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The Saturated Fat, Cholesterol, and Statin Controversy A Commentary a

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Stephen T. Sinatra MD, FACN , Beverly B. Teter PhD, MACN , Jonny Bowden CNS , Mark C. c

Houston MD, FACN & Miguel A. Martinez-Gonzalez MD, PhD, MPH

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University of Connecticut School of Medicine , Farmington , Connecticut

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University of Maryland , College Park , Maryland

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Vanderbilt University School of Medicine , Nashville , Tennessee

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Department of Preventive Medicine and Public Health , University of Navarra , Spain , CIBEROBN-Spain Published online: 17 Feb 2014.

To cite this article: Stephen T. Sinatra MD, FACN , Beverly B. Teter PhD, MACN , Jonny Bowden CNS , Mark C. Houston MD, FACN & Miguel A. Martinez-Gonzalez MD, PhD, MPH (2014) The Saturated Fat, Cholesterol, and Statin Controversy A Commentary, Journal of the American College of Nutrition, 33:1, 79-88, DOI: 10.1080/07315724.2014.878633 To link to this article: http://dx.doi.org/10.1080/07315724.2014.878633

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Commentary

The Saturated Fat, Cholesterol, and Statin Controversy A Commentary Stephen T. Sinatra, MD, FACN, Beverly B. Teter, PhD, MACN, Jonny Bowden, CNS, Mark C. Houston, MD, FACN, Miguel A. Martinez-Gonzalez, MD, PhD, MPH

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University of Connecticut School of Medicine, Farmington, Connecticut (S.T.S.), University of Maryland, College Park, Maryland (B.B.T.), Vanderbilt University School of Medicine, Nashville, Tennessee (M.C.H.); Department of Preventive Medicine and Public Health, University of Navarra, Spain, and CIBEROBN-Spain (M. A. M.-G.)

SATURATED FAT AND CHOLESTEROL CONTROVERSY

but they ultimately need to be tested in humans. Many of the early studies were used rabbits feeding a high cholesterol diet. Rabbits in the wild never eat cholesterol since they are herbivores and plants do not make appreciable cholesterol, so the animals would not normally eat cholesterol in their diet. Additionally, the cholesterol consumed by the test animals contained “bare” cholesterol, chemically prepared and added to the diets, so quite likely was oxidized by the time the animals ate it. The cholesterol in human diets is a component of a food tissue and often bound with a fatty acid and protected from oxidation. Rodent models are not a good model for humans since most of them have high HDL and very little LDL as opposed to humans who have more LDL than HDL in the blood. So feeding rabbits a high cholesterol diet and rendering them athrogenic does not prove causality. Just because two conditions may be correlated or appear together does not explain the cause of the disease. For example, vitamin deficiencies may be present but not obvious. In the case of scurvy, the sailors noticed that the lack of fruit on long voyages was associated with the development of scurvy. In reality, it wasn’t the lack of fruit, it was the lack of vitamin C in the fruit that caused the problem. The disease beriberi, which is caused by a deficiency of thiamine, displays neurological symptoms, cardiovascular abnormalities, and edema. These symptoms are so different that it could be assumed that the edema was from too much salt intake; the neurological symptoms could be from drugs, injury etc.; and the CVD symptoms could be thought to be from cholesterol. In reality they have a common cause: thiamine deficiency. The cause(s) of heart disease are not unlike the above example. For example, consider the vilification of saturated fat

In the 1930s, there were advertisements run in JAMA with testimonials from MDs saying that smoking cigarettes did not harm your lungs. It took many years of increasing lung cancer incidence to convince people that this was not a true statement. The current situation with serum cholesterol and coronary heart disease is very similar in concept, though this time doctors are widely convinced that the former causes the latter, despite a glaring lack of scientific evidence. There have been no studies that prove dietary cholesterol levels directly cause atherosclerosis. There are many correlation studies that may suggest an association but none that show cause and effect. In fact, if analyzed carefully, there are more studies that disprove the “cause and effect” hypothesis than even come close to proving it. One basic tenant of biostatistics and epidemiologic research is that you can never prove a hypothesis - you can only fail to disprove it. Experimental design has three essential components: 1) Estimate of error, 2) Control of error and 3) Proper interpretation of results [1]. Correlation studies indicate a possible relationship between two factors, i.e, blood cholesterol and CVD, but they do not prove cause and effect. Correlations are often observed in epidemiological studies, but carefully designed studies with sufficient control of confounding factors and avoidance of other potential bias needs to be conducted to demonstrate cause and effect. In these cases, small differences in the design of the study can cause different outcomes. Most of the studies in animal models are not a good model to compare the same systems as in humans. They may give hints,

