|NIH Vitamin Study|
Preliminary Rebuttal to Recent Attacks
Against Dietary Supplements
By William Faloon
The media recently ran headline news stories claiming that vitamins C, D and E do not prevent heart attack, stroke or breast cancer. This report represents Life Extension’s preliminary response to these media attacks that are based on egregiously flawed studies. We will submit this report for formal peer review and referencing and expect to post our official report within a few weeks.
Needless to say, when these biased attacks are launched, we are not given prior notice so that our side of the story makes it into the mass media.
In the early 1990s, several large population studies showed significant reductions in cardiovascular disease in those who consumed vitamin C or vitamin E.
The most widely reported study emanated from UCLA, where it was announced that men who took 800 mg a day of vitamin C lived six years longer than those who consumed the recommended daily allowance of 60 mg a day. The study, which evaluated 11,348 participants over a 10-year period of time, showed that higher vitamin C intake reduced cardiovascular disease mortality by 42%.
These kinds of findings did not go unnoticed by the federal government, who subsequently invested hundreds of millions of dollars in an attempt to ascertain if relatively modest vitamin doses could prevent common age-related diseases.
In a study that received extensive media coverage, four groups of male doctors were given various combinations of vitamin C and/or vitamin E or placebo. After eight years, there was no reported difference in heart attack or stroke incidence among the groups. This led the media to state that consumers should not buy these supplements.
As you will read, there were so many egregious flaws in this study that the findings are rendered meaningless. Regrettably, consumers who trust their lives to the mainstream media may fall victim to this latest charade to discredit validated methods to reduce cardiovascular disease risk.
Do you take your vitamins every other day?
The study subjects in the vitamin E groups were told to take one 400 IU capsule of synthetic alpha tocopherol every other day. This design flaw raises several issues that are rather obvious to serious supplement takers.
First of all, we don’t take our vitamins every other day. Free radicals are constantly being generated in our bodies, and supplement users today seek to take their antioxidants with most meals, as oxidative damage is generally the greatest after eating.
It is rather ludicrous to think that these study subjects would reduce their vascular disease risk by taking modest dose, every other day, of a form of vitamin E with inferior anti-oxidant capacity.
If one were to rely only on synthetic alpha tocopherol, the minimum daily dose needed has been shown to exceed 800 IU, far greater than the 400 IU ingested every other day by the subjects in this poorly designed study.
Serious supplement users normally take 400 IU every day of natural vitamin E along with a plethora of complimentary nutrients. We would not expect 400 IU of synthetic vitamin E taken every other day to produce much of an effect. Yet that is the dose given to these study subjects with the expectation that this would show a reduction in cardiovascular disease. This is by no means the only flaw of this study.
Natural versus synthetic vitamin E
There was a long standing debate as to whether natural or synthetic vitamin E is better. For most vitamins, there is no difference between natural and synthetic. In fact, for most vitamins, the only forms available are synthetic. With vitamin E, however, the natural form has proven far superior.
Natural vitamin E is distributed through the body much better than the synthetic form. The reason is that specific carrier proteins in the liver selectively bind to natural vitamin E and transport it through the blood to cells throughout the body. These carrier proteins only recognize a portion of synthetic vitamin E and ignore the remainder.
Japanese researchers gave natural or synthetic vitamin E to young women to measure how much vitamin E actually made it into their blood. It took only 100 mg (149 IU) of natural vitamin E to produce blood levels that required 300 mg (448 IU) of synthetic vitamin E.
Most studies show that synthetic vitamin E is only half as active in the body as the natural form. As it relates to the flawed study claiming that vitamin E does not prevent heart attack, the 400 IU of synthetic alpha tocopherol given every other day equates to only 100 IU a day of the natural form.
We would not expect 100 IU of natural vitamin E a day by itself to necessary reduce vascular disease risk. As you continue to read, however, there are many other flaws in this study that render its conclusions useless.
