n Part 1 of this series on dietary fat, I arrived at two conclusions that appear to be inconsistent with each other: (1) there is a considerable amount of data indicating that dietary saturated fat may not really be a “bad actor”, and (2) there is also a substantial amount of data indicating that decreasing saturated fats may be beneficial.
However, the story is complicated by the fact that a decrease in the consumption of saturated fat is almost inevitably accompanied by an increase in the consumption of unsaturated fats, and it appears that some polyunsaturated fatty acids may be “bad” and some may be “good”, or at least neutral. (We’ll leave the issue of monounsaturated fats for another day.)
Dietary recommendations to increase polyunsaturates are probably useless because there are two polyunsaturated fatty acids that are essential to one’s diet, yet appear to have opposite effects. I’m talking about omega-6 fatty acid and omega-3 fatty acid. And many foods, especially some vegetable oils (such safflower, sunflower, SOYBEAN, and CORN oils) are very rich in omega-6 fatty acids, which seem to be the primary culprit. Soybean oil and corn oil—I think you may know where I’m going here. It seems that almost every food in the so-called “Western diet” contains one of these two oils.
Now, the science around omega-6 fatty acids is really very deep, not the nutritional aspects, but rather the relationship between omega-6 fatty acids and inflammation—at least one Nobel Prize has been awarded in this area. It turns out that the omega-6 fatty acids are part of the inflammatory process, and many drugs that have been developed to reduce pain target that process, which involves the conversion of omega-6 fatty acids to inflammatory compounds such as prostaglandins. So when you take aspirin or ibuprofen, for example, what you are really doing is trying to inhibit the formation of inflammatory compounds.
Pain reduction, of course, is a huge area of research. And since much pain is caused by inflammation, there is a lot of money pouring into the effort to reduce inflammation. Moreover, inflammation seems to be the foundation not only of pain, but also heart disease and many other problems, from multiple sclerosis to dry eyes. As a result, a lot is known about omega-6 fatty acids and their conversion into inflammatory compounds.
Omega-6 was the first polyunsaturated fatty acid to be discovered, and in the 1960’s it was thought that omega-6 was the ONLY one. So, when studies first came out showing a correlation between saturated fatty acids and cardiovascular disease (now increasingly questionable, see Part 1 of this series), nutritionists recommended that we all decrease our saturated fats and increase our polyunsaturated fats—and who knew, at the time, WHICH fatty acid we were increasing? I’m sure the dieticians said something like, “Oh, just use corn oil or olive oil, or palm oil, or peanut oil—you know, they’re all the same.”
Not.
No wonder the results of the many dietary fat studies have been so goofy and variable.
So what does the scientific data say about omega-6 fatty acid as it relates to nutrition?
First, omega-6 fatty acid has the “common name” linoleic acid. That’s linoLEic acid. (Omega-3 fatty acid has the common name linolenic acid. Read: linoLENic acid. Easy to confuse.)
Linoleic acid is commonly found in vegetable oils. You can look these up on the web yourself, but what is important here is that corn, soybean, and safflower oil are very rich in linoleic fatty acid.
In 2013 scientists reanalyzed the data generated in a 7-year Australian study (1966 to 1973) involving 458 men, aged 30-59 years, each of whom had had a recent coronary event. The “reduced polyunsaturated fatty acid” group was given liquid safflower oil (high in omega-6 fatty acid) as a dietary substitute for animal fats and vegetable shortenings in cooking oils, salad dressings, and baked products, and safflower oil margarine to be used in place of butter and common margarines. Guess what they found—substituting omega-6 fatty acids for saturated fat RESULTED IN A STATISTICALLY SIGNIFICANT 6% INCREASE IN DEATHS, AND A 6% INCREASE IN CARDIOVASCULAR DISEASES. How about that—you think you are going to show that decreasing saturated fats is a “good” thing, and you end up killing some of your patients.
And interestingly, this negative result occurred in spite of the fact that substituting safflower oil for other dietary fats caused a decrease in the subjects’ total cholesterol, primarily by reducing levels of low-density lipoprotein (the “bad” cholesterol)—which you would also expect to be a good thing. The scientists who did the reanalysis have proposed a model to explain why this may be so, but a detailed examination of their theory will have to be the subject of another blog post (perhaps). Suffice it to say that the omega-6 gets oxidized to a form that binds with low-density cholesterol, which then ends up as arterial plaque. Get it? The omega-6 lowers low-density cholesterol because it is changing it into a form that is actually harmful. Oh dear.
