BY DR. BAYNE FRENCH, MD DC
There are five main lipoprotein particles that vary in diameter, density, what protein is attached to them, and the payload they carry HDL, LDL, IDL, VLDL, and Chylomicrons. There are many subtypes of each. Below is a representation of their relative sizes. They are microscopic, their diameter measured in nanometers (billionths of a meter).
Notice the protein on the surface of the particle? There are several different ones but a couple of main players. They serve vital functions for the particle and allow it to interact with receptors on the surface of cells for the exchange of cargo (lipids).
See how the triglyceride and chol are packaged inside? The intestine packages fats from our diet into chylomicrons, which make their way to the liver for processing. The liver makes primarily VLDL, which is released into the bloodstream. The VLDL is acted on by various enzymes in different tissues and organs and transitions to other particles along that continuum. The below graphic shows this interplay:
The “good” and “bad” story:
It’s a long and sordid tale. HDL particles received the moniker “good” when it was observed that they received chol from the periphery (tissues and blood vessels) and transported it back to the liver. This is Reverse Cholesterol Transport. Although more recently, it's been discovered that most of this reverse chol movement is actually done by LDL, the “bad” chol. So why the bad designation for LDL? Follow the arrows in the above graphic. Most LDL is formed as other particles exchange and shed their fatty payload creating relatively less tg and relatively more chol within the LDL particle. So…the LDL particle has the highest relative cholesterol mass within it. Given our cholesterol-is-bad dogmatic, bullshit, brainwashing, LDL is then BAD, BAD, BAD.
Let’s take it a step further. The heart pumps blood through arteries. Arteries narrow over time. That narrowing is called atherosclerosis (or more generally referred to as CVD), and most of us will die from it. It's a more prevalent cause of mortality than all cancers added together. The primary constituent of atherosclerosis is cholesterol.
It's a pretty easy knee-jerk then to malign LDL, isn't it? LDL has the highest chol density…atherosclerosis is mostly chol…we die of atherosclerosis in droves…LDL is bad. Dr. Roth: -that an event that follows another was a consequence of the first-is described as post hoc ergo propter hoc (Latin for “after this, therefore because of this”). This is a common human fallacy.
The formation of atherosclerosis, like dementia, cancer, diabetes, and numerous other diseases, is an accumulation of metabolic dysfunction. A vastly complicated interplay of environment (our behaviors, diet, level of conditioning, toxin exposure, stress management, sleep quality, etc. x hundreds) with our genetics. Might the inside slippery lining of an artery become damaged over time? And cholesterol recruited to help heal the area? Yes. If you are fortunate enough as I am to hunt and kill the majority of the animal product you consume, you may also be adventurous enough to butcher that animal. Cut open a big artery next time, and feel how slippery it is inside. You’re looking at and feeling where the majority of homo sapiens will cease the living state, the interface between blood and tissue.
A brief chol testing history:
Initially (70 years ago), only total chol could be measured. All chol-containing particles were ripped apart, and the total mass/weight of chol per a specified volume of blood was measured and reported as mg/dl or mmol/L. Later, tg and chol within HDL particles could be measured. In the mid-1970’s, the Friedewald Formula was developed based on the premise that all tg is in VLDL particles and that they have 5x more tg than chol.
LDL = TC-HDL -Tg/5
Understand that your LDL is not a directly measured test but rather a value determined using non-individualized math. HUGE decisions are based on the result of this calculation (like who takes Lipitor for the rest of their lives), all hinging on the assumption that LDL actually matters. Many feel it does not.
For example, several labs have developed ways to directly measure LDL (Atherotech’s VAP panel; Liposciences’NMR panel), which is obviously more precise than a one-size-fits-all estimate from an equation. Probably, more importantly, LDL sub-particles and total particles may be measured, which we'll talk about later.
Is FASTING really necessary?
In 2016 Harvard Health Publishing posted an article on their blog from Dr. Fisher MD titled Farewell to the fasting cholesterol test? Dr. Fisher describes a study in the European Heart Journal (Nordestgaard et al. April 2016) supporting lipid testing in a non-fasting state and discusses the burden that fasting represents. Aside from the veritable emergency most Americans are faced with if they go a few minutes without eating, there are return visits to the clinic, more scheduling, and just overall more hassles associated with testing blood in a fasting state. Agreed. It certainly would be easier to just send a patient down the hall for a blood draw while they’re in the office.