Address correspondence to: Dr. Stephen Sinatra, 257 East Center Street, Manchester, CT 06040. E-mail: [email protected] Stephen T. Sinatra, M.D., FACN has indicated that he is a consultant for Healthy Directions and a co-author of The Great Cholesterol Myth and The Great Cholesterol Myth Cookbook. Jonny Bowden, CNS is a co-author of The Great Cholesterol Myth and The Great Cholesterol Myth Cookbook. Mark Houston, M.D., FACN, has indicated that he received a research grant from Biotics, Neogenics and is a consultant/speaker for Thorne, Biotics, Designs for Health.

Journal of the American College of Nutrition, Vol. 33, No. 1, 79–88 (2014) C American College of Nutrition Published by Taylor & Francis Group, LLC 79

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Saturated Fat, Cholesterol, and Statin which has a long and interesting history beginning after World War II and continuing through the cold war. Around that time, ex-President Eisenhower had a heart attack and it was a wellknown fact that he loved his bacon, eggs and butter. Under President Nixon, a committee to investigate malnutrition in the United States was formed with Senator George McGovern at the helm. It was called the United States Select Committee on Human Nutrition also known as the McGovern Committee. Even though their mandate was to investigate ways to end malnutrition, as the Committee’s term was coming to an end, they decided that they should accomplish something significant. So they decided that they would make some much overdue recommendations to the American people about diet. They felt the need to make these recommendations particularly pressing given the perceived increase in heart disease. The villain that started to emerge in the 1950’s was saturated fat present in meat, dairy, eggs and even plant sources which, when consumed, increases total cholesterol in the blood. Ancel Keys, a prominent researcher, had just begun his investigations of the Mediterranean Diet. He was convinced that despite no evidence, that one of the main reasons folks were healthier in the Mediterranean region was that they ate less saturated fat, and that was his single area of focus. He presented a paper at the World Health Organization (WHO) conference in 1955 (the Six Countries Study) with very questionable research that seemed to bolster his argument, but met with much-deserved resistance. So he designed the Seven Countries Study [2,3], which purported to show a direct relationship between the amount of saturated fat in the diet and the amount of heart disease, precisely the result he was aiming for. The ecological design adopted by the Seven Countries Study was very weak. An ecological design with aggregated data as units of research instead of using individual data is not able to provide valid inferences, because of the socalled “ecological fallacy.” This fallacy means that correlation between individual features cannot be deduced from the correlation of the variables collected for the group (countries or regions in the Seven Countries study) to which those individuals belong. Meanwhile, on the other side of the pond, British physician and researcher John Yudkin was arguing that sugar “tracked” with heart disease far better than saturated fat ever did, but Ancel Keys didn’t look at sugar, nor did he care about it. He was convinced saturated fat was the demon in heart disease; and a cynic might say he designed his 7 Countries Study to prove it. (One might say that the 7 Countries Study is a textbook example of “confirmation bias”). Because Keys was extremely persuasive, he managed to get himself a position on the American Heart Association’s advisory committee. Because there was a great public pressure to come out with strong recommendations about diet, he was able, over considerable objection, to get his “theory” accepted at the 1984 “consensus committee” hearings on diet. The “diet-heart hypothesis” was born.

