Safety and lipid-altering efficacy of a new omega-3 fatty acid and antioxidant-containing medical food in men and women with elevated triacylglycerols

Maki KC, Geohas JG, Dicklin MR, Huebner M, Udani JK.

Prostaglandins Leukot Essent Fatty Acids. 2015 May 30.

Abstract

This randomized, double-blind, placebo-controlled multi-center trial investigated the lipid-altering effects of a medical food (PDL-0101) providing 1.8g/d eicosapentaenoic acid; 12mg/d astaxanthin, a marine algae-derived carotenoid; and 100mg/d tocopherol-free gamma/delta tocotrienolsenriched with geranylgeraniol, extracted from annatto, on triacylglycerols (TAG), other lipoprotein lipids, and oxidized low-density lipoprotein (LDL) in 102 subjects with TAG 150-499mg/dL (1.69-5.63mmol/L) and LDL cholesterol (LDL-C) ≥70mg/dL (1.81mmol/L). Compared to placebo, after eight weeks of treatment, PDL-0101 significantly reduced median TAG (-9.5% vs. 10.6%, p<0.001), while not significantly altering mean LDL-C (-3.0% vs. -8.0% for PDL-0101 and placebo, respectively, p=0.071), mean high-density lipoprotein cholesterol (~3% decrease in both groups, p=0.732), or median oxidized LDL concentrations (5% vs. -5% for PDL-0101 and placebo, respectively, p=0.112). These results demonstrate that PDL-0101 is an effective medical food for the management of elevated TAG.

Cicero AF, Rosticci M, Parini A, M M, Urso R, Grandi E, Borghi C.

Nutr J. 2015 Mar 28;14(1):30.

Abstract

BACKGROUND:

Overweight subjects easily develop alterations of the glucose and lipid metabolism and are exposed to an increased cardiometabolic risk. This condition is potentially reversible through the improvement of dietary and behavioural habits. However, a well-assembled nutraceutical would be a useful tool to better improve the metabolic parameters associated to overweight and insulin resistance.

METHODS:

To evaluate the effect of a combined nutraceutical containing berberine, chlorogenic acid and tocotrienols, we performed a double blind, cross-over designed trial versus placebo, in 40 overweight subjects with mixed hyperlipidaemia. After the first 8 weeks of treatment (or placebo), patients were asked to observe a 2-week washout period, and they were then assigned to the alternative treatment for a further period of 8 weeks. Clinical and laboratory data associated to hyperlipidaemia and insulin resistance have been obtained at the baseline, at the end of the first treatment period, after the washout, and again after the second treatment period.

RESULTS:

Both groups experienced a significant improvement of anthropometric and biochemical parameters versus baseline. However, total cholesterol, LDL cholesterol, triglycerides, non-HDL cholesterol, fasting insulin, HOMA-IR, GOT and Lipid Accumulation Product decreased more significantly in the nutraceutical group versus placebo.

CONCLUSIONS:

This combination seems to improve a large number of metabolic and liver parameters on the short-term in overweight subjects. Further studies are needed to confirm these observations on the middle- and long-term.

Schuchardt JP, Heine S, Hahn A.

Eur J Clin Nutr. 2015 Apr 1

Abstract

BACKGROUND/OBJECTIVES:

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.

SUBJECTS/METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

Tocotrienol Supplementation Improves Lipid Profiles in Chronic Hemodialysis Patients

Scientists have found tocotrienol supplementation lower plasma triglyceride levels in patients undergoing chronic hemodialysis.

The study was conducted by Professor Pramod Khosla’s group in Wayne State University. End-stage renal disease patients on chronic (at least 3 months prior to the study) dialysis treatment were recruited from a local dialysis clinic in Detroit. 81 Patients were randomized to receive either 180 mg tocotrienol rich fraction or placebo daily for 16 weeks. The patient compliance was measured by pill counting. After 12 weeks supplementation, the group receiving tocotrienol supplementation have decreased plasma triglyceride levels from 144 ± 91mg/dL to 113± 47 mg/dL (p <0.05). The triglyceride levels remained low (103± 45 mg/dL) at week 16. In the control group, the plasma triglyceride levels were unchanged.

Triglycerides are produced from energy sources like carbohydrates. High plasma triglyceride levels (> 150 mg/dL) indicate increased risk of cardiovascular diseases. In end-stage renal disease patients, dyslipidemia is highly prevalent with elevated plasma triglyceride levels. This study indicated the lipid-regulation and potential cardio-protection effect of tocotrienol in these patients.

The triglyceride-lowering effect of tocotrienol observed in this clinical study agrees with a previous publication by Davos Life Science, in which supplementation with 120 mg γδ-tocotrienol in 10 hypercholesterolemic subjects for 8 weeks led to a 28% reduction in plasma triglyceride levels.

Both the tocotrienol supplementation group and the control group have decreased levels of total cholesterol, higher levels of high density lipoprotein cholesterol (HDLC) and decreased levels of low-density lipoprotein cholesterol (LDLC) at week 16. This could be due to the effect of the cholesterol-lowering drug statin of which 30-40% of the patients were taking concurrently.

This study reinforced the cardiovascular benefits of palm-derived tocotrienols in lowering triglyceride levels in subjects with mild to moderate dyslipidemia.

Vitamin E tocotrienol supplementation improves lipid profiles in chronic hemodialysis patients

Daud ZA, Tubie B, Sheyman M, Osia R, Adams J, Tubie S, Khosla P.

Vasc Health Risk Manag . 2013;9:747-61. doi: 10.2147/VHRM.S51710. Epub 2013 Nov 28.