Well, this study is causing a bit of a stir, as you might imagine. The British Medical Journal, the one that published the original report in the 1970s (without the newly-analyzed data), has a bit of egg on its face. One has to wonder why this startling information was not reported until 2013, when the trial ended way back in 1973? Apparently the answer is that the authors ran out of money to do a more thorough analysis. Well, you can’t do research without money, so maybe so. CBC News reported in February 2013 that perhaps one-half of clinical trials are NEVER published. (This too will perhaps be the subject of another blog post.)
On February 5, 2013, the British Medical Journal published a “comment” on this paper, and I include a portion of it here:
“The American Heart Association recently repeated advice to maintain, and even to increase, intake of omega 6 PUFAs (polyunsaturated fatty acids). This advice has caused some controversy, because evidence that linoleic acid lowers the risk of CVD (cardiovascular disease) is limited—most trials that claimed to investigate the effect of exchanging saturated fat for linoleic acid involved multiple dietary changes or multiple interventions (or both). In particular, studies lowered trans fatty acid intake or increased omega 3 PUFA intake (or both) at the same time as increasing linoleic acid intake. The impact on CVD risk or mortality of replacing saturated fat with linoleic acid without changes in other fatty acids has rarely been investigated, and no large randomized controlled trial has recently explored this important question…. The new analysis of these old data provides important information about the impact of high intakes of omega 6 PUFAs, in particular linoleic acid, on cardiovascular mortality at a time when there is considerable debate on this question. The findings underscore the need to properly align dietary advice and recommendations with the scientific evidence base. It is important when assessing this evidence base that subtle, and in some cases unsubtle, aspects of study design are properly considered. For example, outcome of studies in which intakes of saturated and trans fatty acids are lowered while intakes of omega 6 fatty acids and omega 3 PUFAs are increased may be most strongly influenced by changes in trans and omega 3 fatty acids. They should not be interpreted as showing an effect of omega 6 PUFAs.”
I have to say that this is very cool. I don’t mean it’s cool that there may be misleading advice out there that is killing people, but that the interplay between advancing science and public policy is cool. It also reiterates what I said at the beginning of this blog series—the data is too sketchy to be making policy recommendations.
I wonder what the American Medical Association thinks about this? Oh, wait, here we go—on February 7, 2013, the AMA had this to say:
“The British Medical Journal study is interesting, but not conclusive. It is offset by a large body of scientific evidence that continues to show cardiovascular benefits associated with eating mono- and poly-unsaturated fat, rich in Omega-6 linoleic acids, in place of saturated fat. . . .”
I don’t know about you, but I find this to be quite surprising—no change in the AMA’s position on omega-6’s? Not even a statement that they will give this new data “due consideration”? One has to wonder about this, especially since everybody else seems to be pretty excited by the new data. Well, my understanding is that the U.S. edible oils manufacturing industry is $55 Billion—and that figure doesn’t even include farm production of corn and soybeans (grains that are high in omega-6’s). What influence do you think these industries could have on the federal government’s interest in doing research in this area—research possibly showing that consuming omega-6’s in the form of corn oil and soybean oil might have negative effects on our health?
What fun!
We must keep in mind, however, that this reanalysis doesn’t stand alone—it follows numerous studies indicating that the story isn’t as simple as omega-6 fatty acids just being “bad.” They are, in fact, essential to our health—they seem to be “bad” only when they are consumed in excess relative to omega-3 fatty acids. In other words, what seems to be emerging is that it is the ratio of omega-6 fatty acids to omega-3 fatty acids that is important.
But first a little history about omega-3 fatty acid, or linoLENic acid.
Unlike omega-6 fatty acid, the importance of omega-3 fatty acid really started to emerge in 1975 with the discovery that the Greenland Inuit Eskimos had a level of cardiovascular disease that ranged from very low to virtually nonexistent—and that they had two times as much omega-3 fatty acid in their blood as the Eskimos living in Denmark. The Greenland Eskimos also consumed very low amounts of omega-6 compared to their cousins living in Denmark. Oh, and the Greenland Eskimos had higher levels of saturated fat and lower levels of both triglycerides and cholesterol in their blood plasma than the Danish Eskimos did. Interestingly, an analysis comparing the diets of Greenland Eskimos and with the diets of Danes (not Danish Eskimos in particular) showed that the Greenland group consumed less carbohydrates, more protein, about the same amount of fat, more cholesterol, LESS saturated fatty acids, and less omega-6 fatty acids.