Lipids have traditionally been checked in a fasting state to minimize the variation that food consumption may cause. The Friedewald equation above used to calculate the LDL may be less reliable. It is now known that eating results in insignificant effects on total chol, HDL, and LDL. Eating does affect tg levels more. And since tg is a big part of the Friedewald equation, perhaps LDL levels will be inaccurate. Direct measurement of LDL (as VAP and NMR panels can do, discussed later) truly makes fasting unnecessary. But tg may still widely fluctuate.
We need to ask ourselves just what in the hell are we trying to do with lab testing anyway! We’re trying to determine if there’s an increased risk of CVD. I dispute that LDL is good at predicting who’s at risk. It is apparent to me that tg, and especially the TG/HDL ratio is a much better marker. Checking lipids in a fasting state does NOT represent how most people spend their time. We are usually in a fed state, unfortunately. So maybe “random” testing of lipids is more suggestive of the usual state of affairs.
Blah blah. So what do I do? I want to compare apples to apples. I want to see uniformity in testing circumstances to accurately determine what some intervention has done. These interventions almost always involve a drastic reduction of sugar, overall reduction of all sources of carbs, intermittent fasting, and sometimes medication. Therefore I continue to check lipids in a fasting state. Usually, other labs are also ordered that require fasting, like insulin, testosterone, and blood sugar (although the hemoglobin A1c is MUCH better to evaluate a person's blood sugar handling and does not require fasting).
How many times have I said carbs are converted to fat? Seriously. Fifty? Sixty-three? A lot. You must understand that carbohydrate is a survival food. Found in very small amounts in nature. I know this because I’m in nature a lot. Much more than my wife would prefer and possibly a reason she will soon be my ex-wife. Some people bowl, others play poker. I’m with my kids or roaming around the Montana mountains looking for things to eat, trying to avoid being eaten. Our early fore-people that found natural carb and biochemically converted it to fat efficiently survived. They had babies, who had babies and if they were good storers of fat, also lived to have babies, who had babies who were your great x 1000 grandparents. We’re so similar to our fore-people in that we are also driven to seek out this survival food. Which is now everywhere and makes up the basis of the Obesity Pyramid, I mean Food Pyramid. Oopsy.
Carb eating begets carb eating. There are hormonal drivers of hunger, namely Ghrelin, that spike after a carby meal, driving us to eat more. And carb consumption drives triglyceride formation. Triglyceride (TG) is one of the basic elements of a standard cholesterol panel. Decades ago, I observed that heavy carb and sugar eating patients almost always had the disease of Obesity. They also almost always had some combination of diabetes, high TG, low HDL ("good" cholesterol), and a massive CVD burden. Yet all we talked about was LDL ("bad" cholesterol). LDL is still primarily what medical providers and non-provider want to talk about.
A quote by the German physicist Max Planck is coming to mind, as I’ve quoted before:
“A new scientific truth does not triumph by convincing its opponents and making them see the light, but rather because its opponents eventually die, and a new generation grows up that is familiar with it”.
Such is the power of the status quo. In medicine, the dogma around fats and cholesterol reigns supreme. So many institutions, groups, societies, behaviors, and ways of thinking in our society today would make no sense if there were not a lot of people participating in them. It makes the point that if enough people do it, it stops being crazy and instead becomes the accepted norm, as Dr. Roth points out.
The Traditional Chol Panel:
Dr. Kuijpers wrote a fascinating article, History in Medicine: The Story of Cholesterol, Lipids, and Cardiology, where he details the complete history of cholesterol discovery. A history that has resulted in over 10 Nobel Peace Prizes.
The components of a standard cholesterol panel include total cholesterol, HDL (good chol), LDL (bad chol), triglycerides, and total chol/HDL ratio. This "panel" has been available for many decades. There is tremendous dogma surrounding this lab test. Many still view it as the end-all-be-all for determining heart attack risk. I think it sucks. I've never found it helpful in lowering an individual's risk of heart disease. Most of my patients that have a heart attack are already on cholesterol-lowering medications. Apparently, others over the years have felt a bit let down by this test as well, and there is a lot of interest in ratios of the above components. If individually they’re not too helpful, maybe putting one over the other is better? The total chol/HDL ratio is most widely known.
