What if gluten sensitivity doesn’t exist?

How can I possibility make that statement?  Two recent best-selling diet books have maintained that gluten makes us fat and dumb (1,2). Billions of dollars are spent on gluten-free (but carbohydrate-rich) food products.  And people feel better when they don’t eat bread.

Before explaining my statement, let me make two things very clear.  First, I am not a big believer in bread.  In 1997, in a Time magazine interview I said, “If all the bread left the face of the earth, we would have a much healthier planet.” (3)  I stand by that statement.

Second, gluten “sensitivity” is not celiac disease.  Celiac disease is a clinically proven autoimmune response to the proteins in gluten (4).  I know since my wife has severe celiac disease.

However gluten sensitivity is different.  Most of the people who pretend to be experts in gluten sensitivity usually have no background in gastrointestinal research.  After all, why try to back up your claims with real research that is very difficult to do?  So it came as a great initial salvation to those people when a real expert from Australia published a paper indicating that gluten sensitivity may exist but with no clues to the mechanism (5).  In this study subjects with irritable bowel syndrome (IBS) and no evidence of celiac disease were put on a gluten-free diet for six weeks and then either challenged daily with muffins and bread either containing gluten (16 grams per day) or without gluten.  Even though both groups were on a gluten-free diet, they were both having more symptoms, although the group getting the extra gluten had more symptoms of IBS, including being more fatigued than the control group (5).


What was also strange about the results of this study was there were no differences in the intestinal inflammation or any increase in the permeability of the intestinal wall in either group.  This caused the researchers to ponder if they had been too simplistic in their experimental design.   So they went back to do another experiment in which a diet that was far more rigorous in reducing other potential food allergens, such as FODMAPs, which stand for Fermentable, Oligo-, Di-, Monosaccharides And Polyols.  These are poorly absorbed short-chain carbohydrates, which means that many of these dietary carbohydrates reach the colon where the trillions of bacteria are waiting to begin fermenting them. FODMAPs are found in foods, such as those containing free fructose (found in apples, cherries, pears, asparagus, artichokes, etc.), foods that can be easily broken down into free fructose (such as high-fructose corn syrup and table sugar), free lactose (found in milk, yogurt, soft cheeses, etc.), polymers of fructose known as fructans (found in peaches, artichokes Brussels sprouts, fennel, onion, wheat, barley, and rye), polymers of galactose known as galactans (found in legumes, chickpeas, lentils, etc.) and polyols (found in apricot, avocado, blackberries, plums, cauliflower, mushrooms, snow peas, etc.).  This is a lot more complex dietary undertaking than putting all of your bets on gluten (6).

So when the researchers repeated their experiment and removed many of the FODMAPs from the diet of the sufferers with “gluten sensitivity” and then added back bread and muffins consisting of either high gluten (16 grams per day), low gluten (2 grams per day), or a placebo, they got a very different response as shown below (7).


Now you get a very different picture than the earlier study in which the researchers had not removed many of the FODMAPs from the diets of their subjects.  Furthermore, there was no increase in fatigue in those getting the gluten compared to the placebo, even though more than half of the subjects had the genetic susceptibility marker for celiac disease (DQ2 or DQ8 positive HLA), and a quarter of them had anti-bodies to gliadin (one of the proteins in the overall family of protein collectively called gluten).

These new results with the low-FODMAPs diet led the researchers to conclude:  In a placebo-controlled, cross-over rechallenge study, we found no evidence of specific or dose-dependent effects of gluten in patients with non-celiac gluten sensitivity placed on diets low in FODMAPs.  That’s a mouthful, but in essence the benefits of a gluten-free diet may not be the removal of gluten but the removal of various FODMAPs found in the wheat, rye, and barley that just happen to also contain gluten.

What remains unknown is whether it is the FODMAPs or a unique bacteria composition in the guts of the “gluten-sensitive” people interacting with the FODMAPs that can cause the problems that lead to IBS and the designation of being “gluten-sensitive”.

However one thing is certain: This new research will not stop the continuing flow of “gluten-free” products rich in carbohydrates coming from the food industry and more popular diet books “discovering” the real reason we are getting fatter and dumber.  Maybe I was on the right track in 1997 when I stated that bread removal is not such a bad idea for mankind.  That’s because I also believe that it is increased diet-induced inflammation, not simply gluten, that is the real cause of our growing epidemics of obesity, type 2 diabetes, and Alzhemier’s.


1.  Davis W.  Wheat Belly: Lose the Wheat, Lose the Weight, and Find Your Path Back to Health. Rodale Books.  Erasmus, PA (2011)

  1.  Perlmutter D.  Grain Brain: The Surprising Truth about Wheat, Carbs, and Sugar-Your Brain’s Silent Killers. Little, Brown and Company.  New York, NY (2013)
  2.  Ratnesar R.  “Against the grain.”  Time. December 15, 1997 (1997)
  3. Fasano A. Gluten Freedom: The Nation’s Leading Expert Offers the Essential Guide to a Healthy, Gluten-Free Lifestyle. Wiley.  New York, NY (2014)
  4. Biesiekierski JR, Newnham ED, Irving PM, Barrett JS, Haines M, Doecke JD, Shepherd SJ, Muir JG, and Gibson PR.  “Gluten causes gastrointestinal symptoms in subjects without celiac disease: a double-blind randomized placebo-controlled trial.”  Am J Gastroenterol 106:508-514 (2011)
  5. Gibson PR and Shepherd SJ.  “Food choice as a key management strategy for functional gastrointestinal symptoms.” Am J Gastroenterol 107:657-666 (2012)
  6. Biesiekierski JR, Peters SL, Newnham ED, Rosella O, Muir JG, and Gibson PR.  “No effects of gluten in patients with self-reported non-celiac gluten sensitivity after dietary reduction of fermentable, poorly absorbed, short-chain carbohydrates.” Gastroenterology 145:320-328 (2013)

Trying to Make Science Out of Sausage

Epidemiology is the study of associations and not causality. It essentially began in 1854 when John Snow noticed that there seemed to be a higher concentration of cholera patients in a certain area in London during one of its many cholera epidemics in the 19th century. That’s an association. The real breakthrough for John Snow was to remove the pump handle on the suspected water source and then observe a significant reduction in the cases of cholera in that area. That’s called an intervention study based on epidemiology. Now in the 21st century we seem very reticent to do any type of intervention studies and rely more on epidemiology to guide our medical decisions. This is made even more confusing with the introduction of meta-analysis into the picture. Meta-analysis is taking a large number of studies (often done under very different conditions), pretending they are all valid and then coming up with a conclusion. When you do a meta-analysis on epidemiology studies, it’s like trying to separate a piece of filet mignon from intestines used to make sausage.

This month an article from the Annals of Internal Medicine suggested that there is no relationship of any type of fatty acid with heart disease (1). Well, if there is no association of any type of fatty acid with heart disease, why not just eat lard instead of salmon? If this sounds a little fishy to you (pardon the pun), it does to me too. As I stated earlier, the problem with meta-analysis is that good studies are added to bad ones. Here’s a dirty secret about medical research. There are a lot of bad studies that get published. Usually if you can’t get the funds to do original research, then you write a review paper, and if you can’t write a review paper, then you do a meta-analysis of all published studies and pretend it’s original research. The media might buy that, but I don’t.

The irony of this study is that one of the authors had actually published a good article using good controls in the same journal a year earlier indicating that the higher the levels of omega-3 fatty acids in the blood, the less heart disease death and the greater the longevity of the individuals (2). Maybe he forgot that article when publishing this new sausage publication (1).

That notwithstanding, the problem with these types of published studies is that they miss the point of what causes heart disease in the first place. It is not fatty acids or cholesterol, but inflammation. The best way to measure inflammation is the ratio of AA to EPA in the blood. This was first reported in the New England Journal of Medicine some 25 years ago (3). High-dose fish oil in healthy volunteers (5 grams of EPA and DHA per day) reduced the AA/EPA ratio from 21 to 2.5 within six weeks. During that time many of the additional markers of cellular inflammation also dropped. When they stopped the omega-3 fatty acid supplementation, the AA/EPA ratio gradually returned to its initial high level with a corresponding increase in the depressed inflammatory proteins to their initial levels. A very nice intervention study.

