Doc Gumshoe is not in the habit of contradicting the conclusions, backed by research, that are stated in papers published by the Journal of the American Medical Association, commonly referred to as JAMA.    JAMA is, after all, one of a handful of the most prestigious medical journals on the planet, along with the New England Journal of Medicine (NEJM), Lancet, and the British Medical Journal (BMJ).

The JAMA paper rocketed around the media like hot news about one of those current celebrities whose names I barely recognize, but everybody else seems obsessively to follow.   There are 718,000 Google links to the subject line “JAMA eggs are bad.”   

What the JAMA paper concluded was that “Among US adults, higher consumption of dietary cholesterol or eggs was significantly associated with higher risk of incident CVD and all-cause mortality in a dose-response manner.”   Specifically regarding eggs, the paper’s conclusion was that each additional half an egg consumed per day was associated with a 6% higher risk of cardiovascular disease and an 8% higher risk of all-cause death.   (Zhong VW et al. JAMA 2019:321(11):1081-1095).   (More about the specifics of that study later.) 

Anti-egg bias has a long and distinguished history.   It is not, for example, in any way comparable to the many totally irrational biases that plague honest health-care professionals and cause harm to the commonwealth.   I will quote from an excellent book, Medicine’s Ten Greatest Discoveries, by Meyer Friedman, MD, and Gerald Friedland, MD (Yale University Press, 1998):

“Ask any zoologist or epidemiologist what animal has killed and is still killing more humans than any other animal.   The answer would surely be the cobra.   Despite the availability of anti-venom therapy, this wretched snake still kills five thousand to ten thousand Indians alone each year.   A herpetologist would incriminate not the relatively long (10 – 15 feet) king cobra, but the short (5 feet) Indian snake (naja naje).   This reptile ranks as the most deadly because of its habit of slinking into houses at dusk in search of rats and mice, then being surprised ay an unsuspecting human victim, into who it buries its lethal fangs.

The specialists would be in error.   The most murderous animal for millennia has been and still is the seemingly gentle hen.   She does not kill us by fang or claw, but by presenting us with the product of her ovary.   The yolk of her egg contains ten times as much cholesterol as is found in a similar quantity of beef, pork, fish, or even chicken flesh.   No other body organ or tissue (except the brain) is so loaded with this lethal substance.”

In order to understand why pinning the cause of cardiovascular disease on eggs because of their high cholesterol content is still controversial, we have to take a look at the history of the relevant medical and physiological discoveries. 

More about cholesterol

The role of cholesterol in cardiovascular disease (CVD) began to be understood in the first decade of the 20^th century.   There had been several theories about the cause of what was then called “hardening of the arteries” or “arteriosclerosis,” including that it was simply the result of aging, or that it was due to disturbed metabolism of the artery itself, or that the process evolved from clots adhering to the arteries which then absorbed the clots, becoming arteriosclerotic plaques.   The first real breakthrough came in 1910 when a scientist named A. Windhaus published a paper reporting that lesions in the inner lining of sclerotic arteries contained six times as much free cholesterol as normal arteries, and about 20 times more esterified cholesterol.         

Around that time, a Russian scientist named Nikolai Anichkov directed an experiment in which rabbits were fed three different diets.   One group got a supplement made from muscle fluid, a second group was on a diet of egg whites, and the third group was fed egg yolks.   Only the third group of rabbits developed the characteristic deposits in the lining of the arteries.   The deposits were identified as cholesterol.   Further research seemed to establish that cholesterol alone was the cause of those arterial changes, and Anichkov published an influential paper in 1913 citing the evidence that demonstrated that the arterial deposits were directly caused by cholesterol in the diet.   That finding has been called one of the ten greatest discoveries in the history of medicine.   