Note: When checking vitamin labels, natural vitamin E is usually stated as the “d” form (for example d-alpha tocopheryl acetate,d-alpha tocopherol, and d-alpha tocopheryl succinate). Synthetic vitamin E will have a “l” after the “d” (for example, dl-alpha tocopheryl acetate, dl-alpha tocopheryl succinate, dl-alpha tocopherol). Remember – “dl” signifies synthetic vitamin E, whereas “d” signifies natural vitamin E. Remember that if you are getting 400 IU of natural d-alpha tocopherol (d-alpha tocopheryl succinate or acetate) it is equal to about 800 IU of synthetic dl-tocopherol (dl-alpha tocopheryl acetate or succinate).
Vitamin C potencies too low
If all you are going to take to protect against free radical damage is vitamin E and/or vitamin C, then you will need far greater potencies than were given to the study subjects in this flawed study.
Published studies that document vascular benefits in response to vitamin C typically use doses of 1,000-6,000 mg each day. The authors of the flawed study alluded to this when they stated:
“In a pooled analysis of 9 cohorts, vitamin C supplement use exceeding 700 mg/day was significantly associated with a 25% reduction in coronary heart disease risk.”
Since the doctors who designed the flawed study knew that vitamin C intakes exceeding 700 mg a day significantly reduce heart attack rates, we can not figure out why they limited their subject’s daily dose to only 500 mg.
Two-time Nobel Prize laureate Linus Pauling and his associates advocated daily doses of vitamin C ranging from 10,000 to 20,000 mg to protect against heart attack. Linus Pauling’s theory was that atherosclerosis is primarily caused by insufficient vitamin C intake. Dr. Pauling compared the high amount of vitamin C naturally synthesized in the bodies of animals that don’t typically die of heart attacks. A 150 pound goat, for example will maintain an ascorbate blood concentration equivalent to ingesting 13,000 mg of vitamin C.
Unlike most animals, humans lack an internal enzyme needed to manufacture vitamin C in their body. If humans don’t obtain enough vitamin C from external sources, they die acutely from scurvy, or according to Linus Pauling…slowly suffer atherosclerotic occlusion. Dr. Pauling crusaded to educate humans about the need to take mega-doses of vitamin C.
Dr. Pauling and his associates published papers stating that when vitamin C levels are insufficient, the body uses cholesterol to repair the inner lining of arteries. Dr. Pauling believed that cholesterol’s involvement in atherosclerosis was a direct result of insufficient vitamin C.
Life Extension has long recommended that its members take at least 2,000 mg a day of vitamin C, along with potent plant extracts to enhance the biological benefits of ascorbate inside the body. The 500 mg daily dose of vitamin C given to the subjects of this flawed study was clearly inadequate. This did not stop the headline-hungry media and many conventional doctors from recommending that aging humans avoid these supplements altogether.
As we noted already, the dose of vitamin E used in this study was also too low to expect a reduction in vascular disease events. While alpha tocopherol vitamin E is a classic antioxidant, its free radical quenching efficacy pales in comparison to polyphenol extracts from green tea, pomegranate, grape-seed and blueberry.
Based on the superior antioxidant properties of plant extracts such as pomegranate, health conscious people today are able to obtain greater protection against free radicals and enhance the efficacy of the vitamin C without necessarily having to take the mega-doses recommended by Linus Pauling. On the flip-side, to attack the value of vitamin C based on a group of doctors who took only 500 mg a day does not correspond to the doses scientific studies show are needed to prevent heart attack.
Alpha tocopherol displaces gamma tocopherol
An increasing number of scientists are questioning the wisdom of administering alpha tocopherol vitamin E by itself. The reason is that alpha tocopherol displaces critically important gamma tocopherol in the body. The authors of the flawed study admitted that the failure to include gamma tocopherol may have been a reason that no effect was seen in the alpha tocopherol groups. Here is a quote directly from the flawed study:
"Moreover, PHS II and other prevention trials have used alpha-tocopherol, whereas the gamma-tocopherol isomer also may have a role in cardiovascular disease prevention because it has greater efficacy than alpha-tocopherol to inhibit lipid peroxidation and it may be suppressed in the presence of alpha-tocopherol."