Well, the omega-3 story has evolved since then, and today we know that the “Western diet” is very high in omega-6 and low in omega-3 fatty acids, like that of the Danish group.
And now, of course, I have to report on meta-analyses of omega-3 fatty acids. What is the data showing?
Meta-Analysis #1*. Published in 2012. 20 randomized studies involving 68,680 patients. Examined the effect of omega-3 supplements on cardiovascular disease. The average age of the test subjects was 68; they received supplemental omega-3 for two years. The amount of the supplement was 1 gram or less per day per person. What did they find? The authors concluded there was NO statistically significant correlation between supplementation and cardiovascular disease or death. And that’s it. However, when you look at the actual data, what is interesting is that nearly all the studies showed that the supplemented groups had less cardiovascular disease, but that it wasn’t statistically significant. Well, that’s interesting . . .
Meta-Analysis #2**. Published in 2013. 21 randomized studies involving 46,737 patients. Compared omega-3 fatty acid supplementation (either via capsules or diet alterations) to a normal diet. Most of the studies included patients at high cardiovascular risk. The authors were not specific about the amount of omega-3’s consumed. They found a statistically significant 10% DECREASE in cardiovascular events of any kind and a 9% decrease in cardiovascular death.
So, given these two meta-analyses, I’d say it is looking like the omega-3 fatty acids may have a positive effect on cardiovascular disease.
Today there seems to be an emerging consensus to the effect that increasing our consumption of omega-3 fatty acids and decreasing our consumption of omega-6 fatty acids is beneficial. There are many reports that the typical “Western” diet includes an overabundance of omega-6 fatty acids, probably due in part to the consumption of the corn and soybean oils that are found in so many of our foods. Omega-6 fatty acids are also prevalent in feedlot-produced beef—probably due to the use of corn and soybeans as feed. Think poultry and eggs, too.
In fact, Western diets have ratios of omega-6 to omega-3 fatty acids in the neighborhood of 15:1, although many scientists believe the optimal ratio is closer to 4:1—and some even advocate reversing the ratio to 1:4 (only one-fourth as much omega-6 as omega-3). I don’t know how good the science is here, but apparently the problem with too much omega-6 is that it shifts the omega-3 fatty acids towards the same pathway as omega-6’s, which results in inflammation.
All I know is that I’d sure like an updated analysis of diets, blood plasma, and cardiovascular disease in other “traditional” populations like the Greenland Eskimos.
But, overall, I bet that my prediction at the start of this blog series is correct—the studies that have been done so far have too many unknowns relative to the exact types and quantities of fatty acids consumed by the test subjects. We just haven’t had sufficiently detailed knowledge (either quantitative or qualitative) about what food is going into patients’ mouths during the last 30 or 40 years to be giving accurate advice.
So there.
And how this relates to the whole controversy concerning the Mediterranean Diet vs. the recommended U.S. Food Pyramid vs. the South Beach Diet vs. the Paleo Diet, I don’t know. I see there is a new report out on the results of a study comparing the Mediterranean diet with a low-fat diet. 7,447 people enrolled, ages 55-80. Well, the authors conclude we should consume more olive oil—because the (statistically significant) rate of cardiovascular events among the Mediterranean diet group was 0.6% lower than it was among the low-fat diet group.
Only 0.6%? That seems too small to worry about if you like red meat, statistically significant or not.
But the fat story also includes recent recommendations regarding “trans fats.” You certainly know by now that labeling of trans fats in food is mandatory in the United States. And as of January 1, 2010, California became the first state to ban trans fats in restaurants. Scientifically sound?
Next blog post.
_______________________
*Evangelos C. Rizos, MD, PhD; Evangelia E. Ntzani, MD, PhD; Eftychia Bika, MD; Michael S. Kostapanos, MD; Moses S. Elisaf, MD, PhD, FASA, FRSH (September 2012). "Association Between Omega-3 Fatty Acid Supplementation and Risk of Major Cardiovascular Disease Events A Systematic Review and Meta-analysis". JAMA 308 (10): 1024–1033
**Javier Delgado-Lista, Pablo Perez-Martinez, Jose Lopez-Miranda, Francisco Perez-Jimenez. 2012. “Long Chain Omega-3 Fatty Acids and Cardiovascular Disease: a Systematic Review. British Journal of Nutrition 107: S201-S213
However, the story is complicated by the fact that a decrease in the consumption of saturated fat is almost inevitably accompanied by an increase in the consumption of unsaturated fats, and it appears that some polyunsaturated fatty acids may be “bad” and some may be “good”, or at least neutral. (We’ll leave the issue of monounsaturated fats for another day.)