Taking the cue from those findings, the term “atherosclerosis” began to be employed to describe arteries affected by cholesterol deposits, gradually replacing the earlier term, “arteriosclerosis.”    The “athero” part of the term indicates that the substance that is deposited in the arterial wall is a thick, gruel-like substance, whereas the earlier term just referred to arterial hardening.                                          

From those entirely legitimate findings came the conclusion that, since the deposits in the arteries were cholesterol, the way to prevent the development of atherosclerosis (and the harmful consequences following from atherosclerosis) was to eliminate cholesterol from the diet to the greatest extent possible, and since egg yolks are exceedingly rich in cholesterol, the prime dietary culprit that should be extirpated was the egg.   The logic seemed to be irrefutable.

One would think that for the rest of the 20^th century, the case was evident:  consuming eggs and other cholesterol-laden foodstuffs (e.g., red meat) led directly to gunked-up arteries and heart disease, and that the way to avoid heart disease was to steer clear of those lethal things.   But perhaps it was because Anichkov’s findings took a long time to be known outside Russia that it wasn’t really until mid-century that there began to be warnings about eggs and beefsteaks.   And then, there followed several decades of frustration.   Despite the warnings, the incidence of atherosclerosis and heart disease was unaffected.   Was this because people were not heeding the advice of their doctors to go easy on those carriers of dangerous cholesterol?   Even more frustrating, among those who really avoided high-cholesterol foods, cholesterol levels did not fall that much, and many of those people who were on supposedly healthy diets nonetheless experienced heart attacks and strokes.   In other words, cutting back on eggs and steaks didn’t seem to make much difference.   

Understanding of cholesterol itself and just how it affected our health grew slowly.   It was in 1950 that the results of another breakthrough study were published.   A group of scientists led by John Gofman confirmed Anichkov’s findings that feeding rabbits a diet rich in cholesterol quickly led to the formation of atherosclerosis in the rabbits.   Gofman’s group then did some further investigation.   Serum samples from the cholesterol-fed rabbits were placed in a centrifuge capable of rotating its tubes at 40,000 revolutions per minute.   This caused the serum samples to be separated into two fractions.   The lighter-weight fraction, which floated towards the surface, was designated as low-density lipoprotein cholesterol, and the heavier fraction, which was concentrated at the bottom of the tubes, was designated as high-density lipoprotein cholesterol.   

Both fractions consisted of the same molecules – cholesterol, protein, phospholipid, and triglyceride, but the low-density fraction was lower in protein, which was what gave the high-density fraction its density.   The Gofman group also discovered that, whereas the cholesterol in the blood of normal rabbits consisted almost entirely of the high-density fraction, the cholesterol in the atherosclerotic rabbits was the low-density fraction.   This gave rise to the common way of referring to the low-density lipoprotein cholesterol (LDL-C) as the “bad cholesterol” and the high-density lipoprotein cholesterol (HDL-C) as the “good cholesterol.” 

The “good cholesterol – bad cholesterol” terminology is misleading.   Cholesterol is one single substance.   It is a fairly simple molecule, solid at body temperature, and not soluble in water.   Therefore, in order to be transported in our bloodstream, it has to hitch a ride with substances that can be carried around in blood.   These are lipoproteins – little particles containing both proteins and lipids, not in any fixed chemical combination, but bundles of varying sizes.   Cholesterol attaches to the lipid part of these bundles, and the protein part permits them to be transported in blood.

These particles range in size and density.   The low-density, loosely packed bundles, called low-density lipoprotein cholesterol, or LDL-cholesterol, are the ones nicknamed “bad” cholesterol, because they are the ones that are apt to shed the cholesterol molecules themselves, which can attach to the walls of the arteries.   But, we have to remember, the LDL-C is absolutely essential to our lives, because those particles are the ones that convey cholesterol to where it’s needed, which is pretty nearly everywhere in our bodies.

The smaller, denser bundles, called high-density lipoprotein cholesterol, or HDL-cholesterol, carries cholesterol back to the liver, where it is taken up by the bile and carried in the bile duct to the colon for excretion in the feces.   Therefore, HDL-C is dubbed “good cholesterol.”   It’s the lipoprotein bundles that are “good” or “bad,” not the cholesterol itself.

