Posted on 12th Jul 2009 @ 4:57 AM

ADVANCES in orthomolecular research pg. 22
In December 2004, the Annals of Internal Medicine
announced the pre-press results of a new study on the
effects of high-dose “vitamin E” supplements on the death
rate in patients at high cardiovascular risk.1 Pooling the
results of 19 randomized, controlled trials of “vitamin E”
supplements, the authors concluded that “High-dosage (400
IU/d) vitamin E supplements may increase all-cause
mortality and should be avoided.”
If you’ll pardon the gallows humor: many supplement users
nearly had a heart attack.
How could this be? Vitamin E is, along with vitamin C,
probably the most widely-used antioxidant supplement in
the world, taken daily as a stand-alone supplement by
22% of American adults over 55 years of age.2 And its role
in heart health has been taken as health-food-store dogma
for decades. Even medical doctors – amongst the most
conservative people when it comes to the benefits of
supplements – take vitamin E pills at about the same rate
as the population at large.3,4
If you’ve listened to the mainstream press for
the last decade or so, you’ve probably
heard at least a few press reports on
studies that failed to find a benefit to vitamin
E in heart patients. But to suggest that
vitamin E might actually increase the death
rate is straight out of left field. It can’t be right.
Can it?
Well, yes, it can. All of those studies reporting “no effect”
have actually been finding very small increases in the death
rate in people taking the “vitamin E” supplements
compared to those taking the placebo dummy pills. But the
difference between the two groups has been so small as to
be statistically insignificant. No responsible scientist would
report a result that appeared to be nothing more than a
statistical fluke as a real increase in mortality.
It’s only when these many trials were combined into one
“supertrial” (meta-analysis) that it became clear. The
assembled trials showed no harmful effect from low-dose
(less than 50 IU per day) “vitamin E” supplements. In fact,
there even appeared to be a small benefit – but it’s hard
to say, because most of these low-dose studies (the Linxian,
MIN.VIT.AOX., and SU.VI.MAX. trials) also included
selenium and other beneficial nutrients that might have
been responsible for the positive results. But the pooled
results for the “high dose” (>400 IU) trials were clear:
people taking 400 IU or more of alpha-tocopherol a day
are actually increasing their risk of death (Figure 1)!1
If all you’ve heard about vitamin E and heart health has
come from the mainstream press and “establishment”
supplement companies, then this result will come as a
complete shock. But if
you’ve been watching
the research that’s been
accumulating on “vitamin
E” for the last decade or
so a bit more carefully,
you’ve spent much of the last decade waiting for this
second shoe to drop.
Alpha Tocopherol is Not “Vitamin E”
The starting point for an understanding of this apparent
In The News “Alpha-
Tocopherol Kills”?
“Vitamin E Kills”? Is
Total E The Answer?
Making Sense of the New Study
People taking 400 IU or more of
alpha-tocopherol a day are actually
increasing their risk of death.
Figure 1: Death from all causes goes up with increasing
doses of unbalanced alpha-tocopherol. Redrawn from (1).
pg. 23 ADVANCES in orthomolecular research
hairpin turn is to realize that supplements commonly
labeled “vitamin E” – including the ones used in the clinical
trials underlying the newly-discovered increase in death
rate from high-dose supplementation – are mislabeled.
They do not contain “vitamin E,” because there’s no such
thing. Alpha-tocopherol is no more “vitamin E” than
pyridoxine is “vitamin B.” Like “vitamin B,” vitamin E is a
complex – a family of eight molecules: four tocopherols and
four tocotrienols. These eight E-complex family members
work together in the body to support its health.
Even vitamin E “with mixed tocopherols” still leaves you
missing half of the E-complex: the tocotrienols. On top of
this, the proportions of the different tocopherols
contained in most “mixed tocopherol” supplements are
completely unbalanced. These products typically contain
five times as much alpha-tocopherol as the other three
tocopherols combined – a heavy-handed formulation which
guarantees that you won’t gain any health benefits from
these “other” vitamin E molecules.
