping Zuo, Guiping Wang, QuanLe Han, Hongling Xiao, Heitor O Santos, David Avelar Rodriguez, Vahid Khani, Jianlei Tang

Complement Ther Med . 2020 Aug;52:102450. doi: 10.1016/j.ctim.2020.102450. Epub 2020 May 25.


Background & objective: Tocotrienol supplementation has been emerged as a potent candidate for the treatment of dyslipidemia. In the present study, a systematic review and meta-analysis of randomized controlled trials was performed with the aim of examining the effects of tocotrienol supplementation on the lipid profile.

Methods: Four databases (Scopus, PubMed/Medline, Web of Science and Embase) were used to accomplish the literature search up to November 2019. Clinical trials encompassing the impact of tocotrienol supplementation on lipid profile were extracted regardless of clinical condition, with studies included involving only adults patients.

Results: A total of 15 articles with 20 arms were eligible and included in the meta-analysis to estimate the pooled effect size. Overall results showed a significant effect of tocotrienol supplementation on increasing high-density lipoprotein cholesterol (HDL-C) levels (weight mean difference (WMD): 0.146 mmol/L, I2 = 85.9%) and a non-significant influence on total cholesterol (TC) (WMD: 0.010 mmol/L, I2 = 64.5%), low-density lipoprotein cholesterol (LDL-C) (WMD: 0.095 mmol/L, I2 = 87.4%), and triglycerides (TG) (WMD: -0.112 mmol/L, I2 = 67.4%) levels. Increment in HDL-C levels was significant greater for the tocotrienol dosage ≥ 200 mg/d (WMD: 0.202 mmol/L) and ≤8 weeks (WMD: 0.278 mmol/L). Moreover, studies that investigated tocotrienol dose ≥200 mg had no heterogeneity, while showing a significant decrease in TG levels (WMD: -0.177 mmol/L).

Conclusion: The present meta-analysis demonstrated that supplementing with tocotrienols does not decrease the concentrations of LDL-C, TC and TG. However, tocotrienol supplementation was considered a candidate for increasing HDL-C levels.

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Effect of Tocotrienols enriched canola oil on glycemic control and oxidative status in patients with type 2 diabetes mellitus: A randomized double-blind placebo-controlled clinical trial

Vafa M, Haghighat N, Moslehi N, Eghtesadi S, Heydari I.

J Res Med Sci. 2015 Jun;20(6):540-7



Tocotrienols have been shown to improve glycemic control and redox balance in an animal study, but their effects on patients with diabetes are unknown. The study aimed to investigate whether tocotrienols improves glycemic control, insulin sensitivity, and oxidative stress in individuals with type 2 diabetes mellitus (T2DM).


This study was a double-blinded, placebo-controlled, randomized trial. A total of 50 patients, aged 35-60 years, with T2DM treated by noninsulin hypoglycemic drugs were randomly assigned to receive either 15 mL/day tocotrienols (200 mg) enriched canola oil (n = 25) or pure canola oil (n = 25) for 8 weeks. Fasting blood sugar (FBS), fasting insulin, total antioxidant capacity (TAC), malondialdehyde (MDA), and homeostatic model assessment for insulin resistance (HOMA-IR) were determined before and after the intervention. The data were compared between and within groups, before and after the intervention.


Baseline characteristics of participants including age, sex, physical activity, disease duration, and type of drug consumption were not significantly different between the two groups. In tocotrienol enriched canola oil, FBS (mean percent change: -15.4% vs. 3.9%; P = 0.006) and MDA (median percent change: -35.6% vs. 16.3%; P = 0.003) were significantly reduced while TAC was significantly increased (median percent change: 21.4% vs. 2.3%; P = 0.001) compared to pure canola oil. At the end of the study, patients who treated with tocotrienols had lower FBS (P = 0.023) and MDA (P = 0.044) compared to the pure canola oil group. However, tocotrienols had no effect on insulin concentrations and HOMA-IR.


Tocotrienols can improve FBS concentrations and modifies redox balance in T2DM patients with poor glycemic control and can be considered in combination with hypoglycemic drugs to better control of T2DM.

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Focus on Pivotal Role of Dietary Intake (Diet and Supplement) and Blood Levels of Tocopherols and Tocotrienols in Obtaining Successful Aging

Rondanelli M, Faliva MA, Peroni G, Moncaglieri F, Infantino V, Naso M, Perna S.

Int J Mol Sci. 2015 Sep 25;16(10):23227-49.