Abstract

PURPOSE:

Chronic hemodialysis patients experience accelerated atherosclerosis contributed to by dyslipidemia, inflammation, and an impaired antioxidant system. Vitamin E tocotrienols possess anti-inflammatory and antioxidant properties. However, the impact of dietary intervention with Vitamin E tocotrienols is unknown in this population.

PATIENTS AND METHODS:

A randomized, double-blind, placebo-controlled, parallel trial was conducted in 81 patients undergoing chronic hemodialysis. Subjects were provided daily with capsules containing either vitamin E tocotrienol-rich fraction (TRF) (180 mg tocotrienols, 40 mg tocopherols) or placebo (0.48 mg tocotrienols, 0.88 mg tocopherols). Endpoints included measurements of inflammatory markers (C-reactive protein and interleukin 6), oxidative status (total antioxidant power and malondialdehyde), lipid profiles (plasma total cholesterol, triacylglycerols, and high-density lipoprotein cholesterol), as well as cholesteryl-ester transfer protein activity and apolipoprotein A1.

RESULTS:

TRF supplementation did not impact any nutritional, inflammatory, or oxidative status biomarkers over time when compared with the baseline within the group (one-way repeated measures analysis of variance) or when compared with the placebo group at a particular time point (independent t-test). However, the TRF supplemented group showed improvement in lipid profiles after 12 and 16 weeks of intervention when compared with placebo at the respective time points. Normalized plasma triacylglycerols (cf baseline) in the TRF group were reduced by 33 mg/dL (P=0.032) and 36 mg/dL (P=0.072) after 12 and 16 weeks of intervention but no significant improvement was seen in the placebo group. Similarly, normalized plasma high-density lipoprotein cholesterol was higher (P<0.05) in the TRF group as compared with placebo at both week 12 and week 16. The changes in the TRF group at week 12 and week 16 were associated with higher plasma apolipoprotein A1 concentration (P<0.02) and lower cholesteryl-ester transfer protein activity (P<0.001).

CONCLUSION:

TRF supplementation improved lipid profiles in this study of maintenance hemodialysis patients. A multi-centered trial is warranted to confirm these observations.

David Heber, Center for Human Nutrition, UCLA

Terminated

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

Methodology:

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

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

Dr Teng Kim Tiu, PhD, Universiti Malaya

Completed

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.

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

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

Published

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.

Qureshi AA, Khan DA, Mahjabeen W, Papasian CJ, Qureshi N.

J Clin Exp Cardiolog. 2012 Jun 7;S5:8.

Published

Objectives: To determine whether serum nitric oxide (NO) levels increase with age in humans, and whether the combined cholesterol-lowering and inflammation-reducing properties of resveratrol, pterostilbene, morin hydrate, quercetin, δ-tocotrienol, riboflavin, and nicotinic acid would reduce cardiovascular risk factors in humans when used as nutritional supplements with, or without, other dietary changes.

Subjects: Healthy Seniors and Hypercholesterolemic Subjects

Intervention: δ-tocotrienol, resveratrol, pterostilbene, Morin hydrate, quercetin, riboflavin, and nicotinic acid

Primary outcome: Serum NO, C-reactive protein (CRP), γ-glutamyltransferase (γ-GT) activity, uric acid, total antioxidant status (TAS), total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides levels

Methodology: Elderly human subjects were stratified into two groups based on total serum cholesterol levels. Initial total serum cholesterol levels were normal and elevated in Group 1 and 2 subjects, respectively. Baseline serum NO, C-reactive protein (CRP), γ-glutamyltransferase (γ-GT) activity, uric acid, total antioxidant status (TAS), total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides levels were established over a four week period. Group 1 subjects subsequently received nutritional supplementation with one of two different combinations (NS-7 = 25 mg of each, resveratrol, pterostilbene, quercetin, δ-tocotrienol, nicotinic acid, morin hydrate or NS-6 = morin hydrate replaced with quercetin, 50 mg/capsule). Group 2subjects also received these nutritional supplements (two capsules/d), but an AHA Step-1 diet was also implemented. After these interventions were administered for four weeks, the above parameters were re-measured and changes from baseline levels determined. Nitric acid (NO) levels in children, young adults, and seniors were also compared.

Results: The key results of the current study were: 1) that serum NO levels were significantly increased in seniors compared to both children (~80%) and young adults (~65%); 2) that the intake of two capsules/d of NS-7 or NS-6 for four weeks significantly (P < 0.05) decreased serum NO (39%, 24%), CRP (19%, 21%), uric acid (6%, 12%) levels, and γ-GT activity (8%, 6%), respectively in free-living healthy seniors; 3) that serum NO (36%, 29%), CRP (29%, 20%), uric acid (6%, 9%) γ-GT activity (9%, 18%), total cholesterol (8%, 11%), LDL-cholesterol (10%, 13%), and triglycerides (16%, 23%) levels were significantly (P < 0.02) decreased in hypercholesterolemic subjects restricted to AHA Step-1 diet plus intake of SN-7 or SN-6 (two capsules/d), respectively; 4) that TAS was increased (3%, 9%; P < 0.05) in free-living healthy seniors receiving NS-7 or NS-6 alone, and in hypercholesterolemic subjects plus AHA Step-1 diet (20%, 12%; P < 0.02) with either of the combinations tested.

Conclusions: Serum NO levels are elevated in elderly humans compared to children or young adults. Diet supplementation with combinations of resveratrol, pterostilbene, morin hydrate, quercetin, δ-tocotrienol, riboflavin, and nicotinic acid reduce cardiovascular risk factors in humans when used as nutritional supplements with, or without, other dietary changes.

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

Abstract

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.