Then there is the disturbing fact that Japanese males have essentially the same LDL cholesterol levels as Americans, but Americans have 3.5 times the age-adjusted death rate. In fact, the LDL cholesterol levels of the Japanese having been rising since 1980, whereas American’s LDL cholesterol levels have been dropping. In addition, Japanese males in the study were about 7 times more likely to smoke than Americans. Let’s see, rising LDL cholesterol levels coupled with more smoking, but they have 72% fewer deaths from heart disease (4). Maybe the AA/EPA ratio as a marker of inflammation might be a key? The AA/EPA ratio of the Japanese in that study was 2.6, whereas the Americans were 11.1. Actually the Americans in this study were less inflamed than the general American population that has an AA/EPA ratio of 20 (5). But even in the above study, the Japanese AA/EPA ratio was 76% lower than the Americans (4). Let’s see, the Japanese had 76% lower inflammation and 72% lower mortality from heart disease compared to the Americans even through their LDL cholesterol levels were the same and they smoked like chimneys. If I was a betting man, I would put my money on doing an intervention study to see what the effect on heart disease would be if I lowered the AA/EPA ratio. That’s exactly what the Japanese did with the JELIS trial that was one of the largest cardiovascular trials ever undertaken with some 18,000 subjects (6). All of them had high cholesterol, so all of them were put on statins. The average AA/EPA ratio of these subjects was 1.6 compared to the 20 in Americans (5,6). Half the subjects were then given more omega-3 fatty acids. If the meta-analysis study recently published was valid (1), then these extra omega-3 fatty acids would have no benefit especially since everyone was getting a statin. Actually, just the reverse occurred after 3 ½ years. Those who lowered their AA/EPA ratio had 20% fewer cardiovascular events compared to those that didn’t see a change in the placebo group. Further sub-group analysis indicated that the change in the AA/EPA ratio was the overriding factor (7) behind these cardiovascular benefits. This is a complicated way of saying that if you lower inflammation, you lower cardiovascular risk.

So the next time you read about a meta-analysis study on the lack of effect of fatty acids on heart disease, ask to see a real intervention trial that lowers the levels of inflammation. When you do, then you see a very different picture of the role of fatty acids in heart disease than you do by reading more sausage studies (1,8). And if you do an intervention trial with omega-3 fatty acids, make sure that you lower the AA/EPA ratio to the level found in the Japanese. Based on published dose-response studies, this will take a minimum of 5 grams of EPA and DHA per day (9). Up to this point in time, no such cardiovascular studies have been conducted with that level of omega-3 fatty acids. If you are not using at least that level of omega-3 fatty acids to study cardiovascular disease, then you are probably using a placebo dose and should expect placebo results.


  1. Chowdhury R et al. “Association of dietary, circulating, and supplement fatty acids coronary risk.” Ann Intern Med 160:396-406 (2014)
  2. Mozaffarian D et al. “Plasma phospholipid long-chain omega-3 fatty acids and total and cause-specific mortality in older adults.” Ann Intern Med 158:515-525 (2013)
  3. Enders S et al. “The effect of dietary supplementation with n-3 polyunsaturated fatty acids on the synthesis of interleukin-1 and tumor necrosis factor by mononuclear cells.” New Engl J Med 320:265-271 (1989)
  4. Sekikawa A et al. “Serum levels of marine-derive n-3 fatty acids in Icelanders, Japanese, Koreans and Americans.” Prostglandins Leukot Essent Fatty Acids 87:11-16 (2012)
  5. Harris WS et al. “Erythrocyte omega-3 fatty acids increase and linoleic acid decreases with age: observations from 160,000 patients.” Prostaglandins Leukot Essent Fatty Acids 88:257-263 (2013)
  6. Yokoyama M et al. “Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis.” Lancet 369:1090-1098 (2007)
  7. Matsuzaki M et al. “Incremental effects of eicosapentaenoic acid on cardiovascular events in statin-treated patients with coronary artery disease.” Circ J 73:1283-1290 (2009)
  8. Rizos EC et al. “Association between omega-3 fatty acid supplementation and risk of major cardiovascular disease events: a systematic review and meta-analysis.” JAMA 308:1024-1033 (2012)
  9. Yee LD et al. “Omega-3 fatty acid supplements in women at high risk of breast cancer have dose-dependent effects on breast adipose tissue fatty acid composition.” Am J Clin Nutr 91:1184-1194 (2010)

Practical hints for helping to manage brain trauma

Since the recent story on CNN (“He’s going to be better than he was before,” Jan. 18, 2014,) about the extraordinary recovery of Grant Virgin from severe brain trauma, I have gotten a lot of requests for information. Since I have been doing this protocol for more than seven years after first working with Dr. Julian Bailes on the equally remarkable recovery of Randal McCloy Jr. (the sole survivor of the Sago mine disaster in 2006) and others (1,2), I can offer some broad guidelines. Make no mistake, each case is different, but these guidelines will considerably help your decision-making process.

What Type of Fish Oil to Use


When is comes to treating brain trauma, purity and potency of the omega-3 product count. All fish and all fish-oil products are contaminated with various toxins. The most important is polychlorinated biphenyls or PCBs. These are known neurotoxins. It makes little sense giving someone a fish-oil product that is rich in PCBs. One of the dirty secrets of the fish-oil manufacturing industry is that it is extremely difficult to remove PCBs from a final product. In fact, it is so difficult, the industry tries to ignore it. Making a statement that a fish-oil product is free from PCBs is an outright lie. It is equally ridiculous to state that the PCBs levels in its products are lower than the international standards. Those international PCB standards (90 parts per billion or ppb) are so lax that virtually any fish-oil product in the supermarket is going to exceed them. Of course, if you want to heal the brain, then I would recommend looking for the purest fish oil you can find. If you are even considering using fish oil, make sure that the levels of total PCBs are less than 5 ppb. This is 18 times lower than the international standard. Using this more rigorous criterion of purity, your choices become very limited. Furthermore, PCB levels will vary from lot to lot. So you want to make sure that the lot you are actually using contains less than 5 ppb. Go to the product’s website or call the manufacturer. If the manufacturers can’t supply that data, it means they don’t know. If they said it is pure, then they mean it might pass the very lax international standards. Here’s a good rule about fish oils: Trust but always verify. PCB testing is expensive but so is saving a brain. Of course, if you don’t care about potential PCB accumulation in the brain, then use the cheapest fish-oil product you can find.


You are going to have to use a lot of fish oil to put out the inflammation in the brain and to rebuild it. Therefore, the potency of the fish oil counts. I would never recommend any fish-oil product containing any less than 60% EPA and DHA. Usually the higher the potency of the fish oil, the higher the purity, but not always. Removal of PCBs is very different than increasing omega-3 fatty acid potency. I have tested many high-potency fish oils that also have high PCB levels. Likewise, the omega-3 fatty acids levels will vary from lot to lot. Before you use any omega-3 fatty-acid product, ask for the potency of that particular lot. If company representatives can’t provide it or say it meets their standards, then it means they don’t really know.

The fish oil needs to contain both EPA and DHA. EPA puts out the inflammation in the brain, and DHA helps rebuild the brain. You need both. I usually recommend a 2:1 ratio of EPA to DHA as that is the ratio I have used for several years with great success.

Omega-3 fatty acids are prone to oxidation, which leads to rancidity. The rancidity comes from breakdown products of the fatty acids into aldehydes and ketones that can cause damage to the DNA. That’s why there is an international rancidity standard (called total oxidation or TOTOX) that governs all edible oil trading in the world. Before you use any fish oil product, ask for the TOTOX levels of the finished product (not the raw materials). If it is less than 26 meq/kg (the upper limit for an edible oil), then it is OK to use. If not, don’t even consider it.


Even if you if you have a high-quality fish-oil product, you are going to need a lot for brain injuries. This will usually be in the range of 10-15 grams of EPA and DHA per day. That’s why you need the high-purity and high-potency fish oil. Because of the high amounts, it will have to be given in a liquid format. Why the high doses? Because you have to put out the fire in the brain before you can rebuild it.

The levels of fish oil needed are based on testing, not guessing. The best test for the levels of fish oil required is the ratio of two fatty acids in the blood. One is arachidonic acid (AA), and the other is EPA. Why this is important is because AA causes inflammation, and EPA reverses inflammation. You measure the levels of AA and EPA using a simple finger-stick blood test. The AA/EPA ratio is not a standard clinical test, but it has been in medical research for nearly 30 years, starting first at Harvard Medical School (3). The AA/EPA ratio will tell you how much a pure fish oil product you need as you want the AA/EPA ratio to be in the range of 1.5 to 3. If the AA/EPA ratio is higher than 3, you will need more fish oil. If AA/EPA is less than 1.5, you will need less fish oil. Maintaining the AA/EPA between 1.5 and 3 addresses the largest concern of using high-dose fish oil, which is potential bleeding. I chose an AA/EPA ratio of 1.5 as my lower limit since that is what it is in the Japanese population, and they don’t bleed to death (4-11).

