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Out of Date: Why LDL-Cholesterol (LDL-C) should be replaced with LDL-Particle (LDL-P)

Note: This post is out of date. While LDL-P is a good metric for following cardiovascular risk, apoB measures all atherogenic particles, including LDL, VLDL, IDL, Lp(a) and chylomicrons, and is thus a better marker. We are working on a new post discussing apoB! See this link for a good review.


The Takeaway:

  • LDL-C tests are used rather than LDL-P despite well-documented faults because: A) They are cheaper and covered by insurance; B) It is widely accepted by, and taught to, doctors in medical school; and C) Current cholesterol guidelines use LDL-C

  • LDL-C measures the concentration of cholesterol per unit volume of LDL particles, but tells you nothing about the number of LDL particles in your blood - which is what matters most

  • LDL-P tests measure the number of LDL particles (nmol/L) in serum - which has far greater predictive value for cardiovascular disease risk than LDL-C or total cholesterol

  • Order both an LDL-P and apoB

Discussion

What is apoB and what is the difference between LDL-C and LDL-P?

  • ApoB is an apolipoprotein that sits on certain particles found in the blood. Each particle has one molecule of apoB on its surface. These include chylomicron remnants, very-low-density lipopoprotein (VLDL), intermediate-density lipoprotein (IDL), LDL, and Lipoprotein(a) – this particle will be discussed in a future post.

  • LDL-C is a calculated value and represents the concentration of cholesterol per unit volume of LDL particles. In other words, it is the density of the cholesterol in LDL. It is reported in milligrams of cholesterol per deciliter of LDL volume.

  • LDL-P is the actual number of LDL particles per liter of serum and is usually measured directly rather than calculated. It is reported in nmol/L of serum.

The figure below illustrates a typical LDL particle with concordant and discordant measurements between LDL-C and LDL-P. That is, there are four possible outcomes for two tests that are binary, in this case normal vs high: Low (LDL-C = LDL-P) concordance, (LDL-C> LDL-P) Discordance, (LDL-P> LDL-C) Discordance, and High (LDL-C=LDL-P) concordance, in order on the picture from left to right. The clinical problem arises when discordant cases occur as patients will be incorrectly triaged into low or high risk states when in fact they are the opposite. This can have dangerous implications because:

  • In the (LDL-C>LDL-P), or the false-high risk group, a patient may experience a medication side effect when they might not actually need that medication

  • In the (LDL-P>LDL-C), or the false-low risk group, a patient may not be advised on proper lifestyle modifications or started on a critical medication that could save their life

How is LDL-C calculated?

There are two main formulas that are used to calculate LDL-C. The Friedewald equation has been used for decades [1] and is shown below:


LDL-C (mg/dL) = Total cholesterol – HDL-C – (Triglycerides/5)


Recently some labs (like ultalabs) started using the Martin/Hopkins method [1] to calculate the LDL-C. It is also based off total and HDL cholesterol and triglycerides. However, it uses a conversion factor that varies based on each patient’s triglyceride and non-HDL-C value and is therefore more personalized and accurate.


LDL-C (mg/dL) = Total cholesterol – HDL-C – (Triglycerides/personalized factor)


Why should you measure both LDL-P and apoB?

Up to 95% of the particles to which apoB attaches are LDL, making apoB a good marker for LDL particle count and vice versa.[2] Therefore if you know either your LDL-P or your apoB you likely have a good estimate of the number of atherogenic particles floating around in your blood and your risk for atherosclerosis. While it is possible for apoB and LDL particle counts to be discordant, it is much less common than discordance between LDL-C and LDL-P. That is why it may be important to know both values.


Why does LDL-C vs LDL-P matter?

Elevated LDL-C is used as a justification to start patients on medications or stratify them into a higher cardiovascular disease risk group. We know that being on a medication that lowerss your cholesterol is not benign, especially if it is not needed. On the flip side, having a low LDL-C can be a false-negative, causing physicians to forego treating patients who in fact do require treatment. The problem is that elevated LDL-C often doesn’t paint an accurate picture of cholesterol related cardiovascular risk. Evidence that LDL-P should be the standard LDL test abounds.


