What Is LDL Cholesterol And Is It Dangerous?

The most common question I am asked on social media is about LDL cholesterol. This molecule is teh most studied molecule in all of medicine. We spend billions of dollars studying LDL cholesterol and LDL particles, because they have been shown to cause heart disease.

LDL Causes Heart Disease?

If you do not cherry pick studies, and include every study that has ever been done on LDL cholesterol, you will find that LDL cholesterol has met the criteria for causation of atherosclerotic heart disease.

When you do not exclude studies, and you do not cherry pick data, you end up with over 20 million person years of follow up and the data continues to point to the same conclusions. Those with high LDL cholesterol end up with heart disease, those with low levels do not. It's a linear relationship and their is a dose response.

The above graphic shows what over 20 million data points have shown. Reducing LDL cholesterol, in any way, will reduce cardiovascular event rates..

Studies: LDL causes ASCVD Ference and Boren EAS:

Ference:
https://academic.oup.com/eurheartj/article/38/32/2459/3745109 

Boren:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308544/ 

Pathophysiology of Coronary Artery Disease

Good place to start if you want an introduction to coronary artery disease.

https://www.ahajournals.org/doi/full/10.1161/CIRCULATIONAHA.105.537878 

LDL Cholesterol: The Key Player in Cardiovascular Health

When discussing cardiovascular health, few topics are as critical as low-density lipoprotein cholesterol (LDL-C). Often referred to as "bad cholesterol," LDL-C plays a pivotal role in the development of atherosclerotic cardiovascular disease (ASCVD). Renowned cardiologist Dr. Thomas Dayspring frequently emphasizes the importance of understanding and managing LDL cholesterol to prevent heart attacks, strokes, and other cardiovascular events.

What is LDL Cholesterol?

LDL cholesterol is one of the major lipoproteins that transport cholesterol in the blood. It delivers cholesterol to cells, which is essential for cell membrane integrity, hormone production, and vitamin D synthesis. However, when LDL levels become elevated, they contribute to the formation of fatty deposits (plaques) in the arteries—a condition known as atherosclerosis.

How Is LDL Cholesterol Measured??

Directly measuring LDL cholesterol can be easily done using a specific assay but it does have additional costs involved. Hence, most labs just use one of many formulas to calculate LDL cholesterol because it is free and readily available.

The most commonly used formula is the Friedewald equation which was developed in the 1970s when population cholesterol levels were much higher and rarely low (drug induced) as they are today. The formula becomes less accurate as TG levels rise and LDL-C falls below 70 mg/dL.

When your triglycerides are elevated, you end up with less HDL-C, because the HDL particles fill up with triglycerides and contain less cholesteryl ester. The same happens with LDL particles. This lower HDL cholesterol level does not affect the equation much, because as HDL cholesterol drops, you have more cholesterol laden VLDLs.

Why Is LDL Cholesterol Calculated? 

Directly measuring LDL cholesterol can be easily done using a specific assay but it does have additional costs involved. Hence, most labs just use one of many formulas to calculate LDL cholesterol because it is free and readily available. Below is an example of how the various lipoproteins can be separated based on size or density.

The most commonly used formula is the Friedewald equation which was developed in the 1970s when population cholesterol levels were much higher and rarely low (drug induced) as they are today. The formula becomes less accurate as TG levels rise and LDL-C falls below 70 mg/dL.

When your triglycerides are elevated, you end up with less HDL-C, because the HDL particles fill up with triglycerides and contain less cholesteryl ester. The same happens with LDL particles. This lower HDL cholesterol level does not affect the equation much, because as HDL cholesterol drops, you have more cholesterol laden VLDLs.

Direct vs Calculated LDL Cholesterol

What is direct LDL cholesterol? Can you order a direct LDL-C?

Sure, you can!

First, HDL particles are separated by precipitation using apoA-I antibodies. Then VLDL and IDL particles are removed by precipitation of apoE particles. Finally, only LDL particles are left, and the cholesterol is easily measured via oxidative chemicals.

In most cases, a direct LDL closely approximates the calculated LDL. In cases where triglycerides are over 200 mg/dL, then this would not be true.  