It’s worth just mentioning that only about 15% to 20% of the total cholesterol in our bodies enters our digestive systems as cholesterol.   The rest we synthesize daily.   Some of the foods we eat are more easily transformed into cholesterol, such as solid fats, especially partially hydrogenated fats (transfats).   But no matter what we eat or don’t eat, we’ll go on synthesizing cholesterol, because we need it.

It wasn’t until 1984 that a legitimate clinical trial was published demonstrating that lowering blood cholesterol levels would have a beneficial effect in terms of lowering the incidence of heart disease events.   The Coronary Primary Prevention trial was the first large, randomized double-blind trial showing that decreasing cholesterol levels using cholestyramine reduced coronary heart disease events.

Cholestyramine removes bile acids from the body by forming insoluble complexes with bile acids in the intestines, which are then excreted.   To maintain normal and necessary levels of bile acids, more cholesterol is converted to bile acids in the liver, lowering the amount of cholesterol in the plasma.

The trial followed 3,806 middle-aged men between the ages of 35 and 59 with no symptoms of heart disease, but with elevated cholesterol levels.   To be included in the study, the men had to have a total cholesterol level of 265 mg/dL or higher, and an LDL-cholesterol level of 190 mg/dL or higher.   The trial’s primary endpoint was a composite of death from coronary heart disease and non-fatal myocardial infarction.   

The trial subjects were followed for an average of 7.4 years, at the end of which it was found that cholestyramine reduced total cholesterol levels by 8.5% and LDL-cholesterol by 12.6%; both findings were evaluated as being significant (P < 0.001).    At 7 years, the primary endpoint occurred less frequently in the group treated with cholestyramine than in the placebo group, in 8.1% of the treated subjects compared with 9.8% in the placebo group.   There were no significant differences in brain infarcts, peripheral vascular disease, or all-cause mortality.   Particularly in the early years of the trial, the rate of GI side effects was quite high, affecting 68% of subjects in the cholestyramine group.

Employing cholestyramine to treat patients with elevated cholesterol never became a standard of treatment, likely because of the relatively small size of the beneficial effect and the considerable incidence of side effects.

The statins appear on the scene

Although the correlation between total cholesterol and heart disease had been incontestably confirmed, the benefits of lowering cholesterol through drug treatment remained elusive.   As recently as the early 1990s, a meta-analysis of 22 controlled trials concluded that “lowering serum cholesterol concentrations does not reduce mortality and is unlikely to prevent coronary heart disease.”   It is in the context of these numerous inconclusive trials that the Scandinavian Simvastatin Survival Study (4S) in 1994 stands out as a ground-breaking trial, announcing a new era in coronary heart disease (CHD) prevention.   The 4S trial prospectively followed 4,444 subjects with established CHD and baseline cholesterol levels defined as very high (261 mg/dL).   Patients treated with simvastatin achieved average total cholesterol (TC) reductions of 28%, low-density lipoprotein cholesterol (LDL-C) reductions of 38%, triglyceride reductions of 15%, and high-density lipoprotein cholesterol (HDL-C) increases of 8%.   Simvastatin-treated patients had a relative risk of coronary death of 0.58, 42% lower than in the placebo group.   

The 4S trial was the first of a series of trials that employed a new generation of cholesterol-lowering agents, the hydroxymethyl glutaryl coenzyme A (HMG-CoA) inhibitors, generally known as statins, which block an enzyme employed by the liver to produce cholesterol.   These trials enrolled different patient populations and employed different drugs of the statin class.   

• The Cholesterol and Recurrent Events (CARE) trial enrolled 4,159 men and women with previous myocardial infarction (MI) and TC levels below 240 mg/dL.  The study drug was pravastatin, and in these patients the risk reduction was 24%.   

• The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) trial enrolled 9,014 subjects who had had either an acute MI or been hospitalized for unstable angina in the previous 3 years; subjects had a wide range of pretreatment TC levels, between 155 and 271 mg/dL.   Compared with placebo-treated patients, in pravastatin patients there was a 24% reduction in CHD death.    

