Tocotrienols in the Management of Hypercholesterolemia and Atherosclerosis
September 2000; Volume 3; 101-105
By Philippe O. Szapary, MD, and Michael D. Cirigliano, MD, FACP
Commercial vitamin e (tocopherol) is the best-selling single vitamin supplement in the United States and is the dietary supplement most frequently taken by cardiologists. Its popularity as a useful antioxidant in atherosclerotic cardiovascular disease (ASCVD) prevention comes from multiple observational studies and the much-publicized Cambridge Heart Antioxidant Study (CHAOS).1 Two large, recently published intervention studies (GISSI, HOPE) done in patients with recognized ASCVD, however, have not shown any benefit of tocopherol supplementation, raising doubts about the usefulness of tocopherols in secondary prevention of ASCVD.2,3
While tocopherols have been the subject of extensive study as antioxidants, their lesser-known relatives, tocotrienols, hold promise as potent antioxidants with the additional capacity to lower serum cholesterol. Tocotrienols (T3) have been shown to be more potent antioxidants than tocopherols, and based on animal and human trials, have the added advantage of probably lowering serum cholesterol, making these agents potentially useful adjuncts in the management and prevention of ASCVD.
Chemical Structure
Tocotrienols are naturally occurring analogues of tocopherols, differing only in their chemical structure. Evans and Bishop discovered vitamin E as a factor essential in rat reproduction in 1922.4 The name tocopherol came from "tokos" (childbirth) and "phorein" (to bring forth) and the suffix "-ol" was added to describe its phenolic nature.
Most physicians use the term "vitamin E" to describe all chromanols (tocopherols and tocotrienols).5 There are four naturally occurring isomers of tocopherols (a, b, g, d) and four isomers of tocotrienols (a, b, g, d). Tocotrienols differ from tocopherols in that tocotrienols, as the name implies, have three double bonds in their side chain while tocopherols have none.
Dietary Sources
Tocopherols are naturally found in seeds, nuts, and greens while tocotrienols are typically found in oils, bran, and cereal.
In Western culture, a-tocopherol is the most commonly ingested chromanol, making up 85% of the total vitamin E compounds ingested in the diet—usually in the form of vegetable oil and margarines.6 The highest concentrations of T3 are found in palm and coconut oils, which have generally been discouraged by nutritionists because they also contain large amounts of saturated fats.
In Asian diets, an important source of T3 comes from rice bran oil (RBO) which also contains large amounts of cholesterol-lowering phytosterols and g-oryzanol.7 Its low flavor transference and high smoke point makes RBO well suited for sautéing and frying, and because of its delicate flavor, it can also be used on salads.
Mechanism of Action
T3 appear to be 45% more potent as in vitro inhibitors of oxidant stress than tocopherols as measured by TBARS, conjugated dienes, and lipid hydroperoxide assays.8,9 In these two studies g-T3 was more potent than a-T3 than d-T3. Much more is known about the anti- oxidant properties of tocopherols than those of T3.
T3 but not tocopherols have been shown to regulate the post-transcriptional suppression of 3-hydroxy-3-methylglutaryl-Coenzyme A reductase (HMG-CoA reductase), a key enzyme in cholesterol biosynthesis.10 From these studies it appears that the g-isomer of T3 is the most potent inhibitor of HMG-CoA reductase followed by d-T3. Interestingly, one animal study found that at concentrations of greater than 30%, a-tocopherol diminished the cholesterol-reducing effect of g-T3.11
Animal Studies
Numerous case series have suggested that T3 reduce serum cholesterol. One study in hypercholesterolemic pigs found that feedings with a tocotrienol-rich fraction (TRF) derived from palm oil decreased low-density lipoprotein (LDL-C) by as much as 60% while also decreasing apolipoprotein B and platelet-activating factor.12 In a hypercholesterolemic rabbit model, 15 animals were randomized to T3-enriched, a-tocopherol-enriched, or control feeds for 12 weeks.13 At the study’s end, only those animals receiving the T3 showed statistically significant reductions in serum cholesterol as compared to a-tocopherol or controls. Both T3 and a-tocopherol equally seemed to reduce lipid peroxides and attenuate atheroma formation.13
Clinical Trials
Through a search of MEDLINE, IBIDS, NCCAM Citation Index databases, as well as a review of cited references and personal communications with experts, we identified 14 human clinical trials published in English of tocotrienols either used alone in capsule form or as an oil from either palm or rice bran. Of these trials, 11 were randomized, double-blind, controlled trials (RDBCT) with one of these trials only being reported in abstract form14 and another published only as a proceeding from a conference.15 Excluding these two reports, four of the RDBCTs showed a positive hypolipidemic effect16-19 while five others showed no effect on lipids.20-24 All studies used a naturally derived form of mixed tocotrienols with varying amounts of tocopherols.