The ratio of tg/HDL, my favorite, was first proposed by Dr. Gaziano et al (Circulation. 1997). Lemos da Luz et al (Am J Cardiol. 2005) reported that the ratio of triglyceride and HDL cholesterol was the “most powerful” independent predictor of coronary artery disease (CAD, or heart disease). It is, frankly, the only ratio I care about. Specifically, a ratio >4 was a powerful predictor of CAD. For example, a ratio of 4 would be tg of 200 and HDL of 50. Dr. da Luz and others (Clinics. Aug 2008) performed another study showing that the TG/HDL ratio was most strongly associated with the extent of CAD, which means how advanced and widespread heart disease (severity of artery narrowing, and how many arteries in the heart were involved).
For this second study, nearly 400 individuals had their cholesterol panels checked and underwent the injection of dye into their heart blood vessels (coronary angiography). A strong relationship between triglycerides, HDL, and TG/HDL ratio was found with the severity of heart disease. But total cholesterol and the much-revered LDL were NOT associated with the extent of heart disease. Know however that LDL is not LDL. There are many different subtypes, sizes, and densities. A high TG/HDL ratio correlates strongly with small, dense LDL particles that are much more apt to contribute to heart disease (Williams et al. Arterioscler Thromb. 1992). As discussed later, analysis of these LDL subtypes (advanced lipoprotein testing) may not be an option for many patients. Thus the TG/HDL ratio "shows promise as an attractive surrogate index" of just how contributory your cholesterol panel may be to the development of heart disease.
Packard et al (Arterioscler Thromb Vasc Biol. 1999) and Brinton et al (J Clin Invest 1991) both describe the snapshot that the tg/HDL offers: Tg are packaged in the liver in VLDL particles. High tg results in high VLDL. These particles are released by the liver into the bloodstream and come into contact with numerous tissues, exchanging their payload (lipid exchange and lipolysis) and morph into small, dense LDL particles (the worst type of LDL).
Let's take a look at a multi-decade study done on almost 40 thousand men - dead men, but men nevertheless. Dr. Vega et al (BMJ Journals 2013) examined the National Death Index from 1970 to 2008. The tag/HDL ratio was used in the analysis to correlate death from CVD. Men with a ratio of >3.5 had a much higher incidence of CVD death and a 200% increased incidence of Type 2 Diabetes. This point is critical for you to understand…a high TG/HDL ratio implies sick metabolism. Sick metabolism leads to high insulin levels, insulin resistance, weight gain, diabetes, and eventual heart disease and early death.
The "Father of Aerobics", Dr. Kenneth Cooper MD, MPH founded the Cooper Institute in 1970, renowned for comprehensive and preventative-oriented medical analyses of patients. Dr. Farrell, Ph.D., helped evaluate the medical records of over 40 thousand healthy men who received physical exams at the Cooper Institute between 1978 and 2010. These men were categorized based on their treadmill fitness and TG/HDL ratios. The figure below summarizes the findings:
- Group 1 has the lowest tg/HDL ratio. In that group, the "H" patients were in the best shape. They had the LOWEST risk of dying from heart disease.
- Group 4 had the highest TG/HDL ratio. In that group, the "L" patients were in the worst shape. They had the HIGHEST by far risk of dying from heart disease.
Caselli et al. (Scientific Reports 2021) looked at 355 patients and followed them for 4.5 years. They found that patients with the highest TG/HDL ratio had the highest risk of dying and having a non-fatal heart attack. This risk increased over time, even though LDL cholesterol was lowered with medication.
Dai et al. (Lipids in Health and Disease 2019) evaluated over 3000 patients over approximately four years. They were stratified into a lower TG/HDL ration (<2.84) and a higher TG/HDL ratio (>2.84). For example, a ratio of 3 would be a tg level of 150 and an HDL level of 50. All unfavorable outcomes were significantly elevated in the higher ratio group, including all-cause mortality, major adverse cardiac events, stroke, and heart failure. Dr. Dai noted several other findings:
- Dai et al (and many other researchers) found a much higher incidence of insulin resistance and diabetes in patients with a higher TG/HDL ratio.
- An inverse relationship was noted between tg and HDL, which means the higher the tg, the lower the HDL. Thus, higher the TG/HDL ratio.