The most inexpensive test for the AA/EPA ratio can be found at www.zonediagnostics.com.

Why drugs don’t work, and fish oil does

With severe brain trauma, the usual response of the physician is “we just have to wait”. The reason why is because there are no drugs that can cross the blood-brain barrier to put out the inflammation in the brain. That is not true with omega-3 fatty acids. They can easily enter the brain if there are high enough levels in the blood. What is the correct level in the blood? The AA/EPA ratio will tell you. Not only should the AA/EPA ratio be between 1.5 and 3, but also the EPA levels should be greater than 4% of the total fatty acids in the blood.

What Else?

When using high levels of fish oil even if it is pure and potent, you still have to emulsify it to reduce the size of oil droplets for better absorption. One of the best methods to emulsify liquid fish oil is to mix it with either a seaweed or an aloe vera product to reduce the size of the oil droplets to increase the absorption into the blood.

You also have to provide extra anti-oxidant protection to protect the omega-3 fatty acids from oxidation. The best way is using polyphenols to be mixed with the fish oil before administration. Adding extra virgin olive oil is a good choice. Adding highly purified polyphenol extracts to the liquid fish oil is a better choice.

What to expect

Each case is different. Based on my experience if you are using the correct amount of omega-3 fatty acids, you should see the beginnings of a response within 60 days. In Grant’s case, it was two days. If you do, then continue the same level of fish oil since putting out the inflammatory fire is only the first step of the process. The next step is rebuilding the brain. I would suggest monitoring the AA/EPA ratio every 30 days for the first 60 days and then every 60 days thereafter to make sure you are giving the right amount of fish oil.

Most importantly, this is not a Mr. Wizard home experiment. You should always be working with your physicians, not against them. They will also need education in the use and safety of high-dose fish oil, but this short summary is a good start.

Don’t expect any reimbursement from your insurance company for the use of the fish oil or AA/EPA testing. It may seem expensive, but compared to the human suffering of not trying to rebuild the brain, the costs of both the fish oil and AA/EPA testing are minor. I would also consider using flexible- spending health-care accounts if you have access to them to lower the overall cost, since they are based on pre-tax income.

Taking fish oil and following an anti-inflammatory diet is key

One of the reasons for Grant Virgin’s rapid progress was the fact that he was already taking moderate doses of fish oil for a medical condition. This meant he already had some reserve capacity in the body and the brain to reduce the inflammatory burden caused by a hit-and-run accident. You never know when brain trauma will occur. Maintaining a relatively low AA/EPA ratio in the blood is your best insurance policy for protection against future brain trauma if it does strike. You don’t have to be as aggressive as in the treatment phase, but aim for keeping the AA/EPA ratio between 5 and 10 in the blood. For comparison, the average American has an AA/EPA ratio of 20 (12). When dealing with brain trauma, an ounce of prevention is worth pounds of cure.

Finally, to accelerate the healing and rebuilding of the brain, you want to be following an anti-inflammatory diet (13-15). An anti-inflammatory diet is one that reduces the production of AA that drives inflammation in the brain. The less AA you have in the blood, the less AA gets into the brain. Try to keep the AA level in the blood to less than 9% of the total fatty acids. This takes more work than simply giving fish oil, but the more you reduce the levels of AA in the blood, the less high-dose fish you will need to maintain the AA/EPA ratio required to accelerate the healing and rebuilding process in the brain.


  1. Roberts L, Bailes J, Dedhia H, Zikos A, Singh A, McDowell D, Failinger C, Biundo R, Petrick J, and Carpenter J. “Surviving a mine explosion.” J Am Coll Surg 207:276-283 (2008)
  2. Sears B, Bailes J, and Asselin B. “Therapeutic use of high-dose omega-3 fatty acids to treat comatose patients with severe brain injury.” PhamaNutrition 1: 86-89 (2013)
  3. Endres S, Ghorbani R, Kelley VE, Georgilis K, Lonnemann G, van der Meer JW, Cannon JG, Rogers TS, Klempner MS, Weber PC, Schaefer EJ, Wolff SM, and Dinarello CA. “The effect of dietary supplementation with n-3 polyunsaturated fatty acids on the synthesis of interleukin-1 and tumor necrosis factor by mononuclear cells.” N Engl J Med 320:265-271 (1989)
  4. Swails WS, Bell SJ, Bistrian BR, Lewis EJ, Pfister D, Forse RA, Kelly S, Blackburn GL. “Fish-oil-containing diet and platelet aggregation.” Nutrition 9:211-217 (1993)
  5. Parkinson AJ, Cruz AL, Heyward WL, Bulkow LR, Hall D, Barstaed L, and Connor WE. “Elevated concentrations of plasma omega-3 polyunsaturated fatty acids among Alaskan Eskimos”. Am J Clin Nutr 59:384-388 (1994)
  6. Eritsland J, Arnesen H, Seljeflot I, andKierulf P. “Long-term effects of n-3 polyunsaturated fatty acids on haemostatic variables and bleeding episodes in patients with coronary artery disease.” Blood Coagul Fibrinolysis 6:17-22 (1995)
  7. Watson PD, Joy PS, Nkonde C, Hessen SE, and Karalis DG.
    Comparison of bleeding complications with omega-3 fatty acids + aspirin + clopidogrel–versus–aspirin + clopidogrel in patients with cardiovascular disease. Am J Cardiol 104:1052-1054 (2009)
  8. Salisbury AC, Harris WS, Amin AP, Reid KJ, O’Keefe JH, and Spertus JA.
    “Relation between red blood cell omega-3 fatty acid index and bleeding during acute myocardial infarction.” Am J Cardiol 109:13-18 (2012)
  9. Larson MK, Ashmore JH, Harris KA, Vogelaar JL, Pottala JV, Sprehe M, and Harris WS. “Effects of omega-3 acid ethyl esters and aspirin, alone and in combination, on platelet function in healthy subjects.” Thromb Haemost 100:634-641 (2008)
  10. Harris WS. “Expert opinion: omega-3 fatty acids and bleeding-cause for concern?” Am J Cardiol 99:44C-46C (2007)
  11. Yokoyama M, Origasa H, Matsuzaki M, Matsuzawa Y, Saito Y, Ishikawa Y, Oikawa S,Sasaki J, Hishida H, Itakura H, Kita T, Kitabatake A, Nakaya N, Sakata T, Shimada K, and Shirato K. “Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis.” Lancet 369: 1090-1098 (2007)
  12. Harris WS, Pottala JV, Varvel SA, Borowski JJ, Ward JN, and McConnell JP. “Erythrocyte omega-3 fatty acids increase and linoleic acid decreases with age: observations from 160,000 patients.” Prostaglandins Leukot Essent Fatty Acids 88:257-263 (2013)
  13. Sears B. The Zone. Regan Books. New York, NY (1995)
  14. Sears B. The OmegaRx Zone. Regan Books. New York, NY (2002)
  15. Sears B. The Anti-inflammation Zone. Regan Books. New York, NY (2005)

The Real Facts about Metabolically Healthy Obesity

One of great paradoxes of our obesity epidemic is that many obese individuals appear to be quite healthy. This makes the true believers in the Holy Grail of BMI as the standard for good health quite livid. They know in their hearts that obesity is a mortal sin. Early this year the Centers for Disease Control (CDC) published another in a long series of articles demonstrating that being overweight significantly decreases your likelihood of dying compared to being “normal weight” (1). Immediately Harvard Medical School went on a rampage crying foul. So you can imagine the delight of the weight-loss experts when a new meta-analysis demonstrated that “there is no healthy pattern of increased weight” (2). Take that, you silly scientists at the CDC. Unfortunately, this article represents another case of a meta-analysis creating meta-confusion.

When you state that someone is metabolically healthy obese, it means just that—they are healthy. So how can you look at someone and say they are healthy? You have to look for accepted signs of health, not whether or not they fit into designer clothing. Fortunately, there is a health ranking of obese individuals that is not based on their actual weight. It is called the Edmonton Obesity Staging System (EOSS). Obviously to be included in this ranking system, an individual has to be obese (BMI > 30). But now they are ranked in terms of health as shown below:

Stage 0: Normal blood pressure, blood glucose, and blood lipid levels and no physical or psychological impairment to being obese.