• The West of Scotland Coronary Prevention Study (WOSCOPS) evaluated fixed dose pravastatin in 6,595 men with elevated cholesterol levels, but no history of MI; these men had a 31% reduction in nonfatal MI or CHD death.

• The Air Force / Texas Coronary Prevention Study (AFCAPS/TexCAPS studied titrated doses of lovastatin in 6,605 men with no previous history of MI and average (221 mg/dL) TC levels.   In treated patients, there was a 37% reduction in unstable angina, fatal or nonfatal MI, or sudden cardiac death.  

• Finally, a very large study in the UK, the MRC/BHF Heart Protection Study, followed 20,536 adults with coronary disease, other occlusive arterial disease, or diabetes, who were randomly assigned to treatment either with simvastatin or placebo, for an average of 5 years.   Treated patients had an 18% reduction in CHD death (P = 0.0005), and a 24% reduction in the first occurrence of major cardiovascular events.

Each of these six trials effectively broadened the population that could be expected to benefit from cholesterol-lowering therapy.   Patients with established CHD had lowered risk of cardiac mortality, but so did patients with no previous evidence of CHD.   Patients with very high TC or LDL-C levels benefited from treatment, but so did those with borderline or low levels.   When data were analyzed to focus on specific populations, women, younger patients, older patients, and those with diabetes or impaired glucose tolerance, all were consistently found to have reduced coronary event rates.   Statin treatment was also shown to be cost effective: the number of patients that had to be treated to prevent one death was quite low, about 30 in the LIPID trial and 33 in the 4S trial.   In addition to cardiac death, the range of cardiovascular events or procedures whose incidence was reduced by statin treatment was wide, and included stroke, unstable angina, coronary or carotid revascularization, congestive heart failure, and lower extremity vascular disease.

Case closed?   Not so fast …

Sounds as though we have all the evidence needed to close the case, right?   Let’s see: we’ve learned that the stuff that lodges in the walls of arteries is cholesterol, also that feeding cholesterol to rabbits produces that clogged artery phenomenon, and that a substance that interferes with the liver’s capacity to synthesize cholesterol reduces the incidence of several types of cardiovascular disease.   So cholesterol is clearly the guilty agent in all this, and simple logic leads straight to the conclusion that reducing the amount of cholesterol in our diet will also reduce the incidence of CVD.   

Except for a few pesky details, to wit: 

One: we ourselves make about four-fifths of the total cholesterol in our bodies – only a small amount enters our bodies as cholesterol  (such as those villainous egg yolks).

Two: yes, some of the cholesterol in our bloodstream winds up lodging in the walls of our arteries forming arterial plaque, but what makes the plaque break loose and form clots that lodge in coronary arteries or in arteries in our brain, causing heart attacks and strokes?

Is it possible that some other factors are at work?

And some other data got in the way of the unitary explanation that cholesterol was the single cause of CVD.   One was that a certain number of individuals who had “normal” cholesterol levels nonetheless experienced the same kind of cardiac events.   Paul Ridker, a cardiologist at Brigham and Women’s hospital and Harvard Medical School, found that these persons, who did not have cholesterol at levels that had been associated with heart disease, did have elevated levels of C-reactive protein (CRP), which for more than 80 years has been known to be associated with generalized inflammation.

At about the same time, another Brigham and Women’s/ Harvard cardiologist, Peter Libby, learned that cholesterol didn’t just swim around in the bloodstream.   It actually worked its way into the arterial wall.   This appeared to constitute a kind of insult to the arterial wall and provoked an inflammatory response, which in turn resulted in the formation of blood clots.   It was these blood clots that, at least in some cases, blocked coronary arteries, causing heart attacks, and also blocked cerebral arteries, causing strokes.   Peter Libby coined the term “vulnerable plaque” for plaque affected by inflammation that was prone to clot formation.