It’s now known that taking too much alpha-tocopherol
actually depletes your body of other E-complex
vitamins,5-9 denying you of their benefits. In fact, when
alpha-tocopherol is taken at doses typical of most “vitamin
E” supplements, even counterbalancing it with an equal
amount of
the “other” E
vitamers isn’t
enough to
prevent this
supplementinduced
deficiency: the excessive alpha-tocopherol still
drives out gamma-, leaving your levels 30% below
what they would naturally be if you just ate a
regular diet.9 And in addition to lowering the level of
other E-complex molecules in your body,
supplements containing too much
alpha-tocopherol can directly counteract some of the
unique effects of the other E vitamins!10-12
The Blocked Benefits
In contrast to the results of trials using alpha-tocopherol
supplements, studies of the health of large populations of
people consistently find that people getting plenty of the
“vitamin E” in food enjoy a reduced risk of heart disease
and heart attacks.13-15 In fact, some studies have specifically
found that a high intake of the “vitamin E” in food is
protective against heart disease, but alpha-tocopherol
supplements are not.14,15
Why the seeming paradox? Perhaps, again, the form of
“vitamin E” is to blame. The vitamin E in food is a mixture of
the whole E complex, while most “vitamin E” supplements
are overloaded with alpha-tocopherol. And as we’ve
emphasized, supplements weighted toward alpha-tocopherol
deplete the body of other E vitamins, and can even
counteract their effects.5-9 So it may be that
conventional “vitamin E” supplements can’t protect your
heart because of all of the vitamin E molecules that are
missing from, or drowned out in, such supplements.
Since gamma-tocopherol is the single largest component of
the vitamin E in the diet,16-20 it makes sense to look into the
role that this E-complex member might play in the
protective effect of the vitamin E family against heart
disease. Such a role would make sense in the context of our
new understanding of the key role played by inflammation
in the development and progression of heart disease.21,22
That’s because of the differing effects of alpha- and
gamma-tocopherol against a class of free radicals known
as “reactive nitrogen species,” such as peroxynitrite,
nitroxyl, and nitrogen dioxide.
Alpha-tocopherol (and alpha-tocotrienol) are the most
important and effective
antioxidants
when it comes to
protecting your biological
membranes
from free radicals whose structure is based on oxygen23,24 –
but they’re almost useless in defending you against the
threat posed by reactive nitrogen species.25-27 And there’s
now significant evidence that much of the damage that
inflammation inflicts on the body is mediated by
reactive nitrogen species.
Unlike alpha-tocopherol, gamma-tocopherol is very
effective in trapping reactive nitrogen species – many
times more effective than its alpha- cousins.25-27 As well,
some evidence suggests that alpha-tocopherol can play a
role in dealing with nitrogen-based free radicals – not
directly, but by lending a helping hand to
gamma-tocopherol, restoring it to active duty after it is
“injured” in the battle against the reactive nitrogen foe.28
And the connection between reactive nitrogen and heart
disease – and the protective role of gamma-tocopherol – is
Too much
alpha-tocopherol actually
depletes your body of other
E-complex vitamins
alpha-tocopherol can directly
counteract some of the unique effects
of the other E vitamins
ADVANCES in orthomolecular research pg. 24
much more than just a reasonable-sounding theory. Plenty
of studies have found that people who have just suffered
a heart attack29 or who are afflicted with heart disease30-
33 have low plasma levels of gamma-tocopherol, while
their alpha-tocopherol levels are normal.
The question of just why heart patients’ gamma-tocopherol
levels are so low may have been answered by a recent
study34 which measured the levels of
5-NO2-gama-tocopherol in such people. (You’ll recall that
the 5-NO2 marker is the telltale residue that’s left over
when gamma-tocopherol detoxifies nitrogen-based free
radicals. High levels of this marker thus indicate that the
body’s gamma-tocopherol is being used up in the fight
against a brutal
onslaught of
reactive nitrogen
species). When
scientists measured
levels of
this waste product
in the bodies
of people suffering
with
c l o g g e d - u p
arteries, they
found that, on top of having somewhat lower levels of
gamma-tocopherol itself, people with coronary heart
disease have three times more used-up
gamma-tocopherol in their plasma than do healthy
people!34 Furthermore, these researchers found similarly
high levels of wasted gamma-tocopherol in the
atherosclerotic plaque itself, tying the suspect directly to the
scene of the crime.33
Other research shows us that gamma-tocopherol has many
heart-health benefits which reach beyond protecting the
body from reactive nitrogen species. For instance, a study
with experimental animals35 found that gamma-tocopherol
is superior to alpha-tocopherol in slowing down the
formation of potentially killer blood clots – clots which
can get stuck in a narrowed blood vessel and trigger a
stroke. The same study found gamma-tocopherol to be better
at preventing free radicals from making “bad” (LDL)
cholesterol more prone to form arteriosclerotic plaque
through oxidative modification, and at boosting levels of
the protective enzyme superoxide dismutase (SOD).