Numerous specific age-related morbidities have been correlated with low intake and serum levels of tocopherols and tocotrienols. We performed a review in order to evaluate the extant evidence regarding: (1) the association between intake and serum levels of tocopherols and tocotrienols and age-related pathologies (osteoporosis, sarcopenia and cognitive impairment); and (2) the optimum diet therapy or supplementation with tocopherols and tocotrienols for the treatment of these abnormalities. This review included 51 eligible studies. The recent literature underlines that, given the detrimental effect of low intake and serum levels of tocopherols and tocotrienols on bone, muscle mass, and cognitive function, a change in the lifestyle must be the cornerstone in the prevention of these specific age-related pathologies related to vitamin E-deficient status. The optimum diet therapy in the elderly for avoiding vitamin E deficiency and its negative correlates, such as high inflammation and oxidation, must aim at achieving specific nutritional goals. These goals must be reached through: accession of the elderly subjects to specific personalized dietary programs aimed at achieving and/or maintaining body weight (avoid malnutrition); increase their intake of food rich in vitamin E, such as derivatives of oily seeds (in particular wheat germ oil), olive oil, hazelnuts, walnuts, almonds, and cereals rich in vitamin E (such as specific rice cultivar rich in tocotrienols) or take vitamin E supplements. In this case, vitamin E can be correctly used in a personalized way either for the outcome from the pathology or to achieve healthy aging and longevity without any adverse effects.

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A combination of palm oil tocotrienols and citrus peel polymethoxylated flavones does not influence elevated LDL cholesterol and high-sensitivity C-reactive protein levels

Schuchardt JP, Heine S, Hahn A.

Eur J Clin Nutr. 2015 Apr 1



Lipid-lowering and anti-inflammatory effects have been individually described for tocotrienols (TTs) and polymethoxylated flavones (PMFs). This study investigated low-density lipoprotein-cholesterol (LDL-C)- and high-sensitivity C-reactive protein (hsCRP)-reducing effects of combined TT-PMF treatment in low doses in hypercholesterolemic individuals with subclinical inflammation.


In the double-blind, placebo-controlled study, 240 Caucasians with LDL-C ⩾3.36 mmol/l and hsCRP ⩾1 mg/l were enrolled and randomized into group S1 (12 mg/day TT and 103 mg/day PMF), group S2 (27 mg/day TT and 32 mg/day PMF) or placebo.


Twenty-three subjects dropped out of the study, 13 were excluded from the analysis because of lack of compliance. A total of 204 subjects per-protocol analysis were included. After 12 weeks of treatment, no significant differences in LDL-C levels (primary outcome) were observed between groups. LDL-C levels significantly decreased in all intervention groups (S1: -5.2%, S2: -4.8% and P: -4.2%). Total cholesterol and hsCRP (secondary outcome) did not change significantly.


PMF-TT supplements had no effect beyond that of placebo on elevated LDL-C and hsCRP levels.European Journal of Clinical Nutrition advance online publication, 1 April 2015; doi:10.1038/ejcn.2015.44.

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Effects of Tocotrienol-Enriched Fraction of Palm Oil of Serum Lipids in Hypercholesterolemic Subjects

David Heber, Center for Human Nutrition, UCLA


Objective: To evaluate cholesterol-suppressive actions of tocotrienol-enriched fractions in hypercholesterolemic human subjects.

Study Type:Interventional

Study Design: Randomized, double-blind, placebo-controlled

Subjects: Hypercholesterolemic subjects

Intervention: Gamma-Delta Tocotrienol (63 mg and 127 mg; Davos Life Science Pte Ltd)

Primary Outcome:

  • Fasting cholesterol levels [time frame: baseline, 4, 8, 12 weeks]
  • Total body fat [time frame: baseline, 4, 8 12 weeks]

Secondary Outcome:

  • Genetic biomarkers for lipid metabolism


The cholesterol suppressive actions of tocotrienol-enriched formulations will be assessed in 99 hypercholesterolemic subjects 37 – 70 years of age, During a two-week run-in period, subjects will be asked to follow the American Heart Association Step 1 dietary regimen and to take a placebo capsule twice daily to determine their ability to comply with the diet and pill regimen. Their fasting cholesterol levels will be tested again after the two-week run-in period.

At this point, they will be randomly assigned to take either a placebo capsule or tocotrienol twice daily. Subjects will have body weight, waist circumference, fasting lipids and other biomarkers measured at 0, 4, 8 and 12 weeks

The Effect of Supplemental Adjuvants for Intracellular Nutrition and Treatment on Diabetic Macular Edema and Neovascular Age-Related Macular Degeneration

Nabil M Jabbour, MD, FACS M.A.R.C., West Virginia University


Objective: Nutritional supplements have an augmentative effect on the outcomes of standard treatment of diabetic macular edema (DME) and Neovascular Age-Related Macular Degeneration (NAMD).