(Now, lest the above information confirm the views of those who claim that it’s not cholesterol but inflammation that is the archvillain, let me insert a modest demurral, viz, lots of factors besides inflammation can cause the formation of blood clots.   Blood tends to clot all on its own, for example in venous thrombosis, and also in conditions such as atrial fibrillation, in which blood pools in the heart antechambers.)       

Paul Ridker followed up his discovery about CRP with a study in which it was shown that treatment with statins not only lowered cholesterol levels, but also lowered levels of this inflammation marker.   And in 2008, Ridker presented the results of the JUPITER trial at the New Orleans meeting of the American Heart Association.   (Ridker P et al. New Engl J Med 2008;359:2195-2207)   This large trial (17,802 subjects) compared two cohorts of persons, all of whom had normal cholesterol levels.   (Let me re-emphasize that point: NORMAL CHOLESTEROL LEVELS.)   One group of 8,901 subjects received 20 mg. of rosuvastatin daily, and the other, also 8,901, got the placebo.   The primary endpoint was incidence of signal cardiac events consisting of nonfatal myocardial infarction, nonfatal stroke, unstable angina, or death from cardiovascular causes.   Subjects receiving rosuvastatin experienced 142 such events, while those on placebo experienced 251 events.   Although the reduction was small in terms of absolute risk – about 1.2% – it was considered highly significant, both statistically and in terms of implications for treatment.   As a result of these results, the trial was stopped after a bit less than two years because the sponsors considered it unethical to continue a large cohort of patients on placebo when significant benefit had been demonstrated in the treatment arm.

The subjects in the JUPITER trial had baseline LDL-cholesterol levels of 108 mg/dL  and CRP levels of 4.2/4.3 mg/L.   Those LDL-C levels are considered desirable in patients with no established cardiac risk factors.   CRP levels > 4.0 mg/L are now considered elevated and associated with significant risk.   

The JUPITER trial cannot be said definitely to demonstrate that lowering CRP was the determining factor in reducing the numbers of signal cardiac events.   Treatment with rosuvastatin not only reduced CRP from the baseline level to about 1.8 mg/L, but also lowered the LDL-C levels from a pretreatment 108 mg/dL to 55 mg/dL, so the benefit may have in part been due to the LDL-C reduction.   But the reduction in that marker of inflammation was certainly an eye-opener.   At the AHA meeting, Steven Nissen of the Cleveland Clinic was quoted as follows: “…if a patient comes to me with normal LDL-cholesterol levels, I tell him to keep doing what he’s doing and to go about his business.   Now, what happens when that same patient arrives in my office and I know his CRP is elevated?   I know that treating him with intensive statins therapy, despite what the guidelines state, is going to cut his risk of cardiovascular morbidity and mortality in half.”

In further analysis of the JUPITER trial results, Ridker came to the conclusion that elevated CRP levels signal more heart disease risk than do elevated LDL-C levels, although the highest risk is in patients in whom both of those are elevated.   CRP levels below 1 mg/L are related to low risk, between 1 and 3 mg/L to medium risk, and higher than 3 mg/L to higher risk.   

Although the data as presented does suggest that inflammation is a greater risk factor for heart disease than elevated cholesterol, it is far from presenting satisfactory vindication for the supporters of the view that inflammation is the whole story and cholesterol is a mere ruse cooked up by the pharmaceutical industry as a way to push their products.  After all, the JUPITER trial demonstrated that a statin lowered both CRP and LDL-C, and in so doing conferred significant reductions in heart disease risk in a cohort of persons who, according to the standards at the time, were not considered to have any heart disease risk at all.  

My own conclusion on this subject is, how shall I put it? – inconclusive.   There’s no doubt that inflammation is an important factor in many diseases.   But at the same time, it’s an immune response, and we absolutely require those immune responses to survive.   Immune responses are what kill newly-formed cancer cells every day of our lives.   Cancer researchers are currently investigating ways to harness immune mechanisms for cancer treatment.   And, of course, without inflammation, healing would not take place.   