The same group of authors performed three out of the four positive trials. Qureshi et al showed that 200 mg of TRF in capsule form derived from palm oil (Palmvitee®) decreased total cholesterol (TC) by 33% compared to a corn oil placebo over four weeks, without a significant change in high-density lipoprotein (HDL-C) or triglycerides (TG).
In a later study, Qureshi and colleagues randomized 36 subjects with an average TC = 277 mg/dL to 260 mg TRF from Palmvitee vs. corn oil placebo after four weeks of American Heart Association Step 1 diet. The T3-treated subjects experienced a statistically significant reduction in LDL-C by 13% (P < 0.05) above and beyond the 11% decrease seen with the Step 1 diet alone. Again there were no changes in HDL-C or TG levels. The Palmvitee preparation used in these two studies contained 15% tocopherols and 85% T3 (primarily the g and d homologues).
More recently Qureshi et al published an industry sponsored RDBCT of 41 subjects randomized to a proprietary rice bran-derived TRF (EvolvE®, Bionutrics, Inc.) vs. placebo over eight weeks after four weeks of a Step 1 stabilization diet. They noted that 200 mg of EvolvE reduced LDL-C 16% above and beyond the diet control group. The investigators also noted a reduction in apolipoprotein-B and lipoprotein (a) [Lp(a)] by 15% and 17% respectively.
These positive results are tempered by a recently published negative study. This RDBCT evaluated the effectiveness of a palm-derived TRF (total T3 = 160 mg/d, total tocopherols = 80 mg/d) in 20 men with TC > 251 mg/dL or Lp(a) > 150 mg/dL.24 In this six-week study without a specific dietary control, there were no differences noted either in any lipoprotein parameters including Lp(a) nor in measures of platelet function. Of note, the placebo group was taking a tocopherol-only preparation, to evaluate the role of T3 alone. This may have attenuated the effect of T3 on measures of fibrinolysis and oxidant stress but should not have affected the lipid measurements.
The largest and longest published study of T3 evaluated the efficacy of Palmvitee over 18 months in 50 subjects with known carotid atherosclerotic disease.23 In this RDBCT, subjects were randomized to two escalating doses of Palmvitee (160 mg and 240 mg T3) or palm oil without T3 placebo, and followed by serial carotid ultrasound (primary endpoint).
Although Palmvitee did not change serum cholesterol, at one year, seven subjects in the T3 group vs. none in the control group showed any evidence of plaque regression (P < 0.002). Additionally, two subjects in the T3 group (8%) vs. 10 subjects in the control group showed evidence of atheroma progression (40%). Also, these investigators showed that T3-treated subjects had increased resistance to oxidant stress measured in vitro. Interestingly, this effect on plaque regression was seen in spite of finding no effects on any lipoprotein fractions.
Taken in aggregate, results from this last study imply that T3, while not affecting lipids, act as antioxidants and seem to stabilize atherosclerotic plaque. Although these results are promising, the trial suffers from a small number of patients and a poor description of statistical methodology.
Adverse Effects and Interactions
Clinical trials to date have not reported adverse effects from T3 up to one year. There are no known drug interactions with T3. Because T3, like tocopherols, inhibit platelet aggregation in vitro, they may cause bleeding when used alone or in conjunction with other antiplatelet agents like aspirin or nonsteroidal anti-inflammatory drugs. Recent large RDBCTs of up to 400 mg of a-tocopherol have not shown excessive bleeding risk.2,3
Formulation and Dosage
Although much of the published literature used Palmvitee, this pill is not commercially available in the United States. Consuming palm oil itself, a reddish-orange oil popular in West African and Brazilian cuisine, is not recommended as a source of T3 because it also contains high levels of saturated fatty acids.