Study Type: Interventional

Study Design: Randomized, Double-blind Study

Subjects: Subjects with age-related macular degeneration

Drug — Neutral pills with no medicinal effect
Dietary Supplement —  Inosine; Tocopherols, Tocotrienol, CoQ10 combination capsule; Niacinamide SR; Viatmin C; N-acetyl Cysteine; Complete Multivitamin with all minerals

Drug: Inosine; Tocopherol, Tocotrienol, CoQ10 combination capsule; Niacinamide; Vitamin C; N-acetyl Cysteine; Complete Multivitamin with all minerals; Minocycline

Primary Outcome: Anatomic and visual outcomes

Secondary Outcome: 1) Effect on HbA1C [ Time Frame: Monthly ]

2) Effect on Blood pressure [ Time Frame: Monthly ]

3) Effect on serum uric acid [ Time Frame: Monthly ]

Methodology: It has been shown that in chronic diseases, oxidative stress results from Nitric acid reacting with oxygen to form toxins that damage both somatic and mitochondrial DNA. The potential for protecting the DNA and promoting repair by using nutritional supplements will be tested by augmenting standard treatments for DME and NAMD with such supplements. The patients will be randomized to treatment group and placebo group and followed up for a year in a double masked fashion. Anatomic and visual outcomes, as well as side effects will be assessed and analyzed. If the results are promising, this pilot study can be used to design alternative (cheaper, better and longer lasting) treatments for DME, NAMD and perhaps other chronic illnesses.

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Acute Effects of Tocotrienols on Insulinaemic and Inflammatory Responses in Metabolic Syndrome Subjects

Dr Teng Kim Tiu, PhD, Universiti Malaya


Objectives: To compare the acute effects of gamma delta rich tocotrienol fractions (gd-TRF) on insulin sensitivity, metabolic risk markers and postprandial lipemia in individuals at risk for metabolic syndrome.

Study Type: Interventional

Study Design: Randomized, double-blind, cross-over

Subjects: Patients at risk for metabolic syndrome

Intervention: Gamma-Delta tocotrienol, placebo

Primary Outcome: C-peptide [ Time Frame: 0, 15, 30, 60, 90, 120, 180, 240, 300, 360 min ]

Secondary Outcome: 1) Insulin sensitivity (insulin, glucose) [ Time Frame: 0, 5, 15, 30, 60, 90, 120, 180, 240, 300, 360 min ]

2) Non-esterified fatty acid (NEFA) [ Time Frame: 0, 5, 15, 30, 60, 90, 120, 180, 240, 300, 360 min ]

3) Non-esterified fatty acid (NEFA) [ Time Frame: 0, 5, 15, 30, 60, 90, 120, 180, 240, 300, 360 min ]

4) Inflammatory markers (IL-6, IL-1β, TNF-α) [ Time Frame: 0, 120, 240, 360 min ]

5) PBMC nuclear factor-κappa B (NF-κB) [ Time Frame: 0, 240, 360 min ]

Methodology: A randomised, double-blind, crossover trial will be undertaken to test the acute effects of supplementation of 200 mg, 400 mg gd-TRF vs. placebo. There are 3 occasions for subjects to attend during postprandial period and these occasions will be separated by at least one week. On the day preceding the postprandial high fat meal challenge, subjects will be asked to avoid food high in fat, alcohol, caffeine and taking part in any strenuous exercise. Subjects will be provided with a standardised low fat meal (containing < 10 g fat) on the day preceding the postprandial study days to consume as their evening meal. They will be asked to fast overnight and instructed to avoid eating or drinking anything, except water, after 10 pm. Fasting blood samples will be collected on the next day and subjects will then consume the test meal, containing 50 g test fat supplemented with gd-TRF. Further venous blood samples will be collected at regular intervals for up to 6 hours postprandially.

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Effects of Tocotrienols Supplementation on Platelet Aggregation in Subjects With Metabolic Syndrome

Ju Yen Fu, PhD, Universiti Putra Malaysia


Objective: The objective of this study is to address the anti-thrombotic effects of tocotrienols supplementation via modulation of platelet activation, thrombotic markers, inflammatory markers and endothelial function.

Study Type: Interventional

Study Design: Randomized, Double-blind

Subjects: Volunteers with metabolic syndrome

Intervention: Tocotrienol-rich fraction 400 mg, placebo

Primary Outcome: Platelet Aggregation. Changes will be measured in between Day 0 and Day 14-fasting, and Day 14-fasting and 4hr.

Secondary Outcome: 1) Platelet activation. Changes will be measured in between Day 0 and Day 14-fasting, and Day 14-fasting and 4hr.

2) Haemostatic markers (Activated factor VII and Plasminogen activator inhibitor type 1) Changes will be measured in between Day 0 and Day 14-fasting. During Day 14, changes of markers when compared to fasting sample will be measured at 2 hours, 4 hours, and 6 hours after high fat breakfast.

3) Inflammatory markers (NF-kB, sICAM-1, and sVCAM-1) Changes will be measured in between Day 0 and Day 14-fasting, and Day 14-fasting and 4hr.