The above admission understates the critical importance that gamma tocopherol plays in maintaining arterial health. While alpha tocopherol helps protect against lipid peroxidation, gamma tocopherol is required to neutralize the dangerous peroxynitrite free radical. Peroxnitrite damages arteries because:
- Peroxnitrite promotes the oxidation of alpha tocopherol, thereby depleting the body of the vitamin E needed to protect against oxidation of the lipid moiety (part) of LDL. LDL is composed of both lipid and protein parts (moieties), and oxidation associated with both moieties has been implicated in atherosclerosis. In a fascinating paradox, when alpha tocopherol is given without gamma tocopherol, the result is that alpha tocopherol itself can be neutralized in the body by the peroxynitrite free radical. This in turn promotes oxidation of the lipid moiety of LDL , a major step on the path towards atherosclerosis.
- Peroxnitrite promotes LDL protein oxidation. While alpha tocopherol inhibits LDL lipid peroxidation, gamma tocopherol is needed to protect against oxidation of the protein moiety (part) of LDL.
In the absence of gamma tocopherol, which can occur when alpha tocopherol is given without gamma tocopherol, both LDL lipid and protein oxidation is increased, which reveals the egregious mistake of trying to prevent vascular disease by administering only alpha tocopherol. Health conscious individuals should be assured that other nutrients such a lipoic acid and polyphenol plant extracts also block protein and lipid LDL oxidation.
Some studies suggest that only gamma tocopherol prevents heart attacks. As it relates to atherosclerosis, gamma tocopherol blood concentrations have been reported to be significantly lower in coronary heart disease patients than in healthy control subjects. While alpha and gamma tocopherols each perform life-sustaining functions, only gamma tocopherol increases endothelial nitric oxide protein expression. As I will describe next, a deficit of nitric oxide in the endothelium is a primary cause of arterial disease.
Primer on Alpha and Gamma Tocopherol
Alpha tocopherol and gamma tocopherol are the two major forms of vitamin E in human plasma. The dietary intake of gamma tocopherol is generally two- to four-fold higher than that of alpha tocopherol. Alpha tocopherol plasma levels, however, are about four-fold higher than those of gamma tocopherol. One reason is that there is a preferential cellular uptake of gamma tocopherol over alpha tocopherol.
Scientific studies consistently show that gamma tocopherol plays a significant role in modulating intracellular antioxidant defense mechanisms. Interestingly, the presence of gamma tocopherol dramatically increases the cellular accumulation of alpha tocopherol.
A hidden cause of heart attack and stroke
Even when all conventional risk factors are controlled for, the progressive decline of nitric oxide involving the arterial wall (the endothelium) too often leads to coronary heart attack and stroke.
Seven years ago, Life Extension researchers identified a critical compound (tetrahydrobiopterin) that is essential for the synthesis of nitric oxide in the endothelium. We spent several hundred thousand dollars trying to develop an affordable way to manufacture this compound as it offered tremendous promise for eradicating atherosclerosis.
We failed to find an affordable way to make tetrahydrobiopterin. The good news is that nutrients that suppress peroxynitrite (like gamma tocopherol and pomegranate) increase endothelial nitric oxide by blocking the oxidation of tetrahydrobiopterin.
Indeed, clinical studies show that supplemental gamma tocopherol enhances platelet endothelial nitric oxide synthase activity. Furthermore, a diet high in gamma tocopherol rich walnuts improved endothelium-dependent vasodilation in those with high cholesterol.
By administering only alpha tocopherol as was done in the flawed study, one would expect gamma tocopherol to be suppressed, peroxynitrite levels to increase, and precious tetrahydrobiopterin to be oxidized, thus depriving the endothelium of the nitric oxide it needs to protect against heart attack and stroke. Is it any wonder that this study failed to show vascular disease reduction in those given only alpha (but not gamma) tocopherol?
Failing to account for all vascular risk factors
Numerous independent risk factors are associated with the development of atherosclerosis and subsequent heart attack and stroke risk. A major flaw in this study was expecting low-dose vitamin C and/or E to somehow overcome all of these underlying causes of artery disease.