Stage 1: Existence of subclinical risk, such as borderline hypertension, impaired fasting glucose, elevated liver enzymes, mild physical symptoms, and mild impairment of well-being.

Stage 2: Established chronic disease (hypertension, type 2 diabetes, sleep apnea, osteoarthritis, etc.) and moderate limitations in physical and psychological well-being.

Stage 3: Established end-organ damage (heart attack, stroke, heart failure, etc.) and significant physical and psychological impairment.

Stage 4: Essentially the walking dead.

My definition of a healthy obese individual is someone who has an EOSS Stage 0 ranking.

So using these EOSS definitions and the NHANES III data from 1988-1994, how many people with excess weight are actually healthy using the standard definitions of excess weight: Overweight being a BMI of 25-30, Grade 1 Obesity having a BMI between 30-35, Grade 2 Obesity having a BMI between 35-40, and Grade 3 Obesity having a BMI > 40?

Overweight Obese 1 Obese 2 Obese 3
U.S. Population 50M 23M 10M 6M
Stage 0 15% 8% 5% 5%
Stage 1 28% 19% 17% 10%
Stage 2 47% 59% 64% 67%
Stage 3 10% 14% 14% 14%

The total number of overweight and obese Americans falling within the four rankings of EOSS accounted for nearly 90 million Americans. You can also see that there is great heterogeneity within each category of excess weight, but between 5 to 8% of obese patients are quite healthy regardless of their weight.

If you have an EOSS Stage 0 ranking regardless of your weight, you are healthy. Obviously, the more things wrong with you health-wise regardless of your weight, the more likely you are to going to have even more health problems in the future.

And here is the problem with the article that generated so much glee at Harvard Medical School—the researchers didn’t distinguish between truly healthy obese (EOSS Stage 0) and not-so-healthy obese (EOSS Stage 1). In fact, 9 of the 12 studies they included for their meta-analysis defined being “healthy” as not having metabolic syndrome (2). To have metabolic syndrome requires having three very different unhealthy factors. The other 3 studies included defined “healthy” as having two or less risk factors for metabolic syndrome. This means someone with hypertension, elevated blood glucose, or elevated triglycerides would be considered “healthy” in this meta-analysis (2). I guess I come from the old school, in that I wouldn’t consider such people healthy.

Now if you go back to the earlier study published by the CDC, these researchers used a very simple clinical end point that can’t be fudged (1). This end point is called death. Their data clearly points out that overweight people had a significantly a lower death rate than normal-weight people. That’s a hard fact. And the Grade 1 Obese individuals have about the same death rate as normal-weight individuals. If the CDC had used the EOSS system instead of relying on BMI, then it is likely that every grade of obese person with an EOSS Stage 0 would be living longer than normal-weight individuals.

Another recent study has indicated that metabolically healthy obesity (again using mixed patient populations) may be a transitory stage (4). However that study also used a combination of EOSS Stage 0 and Stage 1 patients within their definition of “metabolically healthy obese”. When you separate the truly healthy obese (EOSS Stage 0) from the not-so-healthy (EOSS Stage 1), you find that EOSS Stage 0 patients (regardless of their levels of obesity) maintain their health over a long time period (more than 16 years) as shown below (3).


The EOSS Stage 1 individuals in all weight classes become progressively less healthy with time. So if you combine the truly healthy obese (EOSS Stage 0) with not so healthy obese (EOSS Stage 1), then you might come to the wrong conclusion that the concept of metabolically healthy obesity doesn’t exist (2,4).

So what’s the real linkage between weight and mortality? It depends on your levels of cellular inflammation as I explained in my book Toxic Fat, published in 2008. And the less cellular inflammation you have at any weight, the healthier you are. The best measure of your levels of cellular inflammation is the AA/EPA ratio. It should be between 1.5 and 3. The average AA/EPA ratio for Americans is about 19 (5). As you reduce cellular inflammation, the severities of all forms of chronic disease are reduced regardless of your weight.


  1. Flegal KM, Kit BK, Orpana H, and Graubard BI. “Association of all-cause mortality with overweight and obesity using standard body mass index categories: a systematic review and meta-analysis.” JAMA 309:71-82 (2013)
  2. Kramer CK, Zinman B, and Renakeran R. “Are metabolically healthy overweight and obesity benign conditions?” Annals of Internal Medicine 159: 758-769 (2013)
  3. Padwal RS, Pajewshi NM, Allison DB, and Sarma AM. “Using the Edmonton obesity staging system to predict mortality in a population-representative cohort of people with overweight and obesity.” Can Med Assoc Journal 183:E1059-E1065 (2011)
  4. Appleton SL, Seaborn CJ, Visvanathan R, Hill CL, Gill TK, Taylor AW, and Adams RJ. “Diabetes and cardiovascular disease outcome in the metabolically healthy obese phenotype.” Diabetes Care 36:2388-294 (2013)
  5. Harris WS, Pottala JV, Varvel SA, Borowski JJ, Ward JN, and McConnell JP. “Erythrocyte omega-3 fatty acids increase and linoleic acid decreases with age: observations from 160,000 patients.” Prostaglandins Leukot Essent Fatty Acids 88:257-263 (2013)

More Cholesterol Madness

This week the American Heart Association announced a doubling down on its bet on cholesterol and heart disease.  It certainly wasn’t because there was a sudden epidemic of heart disease, because death rates have been falling since 1970 (20 years before statins were introduced).  Nor has there been any new clinical data showing the benefits of lowering cholesterol levels. Although for the last 20 years the use of statins has been said to be the end of the scourge of heart disease, it still remains the number-one killer of Americans.

Furthermore, these newest guidelines essentially recommend that not only should more Americans be put on statins, but they should also start at the highest dose possible.  In actuality, this “dose” is where the toxic effects begin to appear.  What are the toxic effects?  They include muscle weakness, reduction in cardiovascular fitness, increased diabetes, and memory loss.  Whatever happened to the Hippocratic oath of doing the patient no harm?

    All of this might be justified if there were any indication that cholesterol is the driving force behind heart disease.  Unfortunately, the facts simply don’t support the hype.  Remember, before statins arrived in 1994, saturated fat was the villain in heart disease, not cholesterol (1).  Yet in 2010, Harvard Medical School published epidemiological studies that made the connection between saturated fat and heart disease very tenuous at best (2).

So what if cholesterol is not the cause of heart disease?

Actually, there is another drug that also reduces mortality from heart disease, yet doesn’t lower cholesterol.  It’s called an aspirin.  What aspirin does do is to reduce inflammation.

The inflammation versus cholesterol battle for what causes heart disease has been raging for decades.  What gave the cholesterol boys the upper hand was it is easy to measure blood cholesterol.  With the advent of statins, it was simple for doctors to repeat the drug company mantra to their patients, “If your cholesterol levels are high, you are going to die”.  Great marketing, but poor science.

Just to illustrate the importance of reducing inflammation versus LDL cholesterol on mortality from heart disease, we can look at the heart disease mortality rates in 2004 both Japan and the United States (3).  The Japanese had a death rate from heart disease that was 71% lower than Americans, although their LDL cholesterol levels were virtually the same.  What was different between the two populations were their levels of inflammation as measured by the AA/EPA ratio.  The Japanese levels of inflammation were 76% lower than Americans.  These changes are shown in the following figure.

Figure 1.  Per Cent Differences Between Japanese and Americans


Even without advanced statistics, I think you can see there is a much better correlation between the reduction of the AA/EPA ratio between the Japanese and Americans relative to the reduction in mortality from heart disease than there is between differences in LDL cholesterol levels in Japanese and Americans relative to mortality from heart disease.

    The only way to explain this new madness for lowering cholesterol is it is a last-gasp effort of the cardiologists, who have spent their entire careers on the cholesterol bandwagon and will defend their faith to the death.  Unfortunately, it may be their patients who will have to pay the ultimate price for not being told the real enemy is inflammation.



