I was happy to see last night that the two letters to the editor I've written about vitamin E have been cited recently.
I'm sad that another recent paper did not cite my letter about why their drug might be killing people, which we'll get to below.
The first letter was published in the Journal of the American College of Cardiology. It was a response to the famous "one meal of saturated fat will kill you" study where the authors found that making a carrot cake and a milk shake with coconut oil rather than safflower oil led to lower anti-inflammatory properties of HDL particles isolated from the subjects' blood. They attributed the effect to the saturated fat in the coconut oil, and I pointed out that it was probably a result of the vitamin E in the safflower oil. I developed this argument in much greater detail in my article on this site, "Myth: One Meal of Saturated Fat Can Be Bad."
Little did I know until last night that the widely buzzed-about Krauss paper debunking the association between saturated fat and heart disease in the American Journal of Clinical Nutrition.
They cited my letter very accurately, apart from the little typo at the end:
In the acute postprandial phase following a meal enriched in saturated or polyunsaturated fat, HDL collected from individuals after a coconut meal compared with a safflower or unsaturated fat meal was associated with a 50-70% increase in intercellular adhesion molecule and vascular cell adhesion molecule (131). Attribution of this effect specifically to the saturated fat of the coconut meal may, however, be confounded by the high [low] concentrations of tocopherol found in coconut oil (132).Thanks guys! If they liked my vitamin E letter, I hope I can convince them in the future to change their minds that "substitution of dietary polyunsaturated fat for saturated fat has been shown to lower CVD risk." But I'm certainly happy that they concluded that "there are few epidemiologic or clinical trial data to support a benefit of replacing saturated fat with carbohydrate" and that "dietary efforts to improve the increasing burden of CVD risk associated with atherogenic dyslipidemia should primarily emphasize the limitation of refined carbohydrate intakes and a reduction in excess adiposity."
On the other hand, a paper about aromatherapy massage oils prepared from virgin coconut oil published in the Journal of the American Oil Chemists' Society used my letter in the most preposterous way imaginable:
Masterjohn  demonstrated that coconut oil had anti-inflammatory properties, which could help to reduce the inflammation occurring in muscles.I did? I wasn't even a graduate student yet when I wrote that letter. I'm baffled that I "demonstrated" anything in my bedroom where I typed that letter, except the logical flaws in the paper I was responding to. The study I commented on was about coconut oil diminishing the anti-inflammatory properties of isolated HDL. I don't think that study design provided a realistic evaluation of the physiological effects of the coconut oil, but it certainly didn't demonstrate an anti-inflammatory effect of coconut oil! And what it had to do with muscular function is beyond me.
I imagine they did a pubmed search for "coconut oil anti-inflammatory." My letter is fourth out of twelve results. Its title is "The anti-inflammatory properties of safflower oil and coconut oil may be mediated by their respective concentrations of vitamin E." The authors must have taken "no abstract available" to mean you only have to read the title. But geez, the whole letter is about one paragraph long.
The second letter was published in The American Heart Journal and argued that safety trials of anacetrapib, a cholesterol ester transfer protein (CETP) blocker, should test the effect of the drug on vitamin E transport. This was in response to a short, 8-week study of anacetrapib showing no adverse effects.
CETP blockers are the first drugs ever used to test the "reverse cholesterol transport" hypothesis in humans. This hypothesis says that HDL is beneficial because it takes cholesterol back to the liver and that a high total-to-HDL cholesterol ratio indicates that this process is occuring less efficiently and plays a causal role in atherosclerosis. The first drug used to test this hypothesis, torcetrapib, killed people left and right. But they want to believe this is because it increased blood pressure and had other "off-target toxicity," instead of believing that their hypothesis was falsified. So they invented anacetrapib, another drug that does the same thing without the effects on blood pressure.
My letter cited test tube and cell studies showing that CETP plays an important role in transferring vitamin E to HDL particles, and that HDL particles have a very specific role in delivering vitamin E to the endothelial cells that line the blood vessel wall, where the vitamin E helps suppress the oxidation of LDL and thereby suppresses the development of atherosclerosis. I concluded as follows:
An 8-week preliminary trial of the CETP inhibitor torcetrapib found no increase in adverse effects , but this drug ultimately increased the risk of cardiovascular events and death from all causes . Because part of the protective effect of HDL may be due to its role in vitamin E transport, safety and efficacy trials of CETP inhibitors should take into account their effect on this process.