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The diet-heart hypothesis holds that saturated fat in the diet— and, in some versions of the hypothesis, dietary cholesterol— contributes to heart disease. And it was accepted by the major health organizations in America (though there have always been some naysayers who felt that the decision to blame heart disease on saturated fat and cholesterol was both premature and unwarranted). The demonization of saturated fat was made complete with a Time magazine cover showing two eggs and a strip of bacon making the shape of a frowning face with the headline “And now the bad news: Cholesterol”. Food companies started switching to hydrogenated vegetable oils (because anything was “better” than saturated fats); no-fat foods became all the rage; and a multibillion dollar pharmaceutical industry developed around lowering the molecule said to be at the heart of the problem—cholesterol, which, coincidentally, appeared to be raised by saturated fat. This perception, and the idea that “saturated fat and cholesterol clog your arteries”, became the cultural theme of the day and we are still living with it today, despite the fact that it is wildly past its expiration date and simply not supported by the evidence. Recent research has exonerated the role of saturated fat in heart disease. A meta-analysis [4] done by researchers at Children’s Hospital Oakland looked at all the studies on saturated fat in the diet and hard end points such as heart attacks or cardiovascular disease. After examining 21 studies and nearly 350,000 people on the subject and analyzing the combined data carefully, the authors concluded that “there is no significant evidence for concluding that dietary saturated fat is associated with an increased risk of coronary heart disease or cardiovascular disease”. The medical community was stunned. Then another researcher, Robert Hoenselaar, published a paper in 2012 [5] in which he examined the dietary advice of leading advisory committees from the U.S. and Europe and compared it to the actual evidence upon which the advice was supposedly based. His summation: “Results and conclusions about saturated fat intake in relation to cardiovascular disease, from leading advisory committees, do not reflect the available scientific evidence.” Saturated fats are the end-product of lipogenesis in the human body. The excess dietary carbohydrates are enzymatically made into saturated fatty acids containing up to 16 carbon atoms and a carboxyl group at one end. Another set of enzymes can elongate the chains up to 22 + carbons. It is doubtful that the body would make a substance as toxic as the saturated fatty acids have been made out to be. Shorter chain fatty acids are also made by our bodies and serve many important functions such as attaching to proteins and sugars to alter their functions, etc. Fatty acids (FAs) can be attached to glycerol to form triglycerides and phospholipids, major components of all cell membranes. Our lung surfactant is di-palmitylphosphatidyl choline formed from two molecules of palmitic acid (16 carbons FA). FAs form cholesterol esters for the brain and cell membranes. Saturated fatty acids are stable and do not oxidize when exposed to oxygen

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Saturated Fat, Cholesterol, and Statin as do the polyunsaturated fatty acids. They also produce more energy when burned for fuel for the body. The unsaturated fatty acids do not produce as much ATP due to their double bonds and the additional energy consuming steps needed to deal with the double bonds. Recent papers have begun to appear that support the health benefits of saturated fats. Malhotra from London, publishing in the British Medical Journal in October 2013 [6] argues that saturated fat is not the major issue. He points out that the LDL-C increased with saturated fat intake is the large buoyant (type A) LDL not the small dense (type B) more inflammatory particles that are implicated in CVD and are responsive to carbohydrate intake NOT to saturated fat intake. Saturated fats also provide other benefits. Stearic acid is a saturated fat present in chocolate and beef and it doesn’t raise LDL at all. This type of saturated fat is also one of the major reasons dark chocolate has not been scorned. In small amounts, dark chocolate has been reported to have positive effects on cardiovascular function [7,8]. In one study which examined dark chocolate containing saturated fat and cocoa (flavonoids), beneficial effects on blood lipids were realized [7], and in another investigation, dark chocolate improved endothelial function and reduced blood pressure in younger, hypertensive individuals [8]. Palmitic and myristic look like villians as palmitic is found in palm oil, butter and eggs, and myristic acid is found in cheese, milk, butter and beef, all food items deemed to be dangerous. Even though they increase LDL cholesterol, it is the large type A version that is produced. The rise in LDL is at least partly due to an increase in the size of these LDL particles, which are not as detrimental for CVD as the increase in the number of small particles. These saturated fats also raise HDL which is obviously not a bad situation. Lauric acid, found in coconut oil, is a great oil to cook with; and monolaurin produced from coconut oil, is anti-microbal and therefore touted, not without reason, as an immune system supporter [9]. Milk also contains lauric acid and was used as a ‘cure’ for ulcers. Some years ago, one of our authors, Dr. Teter, worked with an enterologist that was culturing Heliocobacter and found that it killed this organism thought to cause ulcers. The many years of being told that CVD was due to the fats we eat (The Diet/Heart Hypothesis) is slowly being replaced by some better theories with more science behind them. Inflammation is becoming accepted as an important process in the development of CVD [10], mitochondrial dysfunction and ROS (reactive oxygen species) produced from excess dietary carbohydrates and polyunsaturated fats such as vegetable oils. Trans fatty acids have been shown to be involved in cardiac dysfunction and blood lipid abnormalities [11] causing significant cardiac pathology. Many of these factors are because of the types of fat in the diet but none of them involve the saturated fats. This is not unlike the scurvy theories of which there were many before the true cause of scurvy was identified. The polyunsaturated fatty acids (PUFAs) are the most unstable and easily oxidized FAs, even within the body. However, they JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION

are extremely important for many functions of the body. They also modify cellular membrane’s fluidity and are considered ‘essential fatty acids’ since the omega-3 and omega-6 PUFA cannot be made in our body. Linoleic acid and linolenic acid have to be obtained from our foods. They then can be elongated and further desaturated to long chain PUFA and modified to become prostaglandins, leukotrienes, and other eicosanoids. They are critical for the proper functioning of our bodies and immune systems as well as abundant in the brain. However, they are susceptible to oxidation and very delicate with which to work. We absolutely need them– but not in excess. A few grams a day in our diet will supply our needs and not run the risk of excess oxidation products. Fish oil from cold water fish (warm water fish do not contain many PUFA) can serve as a ready-made source of omega-3 fatty acids but must be stored carefully to prevent oxidation. The ratio of omega-6 to omega-3 is turning out to be an important metric for health, possibly more important than cholesterol ever was. Both omega-6 and omega-3 compete for the same enzymes for elongation and desaturation to produce the long chain PUFAs known as DHA and EPA. The end products of the omega-6’s metabolism tend to be inflammatory and those of the omega-3’s tend to be anti-inflammatory. A balanced ratio of omega-6 to omega-3 is vital for cardiovascular health because when more omega-6 than omega-3 is consumed, more inflammatory cytokines and other bioactive compounds with adverse effects will be formed. In volume 100 of the World Review of Nutrition and Dietetics, entitled “A Balanced Omega-6/Omega3 Fatty Acid Ratio, Cholesterol and Coronary Heart Disease” [12] Simopoulos and others argue that the ideal ratio of omega6 to omega-3 in the human diet is somewhere between 4:1 and 1:1, yet the western diet is at least 16:1 (in favor of the inflammatory omega-6’s) and in some areas, even higher. The overconsumption of vegetable oils and the UNDER consumption of omega-3’s is a much bigger problem than saturated fat intake because that imbalance is a substantial factor in creating inflammation. There is no single cause of heart disease, but there are a number of major promoters, including inflammation, oxidative damage, emotional stress, and glycation. Toxins, microbes and viruses may play a role as well. Without inflammation, there is no plaque, which is, after all, an attempt by the body to “patch up” an injury. While saturated fat has been blamed, the real villains in the American diet are trans FAs, sugar, and foods that convert to sugar like high-glycemic, processed cereals, pastas, breads, and starchy high-glycemic carbs like rice and potatoes. Our nutritional courts tried and convicted the wrong man. It was never saturated fat that was killing us, it’s been sugar all the time and we’re consuming record amounts of it, unprecedented in human history. Replacing processed carbs with proteins and healthy fats (saturated, polyunsaturated and monounsaturated), is a step in the right direction. The monounsaturated fatty acids are important components of the cell membranes since they can modify the fluidity of the cell membranes and are more stable that the polyunsaturates. 81

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Saturated Fat, Cholesterol, and Statin They are incorporated in the same way as the saturates and can be used for energy as well. Monounsaturated fats are also resistant to oxidation; and like saturated fats, do not elicit an insulin response. Olive oil, an omega-9, is mostly monounsaturated fat with some saturated fat and may actually be the most important element of the Mediterranean Diet. For example in the PREDIMED Study [13] 4 tablespoons a day did not only have a significant impact on primary prevention, but it may also have been the major factor in reduced myocardial infarction and stroke despite the fact that the participants were ingesting an additional 50 grams of fat a day. The PREDIMED (“Prevenci´on con dieta Mediterr´anea”) trial involving 7,447 Spanish men and women at high cardiovascular risk was the first randomized primary-prevention trial that demonstrated a significant reduction in major cardiovascular events (myocardial infarction, stroke or cardiovascular death) among participants assigned to a Mediterranean diet, supplemented with extra-virgin olive oil or mixed nuts (specially walnuts—high in omega-3, and also hazelnuts, or almonds) as compared with a control diet (advised to follow a low-fat diet). The PREDIMED trial is one of the largest trials ever conducted in nutrition with 7,447 participants followed-up for a median of 4.8 years [13]. The relative risks were 0.70 (95% confidence interval [CI], 0.54 to 0.92) and 0.72 (95% CI, 0.54 to 0.96) for the group assigned to a Mediterranean diet with extra-virgin olive oil and the group assigned to a Mediterranean diet with mixed nuts (mainly alpha-linolenic-rich walnuts), respectively, versus the control group. No diet-related adverse effects were reported. Consistent with these findings, a recent report from two large independent American cohorts found an inverse association between nut consumption and total mortality, with a clear inverse dose-response trend. This study included more than 115,000 participants with up to 30 years follow-up [14]. During 30 years of follow-up among women, the investigators documented 16,200 deaths; and during 24 years of follow-up among men, they documented 11,229 deaths. The relative risks of death for participants who ate nuts, as compared with those who did not eat nuts, were 0.93 (95% CI, 0.90 to 0.96) for nut consumption (1 serving of 1 ounce) less than once per week, 0.89 (0.86 to 0.93) for once per week, 0.87 (95% CI, 0.83 to 0.90) for two to four times per week, 0.85 (95% CI, 0.79 to 0.91) for five or six times per week, and 0.80 (95% CI, 0.73 to 0.86) for seven or more times per week (P < 0.001 for trend). The strongest reduction in mortality associated with nut consumption was seen for cardiovascular mortality. Therefore, both virgin olive oil and mixed nuts, which are fatrich foods (olive oil is of course, 100 percent fat, as is fish oil), have been shown to be associated with lower risk of cardiovascular disease and cardiovascular mortality. In contrast, poorer or null results have been observed when the low-fat diet paradigm has been selected, with little to no evidence of a cardiovascular protection after long-term trials educating participants in adopting a low-fat dietary pattern [15,16]. In addition, long-term compliance with, and sustainability of, low-fat diets are subopti-