Dietary recommendations to increase polyunsaturates are probably useless because there are two polyunsaturated fatty acids that are essential to one’s diet, yet appear to have opposite effects. I’m talking about omega-6 fatty acid and omega-3 fatty acid. And many foods, especially some vegetable oils (such safflower, sunflower, SOYBEAN, and CORN oils) are very rich in omega-6 fatty acids, which seem to be the primary culprit. Soybean oil and corn oil—I think you may know where I’m going here. It seems that almost every food in the so-called “Western diet” contains one of these two oils.
Now, the science around omega-6 fatty acids is really very deep, not the nutritional aspects, but rather the relationship between omega-6 fatty acids and inflammation—at least one Nobel Prize has been awarded in this area. It turns out that the omega-6 fatty acids are part of the inflammatory process, and many drugs that have been developed to reduce pain target that process, which involves the conversion of omega-6 fatty acids to inflammatory compounds such as prostaglandins. So when you take aspirin or ibuprofen, for example, what you are really doing is trying to inhibit the formation of inflammatory compounds.
Pain reduction, of course, is a huge area of research. And since much pain is caused by inflammation, there is a lot of money pouring into the effort to reduce inflammation. Moreover, inflammation seems to be the foundation not only of pain, but also heart disease and many other problems, from multiple sclerosis to dry eyes. As a result, a lot is known about omega-6 fatty acids and their conversion into inflammatory compounds.
Omega-6 was the first polyunsaturated fatty acid to be discovered, and in the 1960’s it was thought that omega-6 was the ONLY one. So, when studies first came out showing a correlation between saturated fatty acids and cardiovascular disease (now increasingly questionable, see Part 1 of this series), nutritionists recommended that we all decrease our saturated fats and increase our polyunsaturated fats—and who knew, at the time, WHICH fatty acid we were increasing? I’m sure the dieticians said something like, “Oh, just use corn oil or olive oil, or palm oil, or peanut oil—you know, they’re all the same.”
Not.
No wonder the results of the many dietary fat studies have been so goofy and variable.
So what does the scientific data say about omega-6 fatty acid as it relates to nutrition?
First, omega-6 fatty acid has the “common name” linoleic acid. That’s linoLEic acid. (Omega-3 fatty acid has the common name linolenic acid. Read: linoLENic acid. Easy to confuse.)
Linoleic acid is commonly found in vegetable oils. You can look these up on the web yourself, but what is important here is that corn, soybean, and safflower oil are very rich in linoleic fatty acid.
In 2013 scientists reanalyzed the data generated in a 7-year Australian study (1966 to 1973) involving 458 men, aged 30-59 years, each of whom had had a recent coronary event. The “reduced polyunsaturated fatty acid” group was given liquid safflower oil (high in omega-6 fatty acid) as a dietary substitute for animal fats and vegetable shortenings in cooking oils, salad dressings, and baked products, and safflower oil margarine to be used in place of butter and common margarines. Guess what they found—substituting omega-6 fatty acids for saturated fat RESULTED IN A STATISTICALLY SIGNIFICANT 6% INCREASE IN DEATHS, AND A 6% INCREASE IN CARDIOVASCULAR DISEASES. How about that—you think you are going to show that decreasing saturated fats is a “good” thing, and you end up killing some of your patients.
And interestingly, this negative result occurred in spite of the fact that substituting safflower oil for other dietary fats caused a decrease in the subjects’ total cholesterol, primarily by reducing levels of low-density lipoprotein (the “bad” cholesterol)—which you would also expect to be a good thing. The scientists who did the reanalysis have proposed a model to explain why this may be so, but a detailed examination of their theory will have to be the subject of another blog post (perhaps). Suffice it to say that the omega-6 gets oxidized to a form that binds with low-density cholesterol, which then ends up as arterial plaque. Get it? The omega-6 lowers low-density cholesterol because it is changing it into a form that is actually harmful. Oh dear.