4) Lipid Profile. Changes will be measured in between Day 0 and Day 14-fasting

5) D-dimer. Changes will be measured in between Day 0 and Day 14-fasting, and Day 14-fasting and 4hr.

Methodology: A double-blind, randomized, crossover study comparing the effects of tocotrienols vs. placebo will be conducted in subjects with metabolic syndrome. Subjects will be supplemented with Tocovid Suprabio 200 mg twice daily (or placebo) for 2 weeks followed by a postprandial challenge on Day 14. During the postprandial challenge, venous blood samples will be collected during fasting. Subjects are then required to consume a high fat breakfast meal containing 50g fat and 100mL milkshake, followed by the assigned capsules. Venous blood samples will be drawn at 2, 4 and 6 hours after consumption of capsules. A washout period of at least 14 days will be in place before the commencement of the second treatment.

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Effect of Mixed-Tocotrienols in Hypercholesterolemic Subjects

Kah Hay Yuen, Jia Woei Wong, Ai Beoy Lim, Bee Hong Ng, Wai Peng Choy

Functional Foods in Health and Disease: 3:106-117


Objectives: Aims to investigate the cholesterol lowering activity of tocotrienols.

Study design: Randomized, double blind study

Subjects: Hypercholesterolemic patients

Intervention: Mixed tocotrienol 300 mg versus placebo (soya bean oil 300 mg)

Primary outcome: Tocotrienol and tocopherol concentrations and serum cholesterol levels

Methodology: Thirty-two hypercholesterolemic subjects were randomly assigned to orally receive either 300 mg of mixed tocotrienols capsules daily or placebo capsules containing 300 mg of soya bean oil for a period of 6 months. The subjects were monitored before supplementation and monthly thereafter for their serum cholesterol as well as tocotrienol and tocopherol concentrations.

Results: The serum total cholesterol and low density lipoprotein (LDL) cholesterol of the subjects in the tocotrienol supplementation group were decreased significantly by 8.9 ± 0.9% and 12.8 ± 2.6% respectively after 4 months of supplementation and the reduction persisted till the end of the 6-month study, with a reduction of 10.8 ± 1.0% and 17.3 ± 1.8%, respectively from baseline. Moreover, there was a 22fold increase in the total tocotrienol concentrations from baseline during supplementation compared to the placebo group, while the concentration of α-tocopherol recorded only a modest increase. On the other hand, the serum cholesterol, total tocotrienol and α-tocopherol concentrations of subjects in the placebo group remained essentially unchanged.

Conclusion: Supplementation with mixed tocotrienols at dose of 300 mg per day resulted in the lowering of the serum total and LDL cholesterol levels after 5 months of supplementation.

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Tocotrienol rich fraction supplementation improved lipid profile and oxidative status in healthy older adults: A randomized controlled study

Chin, S. F.,Ibahim, J.,Makpol, S.,Abdul Hamid, N. A.,Abdul Latiff, A.,Zakaria, Z.,Mazlan, M.,Mohd Yusof, Y. A.,Abdul Karim, A.,Wan Ngah, W. Z.

Nutr Metab (Lond) 2011;8(1):42


Background: Vitamin E supplements containing tocotrienols are now being recommended for optimum health but its effects are scarcely known. The objective was to determine the effects of Tocotrienol Rich Fraction (TRF) supplementation on lipid profile and oxidative status in healthy older individuals at a dose of 160 mg/day for 6 months.

Methods: Sixty-two subjects were recruited from two age groups: 35-49 years (n = 31) and above 50 years (n = 31), and randomly assigned to receive either TRF or placebo capsules for six months. Blood samples were obtained at 0, 3rd and 6th months.

Results: HDL-cholesterol in the TRF-supplemented group was elevated after 6 months (p < 0.01). Protein carbonyl contents were markedly decreased (p < 0.001), whereas AGE levels were lowered in the > 50 year-old group (p < 0.05). Plasma levels of total vitamin E particularly tocopherols were significantly increased in the TRF-supplemented group after 3 months (p < 0.01). Plasma total tocotrienols were only increased in the > 50 year-old group after receiving 6 months of TRF supplementation. Changes in enzyme activities were only observed in the > 50 year-old group. SOD activity was decreased after 3 (p < 0.05) and 6 (p < 0.05) months of TRF supplementation whereas CAT activity was decreased after 3 (p < 0.01) and 6 (p < 0.05) months in the placebo group. GPx activity was increased at 6 months for both treatment and placebo groups (p < 0.05).

Conclusion: The observed improvement of plasma cholesterol, AGE and antioxidant vitamin levels as well as the reduced protein damage may indicate a restoration of redox balance after TRF supplementation, particularly in individuals over 50 years of age.

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