LDL Cholesterol is Not the Best Assessor of Cardiovascular Risk

There continues to be a reliance on LDL cholesterol (LDL-C) as the main means to assess cardiovascular (CVD) risk, despite the fact that apolipoproteinB (apoB) has been found to be a much better predictor. This new article looks at why total LDL cholesterol is inadequate to assess cardiovascular risk, what apoB is and why it is considered a better assessor, and how apoB, apoB/apoA ratio and its proxy TG:HDL ratio could be used to assess CVD risk.

An article published in Current Opinion in Lipidology (April 16, 2021) [1] states;

There is now a robust body of evidence demonstrating the superiority of apoB over LDL-C and non-HDL-C as a clinical marker of cardiovascular risk. LDL-C is not the appropriate marker to assess the benefits of statin / ezetimibe / PCSK9 therapy”

The paper outlines that in 2019 the European Society of Cardiology and the European Atherosclerosis Society Guidelines both concluded that apolipoprotein B (apoB) was a more accurate measure of cardiovascular risk and a better guide to using lipid lowering medication, than low-density lipoprotein cholesterol (LDL-C) or non-high-density lipoprotein cholesterol (HDL-C) — yet the American College of Cardiology and the American Heart Association continue to use both LDL-C as the primary means to assess CVD risk and to guide statin therapy.

To understand why apoB is a more accurate measure of cardiovascular risk than LDL, as well as how apoB/apoA ratio and its proxy triglyceride to HDL ratio (TG:HDL) can be used, a simple overview of the different types of cholesterol is needed — and it holds some surprises when it comes to both what we’ve believed about HDL being “good cholesterol”, and LDL being “bad cholesterol”.

Different Types of Cholesterol

What we call “cholesterol” are really lipoproteins which are particles made up of lipids (fat) and protein and that vary in size, density, and lipid and apolipoprotein composition. They can be separated into different classes based on physical and chemical parameters and include;

    • high density lipoprotein (HDL)
    • low density lipoprotein (LDL)
    • very low density lipoprotein (VLDL)

High Density Lipoprotein (HDL) – so-called “good cholesterol”

Most people think of high density lipoprotein (HDL) as “good cholesterol” and while it is known as a strong inverse indicator of CVD risk, HDL cholesterol is not one entity, but there are different sub-classes of HDL.

We have known since the 1990s that there are several sub-particles of LDL and we now know that HDL is made up of 5 different sub-fractions based on their size and density (very large, large, medium, small, and very small)  and that these five subclasses seem to be associated with different levels of CVD risk [2]. HDL Cholesterol measured on blood tests measures the total cholesterol content in all the different sub-fractions of HDL (HDL-C)[2].

Each High Density Lipoprotein (HDL) carries one apolipoprotein-A (apoA) which makes up ~65% of its mass and has been found in most studies to not to be associated with CVD risk [2].

When apoA is measured along with apoB (found in Very Low Density Lipoprotein (VLDL) and Low Density Lipoprotein (LDL)), it is considered to be an even better predictor of CVD risk than apoB alone [2]. More on this below.

Low Density Lipoprotein (LDL) – so-called “bad cholesterol”

Most people think of low density lipoprotein (LDL) as “bad cholesterol” — but low density lipoprotein (LDL) is not a single entity either — but is made up of four subclasses of LDL particles[2] where decreased size and increased density of LDL are associated with increased cardiovascular risk [3,4].

It is the small, dense LDL sub-fraction (sdLDL) that is associated with atherosclerotic plaque, whereas the large, fluffy (or buoyant) LDL sub-fraction is not [3].

Here’s an analogy that may help think of the different sub-fractions of LDL.

If I have a basket filled with balls — is how many I can get inside a basket affected by whether they are basketballs, or golf balls?

Of course it is!

I can put many more golf balls in a basket, than I can basketballs.

Think of golf balls as small, dense LDL (sdLDL) and basketballs as large, buoyant LDL.

LDL Cholesterol on Lab Test Results

LDL cholesterol measured on lab tests indicates total LDL-cholesterol (LDL-C) — that is, the total concentration of cholesterol within all four sub-fractions of LDL sub-particles. What is very important to note is that total LDL cholesterol (LDL-C) is what is usually used in studies that report an association between higher levels of LDL and cardiovascular disease, but these studies fail to distinguish between small dense LDL which are atherosclerotic, and the large, buoyant LDL which are not.  All the different subtypes of LDL are lumped together as if they were a one thing — and they are very different!

Usually, when someone is told their “cholesterol is high” it usually means that their LDL cholesterol is high — but many doctors are unaware of the different sub-fractions of LDL and that it is only the small, dense LDL (sdLDL) ones that pose a risk.  This is why I encourage my clients when told their LDL is high to ask “which LDL“? 