Studies

In a study recently published in JAMA (January, 2019), there was no benefit of lowering LDL-C or plasma triglycerides unless there was also a lowering of apoB. All apoB containing particles <70nm in diameter have a similar effect on the risk for cardiovascular disease per particle.[3]


Approximately 50% of people who have heart disease have normal lipids (LDL-C, total cholesterol, etc) as measured by a typical lipid panel. In a large study published in the American Heart Journal of 136,905 patients hospitalized for a heart attack who had their lipids drawn at admission: a) among those without prior cardiovascular disease or diabetes, 72.1% had LDL-C less than 130mg/dL. Nearly 50% of patients with a history of heart disease had LDL-C less than 100mg/dL, and 17.6% had LDL-C less than 70mg/dL.[4]


Rises in LDL-P correlated with intima-media thickness in the multi-ethnic study of atherosclerosis. [5] In many patients, the LDL-P and LDL-C were discordant, meaning the LDL-P was high and LDL-C was low or LDL-P was low and LDL-C was high. Only the patients that were (LDL-P > LDL-C) discordant had increased risk for cardiovascular disease.[5] That is, a physician would be incorrectly comforted by the low LDL-C measurement in these patients; in reality they would be very high risk.


In the Improving Care for Cardiovascular Disease in China project, a group of 6,523 patients with a history of MI or revascularization, presented to 192 hospitals with acute coronary syndrome. Their LDL-C was taken at admission, and 63.8% had LDL <100mg/dL (30.1% had LDL-C <70mg/dL and another 33.7% had LDL-C between 70-100mg/dL).[6]


Metabolic syndrome is an important confounder

Metabolic syndrome is another important factor in the discordance of LDL-P and LDL-C. In a study of 2,000 diabetic patients, the prevalence of discordance between LDL-C and LDL-P was shown to be 78%.[7] Of note, it has been found that LDL-C and LDL-P are more commonly discordant in patients with a few or more components metabolic syndrome or diabetes.[6, 7] To further complicate things, in 11-13% of subjects who were insulin resistant there was discordance between LDL-P and apoB.[3] If the LDL-P is found to be low, the apoB could still be high due to an increase in Lp(a). If the LDL-P is high but the apoB is low, then you are still high risk and there are only hypotheses currently proposed to explain this discordance. Metabolic syndrome means having any three or more of the following:

  • Waistline of 40 inches or more in men, 35 inches or more in women

  • Blood pressure 130/85 or higher, or taking blood pressure medication

  • Triglyceride of 150mg/dL or higher

  • HDL-C less than 40mg/dL in men or less than 50mg/dL in women

  • Fasting blood glucose greater than 100mg/dL or taking glucose lowering medication

How can I find out my LDL-P?

There are two tests that (I am aware of) you can order without a doctor to test LDL-P, an NMR Lipoprofile and an Ion mobilization test. A benefit of the NMR Lipoprofile test is that it will give you an insulin resistance score (LP-IR) based on six of the lipoprotein particles that are obtained with the test. This is an earlier sign of insulin resistance than you can see with A1c levels or fasting glucose, and will help you better stratify risk for diabetes onset.[8]


Additionally, in a study comparing ion mobilization vs. NMR vs. a third method not discussed, they were discordant 37% of the time.[9] NMR is the gold standard that has been used in many of the large studies showing that LDL-P is a better marker than LDL-C (Multi-Ethnic Study of Atherosclerosis, Framingham Offspring). I was curious as to the difference between the two exams so I ordered both at the same time, and had them drawn the same morning one after the other. My lab values for both were almost identical. However, as said above, they can be discordant fairly often!


Ion mobilization costs $42 from ultalabtests.com

NMR lipoprofile costs $117 from dhalab.com


A future post will be completed on different ways that have been studied to lower your LDL-P.


For an incredible in-depth exploration of this topic, see Peter Attia’s “Straight Dope on Cholesterol” – a 9 part series. Link provided is to part 1, and you can also listen to his podcast – The Drive – and look for his interview with Thomas Dayspring.

https://peterattiamd.com/the-straight-dope-on-cholesterol-part-i/


References:

1 https://jamanetwork.com/journals/jamacardiology/fullarticle/2684503

2 http://clinchem.aaccjnls.org/content/clinchem/55/3/407.full.pdf

3 https://jamanetwork.com/journals/jama/fullarticle/2722770?widget=personalizedcontent&previousarticle=2731736&fbclid=IwAR0PJfAyGaD8O4R8YlhEa_ZMLuiRNnhV7uJBS0BxRzzA_bGZVZ-viKt887w

4 https://www.sciencedirect.com/science/article/pii/S0002870308007175?via%3Dihub

5 https://www.lipidjournal.com/article/S1933-2874(11)00027-4/abstract

6 https://www.ajconline.org/article/S0002-9149(12)01243-X/fulltext

7 https://www.lipidjournal.com/article/S1933-2874(14)00404-8/fulltext?fbclid=IwAR037GflD4vbQkN1Vy4vx0ckrpM1q-tLL1BiBSu7WXRAVOUjJwP0RVPEJC0

8 https://www.sciencedirect.com/science/article/pii/S1933287417303525?via%3Dihub

9 https://www.ahajournals.org/doi/10.1161/circ.132.suppl_3.18619


#apoB #LDL #glucose #cardiacdisease

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