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mal. Both observational epidemiologic studies and randomized trials concur in showing that a Mediterranean-type fat-rich diet, with olive oil and mixed nuts as major sources of fat, is likely to be the most sensible approach for cardiovascular prevention [17]. However, when it comes to saturated fats, we must make smart choices. Saturated fats from healthy, whole foods such as: grass-fed beef, coconut oil, organic eggs, Malaysian palm fruit oil, or organic butter are NO problem. Since lard and tallow have been replaced with vegetable oils for deep fat frying the risk of oxidation has greatly increased. Lard and tallow are much more stable to oxidation than are the vegetable oils which are highly unsaturated and form oxidation products very quickly. Saturated fat stands up to heat much better than the others and is far less likely to be “damaged” by frying or high heat. However, fat on an animal, including humans, is where we store toxins including chemicals, insecticides and pesticides. So when you eat meat from factory farmed feedlot animals, you’re getting all those toxins that are stored in their fat, whether it’s saturated or unsaturated. When you eat grass-fed meat, not GMO fed cattle, there are far less toxins and therefore far fewer worries about the fat on the meat. To summarize, saturated fat deserves more respect and is not the villain causing cardiovascular disease. Yes, it will increase total cholesterol in the body but is cholesterol the major cause of heart disease? And is cholesterol lowering really the gold standard for treating patients with cardiovascular risk and disease [18]? Current evidence would say no, it is most likely inflammation!

2013 STATIN CHOLESTEROL GUIDELINES The National Cholesterol Expert Panel, Adult Treatment Panel III treatment recommendations targeting low-density lipoprotein cholesterol (LDL-C) as an entity to be treated aggressively by the use of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) was launched in 2001. One in 6 American adults could potentially be advised to take these drugs, at a cost of approximately 30 billion a year [19]. In 2004, the therapeutic guidelines emphasized reaching a more targeted LDL level. The US National Education Cholesterol Program Guidelines suggested that the objective in high-risk patients should generally be to reduce LDL cholesterol to below 100 mg/dL or optimally, for very high risk patients, to below 70 mg/dL [20]. For more than a decade, the doctrine and established medical dogma was to get lower and lower LDL levels. Early clinical investigations and studies, however, seemed to question the validity of this approach. In a study involving 1,707 consecutive patients undergoing coronary arteriography, 985 were found to have severe coronary

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Saturated Fat, Cholesterol, and Statin artery disease. More than 100 of these patients died within 3 years, yet lipid measurements failed to predict survival [21]. In a study of 1,616 patients [22], patients hospitalized for an acute coronary event, whose statin drug was discontinued, were nearly three times as likely to have a nonfatal myocardial infarction or die, compared with their counterparts who continued to receive statin therapy. Investigators proposed that those taking the HMG-CoA drugs appreciated a smoother course because of an entirely different mechanism than the reduction of cholesterol. The Heart Protection Study (HPS) [23] evaluated women, the elderly, diabetics, people with low baseline cholesterol levels, and those with prior occlusive non-coronary vascular disease. Results demonstrated the positive impact of Simvastatin therapy across all patient groups, independent of cholesterol levels. Even in subjects with acceptable LDL-C levels (

The saturated fat, cholesterol, and statin controversy a commentary.

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