1.  American Heart Association.  “Dietary guidelines for healthy American adults.  A statement for physicians and health professionals by the Nutrition Committee, American Heart Association.”  Circulation 77: 721-724A (1988)

2.  Siri-Tarino PW, Sun Q, Hu FB, and Krauss RM.  “Meta-analysis of prospective cohort studies evaluating the association of saturated fat with cardiovascular disease.”  Am J Clin Nutr 91:535-546 (2010)

3.  Sekikawa A, Steingrimosdotir L, Ueshima H, Shin C, Curb JD, Evans RW, Hauksottir AM, Kadota A, Choo J, Masaki K, Thorsson B, Launer LJ, Farcia ME, Maegawa H, Willco BJ, Eirksdottir G, Fujyoshi A, Miura K, Harris TB, Kuller LH, and Gudnason V.  “Serum levels of marine-derived n-3 fatty acids in Icelanders, Japanes, Korean, and Americans.”  Prostaglandins Leukotrienes and Essential Fatty Acid 87:11-16 (2007)

YWikipedia: Y (named wye plural wyes) is the twenty-fifth letter in the ISO basic Latin alphabet (next to last letter) and represents either a vowel or a consonant in English.

What’s in it for us?

In this day and age when we hear about selfish genes and winner-takes-all outcomes in evolution, it is refreshing to come across a scientific paper that redeems your faith in doing the right thing. In this case, there is strong support that being a giving person may let you potentially have a longer lifespan (1).

This research focused on hedonic behavior. There are two forms of hedonism. One is the classical desire for pleasures that are simply self-gratification. The other is called eudaimonic hedonism that comes from striving toward meaning and a noble purpose in life. Classical hedonism is deeply embedded in our genes. That’s why we eat to stay alive and have sex to propagate the species. That’s also why it is also highly related to fame and wealth so that you can get more food and sex. On the other hand, eudaimonic hedonism appears to motivate us toward more complex social and cultural activities that go beyond our individual lifespans.

One of the reasons why stress reduction is so important in living a good life is that there are a number of genes that seem to be up regulated in response to extended periods of stress and uncertainties. In particular, these are pro-inflammatory genes. This is known as the conserved transcriptional response to adversity or CTRA.

What this study did was to take healthy people and through a series of questions determine the balance of the two types of hedonism. Not surprisingly, nearly 80% of the subjects had higher levels of self-gratification (what’s in it for me) compared to those who had higher levels of eudaimonic hedonism (what’s in it for us). Then the researchers looked at the levels of activity of the genes that comprise the CRTA cluster of genes. Those who fell in the self-gratification group had higher levels of pro-inflammatory gene expression (as well as decreased expression of the genes required for immunity) compared to the subjects who were in the group that had a higher level of eudaimonic hedonism. These changes in gene expression should translate into a longer and healthier life. There is some indication that this may be true (2,3).

Conversely, it is known that increased inflammation reduces hedonic well being (4,5). This would explain why high-dose omega-3 fatty acids rich in eicosapentaenoic acid (EPA) seem to have such clinical benefits in treating depression (6-8).

So if you want to live a longer (and probably better) life, then try to start thinking of others beside yourself. If that is too hard, then consider taking high-dose fish oil rich in EPA. You will be happier, probably have a longer and healthier life, and may even become nicer to your fellow man.


  • 1. Fredrickson BL, Grewen KM, Coffey KA, Algoe SB, Firestine AM, Arevalo JMG, Ma J, and Cole SW. “A functional genomic perspective on human well-being.” Proc Nat Acad Sci USA 110: 13684-13689 (2013)
  • 2. Hummer RA, Rogers RG, Nam CB, and Ellison CG. “Religious involvement and U.S. adult mortality.” Demography 36:273-285 (1999)
  • 3. Helm HM, Hays JC, Flint EP, Koenig HG, and Blazer DG. “Does private religious activity prolong survival? A six-year follow-up study of 3,851 older adults. J Gerontol A Biol Sci Med Sci 55: M400-405 (2000)
  • 4. Dantzer R, O’Connor JC, Freund GG, Johnson RW, and Kelley KW. “From inflammation to sickness and depression: when the immune system subjugates the brain.” Nat Rev Neurosci 9:46-49 (2008)
  • 5. Eisenberger NI, Berkman ET, Inagaki TK, Rameson LT, Mashal NM, and Irwin MR. “Inflammation-induced ahedonia.” Bio Psychiatry 68:748-754 (2010)
  • 6. Stoll AL, Severus WE, Freeman MP, Rueter S, Zboyan HA, Diamond E, Cress KK, and Marangell LB. “Omega 3 fatty acids in bipolar disorder: a preliminary double-blind, placebo-controlled trial.” Arch Gen Psychiatry 56:407-412 (1999)
  • 7. Nemets H, Nemets B, Apter A, Bracha Z and Belmaker RH. “Omega-3 treatment of childhood depression: a controlled, double-blind pilot study.” Am J Psychiatry 2006 163:1098-1100 (2006)
  • 8. Martins JG. “EPA but not DHA appears to be responsible for the efficacy of omega-3 long chain polyunsaturated fatty acid supplementation in depression: evidence from a meta-analysis of randomized controlled” trials. J Am Coll Nutr 28: 525-542 (2009)

Omega-3 fatty acids and prostate cancer? Oh, really?

There was a recent publication suggesting that higher levels of omega-3 fatty acids are associated with a greater risk of prostate cancer 1. Of course, the immediate media response was to indicate that taking fish oil supplements is dangerous. Of course, let’s not forget, then, that eating fish must also be dangerous.

Before letting the media focus on sound bites, a realistic first step might be to analyze the data and use some common sense to see if it justifies the headlines.

Everyone in the cancer field agrees that inflammation drives cancers. I believe the best marker for inflammation is the AA/EPA ratio as I have outlined in my various books for more than a decade. The reason is simple: As the AA/EPA ratio decreases, you make fewer inflammatory hormones (i.e. eicosanoids coming from AA) and more anti-inflammatory hormones (i.e. resolvins coming from EPA). Bottom line, this means less inflammation in the body. So let’s look at the fatty acid data as percent of the total fatty acids that was presented in this article that were associated with no development of prostate cancer, total prostate cancer incidence, and breaking of the total cancer group into either low-grade or high-grade cancer 1.

Non-cancer Cancer Low-grade cancer High-grade cancer
EPA 0.6% 0.7% 0.7% 0.7%
AA 11.4% 11.2%   11.2%   11.3%  
AA/EPA 19 16 16 16

Having decades of experience of doing fatty acid analyses, I can tell that these numbers are clinically insignificant. What does that mean? The numbers are basically the same. They might be statistically significant, but the differences definitely are not clinically relevant.

I have been very consistent over the years in stating that to have an impact on reducing inflammation, you have to have EPA levels greater than 4% of the total fatty acids, AA levels less than 9% of the total fatty acids and an AA/EPA ratio between 1.5 and 3. As you can see, the subjects in this article were nowhere close to those parameters. In fact, I would say all the subjects in this trial were identical relative to AA, EPA and the AA/EPA ratio. In other words, the analysis is meaningless.

Is there any population in the world that may have the ranges that I recommend? The answer is the Japanese population. Their levels of EPA are about 3% of total fatty acids, and they have an AA/EPA ratio of about 1.6 2. The JELIS study was a long-term study (3 ½ years) of 18,000 Japanese with high cholesterol levels given extra omega-3 fatty acids to lower their AA/EPA an even lower ratio. With this lower AA/EPA ratio (now 0.8), their cardiovascular events were reduced by 20% with no increase in any type of cancer. Likewise, high levels of omega-3 fatty acids have been used as prescription drugs for the treatment of elevated triglyceride levels with absolutely no reports of any increase in any type of cancer.

This is where common sense hopefully comes into play. If the conclusion of the article was correct that higher levels of omega-3 fatty acids increase prostate cancer, then the Japanese male population should be decimated with prostate cancer. So what are the facts? The Japanese have one of lowest rates of prostate cancer incidence in the world. In fact, their rate of prostate cancer incidence is 10 times lower than the United States 3. More importantly, the mortality from prostate cancer is also about 5 times less in Japan than in the United States 4. I emphasize the word mortality since prostate cancer is usually very slow growing so that males usually die with prostate cancer, not because of it. This is why the recent recommendation is to dramatically reduce the screening for prostate cancer because the harm of treatment usually outweighs the benefits of detection.

Common sense (and a little understanding of the biochemistry of inflammation) says that if you reduce inflammation (determined by your AA/EPA ratio), then your likelihood of living longer is greatly increased. The best way to reduce AA is to follow a strict Zone Diet. The best way to increase EPA is to take adequate levels of purified omega-3 fatty acids rich in EPA. It is obvious the subjects of this study were doing neither.