- Patients with high tg also commonly possess small, dense LDL particles, which more strongly correlate with CVD than just LDL chol. They recognize that the advanced measurement of small, dense LDL may not be feasible in a widespread manner and that the tg/HDL ratio may be “utilized as an alternative biomarker indicating increased small dense LDL, which was significantly associated with the incidence of adverse cardiovascular outcomes”.
One final thought. Berneis et al (Journal of Lipid Research. 2002) reported evidence of two pathways of LDL production from the liver that are triglyceride dependent. In a high tg state, small dense LDL is produced. In a low tg state, large LDL particles are produced. Recall that the majority of tg in the body is produced from carbs.
It's also important to know that there is dramatic genetic variability in chol production, both the amount and the particle size. These differences are primarily driven by SNP (single nucleotide polymorphism). These are small genetic differences, not large mutations like with Familial Hypercholesterolemia mentioned below. What's interesting to think about is that these small mutations probably conferred a survival advantage for our forepeople and are now harming us.
Advanced chol testing:
Standard lipid testing is very good at determining how much fat and cholesterol you have in your blood at a given time. But we don't treat lab tests. Instead, we should treat the person and use data to extrapolate risk. A lipid panel is a high-level tool for most providers. A tool without rival and beyond question. It’s not for me.
There exists “advanced lipoprotein testing”. The two panels I have used most extensively are VAP and NMR. There are several other methods. These panels are capable of looking at the size of the cholesterol particle (how big is the boat), how many particles there are (LDL-P…how many boats are on the river), and potentially many other potentially detrimental chol particles like IDL, and lipoprotein (a).
Lipoprotein (a) is a specific, chemically altered form of LDL. Review the continuum of lipoprotein particles above: the liver makes VLDL, which morphs into IDL, then LDL. LDL is acted on in numerous ways in the bloodstream. Lipoprotein (a) is a result, and its presence and amount are largely genetically determined. It contains an additional bound molecule, is elevated in nearly 20% of the world's population and can increase the risk of CVD significantly. It is possible to have very elevated lipoprotein (a) and normal LDL levels.
Let’s look at some studies:
- The Quebec Cardiovascular Study (Circulation 1997) determined that patients with the highest LDL-P (the highest number of boats on the river) and the smallest particle size had a six times higher incidence of CVD.
- The MESA study looked at 7,000 ethnically diverse men and women showed that those with the highest LDL-P number had the thickest inside lining of their arteries.
- Otvos et al. (Journal of Clinical Lipidology 2011) looked at cholesterol in numerous ways. They found discordance between LDL and LDL-P. Meaning:
- Patients may have relatively low “bad” LDL chol but a high LDL-P. Meaning lots of boats on the river but not much chol payload. This could result in the patient being told they are low risk when in fact, their CVD risk is quite high.
- Patients may have high LDL but a low LDL-P. Meaning lots of payload but not many boats on the river. This could result in needless chol medication being prescribed.
- They found that the highest incidence of CVD was in patients with the highest LDL-P and the lowest LDL. This is not a typo.
- Journal of Clinical Lipidology 2007 showed the same thing. This study followed 2,500 patients for 15 years and found the worst survival rates (highest chance of not living) in those with high LDL-P and low LDL.
The next study (American Heart Journal. Jan 2009) did not look at advanced chol testing per se but rather illustrates the shortcomings of our standard, dogmatic view of cholesterol.
- LDL-C is the same as LDL. The chol payload inside the LDL particles.
- CAD is coronary artery disease. Basically, atherosclerosis of the arteries in the heart themselves.
- Tim Russert was a beloved news anchor who died suddenly of a heart attack in June 2008. He had passed a heart stress test in April 2008. He was on chol medication and regularly exercised. His LDL was “optimal”.
- The notable finding of this massive study is that the majority of patients hospitalized with heart disease had excellent LDL.
Before you insist that your health care provider order an advanced panel for you, please consider a few things. Most providers are not taught how to interpret the data. I wasn't and had to learn on my own. They don't want to make time and take responsibility for data they don't understand or don't particularly view as being useful. These panels are more expensive than traditional lipid panels and may not be covered by your insurance. Below is a letter I put together to address rejections from pencil-pushing, dogmatic insurance idiots:
To Whom It May Concern:
I am (patient's) primary care physician and am board certified in Family Practice and Obesity Medicine. I understand that payment for recent medically indicated lab tests I ordered for your client has been denied. After reading this letter, I request that you reconsider and cover the ordered lab work.