Very Low Density Lipoprotein (VLDL)

Very low density lipoprotein (VLDL) is produced in the liver and the best way to understand its role is to think of it as a “taxi” which the liver makes and then releases into the bloodstream to shuttle triglycerides (TG) around the body, to the various tissues.  VLDL cholesterol on blood test results isn’t actually measured, but is estimated as a percentage of the triglyceride value.

It is important to note that very low density lipoproteins (VLDL) and the Low Density Lipoproteins (LDL) that results after it off-loads it triglycerides each carry one apolipoprotein-B (apoB) molecule, and while a high VLDL value is said to be a risk for cardiovascular disease, a more accurate measure is the ratio of Apolipopoprotein B (apoB), the lipoprotein in VLDL compared to Apolipoprotein A (apoA), lipoprotein in HDL. More on that below.

Where does LDL come from?

Once a large amount of triglyceride (TG) has been off-loaded in the tissues by the VLDL “taxi”, it then becomes a new, smaller lipoprotein called low density lipoprotein, or LDL which contains mostly cholesterol, and some protein.  Some LDLs are removed from the circulation by cells around the body that need the cholesterol contained in them and the rest is taken out of the circulation by the liver.

LDL is what is left once the VLDL which is made by the body has offloaded its triglyceride ‘passenger’ to the tissues.

Assessing Cardiovascular Risk – particle number, apoB : apo A and TG:HDL ratio

LDL particle number (LDL-P)

Since the amount of cholesterol in each LDL particle varies, measuring total LDL cholesterol (LDL-C) tells us nothing about the actual number of particles they are or their size but an increased number of LDL particles indicates that a person has more small, dense particles.

To best understand this, think of the ball analogy, above. There will be increased number of balls with golf balls as compared to basketballs in the same size container.

LDL-particle number (LDL-P) has a strong and independent association with the development of atherosclerosis, as well as with CVD events [2] and is considered a more accurate predictor of cardiovascular events, than total LDL cholesterol (LDL-C) [2].

A nuclear magnetic resonance spectroscopy (NMR) lipid profile test directly measures the number of LDL particles (as well as HDL particles). For LDL particles, a value of less  than 1.000 in nmol/L is considered ideal, a value of 1000-1299 is considered moderate,  a value of 1300-1599 is considered borderline high, and a value >1600 is considered high.

Apolipoprotein B:Apolipoprotein A

Apolipoprotein B (apo B), which is the main lipoprotein in VLDL (and in LDL after the VLDL has offloaded its triglycerides to the tissues) and is correlated with LDL particle number, which makes it a very good assessor of cardiovascular disease risk.

Remember, the golf ball / basketball analogy; the higher number of LDL particles means the more small, dense LDL particles there are.

When an apoB test is used in conjunction with an apoA test (which measures the main lipoprotein in HDL), the apoB/apoA ratio is considered to be an even better predictor of CVD risk, than ApoB alone [2].

An apo B / apo A ratio of > 0.9 considered a risk for CVD.

Triglyceride (TG):HDL Ratio

Measuring apoB to apoA requires special blood tests, but reliable proxy can be calculated by dividing triglycerides (TG) by HDL-cholesterol (HDL-C) from a standard lipid panel and studies have found this to be a very good assessor of cardiovascular risk.

TG:HDL ratio reflects LDL particle size, which means it is an excellent proxy for particle number.

Remember, the golf ball / basketball analogy; the more small, dense LDL particles there are, the higher the LDL particle number. 

One study from 2004 reported that almost 80% of people with a TG:HDL-C ratio of greater than 3.8 (when values are expressed in mg/dl) had mostly small, dense LDL particles, indicating cardiovascular risk. This same study found that more than 80% with a TG:HDL-C ratio of less than 3.8 (when values are expressed in mg/dl) had mostly large, fluffy LDL particles, indicating lower cardiovascular risk[5].

A 2005 study [6] reported that a TG:HDL-C ratio of 3.5 or greater was highly correlated with atherosclerosis in men, as well as insulin resistance and metabolic syndrome.

A recent 2014 [7] study found that a high TG:HDL-C ratio was a strong independent predictor of cardiovascular disease, coronary heart disease and all-cause mortality both before- and after adjustment for age, smoking, BMI and blood pressure.

In Canada (as well as Europe), values are expressed as mmol/L and the ratios are interpreted as follows [8];

TG:HDL-C < 0.87 is ideal

TG:HDL-C > 1.74 is too high

TG:HDL-C > 2.62 is much too high

In the US, values are expressed in mg/dl and the ratios are interpreted as follows [8];

TG:HDL-C < 2 is ideal

TG:HDL-C > 4 is too high

TG:HDL-C > 6 is much too high

Final Thoughts…

If someone’s lab test results show they have high LDL cholesterol, all we know for certain is that the total concentration of cholesterol counting all four sub-fractions of LDL sub-particles together is high. 