  1. Brasky TM, Darke AK, Song X, Tangen CM, Goodma PJ, Thompson IM, Meyskens FL, Goodman GE, Minasian LM, Parnes HL, Klein EA, and Kristal AR. “Plasma Phospholipid Fatty Acids and Prostate Cancer Risk in the SELECT Trial.” J Nat Cancer Inst DOIL10.109393 (2013)
  2. Yokoyama M, Origasa H, Matsuzaki M, Matsuzawa Y, Saito Y, Ishikawa Y, Oikawa S, Sasaki J, Hishida H, Itakura H, Kita T, Kitabatake A, Nakaya N, Sakata T, Shimada K, and Shirato K. ” Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis.” Lancet 367:1090-1098 (2007)
  3. Haas GP, Delongchamps N, Brawley OW, Wang CY, and de la Roza G. “The worldwide epidemiology of prostate cancer: perspectives from autopsy studies.” Can J Urol 15: 3866-3871 (2008)
  4. Marugame T and Mizuno S. “Comparison of Prostate Cancer Mortality in Five Countries: France, Italy, Japan, UK and USA from the WHO Mortality Database (1960–2000).” Jpn J Clin Oncol 35: 690–691 (2005)

Good Diet, Bad Study

As the creator of the Zone Diet, I am a strong believer in the Mediterranean diet as a lifetime dietary program for good health. In fact, the Zone Diet can be considered to be the evolution of the Mediterranean diet as it provides even greater anti-inflammatory benefits. That being said, this week’s New England Journal of Medicine contained an article on using the Mediterranean diet with high-risk cardiovascular patients that got great press based on some really poor science1. Let’s get to the bad science first.

The researchers compared two “Mediterranean” diets (one with extra nuts and the other with extra olive oil) to a low-fat diet. Unfortunately, they were unable to get the subjects to follow a low-fat diet. If you are a follower of Dean Ornish, then a low-fat diet means less than 10% of your calories coming from fat. Using that definition of a low-fat diet, you have to throw out one-third of the subjects because they couldn’t reduce their fat intake below 37% of total calories. In fact, at the end of this five-year study, the percentages of protein, carbohydrate, and fat in the diets of all three groups were approximately the same. As a result, you are left with a study with two groups of subjects being compared to another group of subjects who really didn’t change their diet that much.

Even Dean Ornish pointed this out in his rebuttal blog in the Huffington Post to this study2. He wrote that if people had followed his low-fat diet, then the results would have been much different. Well, actually when high-risk cardiovascular patients did follow his diet in a study done 15 years ago, those on his low-fat diet had twice the deaths compared to those in the control group3. So maybe it’s a good thing that the low-fat group couldn’t follow the prescribed low-fat diet.

The reason for adverse effects of a low-fat, low-protein, very high-carbohydrate diet for cardiovascular patients is quite clear. Those subjects following his high-carbohydrate, low-fat, and low-protein diet developed insulin resistance as evidenced by a significant increase in their triglyceride-to-HDL ratio3. If you already have had a heart attack, then an increase in insulin resistance and the accompanying increase in inflammation are almost certain to push you over the edge.

If you really dig deeper into the supplemental material (Table S7 to be exact) of this article (as most journalists neglected to do), you are remarkably unimpressed by the changes in the diet over a five-year period except that the people who got free olive oil and free nuts were consuming more free olive oil and free nuts than those who were not getting free food.

Now, back to the clinical results — a strange brew of stroke, heart attack, and death. Usually when you include a lot of different clinical end points as your primary goal, it means you are not very confident about seeing any real striking clinical benefit. Stroke is primarily associated with high blood pressure, whereas heart attack is associated with the rupture of small vulnerable plaques leading to blockage of the coronary arteries. I personally like death as a clinical end point since you can’t cheat on its definition, thus making it harder to manipulate your statistics to prove your point.

So let’s look at the individual clinical endpoints. There was a reduction in strokes that was statistically significant. Unfortunately, there was no statistically significant reduction in either heart attacks or death. For such a large study, these clinical results are not too impressive. Maybe if the researchers had actually gotten the low-fat group to reduce their fat intake to less than 10% of calories (instead of going from 39% to 37% of calories), there might have been more deaths in that group, which would have made the other two Mediterranean diet groups look better.

Virtually every cardiovascular researcher knows that fatty acid composition of the plasma is an important factor in the prediction of future cardiovascular events. Unfortunately, the authors of the New England Journal of Medicine article apparently didn’t think so. Obviously, they measured one fatty acid (alpha linolenic acid) in Figure 5S (again buried deep in the supplemental material), but somehow forgot to report the other 34 fatty acids also found in the plasma. Two of the most important of these unreported fatty acids would have included arachidonic acid (AA) and eicosapentaenoic (EPA). The AA/EPA ratio in the blood is the best marker of cellular inflammation that drives heart disease4. You would think inclusion of information on this ratio (or at least providing the fatty acid levels) would be important since a far larger JELIS study demonstrated that the lowering of the AA/EPA ratio resulted in a significant reduction of cardiovascular events5.

In contrast to this poorly executed study, there exists a far more powerful study conducted nearly 20 years ago on the benefits of a stricter Mediterranean diet. This is was the Lyon Diet Heart Study6. The primary clinical difference between this new study and older Lyon Diet Heart Study is that the Lyon Diet Heart Study generated a 65% reduction in overall cardiovascular mortality, a complete reduction in cardiac sudden death, and 44% reduction in all-cause mortality6,7. Those are clinical end points to get excited about. On the other hand, this New England Journal of Medicine article showed no impact on mortality. The only striking difference between the two groups in the Lyon Diet Heart Study was the restriction of omega-6 fatty acids in the experimental group. You find omega-6 fatty acids in vegetable oils like corn, safflower, and sunflower oils. They accomplished this dietary change by giving the subjects in the experimental groups margarines rich in omega-3 fats and trans fats. Although there was a dramatic decrease in death between the two groups in the Lyon Diet Heart Study, there were no differences in weight, BMI, blood pressure, cholesterol (good and bad), and blood lipids between the two groups. In other words, all the usual suspects in heart disease were eliminated. The only differences between the two groups were in the fatty acids, both linoleic acid and the AA/EPA ratio. If you again go back to bowels of the recent New England Journal article (in supplemental Table S7), you find out that the levels of linoleic acid (an omega-6 fatty acid) as analyzed from dietary records of the subjects was between 5 and 6% in both of the Mediterranean diets. In the Lyon Diet Heart Study, the investigators were able to reduce to the linoleic levels to 3.6%, which is similar to levels found in the Japanese (actually Okinawans), who have the lowest cardiovascular mortality in the developed world (8). The subjects in the control group of the Lyon Diet Heart Study had a nearly 50% higher level of linoleic acid in their blood compared to the experimental group8. However, those subjects following the “Mediterranean” diets in the new study had even higher levels of linoleic acid than those in the control group of the Lyon Diet Heart Study. That is the most likely reason there wasn’t any change in cardiovascular mortality or overall mortality in the New England Journal of Medicine study. Unlike this more “modern” study, the Lyon researchers further demonstrated that the AA/EPA ratio was reduced by some 30% (from 9 to 6.2) in the active group compared to the control group, and this resulted in a 65% reduction of cardiovascular death.

Bottom line, unless you dramatically reduce omega-6 intake by reducing your consumption of vegetable oils (such as corn, soy and safflower oils), you will not get clear-cut clinical results (like reduction in death) no matter how much hype the media give to the research.

As I said earlier, the Zone Diet can be considered to be the evolution of the Mediterranean diet because it represents a superior dietary program to control inflammation, the true underlying cause of heart disease. This is because the Zone Diet dramatically reduces white carbohydrates (pasta, bread, rice, and potatoes) and replaces them with increased amounts of colorful carbohydrates (vegetables and fruits). Unlike the New England Journal of Medicine article where the subjects were consuming about 5 servings a day of vegetables and fruits, the Zone Diet recommends 10 servings per day. Rather than keeping the linoleic acid content at 6% of the calories (the American Heart Association recommends 10-15%) or even at the 3.6% level as in the Lyon Diet Heart Study, the Zone Diet recommends fewer than 2% of total calories should consist of linoleic acid. Like the JELIS study, the Zone Diet recommends extra supplemental of omega-3 fatty acids to reduce the AA/EPA ratio to 1.5 or less.

Although the jury may still be out on the Mediterranean diet (especially after this poorly executed study) for the primary prevention of heart disease, the data from secondary prevention studies (5-7) strongly suggest that the Zone Diet may be the dietary approach you want to follow if reducing mortality is your personal clinical end point.