In another study,36 the same researchers tested the ability of
two different “vitamin E” preparations to protect heart cells
from the massive spike in free radicals that occurs when the
heart’s oxygen supply is restored after a period of having
been cut off – a model of “reperfusion injury,” which
causes much of the damage to the brain after a stroke, or
to the heart after a heart attack. One group of heart cells
was first pretreated with plain alpha-tocopherol. A second
group had its defenses bolstered with 62%
gamma-tocopherol blend (the remainder contained 25%
delta-tocopherol and just 13% alpha-tocopherol). And a
third group was not given any protective E vitamins. Then,
the cells were subjected to the crisis of simulated
reperfusion.
When heart cells are damaged by free radicals or various
other assaults, an enzyme called lactate dehydrogenase
(LDH) is leaked into the surrounding fluid at higher
concentrations than normal. This lets scientists use LDH levels
as a measure of damage to the heart after reperfusion
injury. In the unprotected cells, reperfusion savaged the
cells, causing levels of LDH in the surrounding medium to
double. As measured by the release of LDH, pretreatment
with alpha-tocopherol somewhat reduced the amount of
damage to the heart cells … but in the cells given the
high-gamma-tocopherol pretreatment, the injury was
People who are afflicted with
heart disease
have low plasma levels of
gamma-tocopherol,
while their
alpha-tocopherol levels
are normal
fig 2. Data on time to thrombus formation and platelet aggregation
from control group, alpha tocopherol and gamma tocopherol. Redrawn
from (1) .
fig 3. Oxidation of LDL by PMA-stimulated leukocytes. Redrawn from
(1).
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pg. 27 ADVANCES in orthomolecular research
nearly abolished (see Figure 2 & 3). The gamma-tocopherol
blend also provided superior protection against an
aggravated inflammatory response (as measured by the
levels and activity of the inflammatory enzyme inducible
nitric oxide synthase (iNOS)), and did a better job of
keeping the defensive SOD enzyme active (whereas
reperfusion normally forces its activity down).36
Toasting the Tocotrienols
Another group of E vitamins not included in standard
“vitamin E” supplements, and likely contributing to the
heart-health benefits of vitamin E-rich diets, are the
tocotrienols. Numerous randomized, double-blind,
placebo-controlled trials have shown that, in combination
with a diet low in
saturated fat, high
doses (usually 200
m i l l i g r a m s ) ,
tocotrienols lower
total and LDL
(“bad”) cholesterol
levels over
and above the
effects of a
heart-healthy diet
alone37-42 – typically
by an additional
10 to 20%.
Tocotrienols do this
through a mechanism
similar to – but
not the same as – the “statin” drugs (such as atorvastatin
(Lipitor®) and simvastatin (Zocor®)), modulating the effects
of an enzyme called hydroxymethylglutaryl CoA
reductase (or HMG-CoA reductase, if you don’t have all
day to spit it out).43,44 By contrast, alpha-tocopherol is unable
to favorably modulate the HMG-CoA enzyme. And in fact,
studies in animals10,11 and humans12 have found that when
tocotrienol supplements contain more than one-third
alpha tocopherol, the cholesterol-balancing benefits of
the tocotrienols are lost!
In the most exciting test of tocotrienols’ heart-health
benefits to date,45 fifty men and women with high
cholesterol and advanced atherosclerotic disease took
either 240 milligrams of tocotrienols or a dummy pill for a
year and a half, without either the patients or their doctors
knowing who got what. Before starting the trial, and every
six months thereafter, scientists used ultrasound to monitor
both groups’ disease status, measuring the thickening of the
main artery leading from the heart to the brain. As you
might expect, 40% of the people taking the placebo got
worse over the course of the trial, and none improved. But
astoundingly, not only did only 8% of the tocotrienol group
suffer any further thickening, but 28% of the people
taking the tocotrienol supplement experienced an actual
reversal of the thickening of their arteries!
This is a far cry from the total failure of alpha-tocopherol
to protect heart health seen in previous studies. The
difference is most striking when you compare these results
with the recent VEPAS trial,58 which found that supplements
containing alpha-tocopherol alone may actually increase
the thickening of your arteries!
Bring the Balance Back
So it’s easy to see how regular, unbalanced
alpha-tocopherol supplementation, by driving down levels
of gamma-tocopherol and the tocotrienols, could negate
these E vitamins’ benefits – leaving people swallowing these
pills at higher risk of heart disease and heart attack. So
let’s say that you’ve decided that you want to take advantage
of this new research, to restore – and even enhance –
the protective role of these “other” vitamin E molecules with
a complete, balanced E-complex formula.