In the United States, commercially available forms of T3 are derived from rice bran oil (RBO). Since T3 standardization is problematic, the exact amount of T3 in RBO is not known, making it difficult to recommend a specific amount of RBO for daily consumption. Other components of RBO, including g-oryzanol and phytosterols, have also been shown to reduce serum cholesterol so RBO’s lipid effect is likely multifactorial.25,26 Of note, a blend of safflower oil and RBO has been shown to enhance the cholesterol-lowering effect of RBO alone.25
For its purported cholesterol-lowering effects, at least 200 mg of T3 are needed, making this therapy more cumbersome and more expensive than low-dose statins. (See Table 1.) For use as antioxidants, T3 remain costly compared to a mixed tocopherol-only preparation, which costs approximately $4/month.
| Table 1-Comparison of tocotrienol preparations for management of hypercholesterolemia | ||||||
| Product (Manufacturer) | Source | Tocotrienols per capsule |
a-tocopherol per capsule |
% a-T | Dose per day* |
Retail cost per month |
| EvolvE®(Bionutrics) | RBO | 10 mg | 3 mg | 6% | 8 capsules | $60 |
| Tocotrien-All (Natrol) | RBO | 50 mg | 30 mg | 60% | 4 capsules | $63 |
| MaxLife Rice Tocotrienols (Twinlab) |
RBO | 51 mg | 35 mg | 68% | 4 capsules | $60 |
| Lovastatin (Merck) | Prescription | 0 mg | 0 mg | NA | 10 mg | $50 |
| EvolvE is a mixed preparation; although it contains less T3 per capsule, it also contains 5% phytosterols and g-oryzanol, which have hypolipidemic effects. | ||||||
| * Dose is approximately equipotent and can be taken once per day with a meal. | ||||||
| Source: online pharmacies, Hospital of the University of Pennsylvania outpatient pharmacy | ||||||
Of interest, animal experiments suggest that T3 preparations containing > 30% a-tocopherol may actually attenuate the beneficial suppression of HMG-CoA reductase by g-T3.11
Conclusion
Tocotrienols have salutary effects in modulating cardiovascular risk, but many questions about the utility of T3 in clinical practice remain. Isolated T3 at doses of 200 mg appear to modestly reduce LDL-C by between 10-20% without affecting other lipoproteins. The data appear stronger and more consistent for T3 derived from RBO (two positive and zero negative studies) than for palm-derived T3 (two positive and seven negative studies). Daily consumption of RBO appears to reduce LDL-C by about 5%, comparable to other "healthy" oils such as safflower and corn oils.19 Dietary ingestion of palm oil is not recommended because of its high saturated fat content.
The purified and concentrated capsule forms of T3, while more effective and potent in reducing cholesterol than dietary sources, are expensive but can be taken all at once with a meal. More research is needed in the role of T3 in combination with other agents such as statins in reducing cardiovascular risk.
As antioxidants, T3 reduce serum markers of oxidant stress and delay atherosclerosis progression in a single one-year clinical trial. Given the recent disappointing results of tocopherol supplementation in high-risk patients,2,3 larger and longer studies using combination chromanol preparations are needed to evaluate the added benefit of T3 therapy in prevention of ASCVD. The question of dose and optimal tocotrienol to tocopherol ratio is very important and still remains open.
Recommendation
In patients at risk for ASCVD, substituting RBO for saturated fats and trans-fatty acids will help maintain healthy serum cholesterol levels. In patients with mild-to-moderate elevations in LDL-C who do not want to take or who cannot tolerate traditional hypolipidemic agents, T3 capsules may modestly reduce LDL-C. In patients at risk for ASCVD who are interested in taking antioxidants, the addition of T3 to tocopherols makes biologic and therapeutic sense but this combination has not yet been evaluated in long-term clinical studies.
Dr. Szapary and Dr. Cirigliano are Assistant Professors of Medicine at the University of Pennsylvania School of Medicine in Philadelphia.
References
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24. Mensink RP, et al. A vitamin E concentrate rich in tocotrienols had no effect on serum lipids, lipoproteins, or platelet function in men with mildly elevated serum lipid concentrations. Am J Clin Nutr 1999;69:213-219.
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September 2000; Volume 3; 101-105
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