  1. Estuch R et al. “Primary prevention of cardiovascular disease with a Mediterranean diet.” N Engl J Med 368: doi10.1056/NEJMoa1200303 (2013)
  2. Ornish D. “Does a Mediterranean diet really beat a low-fat for health?” HuffPost Healthy Living Feb 25 (2013)
  3. Ornish D et al. “Intensive lifestyle changes for reversal of coronary heart disease.” JAMA 280: 2001-2007 (1998)
  4. Sears B. The Anti-Inflammation Zone. Regan Books. New York, NY (2005)
  5. Yokoyama M et al. “Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomized open-label, blinded endpoint analysis.” Lancet 369: 1090-1098 (2007)
  6. de Lorgeril et al. “Mediterranean alpha-linolenic-rich diet in secondary prevention of coronary heart disease.” Lancet 343: 1454-1459 (1994)
  7. de Lorgeril et al. “Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction.” Circulation 99: 779-785 (1999)
  8. Kagawa Y et al. “Eicosapolyenoic acids of serum lipids of Japanese islanders with low incidence of cardiovascular disease.” J Nutr Sci Vitaminol 28: 441-453 (1982)

Put Statins in the Drinking Water? I Think Not.

Put Statins in the Drinking Water?  I Think Not.

It is amazing that only after the patent expiration of the best-selling statin drug of all time (i.e. Lipitor) that the FDA finally admitted that maybe the drug class that many physicians wanted to put into the drinking water might have some problems after all (1). In particular, the FDA issued a warning that use of statins increases the risk of memory loss and diabetes. The FDA said the risk of diabetes is “small;” however, they were playing fast and loose with the data. This is because the weaker the statin, the less the side-effect profile. The stronger (and better selling) the statin, the greater the side effects are (like diabetes and memory loss). You would think that after having Americans spend more than $50 billion in statin sales that the FDA would have asked these safety questions earlier.

How could statins cause memory loss and diabetes? It has been known for nearly 20 years that statins are the only drug that increase the levels of arachidonic acid (AA) by stimulating the enzyme delta 5-desaturase (2-4). This means greater cellular inflammation that leads to insulin resistance (thus increasing diabetes) and disturbances in signaling mechanisms in nerve cells (thus decreasing memory). I guarantee that no physician knows these facts because the drug companies had no reason to lose a potential sale to disclose that information. Apparently the FDA agreed with the drug companies, since that relevant information was never mentioned in any of the side-effect profiles until now.

The drug industry developed a great marketing pitch for statins: “If your cholesterol is high, you are going to die”. Unfortunately, the data never supported that spiffy slogan. Epidemiological studies do indicate that if your cholesterol levels are high and you are less than 50 years of age, then there is an increased risk for mortality. After age 50, that risk of increased mortality with high cholesterol disappears (5).

Furthermore, keep in mind that statins were not the first drugs to lower cholesterol. There were many other drugs before the statins, but they had the unfortunate side-effect of increasing mortality. It was only with use of the first statin drugs that decreased mortality was finally shown in those having had a prior heart attack. This is called secondary prevention trial. Aspirin and fish oil are also effective in secondary prevention trials, but neither of those interventions reduces cholesterol (6). However, in primary prevention trials (done with people with no history of heart attacks), statins aren’t very good. This is estimated by looking at a number known as “number needed to treat” or NNT. This number indicates how many people have to take a drug to prevent a single heart attack. With the newest statins, the NNT is usually 2 percent. That means you have to treat 100 people to prevent two heart attacks. Unfortunately you have no idea who those two people are, which means the other 98 people will have a lifetime of side effects. One of those side effects is developing diabetes, which occurs in about 1 percent of the patients (forget the other side effects, such as memory loss, muscle fatigue, etc). Who that one person is out of 100 who will develop diabetes is also unknown. Therefore your chances of reducing a heart attack are significantly cut by the likelihood of increasing your chances of developing diabetes. Some wonder drug!

Finally, defenders of statins for the primary prevention of heart disease point to the recent JUPITER trial (7). This clinical trial used people that had normal levels of LDL cholesterol, but very high levels of C-reactive protein (CRP). These people were already inflamed. It should be noted that the drug company that markets the statin drug used in the study funded this particular study. In fact, the government had no interest in the trial. Maybe government officials knew from previous statin trials that in people with normal LDL cholesterol levels and normal levels of CRP that statins had absolutely no benefit in reducing future heart attacks (8). Nonetheless in this small subsection of the population (more than 80 percent of the screened patients were rejected), there was a reduction in first-time heart attacks. But since the patients were highly inflamed to begin with, this means that aspirin or fish oil would probably have given the same result had the same population been tested (9,10). In fact, the JELIS study in Japan confirmed this hypothesis (11). Using the same number of patients, with high cholesterol and lows levels of inflammation (as measured by the AA/EPA ratio), it was demonstrated that those patients given more EPA to lower the AA/EPA ratio had significant reduction in future cardiovascular events. I will make a leap of faith that if the population in the JELIS study was as inflamed as that in the JUPITER study, the results with omega-3 fatty acids would have been even more dramatic.

Lost in all this marketing hype is what actually causes LDL cholesterol to increase in the first place. The answer was known in the 1970s. It’s high levels of insulin (12). This is because insulin activates the same enzyme that statins inhibit. Call me crazy, but it seems to make more sense to lower insulin by the diet rather than taking statins for a lifetime if your goal is to live longer. The best way to lower insulin is the anti-inflammatory Zone Diet coupled with enough fish oil to reduce the AA/EPA ratio to the in the Japanese population range. That’s just good science, not good marketing.


  1. Harris G. “Safety alerts cite cholesterol drugs’ side effects.” New York Times, Feb 28. (2012)
  2. Hrboticky N, Tang L, Zimmer B, Lux I, Weber PC. “Lovastatin increases arachidonic acid levels and stimulates thromboxane synthesis in human liver and monocytic cell lines. J Clin Invest 93: 195-203 (1994)
  3. Rise P, Pazzucconi F, Sirtori CR, and Galli C. “Statins enhance arachidonic acid synthesis in hypercholesterolemic patients.”
  4. Nutr Metab Cardiovasc Dis 11:88-94 (2001)
  5. Rise P, Ghezzi S, and Galli C. “Relative potencies of statins in reducing cholesterol synthesis and enhancing linoleic acid metabolism.” Eur J Pharmacol 467:73-75 (2003)
  6. Anderson KM, Castelli WP, and Levy D. “Cholesterol and mortality. 30 years of follow-up from the Framingham study.” JAMA 1987 257:2176-2180 (1987)
  7. Baigent C, Blackwell L, Collins R, Emberson J, Godwin J, Peto R, Buring J, Hennekens C, Kearney P, Meade T, Patrono C, Roncaglioni MC, and Zanchetti A. “Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials.” Lancet 373:1849-1860 (2009)
  8. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico. “Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial.” Lancet 354:447-455 (1999)
  9. Wang C, Harris WS, Chung M, Lichtenstein AH, Balk EM, Kupelnick B, Jordan HS, and Lau J. “n-3 Fatty acids from fish or fish-oil supplements, but not alpha-linolenic acid, benefit cardiovascular disease outcomes in primary- and secondary-prevention studies: a systematic review.” Am J Clin Nutr 84:5-17 (2006)
  10. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM, Kastelein JJ, Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG, Nordestgaard BG, Shepherd J, Willerson JT, and Glynn RJ. “Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein.” N Engl J Med 359:2195-2207 (2008)
  11. Ridker PM, Rifai N, Clearfield M, Downs JR, Weis SE, Miles JS, and Gotto AM. “Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events.” N Engl J Med 344:1959-1965 (2001)
  12. Yokoyama M, Origasa H, Matsuzaki M, Matsuzawa Y, Saito Y, Ishikawa Y, Oikawa S, Sasaki J, Hishida H, Itakura H, Kita T, Kitabatake A, Nakaya N, Sakata T, Shimada K, and Shirato K. “Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis.” Lancet 369:1090-1098 (2007)
  13. Lakshmanan MR, Nepokroeff CM, Ness GC, Dugan RE, and; Porter JW. “Stimulation by insulin of rat liver hydroxy-β-methylglutaryl coenzyme A reductase and cholesterol-synthesizing activities.” Biochem Biophys Res Commun 50:704-710 (1973)

What are the real differences between EPA and DHA?