Well, this study is causing a bit of a stir, as you might imagine. The British Medical Journal, the one that published the original report in the 1970s (without the newly-analyzed data), has a bit of egg on its face. One has to wonder why this startling information was not reported until 2013, when the trial ended way back in 1973? Apparently the answer is that the authors ran out of money to do a more thorough analysis. Well, you can’t do research without money, so maybe so. CBC News reported in February 2013 that perhaps one-half of clinical trials are NEVER published. (This too will perhaps be the subject of another blog post.)
On February 5, 2013, the British Medical Journal published a “comment” on this paper, and I include a portion of it here:
“The American Heart Association recently repeated advice to maintain, and even to increase, intake of omega 6 PUFAs (polyunsaturated fatty acids). This advice has caused some controversy, because evidence that linoleic acid lowers the risk of CVD (cardiovascular disease) is limited—most trials that claimed to investigate the effect of exchanging saturated fat for linoleic acid involved multiple dietary changes or multiple interventions (or both). In particular, studies lowered trans fatty acid intake or increased omega 3 PUFA intake (or both) at the same time as increasing linoleic acid intake. The impact on CVD risk or mortality of replacing saturated fat with linoleic acid without changes in other fatty acids has rarely been investigated, and no large randomized controlled trial has recently explored this important question…. The new analysis of these old data provides important information about the impact of high intakes of omega 6 PUFAs, in particular linoleic acid, on cardiovascular mortality at a time when there is considerable debate on this question. The findings underscore the need to properly align dietary advice and recommendations with the scientific evidence base. It is important when assessing this evidence base that subtle, and in some cases unsubtle, aspects of study design are properly considered. For example, outcome of studies in which intakes of saturated and trans fatty acids are lowered while intakes of omega 6 fatty acids and omega 3 PUFAs are increased may be most strongly influenced by changes in trans and omega 3 fatty acids. They should not be interpreted as showing an effect of omega 6 PUFAs.”
I have to say that this is very cool. I don’t mean it’s cool that there may be misleading advice out there that is killing people, but that the interplay between advancing science and public policy is cool. It also reiterates what I said at the beginning of this blog series—the data is too sketchy to be making policy recommendations.
I wonder what the American Medical Association thinks about this? Oh, wait, here we go—on February 7, 2013, the AMA had this to say:
“The British Medical Journal study is interesting, but not conclusive. It is offset by a large body of scientific evidence that continues to show cardiovascular benefits associated with eating mono- and poly-unsaturated fat, rich in Omega-6 linoleic acids, in place of saturated fat. . . .”
I don’t know about you, but I find this to be quite surprising—no change in the AMA’s position on omega-6’s? Not even a statement that they will give this new data “due consideration”? One has to wonder about this, especially since everybody else seems to be pretty excited by the new data. Well, my understanding is that the U.S. edible oils manufacturing industry is $55 Billion—and that figure doesn’t even include farm production of corn and soybeans (grains that are high in omega-6’s). What influence do you think these industries could have on the federal government’s interest in doing research in this area—research possibly showing that consuming omega-6’s in the form of corn oil and soybean oil might have negative effects on our health?
What fun!
We must keep in mind, however, that this reanalysis doesn’t stand alone—it follows numerous studies indicating that the story isn’t as simple as omega-6 fatty acids just being “bad.” They are, in fact, essential to our health—they seem to be “bad” only when they are consumed in excess relative to omega-3 fatty acids. In other words, what seems to be emerging is that it is the ratio of omega-6 fatty acids to omega-3 fatty acids that is important.
But first a little history about omega-3 fatty acid, or linoLENic acid.
Unlike omega-6 fatty acid, the importance of omega-3 fatty acid really started to emerge in 1975 with the discovery that the Greenland Inuit Eskimos had a level of cardiovascular disease that ranged from very low to virtually nonexistent—and that they had two times as much omega-3 fatty acid in their blood as the Eskimos living in Denmark. The Greenland Eskimos also consumed very low amounts of omega-6 compared to their cousins living in Denmark. Oh, and the Greenland Eskimos had higher levels of saturated fat and lower levels of both triglycerides and cholesterol in their blood plasma than the Danish Eskimos did. Interestingly, an analysis comparing the diets of Greenland Eskimos and with the diets of Danes (not Danish Eskimos in particular) showed that the Greenland group consumed less carbohydrates, more protein, about the same amount of fat, more cholesterol, LESS saturated fatty acids, and less omega-6 fatty acids.