We know it is impossible for vitamins C and E to overcome these many risk factors, but this did not stop the media from recommending that Americans discard their supplements.
The following represents a succinct list of documented vascular disease risk factors:
- Low testosterone (in men)
- Excess fibrinogen
- Low HDL
- Excess LDL and total cholesterol
- Excess glucose
- Excess C-reactive protein
- Excess homocysteine
- Low EPA/DHA
- Low vitamin D
- Excess insulin
- Excess estrogen (in men)
- Oxidized LDL
- Excess platelet activity
- Nitric oxide deficit (endothelial dysfunction)
The basis for doing this study, as outlined by the study’s authors, was to use vitamins C and/or E to:
- Trap organic free radicals
- Deactivate excited oxygen molecules
- Prevent tissue damage
- Inhibit LDL oxidation
- Modify platelet activity
- Reduce thrombotic potential
- Modify vascular reactivity
As one can clearly see, there are 15 documented cardiovascular risk factors. Yet only 3 of these risk factors are what formed the basis for conducting this clinical trial using low-dose vitamin C and/or E. The 3 known risk factors the authors of the flawed study expected to favorably influence with vitamins C and E were:
- LDL oxidation
- Platelet activity and thrombotic potential
- Vascular reactivity (another term for endothelial dysfunction)
For every one mechanism the study’s authors proposed might enable low-dose vitamin C and/or E to work, there were five additional risk factors that would not be corrected. For instance, vitamins C and E in these low doses are not going to reduce C-reactive protein, homocysteine, fibrinogen, or glucose. Vitamins C and E in any dose are not going to increase testosterone, decrease estrogen, or provide cardio-protective EPA/DHA and vitamin D.
On the contrary, as we have already shown, by giving only alpha but not gamma tocopherol, one might expect increased LDL oxidation and impaired endothelial function. That’s because alpha tocopherol displaces gamma tocopherol in the body. Gamma-tocopherol suppresses the peroxynitrite radical that oxidizes both LDL protein and the tetrahydrobiopterin that is needed to produce endothelial nitric oxide.
As far as platelet activity and thrombotic potential (abnormal clotting inside a blood vessel) are concerned, gamma tocopherol is significantly more potent than alpha tocopherol in inhibiting platelet aggregation that can lead to a heart attack or stroke. By displacing gamma tocopherol, the alpha tocopherol used alone in this study may have increased abnormal platelet aggregation risk.
From everything we know today, this study was designed to fail. Not only did it not correct for the major causes of vascular disease, but it may have exacerbated some of the more dangerous ones.
None of what I wrote so far may really matter
You have just learned why low-dose vitamin C and/or E supplementation would not be expected to reduce heart attack and stroke risk.
I have saved the biggest shocker for last. It turns out that a significant number of the study subjects (who were all medical doctors) who were supposed to take the vitamin C and/or E supplements did not take their pills. Yet when the calculations for heart attack or stroke incidence were made, those who took as little as 66% of their low-dose vitamin C and/or E supplements were counted as having taken the entire dose.
At the end of the study, 28% of the study subjects admitted they had not even taken 66% of their low-dose vitamin C and/or E supplements.
Even more troubling is the method used to track who was really taking their supplements. Participants were asked to remember and track supplement usage for over 8 years’ time without any verification of actual pill counts, compliance by plasma antioxidant analysis, or in vivo surrogate markers of oxidant stress. Relying upon participants’ memory & recollection over a lengthy time period of many years is a rather pathetic way of ensuring adherence, and renders the author’s so called “sensitivity analysis” meaningless.
The lack of adherence, i.e. the fact that a significant percentage of the study participants were not even taking their vitamins may be the most significant flaw to this study. No one in the mainstream media bothered to report this, or any of the other flaws that jumped out at us.
Instead, the media’s message was don’t waste your money on vitamin C or E pills. Many supplement users who are taking the right form and dose of their vitamin C and E nutrients may believe the media’s biased reporting. Even those who take low-dose vitamin supplements may discontinue, which as you will read next is regrettable from a public health standpoint (but great news for the pharmaceutical companies).