This still leaves you with some questions. How much of the
various vitamin E family members should you take? The
research on the many E-complex vitamers is still just a tiny
exploratory expedition into a vast, largely unexplored
frontier, so the optimal amounts and ratios of these
molecules remain far from nailed down. And different
people, with different concerns and priorities, will benefit
from different E-complex supplement plans. But we can
gain some clues from the research that’s available to us.
First, obviously, to get the full benefits of the E-complex,
you’ll want to ensure that your supplement contains the
full spectrum of eight E-complex vitamins: four tocopherols
and four tocotrienols, with no missing molecules. Second,
because of its depleting effect on other E-complex
molecules, it’s important that the total amount of
E-complex molecules other than alpha-tocopherol should
significantly exceed the amount of alpha-tocopherol
itself.
In particular, based on what we know about the content of
different tocopherols in a healthy diet,9-13 and of the
28% of the people taking
the tocotrienol supplement
experienced an actual reversal of the
thickening of their arteries!
When tocotrienol supplements
contain more than one-third alpha
tocopherol, the cholesterol-balancing benefits
of the tocotrienols are lost
Palm, Source of
tocotreinols.
depleting effects of excessive alpha-tocopherol,2-6
gamma-tocopherol should make the single greatest
contribution to your E-complex fortification: there should
be at least twice as much gamma- as alpha-tocopherol
in your total supplement plan. Be sure to have a look at
all of your supplements. You may find that your
multivitamin, your antioxidant formula, or a supplement that
you take to address some specific health concern are all
laced with alpha-tocopherol. You’ll want to apply these
rules on the sum of your alpha-tocopherol intake, making
sure that you’re getting enough of the rest of the E-complex
to balance out that “hidden” alpha.
But there will be people who are particularly concerned
with reaping the specific benefits of high-dose tocotrienols.
Such persons might include people looking to restore a
healthy lipoprotein pattern in their blood, or who are at
high risk of breast cancer, or who have existing heart
disease. If you’re one of these people, the research
suggests you’ll want to take considerably more tocotrienols
than would be felt necessary by basically healthy people
who are simply looking to preserve and enhance their
overall health. For people whose situations push them
toward tocotrienols, a separate, high-dose tocotrienol
supplement is an obvious solution. For such use, be sure that
the amount of alpha-tocopherol you’re taking (in
milligrams) does not make up more than 30% of the sum of
alpha-tocopherol plus total tocotrienols combined,10-12
remembering to include the alpha-tocopherol in all of your
supplements in the equation.
Unfortunately, most multivitamin or antioxidant supplements
are formulated in ignorance of this research, with the result
that they often contain hundreds of IUs of alpha-tocopherol
and little to nothing of the rest of the complex. If you can,
it’s probably best to avoid such products altogether; if you
can’t, or choose not to, then you’ll want to take extra
tocotrienols and gamma-tocopherol to meet the guidelines
we’ve discussed. (Since alpha-tocopherol is usually given in
IUs instead of milligrams, you’ll need to multiply the IU
value of alpha-tocopherol by 0.66 to get the true number
of milligrams of alpha-tocopherol in these supplements).
The IU Lies!
And that brings up another point. People making the switch
from conventional alpha-tocopherol or “mixed tocopherol”
vitamin E formulas to a complete E-complex or tocotrienol
supplement often expect to see the “other” vitamin E
molecules measured in the familiar international unit (IU).
But IUs are an inaccurate way to measure vitamin E
activity. The IU only measures one specific function of
vitamin E: its ability to prevent animals from spontaneously
resorbing their fetuses.
Alpha-tocopherol exerts the strongest influence on this
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pg. 29 ADVANCES in orthomolecular research
process, and thus is assigned the highest IU potency per
milligram.What the IU does not measure is the many unique
contributions to your health made by the other E-complex
molecules – contributions that go beyond the maintenance
of basic reproductive functions, which can be met in humans
by 15 milligrams of alpha-tocopherol per day. This means
that measuring vitamin E activity in IU distorts the
contributions made by different E molecules,
exaggerating the importance of alpha-tocopherol and
downplaying the contributions unique to the other E
molecules. It’s as if you were asked to pay for works of
sculpture by the pound, irrespective of the subject or the
sculptor: the real value is obscured by an artificial common
currency.
For too long, health-conscious people have been subjected
to a game of “bait-and-switch,” with the staid old guard of
the supplement industry dangling forth the benefits of the
complete E complex in the diet to sell unbalanced
alpha-tocopherol supplements.
With the new meta-analysis,1 the true costs of these
marketing campaigns have become clear. Complete,
balanced E-complex supplements hold forth the promise of
delivering the full potential of this nutritional “broken
family.”
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