Analyzing Flaws in Studies of Dietary Supplements: A Recent Report on EPA/DHA

So the January 31, 2018 issue of the Journal of the American Medical Association Cardiology focus was quite profound and certainly controversial in publishing the review meta analysis article on the effects of omega 3 fatty acids in cardiovascular disease prevention. And it's created quite a stir. In fact, of all the kind of nutrition articles that have been published over the last few months, this one has certainly generated the most interesting input and controversy. The title of the article is associations of Omega 3 fatty acid supplement Use with Cardiovascular Disease Risk. And it is a meta analysis of 10 trials that were chosen out of the Literally hundreds of different clinical studies have been done of differing sizes on omega 3 fatty acid supplementation. These 10 trials, which had to meet certain criteria, including they had to have at least 500 substance subjects in the trial, they had to go on for at least three years. And the majority of them, eight out of the 10, actually were placebo controlled. And the total number of individuals included in these 10 trials was 77,917. So it's a fairly large number of individuals. Again, I want to emphasize this is a meta analysis of these 10 clinical trials that were kind of chosen out of the wide array of different studies that have been done over many years and the intervention in humans with omega 3 fatty acids. The results, as you know, came out quite controversial. The results were, and I quote, the meta analysis demonstrated that omega 3 fatty acids had no significant association with fatal or non fatal coronary heart disease or any major vascular events. It provides no support for current recommendations for the use of such supplements in people with a history of coronary artery disease. So this kind of flew in the face of a lot of the previous thoughts that we got from clinical trials and it really created quite a stir. And those of us who have been in this field a number of years, in my case nearly four decades, you know that you see the pendulum swinging back and forth whenever there's something that becomes a bandwagon and everyone seems to agree with it in the nutritional area, then suddenly, boom, there's a new bit of information, the pendulum swings back and there's an overreaction. So what is the actual thought that we would take away from this trial? And I really want to compliment Dr. Alex Vasquez for his extraordinary and in depth evaluation of this trial, the methodologies and the inclusion criteria and the various statistical analyses that were used in the conclusion of this JAMA cardiology article. I think Dr. Vasquez and we will be presenting here, providing a website that you can tap into his own analysis, he's done a video blog on this, but I wanted to comment a little bit from my perspective. Dr. Vasquez brings up two important features of this meta analysis. I believe he's actually got five different points that he has raised questions, but I think two of those for me are quite prominent. Number one is what is the effective dose that one would use of omega 3 fatty acid supplementation and a mixture of EPA and DHA for individuals that have an existing history or high risk to cardiovascular or vascular disease. And that's a question that we can get some informative input into from studies that have been published over the last many years and using such tools as Dr. Vasquez points out, like the omega 3 fatty acid index, the so called omega quant index, which is a measurement of the amount of incorporation of omega 3 fatty acids into blood membranes, red blood cell membranes, and generally we would like that number based on statistical data that's been presented over the years of low vascular risk individuals to be somewhere in the 8 to 10% range of their overall fats in their membranes to be omega 3 fats. And what you generally find in people in high risk situations is their omega 3 fats in their red cell membranes are much lower, 2 to 3%. And these are individuals with much higher relative risk. And so what we the Omega 3 quant index for is kind of determining the level of physiological reserves of these omega 3 fatty acids, which tells you a little bit about their status. And in general, what it's been found is that to get a omega quant omega fatty acid level up into that 8 to 10% level, you need somewhere around 1,800 milligrams a day of Omega 3 EPA and DHA, knowing that DHA is probably better in terms of raising the omegaquant index and EPA, but some kind of a balance between the two, maybe slightly favoring DHA summing out to be 1800 milligrams or more. So if that becomes a criteria for therapeutic benefit, or let's call it physiological benefit, then what were the levels of omega 3 fatty acids that were used in these. Excuse me, these 10 studies that were chosen as part of this meta analysis that included the 77,917 individuals. And there's the story gets quite interesting because it turns out that only three of the studies actually used levels of epi DHA supplementation that were at or above the 1800 milligram total daily dose. The others were really in this threshold were under dosing doses that were anywhere between 500 total milligrams to 1,000 total milligrams, but short of the 1,800 milligram threshold, which seems to be very important for determining the appropriate amount of omega 3s for physiological benefit. So when I went to the literature and I actually looked at these three trials of the 10 that had the appropriate levels, the 1800 or more milligrams, it was very interesting. These include, and I'm going to use abbreviations, the JELIS trial, J E L E S that was published actually in the Lancet in 2007 in volume 369, page 1090. That was a randomized open label blinded endpoint analysis trial that used more than 1,800 milligrams of total omega 3 fatty acids a day. The next of the three trials was a trial that was called the DOIT D O I T trial and it was a randomized clinical trial on omega 3 fatty acids and the all cause mortality in elderly men at high cardiovascular risk. This was published in the European Journal of Cardiovascular Prevention and rehabilitation in 2010. And the third was the Italian study, the so called Gissi HF trial which was. The results were published in 2008 in the Lancet. Those were the three of the 10 trials that used the appropriate dose to get into what might be considered the appropriate incorporation levels and the 8 10% EPA levels, DHA levels in the body. And what did we find as the outcome of those three trials? They were all positive. Admittedly, the positive effect in prevention of cardiovascular disease was small, anywhere between a 9% reduction up to a 20% reduction, but statistically significant nonetheless in these trials, suggesting a marginal benefit of value in cardiovascular prevention by supplementation with omega 3 fatty acids. So why did the JAMA cardiology study then come up with saying no value? And it's because the other seven trials which were not dosed properly were trials, trials that had no clinically significant, no statistically significant benefit. So they diluted obviously when included with the three trials that did have benefit, the signal of value that we're seeing with the three positive trials that were done correctly and made the overall aggregate of the 10 trials then not reach the level of significance. So the JAMA Cardiology paper concludes no benefit. So I think there are many different takeaways from this as it relates to study design interpretation in a meta analysis study. I won't get into all the details, but suffice it to say that the data actually shows that if the study is done correctly with the right level of intervention, that in fact there is a positive outcome and a maybe you would call it small but still statistically significant benefit in preventing reoccurrence of cardiovascular disease or other serious sequelae, including all cause mortality, I might add. So just a note, as it relates to some of the negative press and the negative news that's coming out around omega 3 fatty acids, it's really more in the details of looking at these studies and not just taking at face value some author's interpretation. Thanks so much. Hope this helps.