Well, the omega-3 story has evolved since then, and today we know that the “Western diet” is very high in omega-6 and low in omega-3 fatty acids, like that of the Danish group.
And now, of course, I have to report on meta-analyses of omega-3 fatty acids. What is the data showing?
Meta-Analysis #1*. Published in 2012. 20 randomized studies involving 68,680 patients. Examined the effect of omega-3 supplements on cardiovascular disease. The average age of the test subjects was 68; they received supplemental omega-3 for two years. The amount of the supplement was 1 gram or less per day per person. What did they find? The authors concluded there was NO statistically significant correlation between supplementation and cardiovascular disease or death. And that’s it. However, when you look at the actual data, what is interesting is that nearly all the studies showed that the supplemented groups had less cardiovascular disease, but that it wasn’t statistically significant. Well, that’s interesting . . .
Meta-Analysis #2**. Published in 2013. 21 randomized studies involving 46,737 patients. Compared omega-3 fatty acid supplementation (either via capsules or diet alterations) to a normal diet. Most of the studies included patients at high cardiovascular risk. The authors were not specific about the amount of omega-3’s consumed. They found a statistically significant 10% DECREASE in cardiovascular events of any kind and a 9% decrease in cardiovascular death.
So, given these two meta-analyses, I’d say it is looking like the omega-3 fatty acids may have a positive effect on cardiovascular disease.
Today there seems to be an emerging consensus to the effect that increasing our consumption of omega-3 fatty acids and decreasing our consumption of omega-6 fatty acids is beneficial. There are many reports that the typical “Western” diet includes an overabundance of omega-6 fatty acids, probably due in part to the consumption of the corn and soybean oils that are found in so many of our foods. Omega-6 fatty acids are also prevalent in feedlot-produced beef—probably due to the use of corn and soybeans as feed. Think poultry and eggs, too.
In fact, Western diets have ratios of omega-6 to omega-3 fatty acids in the neighborhood of 15:1, although many scientists believe the optimal ratio is closer to 4:1—and some even advocate reversing the ratio to 1:4 (only one-fourth as much omega-6 as omega-3). I don’t know how good the science is here, but apparently the problem with too much omega-6 is that it shifts the omega-3 fatty acids towards the same pathway as omega-6’s, which results in inflammation.
All I know is that I’d sure like an updated analysis of diets, blood plasma, and cardiovascular disease in other “traditional” populations like the Greenland Eskimos.
But, overall, I bet that my prediction at the start of this blog series is correct—the studies that have been done so far have too many unknowns relative to the exact types and quantities of fatty acids consumed by the test subjects. We just haven’t had sufficiently detailed knowledge (either quantitative or qualitative) about what food is going into patients’ mouths during the last 30 or 40 years to be giving accurate advice.
So there.
And how this relates to the whole controversy concerning the Mediterranean Diet vs. the recommended U.S. Food Pyramid vs. the South Beach Diet vs. the Paleo Diet, I don’t know. I see there is a new report out on the results of a study comparing the Mediterranean diet with a low-fat diet. 7,447 people enrolled, ages 55-80. Well, the authors conclude we should consume more olive oil—because the (statistically significant) rate of cardiovascular events among the Mediterranean diet group was 0.6% lower than it was among the low-fat diet group.
Only 0.6%? That seems too small to worry about if you like red meat, statistically significant or not.
But the fat story also includes recent recommendations regarding “trans fats.” You certainly know by now that labeling of trans fats in food is mandatory in the United States. And as of January 1, 2010, California became the first state to ban trans fats in restaurants. Scientifically sound?
Next blog post.
_______________________
*Evangelos C. Rizos, MD, PhD; Evangelia E. Ntzani, MD, PhD; Eftychia Bika, MD; Michael S. Kostapanos, MD; Moses S. Elisaf, MD, PhD, FASA, FRSH (September 2012). "Association Between Omega-3 Fatty Acid Supplementation and Risk of Major Cardiovascular Disease Events A Systematic Review and Meta-analysis". JAMA 308 (10): 1024–1033
**Javier Delgado-Lista, Pablo Perez-Martinez, Jose Lopez-Miranda, Francisco Perez-Jimenez. 2012. “Long Chain Omega-3 Fatty Acids and Cardiovascular Disease: a Systematic Review. British Journal of Nutrition 107: S201-S213
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