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.

References

  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)

Don’t confuse me with the facts

The last couple of months have been hard on obesity experts as they have learned that maybe the obvious is not so obvious.

It started out in October with an article in the New England Journal of Medicine on the substitution of sugar-sweetened beverages with politically correct sugar-free beverage replacements (1). Everyone from Mayor Bloomberg to Dr. Oz knows that soda makes you fat. It is so obvious there is no need to confirm this “fact”. Almost out of due diligence, Harvard Medical School did a two-year study just to confirm this most obvious obesity fact that sugar-sweetened soda makes you fat. Researchers took obese adolescents, who were confirmed soda (containing evil fructose) drinkers. Half were used as the control group; the other half as the experimental group, who were sent regular supplies of “good” beverages (not fruit juices) to replace the sugar-sweetened sodas. They also got motivational phone calls on a monthly basis to urge them on and also to tell them not to watch as much TV.

It worked. At the end of two years, they were drinking fewer sugar-sweetened beverages, watching less TV, and consuming fewer calories and far less sugar than the control group. All of these changes in their lifestyles were strongly statistically significant.

So how did this affect their obesity compared to the control group? There was no difference! Maybe there were just incompetent researchers. I think not, because the research was led by one of the most respected obesity researchers in the world. Maybe the facts that were so obvious to Mayor Bloomberg and Dr. Oz were not so obvious after all.

This was bad enough, but then another article appeared in the January issue of the New England Journal of Medicine stating that we actually know virtually nothing about the treatment of obesity (2). Oh, yes, you can make a lot of correlations (like not drinking sugar-sweetened soda, eating fewer calories and watching less TV) that are associated with lower weight, but no scientific data are there to support this. In fact, the only things we can really be scientifically certain about treating obesity are gastric bypass surgery, some prescription drugs that suppress appetite (like amphetamines) and following a highly structured meal plan using meal replacements with a defined composition. These three factors cause weight loss compared to control groups.

Gee, after 30 years of our obesity epidemic (and millions of research dollars) you would think we would have some more solid scientific data. It turns out that obesity research is more like religion—don’t confuse me with the facts.

Why do we have such ignorance about what causes obesity, let alone how to treat it ? Some of the reasons come from recently published genetic studies with genetically inbred mice (3). Using more than 100 different genetically pure strains with a highly defined diet (rat food pellets), it was found that once they are switched to a high-sugar, high-fat diet that some of the genetic strains gain weight, and some don’t. In fact, the differences in fat gain were nearly 600% among different strains.

What does this mean for humans? Classical genes don’t change quickly; however, epigenetic markers that turn genes on and off can change within one generation. Here lies the problem. Our obesity epidemic is not because of making either bad food or lifestyle choices, but may be due to changes in food composition that our parents were eating that modified the expression of our genes in the womb.

The most likely suspect gene-altering drama is increased consumption of omega-6 fatty acids, such as linoleic acid, which lower the percentage of omega-3 fats in the diet (4). I described this in greater detail in my book “Toxic Fat” (5). Simply stated, in a period of 50 years, we have been become genetically altered by increasing linoleic acid to gain weight rapidly and make it difficult to lose. Those epigenetic changes will not evaporate with simple slogans found on TV talk shows or from a politician’s mouths. They will take probably three generations to return to what they were in an earlier time, and only if there is a radical restriction in the linoleic intake by humans.

Meanwhile, prepare yourself for more political (and scientific) blowhards who have all the answers to a very complex set of problems resulting from a continued modification of our genes and those of our children, making us overweight, sicker, and aging faster.

References
1. Ebbling CB et al. “A randomized trial of sugar-sweetened beverages and adolescent body weight.” N Engl J Med 367:1407-1416 (2012)
2. Casasa K et al. “Myths, presumptions, and facts about obesity.” N Engl J Med 368:446-454 (2013)
3. Parks BW et al. “Genetic control of obesity and gut microbiota composition in response to high-fat, high-sucrose diet in mice.” Cell Metabol 17:141-152 (2013)
4. Hanbauer I et al. “The decrease of n-3 fatty acid energy percentage in an equicaloric diet fed to B6C3Fe mice for three generations elicits obesity.” Cardio Psychiartry Neurology 2009: 867041 (2009)
5. Sears B. Toxic Fat. Thomas Nelson. Nashville, TN (2008)