Shocking deficiencies of vitamin E
The media used this horrifically flawed study as a basis to steer Americans away from vitamin C and E supplements. It’s as if all of the previous positive published studies disappeared overnight.
What was omitted is the fact that 93% of American men and 96% of American women do not consume the recommended dietary allowance of vitamin E in their diet. The federal government says Americans need only 15 milligrams a day of vitamin E, yet even this minute amount is not found in the diets of the vast majority of people.
This means that most Americans require a vitamin E supplement to avoid a chronic deficiency, but this important fact was conveniently left out of the news stories.
Conventional medicine says that severe vitamin E deficiency results mainly in neurological symptoms such as impaired balance and coordination and muscle weakness. These neurological symptoms do not develop for 10-20 years; as it takes time for free radicals to inflict nerve damage in the absence of sufficient vitamin E. The reality is that chronic vitamin E deficiency adversely impacts virtually every cell of the body.
A media coup for pharmaceutical companies
The optimal moment of the year to get your message to the masses is the second week of November. This is a time in between holidays, when winter is setting in, and few people are on vacation. The television networks consider this their most important “sweeps week” as it provides the most accurate measurement of their ratings.
The timing of the release of this horrendously flawed vitamin C and E study could not have been more perfect for pharmaceutical interests. It came out less than one week after the November election when the media was primed to sensationalize any story that would attract viewers for their all important “sweeps week”.
On the very same day the media launched its attack on vitamins C and E, the same news sources reported that the statin drug Crestor® reduced heart attack rates by 44% in healthy people who had high C-reactive protein levels. Just think, as an uneducated consumer, you read on the same day that vitamins C and E are worthless and an expensive statin drug works miracles.
Financial analysts predict a windfall for the makers of Crestor® based on this widely distributed report. In retrospect, conducting this study only on people with high C-reactive protein (but not particularly high LDL) was a brilliant marketing strategy. It had a high probability of a successful outcome, and if the study failed, Crestror® was never approved to lower C-reactive protein or be used in this population group anyway, so the pharmaceutical company had nothing to lose.
We at Life Extension have long warned about the vascular dangers of elevated C-reactive protein and even recommended statin drugs if natural approaches fail to reduce C-reactive protein. We don’t believe most people have to purchase expensive brand name drugs like Crestor®, as generic simvistatin (name brand Zocor®) or pravastatin (name brand Pravachol®) can provide similar benefit at a fraction of the price.
Media also attacks vitamin D
Not content to bash only vitamins C and E, the media the very next day in November ran a headline story stating that “Supplements don’t reduce breast cancer risk”. This story was based on a study of women who received only 400 IU a day of supplemental vitamin D.
As has been reported for years in this and other health publications, 400 IU a day of vitamin D is clearly inadequate. To reduce breast cancer risk by around 50%, a daily dose of 1000 IU and higher is required. The major flaw in this study is that participants in the active and placebo group were allowed to take vitamin D outside the study, which rendered the findings meaningless even if the proper dose has been given.
The fact that the media made this study headline news is regrettable because only about 20% of the study population achieved a 25-hydroxy vitamin D at the minimum dose required to prevent breast cancer (greater than 30 ng/mL). In other words, most participants in the active or placebo group failed to achieve even the minimal blood concentrations of vitamin D that other studies document are needed to protect against breast cancer. So all this study did was help confirm what vitamin D experts have been saying for over five years now, i.e. a minimum of 800 IU to 1000 IU of vitamin D a day is required.
Don’t be a victim of this flawed propaganda
It is in the economic interests of drug companies to steer Americans away from healthier lifestyles and dietary supplements. As more Americans fall ill to degenerative disease, drug company profits increase exponentially.
Enormous amounts of pharmaceutical dollars are spent influencing Congress, the FDA, and other federal agencies. The result is the promulgation of policies that cause Americans to be deprived of effective, low-cost means of protecting themselves against age-related disease.