Going back to our initial subject: the guilt (or innocence) of The Egg

A second look at the JAMA paper that we started out with turns up some interesting and definitely relevant information.   This was a retrospective analysis based on six previous studies, analyzing data gathered between 1985 and 2016.   The diet data were self-reported.   The median time-span covered for the 29,615 subjects in the study was 17.5 years.

Essentially, the study subjects were asked to report their dietary habits during that period.   Based on the reports obtained from those subjects, the study authors came to the conclusion that associated with each additional one-half of an egg consumed per day there was a 6% increased risk of a cardiovascular disease incident and an 8% increased risk of death from any cause.

It seems to the skeptical Doc Gumshoe that this data is exceedingly weak.   Nearly thirty thousand people asked to recall what they ate during the past 17.5 years?   How accurate could that conceivably be?   Who remembers what he/she ate every day for the past week, let alone 17.5 years?   In some individual cases, we might be able to compare the person who regularly had eggs for breakfast every day of his life with another person who has a horror of eggs and never touches them.   But to be able to figure whether cohort A consumed half of an egg per day more than cohort B stretches my credulity to the breaking point.

Beyond that, the data collected does not reflect what else those subjects ate.   Did the dedicated egg-eater consume a hard-boiled egg with a sprinkle of pepper, or eggs scrambled in abundant amounts of butter, accompanied by two or three rashers of bacon?   That could make a lot of difference.

Also, I suspect that there are other differences between the egg-eaters and the egg-shunners.   The egg-shunners are likely more scrupulous observers of careful health practices.   I would bet that the egg-shunners tend more to avoid less healthy foods such as saturated fats, and that would certainly make a difference in their risk for cardiac events.

And there was contrary evidence, or, at least, contrary information based on the Third National Health and Nutrition Examination Survey (NHANES III), which examined the diets of 20,000 participants.   I quote from the conclusion:

“Compared to egg consumers, nonconsumers had higher rates of inadequate intake (defined by Estimated Average Requirements (EAR) of < 70% Recommended Dietary Allowance (RDA)) for vitamin B12 (10% vs. 21%), vitamin A (16% vs. 21%), vitamin E (14% vs. 22%) and vitamin C (15% vs. 20%).   After adjusting for demographic (age, gender, and ethnicity) and lifestyle variables (smoking and physical activity), dietary cholesterol was not related to serum cholesterol concentration.   People who reported eating > or = 4 eggs/wk had a significantly lower mean serum cholesterol concentration than those who reported eating < or = 1 egg/wk (193 mm/dL vs. 197 mm/dL, p < 0.01).”

That conclusion also confirms the high nutritive value of eggs, which are major sources of lutein and zeaxanthin, which, in addition to their recognized protective effects against macular generation and cataract formation, also have a role in preventing the oxidation of LDL-cholesterol.   And eggs also contain choline, an important nutrient, which some experts suggest may play a role in protecting against Alzheimer’s disease.

 I realize that I have led you the long way round the garden to come to the conclusion – inescapable, from where I sit – that eggs are not bad for you and actually, if eaten in moderation, are pretty good for you.

To reiterate – you might want to call it “harping on” – the main points:

While cholesterol is the stuff that builds up in our arteries, potentially leading to serious heart disease, avoiding cholesterol in our diets is not the magic solution, since we make at least 80% of the cholesterol in our bodies – no matter what we eat.   Remember, cattle eat hay and they make lots and lots of cholesterol.

Other things besides the cholesterol in our arteries are important factors leading to heart disease, for instance, inflammation.

Pointing the finger at the egg as the major culprit in heart disease is a blunder, albeit a tempting blunder: when faced with a complex and difficult problem, it is highly tempting to posit a simple, unitary solution.   Tempting, but usually wrong.     

* * * * * * *

As always, Doc Gumshoe invites and welcomes comments of all flavors, from egg lovers and egg shunners alike.   And if you are curious about any health-related subject, do please mention it and I will at least put it in the hopper.   Very best to all, Michael Jorrin (aka Doc Gumshoe).