To say that the standard lipid profile that only looks at LDL, HDL, total chol, and triglycerides are woefully inadequate at predicting cardiovascular risk is an understatement. The seminal article of January 2009 published in the American Heart Journal looked at 136,905 patients hospitalized for heart disease (Sachdeva et al). 41.5% had LDL, <100 mg/dl, and 12.5% had LDL under 70. This is over half of the patients with coronary artery disease with outstanding "bad" cholesterol.
I have no interest in my patients becoming part of that statistic. Fortunately, there is a much better way of predicting who is truly at risk. But unfortunately, this is precisely the testing you are denying for your client.
The Multi-Ethnic Study of Atherosclerosis (MESA) was a multicenter trial looking at almost 7,000 ethnically diverse men and women. LDL, LDL particle number (LDL-P), LDL size and IMT (arterial intima-media thickness, the best non-invasive marker for atherosclerosis) and several other parameters were looked at. It was shown that the patients with the greatest IMT correlated highest with the LDL particle number.
Several studies have examined the amount of LDL cholesterol and the number of LDL particles. These two parameters are concordant in the general population 80% of the time. This means that 1 in 5 patients have discordant values. However, this discordance percentage goes up dramatically with Metabolic Syndrome including Diabetes, conditions that are pervasive in America. This means that LDL simply CAN NOT predict cardiovascular risk, and looking at LDL particle numbers must be done. The MESA data showed that because of the very high discordance of LDL and LDL particle numbers with metabolic syndrome, these patients' cardiovascular risk is under-predicted 63% of the time. A 9/2012 American Journal of Cardiology article looked at 2,000 diabetic patients with "favorable" lipid profiles. 78% of them had discordant numbers, meaning their LDL particle number was high and their risk was much higher than anticipated.
Journal of Clinical Lipidology 3/2011 article showed via data point scatterplot just how discordant LDL and LDL particle number values are (Otvos et al). Furthermore, the cumulative incidence of cardiac death or adverse cardiac event was looked at relative to cholesterol parameters. The highest incidence had elevated LDL particle number but excellent LDL (average 104 mg/dl). The lowest incidence had a low LDL particle number and elevated LDL (average 130 mg/dl). If only a standard cholesterol profile were done, many individuals might have been placed on statin therapy that was actually low risk, and the highest risk individuals would be falsely reassured.
An earlier Journal of Clinical Lipidology article of 12/2007 looked at the probability of cardiovascular event-free survival of 2,500 patients over 15 years. Again the highest risk group had LOW LDL but high LDL particle numbers. And the lowest risk group had low LDL particle numbers and high LDL. The Sachdeva et al article determining that over 50% of patients hospitalized for heart disease had excellent LDL cholesterol should not be surprising if the dramatic limitations of standard lipid testing are understood.
Many studies over many years have shown that determining LDL particle number is a superior way to predict cardiovascular disease, including AMORIS, LIPID, NHANES, Leiden Heart Study, Health Professional Follow-up Study, The Chinese Heart Study, AFCAPS/TexCAPS, Framingham Offspring Study, Cardiovascular Risk in Young Finns, INTERHEART, and IDEAL.
Furthermore, multiple medical organizations support the use of advanced lipoprotein analysis to determine particle numbers, including Current Canadian Lipid Guidelines, American Diabetes Association and American College of Cardiology Consensus Statement in 2008, American Association of Clinical Endocrinology published recommendations, and recommendations from AACC Lipoproteins and Vascular Diseases Division Working Group on Best Practices.
Cardiovascular disease is pervasive and by far the biggest threat to life for adults in America. EVERY possible preventative tool must be employed to mitigate this epidemic. Advanced lipoprotein testing via NMR is irrefutably a superior way to determine which patients are at higher risk, thus allowing for earlier and more concerted treatment efforts involving lifestyle behavioral change and medication. Furthermore, it allows individuals to AVOID unnecessary treatment based on an elevated LDL but actual low risk as determined by the LDL particle number. The testing is widely available, strongly validated, and nominally more expensive.
Your denial of this superior laboratory service has created much hassle on the part of your client and their medical team. Worse yet, your willingness to cover a marginally useful lipid profile and refusal of a far superior and evidenced-based lipid profile is unacceptable and simply must change. The time has come for you to understand this issue and develop new policies.
Bayne French MD