The first casualty of marketing is usually the truth. The reality is that the two key omega-3 fatty acids (EPA and DHA) do a lot of different things, and as a result the benefits of EPA and DHA are often very different. That’s why you need them both. But as to why, let me go into more detail.

Benefits of EPA

The ultimate goal of using omega-3 fatty acids is the reduction of cellular inflammation. Since eicosanoids derived from arachidonic acid (AA), an omega-6 fatty acid, are the primary mediators of cellular inflammation, EPA is the most important of the omega-3 fatty acids to reduce cellular inflammation for a number of reasons. First, EPA is an inhibitor of the enzyme delta-5-desaturase (D5D) that produces AA (1). The more EPA you have in the diet, the less AA you produce. This essentially chokes off the supply of AA necessary for the production of pro-inflammatory eicosanoids (prostaglandins, thromboxanes, leukotrienes, etc.)

DHA is not an inhibitor of this enzyme because it can’t fit into the active catalytic site of the enzyme due to its larger spatial size. As an additional insurance policy, EPA also competes with AA for the enzyme phospholipase A2 necessary to release AA from the membrane phospholipids (where it is stored). Inhibition of this enzyme is the mechanism of action used by corticosteroids. If you have adequate levels of EPA to compete with AA (i.e. a low AA/EPA ratio), you can realize many of the benefits of corticosteroids but without their side effects. That’s because if you don’t release AA from the cell membrane, you can’t make inflammatory eicosanoids. Because of its increased spatial dimensions, DHA is not a good competitor of phospholipase A2 relative to EPA. On the other hand, EPA and AA are very similar spatially so they are in constant competition for the phospholipase A2 enzyme, just as both fatty acids are in constant competition for the delta-5 desaturase enzyme. This is why measuring the AA/EPA ratio is such a powerful predictor of the state of cellular inflammation in your body.

The various enzymes (COX and LOX) that make inflammatory eicosanoids can accommodate both AA and EPA, but again due to the greater spatial size of DHA, these enzymes will have difficulty-converting DHA into eicosanoids. This makes DHA a poor substrate for these key inflammatory enzymes. Thus DHA again has little effect on cellular inflammation, whereas EPA can have a powerful impact.

Finally, it is often assumed since there are not high levels of EPA in the brain, that it is not important for neurological function. Actually, it is key for reducing neuro-inflammation by competing against AA for access to the same enzymes needed to produce inflammatory eicosanoids. However, once EPA enters into the brain, it is rapidly oxidized (2,3). This is not the case with DHA (4). The only way to control cellular inflammation in the brain is to maintain high levels of EPA in the blood. This is why all the work on depression, ADHD, brain trauma, etc., has demonstrated that EPA is superior to DHA (5).

Benefits of DHA

At this point, you might think that DHA is useless. Just the opposite, because DHA can do a lot of different things than EPA and some of them even better.

First is in the area of omega-6 fatty acid metabolism. Whereas EPA is the inhibitor of the enzyme (D5D) that directly produces AA, DHA is an inhibitor of another key enzyme, delta-6-desaturase (D6D), that produces the first metabolite from linoleic acid known as gamma linolenic acid or GLA (6). However, this is not exactly an advantage. Even though reduction of GLA will eventually decrease AA production, it also has the more immediate effect of reducing the production of the next metabolite known as dihomo gamma linolenic acid or DGLA. This can be a disaster as a great number of powerful anti-inflammatory eicosanoids are derived from DGLA. This is why if you use high-dose DHA, it is essential to add back trace amounts of GLA to maintain sufficient levels of DGLA to continue to make anti-inflammatory eicosanoids.

In my opinion, the key benefit of DHA lies in its unique spatial characteristics. As mentioned earlier, the extra double bonds and length of DHA compared to EPA means it takes up a lot more space in the membrane. Although this increase in spatial volume makes DHA a poor substrate for phospholipase A2 as well as the COX and LOX enzymes, it does a great job of making membranes (especially those in the brain) a lot more fluid as the DHA sweeps out a much greater volume in the membrane than EPA. This increase in membrane fluidity is critical for synaptic vesicles and the retina of the eye because it allows receptors to rotate more effectively, thus increasing the transmission of signals from the surface of the membrane to the interior of the nerve cells. This is why DHA is a critical component of these parts of the nerves (7). On the other hand, the myelin membrane is essentially an insulator so that relatively little DHA is found in that part of the membrane.

This constant sweeping motion of DHA also causes the breakup of lipid rafts in membranes (8). Disruption of these islands of relatively solid lipids makes it more difficult for cancer cells to continue to survive and more difficult for inflammatory cytokines to initiate the signaling responses to turn on inflammatory genes (9). In addition, these greater spatial characteristics of DHA increase the size of LDL particles to a greater extent compared to EPA. As a result DHA helps reduce the entry of these enlarged LDL particles into the muscle cells that line the artery, thus reducing the likelihood of developing atherosclerotic lesions (10). Thus the increased spatial territory swept out by DHA is good news for making certain areas of membranes more fluid or lipoprotein particles larger, even though it reduces the benefits of DHA in competing with AA for key enzymes important in the development of cellular inflammation.

Common Effects for Both EPA and DHA

Not surprisingly, there are some areas in which both EPA and DHA appear to be equally beneficial. For example, both are equally effective in reducing triglyceride levels (10). This is probably due to the relatively equivalent activation of the gene transcription factor (PPAR alpha) that causes the enhanced synthesis of the enzymes that oxidize fats in lipoprotein particles. There is also apparently equal activation of the anti-inflammatory gene transcription factor PPAR-gamma (11). Both seem to be equally effective in making powerful anti-inflammatory eicosanoids known as resolvins (12). Finally, although both have no effect on total cholesterol levels, DHA can increase the size of LDL particle to a greater extent than EPA can (10).


EPA and DHA do different things, so you need them both. If your goal is reducing cellular inflammation, then you probably need more EPA than DHA. How much more? Probably twice the levels, but you always cover your bets with omega-3 fatty acids by using both at the same time.


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  3. Chen CT, Liu Z, and Bazinet RP. “Rapid de-esterification and loss of eicosapentaenoic acid from rat brain phospholipids: an intracerebroventricular study. J Neurochem 116:363-373 (2011)
  4. Umhau JC, Zhou W, Carson RE, Rapoport SI, Polozova A, Demar J, Hussein N, Bhattacharjee AK, Ma K, Esposito G, Majchrzak S, Herscovitch P, Eckelman WC, Kurdziel KA, and Salem N. “Imaging incorporation of circulating docosahexaenoic acid into the human brain using positron emission tomography.” J Lipid Res 50:1259-1268 (2009)
  5. Martins JG. “EPA but not DHA appears to be responsible for the efficacy of omega-3 long chain polyunsaturated fatty acid supplementation in depression: evidence from a meta-analysis of randomized controlled trials.” J Am Coll Nutr 28:525-542 (2009)
  6. Sato M, Adan Y, Shibata K, Shoji Y, Sato H, and Imaizumi K. “Cloning of rat delta 6-desaturase and its regulation by dietary eicosapentaenoic or docosahexaenoic acid.” World Rev Nutr Diet 88:196-199 (2001)
  7. Stillwell W and Wassall SR. “Docosahexaenoic acid: membrane properties of a unique fatty acid. Chem Phys Lipids 126:1-27 (2003)
  8. Chapkin RS, McMurray DN, Davidson LA, Patil BS, Fan YY, and Lupton JR. “Bioactive dietary long-chain fatty acids: emerging mechanisms of action.” Br J Nutr 100:1152-1157 (2008)
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  10. Mori TA, Burke V, Puddey IB, Watts GF, O’Neal DN, Best JD, and Beilin LJ. “Purified eicosapentaenoic and docosahexaenoic acids have differential effects on serum lipids and lipoproteins, LDL particle size, glucose, and insulin in mildly hyperlipidemic men.” Am J Clin Nutr 71:1085-1094 (2000)
  11. Li H, Ruan XZ, Powis SH, Fernando R, Mon WY, Wheeler DC, Moorhead JF, and Varghese Z. “EPA and DHA reduce LPS-induced inflammation responses in HK-2 cells: evidence for a PPAR-gamma-dependent mechanism.” Kidney Int 67:867-874 (2005)
  12. Serhan CN, Hong S, Gronert K, Colgan SP, Devchand PR, Mirick G, and Moussignac RL. “Resolvins: a family of bioactive products of omega-3 fatty acid transformation circuits initiated by aspirin treatment that counter proinflammation signals.” J Exp Med 1996:1025-1037