This would be like telling someone that the total number of balls they have is 25 and then asking them if this will fit in their container — but not telling them if they were golf balls or basketballs. We need to know how big they are to know what “25” means.

Someone having “high LDL cholesterol” i.e. high total LDL (LDL-C) tells us nothing in and by itself. We need to know about either particle size or particle number.

This leaves several options;

An LDL-particle (LDL-P) test will indicate the LDL particle number and the higher the number, the more small dense LDL the person would have. While not routinely done, I have had had clients come to me with results from this specialized test.  They had it done when their total LDL cholesterol was found to be high, and their doctor wanted to know if this was problematic. If the number was low, then most of the LDL would be the large, buoyant type and not a problem — it would only be if the number was high, indicating lots of small, dense LDL that high total LDL is indicative of CVD risk.

An apoB test which measures the lipoprotein in VLDL and LDL is a good indicator of LDL particle number, so is a very good assessor of cardiovascular disease risk.

An apoB / apoA ratio is considered to be an even better predictor of CVD risk, than ApoB alone so if someone’s total LDL cholesterol (LDL-C) came back high, an apoB / apoA test would provide information with regards to the LDL particle number compared to the HDL particle number. ..but before requesting any special tests, one can simply look at TG:HDL ratio to see if LDL-C being high may be a concern.

Being told we have high LDL cholesterol doesn’t mean much if we don’t know which LDL is high. Small, dense LDL are a risk, but large, buoyant LDL are not. To assess the need for dietary, lifestyle or medication changes we need to know “how many” or “how big”. We can estimate this using a TG:HDL ratio from routine blood work — all we need is a calculator, and knowing the cut-off points. Then, if warranted, we can run an apoB test or both apoB and apoA tests to assess apoB/apoA and know for sure if there are too many small dense LDL.

Prescribing statins on the basis of high (total) LDL cholesterol alone — without knowing anything about size of the LDL particles or total number of LDL particles is, according to this most recent article, inappropriate.

NOTE (April 26, 2021): It should be noted that while it is the opinion of the writers of the article in Current Opinion in Lipidology, and that of the European Society of Cardiology and the European Atherosclerosis Society that LDL-C is not the best clinical marker of cardiovascular risk or the appropriate marker to assess the benefits of statin medication, an individual should always discuss whether or not to take a medication with their doctor.  Lab tests may not be the only reason for medications to be prescribed — and such a recommendation may also include past medical history, lifestyle factors and/or family risk factors. Always discuss these matters with your doctor.

More Info?

If you’ve been told you have high cholesterol and would like to know if dietary changes might be helpful, please reach out.  I’ll look at your your diet, blood work and family history and let you know what may be the most prudent approach to minimize risk.

To your good health!

Joy

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References

  1. Sniderman A; Langlois M, Cobbaert C, Update on apolipoprotein B, Current Opinion in Lipidology: April 16, 2021 – Volume Publish Ahead of Print – Issue – doi: 10.1097/MOL.0000000000000754
  2. Harada PHN, Akintunde A, Mora S, Advanced Lipoprotein Testing: Strengths and Limitations. 2014 Jun 20, Am Col of Cardiology, Expert Analysis, https://www.acc.org/latest-in-cardiology/articles/2014/08/25/15/07/advanced-lipoprotein-testing-strengths-and-limitations
  3. Diffenderfer MR, Schaefer EJ. The composition and metabolism of large and small LDL. Curr Opin Lipidol. 2014 Jun;25(3):221-6. doi: 10.1097/MOL.0000000000000067. PMID: 24811298.
  4. Ivanova EA, Myasoedova VA, Melnichenko AA, Grechko AV, Orekhov AN. Small Dense Low-Density Lipoprotein as Biomarker for Atherosclerotic Diseases. Oxid Med Cell Longev. 2017;2017:1273042. doi:10.1155/2017/1273042
  5. Hanak V, Munoz J, Teague J, Stanley A Jr, Bittner V. Accuracy of the triglyceride to high-density lipoprotein cholesterol ratio for prediction of the low-density lipoprotein phenotype B. Am J Cardiol. 2004 Jul 15;94(2):219-22. doi: 10.1016/j.amjcard.2004.03.069. PMID: 15246907.
  6. McLaughlin T, Reaven G, Abbasi F, et al. Is there a simple way to
    identify insulin-resistant individuals at increased risk of cardiovascular
    disease? Am J Cardiol. 2005;96(3):399Y404.
  7. Vega GL, Barlow CE, Grundy SM et al, Triglyceride to High Density Lipoprotein Cholesterol Ratio is an Index of Heart Disease Mortality and of Incidence of Type 2 Diabetes Melletus in Men, Journal of Investigative Medicine & Volume 62, Number 2, February 2014
  8. Sigurdsson AF, The Triglyceride/HDL Cholesterol Ratio, updated January 12, 2019, https://www.docsopinion.com/2014/07/17/triglyceride-hdl-ratio/

 

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