In other words, the fact that anacetrapib showed no adverse effects after eight weeks should give us little comfort that longer trials will not show it to kill people left and right, because the early safety trials with torcetrapib showed the same thing!
The authors responded that the role of CETP in transporting vitamin E to HDL had not been demonstrated conclusively in live people, and that since large trials using alpha-tocopherol did not prevent heart disease, it is not clear that alterations in vitamin E metabolism would have any effect either. They came to the following conclusion:
A study to assess long-term efficacy and safety of anacetrapib in patients with coronary heart disease is currently in progress (clinical trials.gov NCT00685776). The safety information provided by this trial will determine whether or not to initiate a phase III outcome trial with anacetrapib. Ultimately, it is only by conducting such an outcome trial that the true efficacy and safety of anacetrapib will emerge.
Indeed. However, it still seems worthwhile to do a very simple measurement of the vitamin E contents of these HDL particles just in case, perhaps, a long-term trial shows that it kills more people.
I was quite happy to see last night that a recent review on vitamin E transport in the journal Molecular Nutrition and Food Research cited this letter. I'm a bit sad, however, that the people who matter -- the people studying anacetrapib -- continue to ignore it.
As Stan (Heretic) and Peter (Hyperlipid) recently pointed out, the initial results from the anacetrapib trial just came in. They are published in the New England Journal of Medicine here.
Searching the pdf for "tocopherol" or even "vitamin" yields no results.
The results are a little disturbing, but almost impossible to interpret.
Among the just over 1600 people who were randomized to receive either anacetrapib or the placebo, forty percent more deaths occurred in the anacetrapib group:
The difference, however, was not statistically significant. This means that we can't be confident it wasn't simply the result of chance. This is unsurprising, given the small number of people that died.
There were four times as many deaths from cardiovascular causes in the anacetrapib group:
Again, the difference was not statistically significant, and again this is unsurprising given that only five people fell into this category.
We could say, well gee, let's conduct a larger study so this massive increase in cardiovascular deaths can be proven with statistical significance. But the layers of uninterpretability just keep piling on.
First, they took 142 out of the 801 people who received anacetrapib off treatment because their LDL-cholesterol fell to less than 25 mg/dL. All of these people were included in the analysis, but it's unclear whether their cardiovascular risk would better reflect the fact that they initially received the drug or the fact that they were taken off of it. This appraoch is called "intention to treat analysis" and it's very useful for making policy decisions (if I tell 100 people to take the drug, assuming some stop taking it, how many die?), but it doesn't help us understand whether the drug saves people or kills them.
Second, 3.5 times as many people in the placebo group underwent a revascularization procedure:
This might indicate that anacetrapib reduced the need for revascularization procedures. On the other hand, the report gives no description of who ordered the revascularization procedure and what criteria they used to order it. Furthermore, it's unclear whether the revascularization procedures helped or hurt the patients, since even the study protocol provides guidelines for assessing heart attacks and deaths that are caused by revascularization procedures. They don't tell us whether anyone died as a result of a revascularization procedure.
Thus, this report makes it quite unclear whether anacetrapib is saving people or killing them, and makes it even less clear whether anacetrapib will save people or kill them when it's tested in a much larger trial.
One little experiment that could be done now would be to take the plasma samples from this trial out of the freezer, isolate the HDL, and measure the vitamin E in it. That would very quickly obviate the authors' concerns expressed in response to my letter last year that "to the best of our knowledge, there are no clinical data indicating a definitive role for CETP in vitamin E exchange," since they could test that hypothesis and either show it true or bury it for good in the course of several days, and would provide some potentially relevant safety data, and would also contribute important knowledge to the body of basic science about vitamin E transport.
But as for saving or killing people, we will have to wait a few years for the final word.
Read more about Chris Masterjohn, PhD, here.