Further reading:
https://pubmed.ncbi.nlm.nih.gov/14998216/
https://pubmed.ncbi.nlm.nih.gov/23524048/
https://pubmed.ncbi.nlm.nih.gov/31928718/

The next graphic may help illustrate better what we are checking with the various labs.

At the very top line you see all apoB containing lipoproteins. You have IDL and LDL particles, all of which carry cholesteryl ester in their core. When you have a standard lipid panel, you end up with calculated LDL-C based on the Friedewald equation. For most people, fasting is not necessary to get an accurate lipid panel.

The “Actual LDL-C” is the cholesterol that is just in the LDL particles (LDL-P), but not in the lipoprotein a (Lp(a)) particles. No lab reports this “Actual LDL-C”. Labs using the Friedewald equation report the cholesterol that is in LDL, IDL, and Lp(a) particles together. A direct LDL-C will give you a measurement of all cholesterol in all LDL particles, which includes LDL particles and Lp(a) particles.

Confusing? It can be because most clinicians and people assume the LDL-C measured is an accurate way to assess LDL particle concentration (which is the driving force for atherogenesis).

Why is LDL Cholesterol Called “Bad Cholesterol”?

LDL cholesterol is termed "bad" because high levels in the bloodstream can lead to:

1. Atherosclerosis
   Excess LDL cholesterol penetrates the arterial walls, triggering an inflammatory response that results in plaque formation.

2. Reduced Blood Flow
   Over time, plaques narrow the arteries, restricting blood flow to vital organs like the heart and brain.

3. Heart Attacks and Strokes
   Plaques can rupture, causing blood clots that block critical blood vessels and lead to potentially fatal events.

How is LDL Cholesterol Measured?

LDL cholesterol levels are typically determined through a fasting lipid panel, using the following formula:

$$\text{LDL Cholesterol} = \text{Total Cholesterol} - \text{HDL Cholesterol} - \frac{\text{Triglycerides}}{5}$$

Optimal LDL Cholesterol Levels (as recommended by the American Heart Association):

• Optimal: <100 mg/dL
• Near Optimal: 100–129 mg/dL
• Borderline High: 130–159 mg/dL
• High: 160–189 mg/dL
• Very High: ≥190 mg/dL

For individuals with high cardiovascular risk, a goal of <70 mg/dL or even <55 mg/dL is often recommended.

Dr. Alo's Lipid Targets

Most people should want to be under the 20th percentile, and others under the 5th percentile depending on history and risks.

Risk Factors That Increase LDL Cholesterol

Several factors can elevate LDL cholesterol levels, including:

• Dietary Habits: High intake of saturated fats, trans fats, and to some extent cholesterol-rich foods.
• Genetics: Familial hypercholesterolemia (FH) leads to very high LDL levels from birth. For most people, their baseline LDL levels are set by genetics. Even if you did everything right, you may not be able to get it down to optimal levels even if you do not have familial hypercholesterolemia.
• Sedentary Lifestyle: Lack of exercise can lower HDL and increase LDL cholesterol.
• Medical Conditions: Diabetes, obesity, and hypothyroidism can negatively affect LDL levels.

LDL Particle Size and Number: Going Beyond the Basics

Myself and world renowned lipidologist, Dr. Thomas Dayspring, prefer to look at LDL particle counts and concentrations. Discussed elsewhere in the book/blog under NMR or apoB. 

• ApoB (Apolipoprotein B): A direct measure of the number of atherogenic particles in a concentration.
• LDL NMR Subfraction Testing: Determines the size and density of LDL particles. Particle number is far more important than size. Regardless of particle size, they are all atherogenic. Read, Does LDL Particle Size Matter?

How to Lower LDL Cholesterol

1. Lifestyle Modifications

• Heart-Healthy Diet: (biggest effect size)
  • Adopt a calorie restricted Mediterranean diet, rich in vegetables, fruits, whole grains, and healthy fats like olive oil.
  • Avoid trans fats and saturated fats from red meat and dairy.
  • Incorporate soluble fiber (e.g., oats, beans) to reduce LDL levels.
• Exercise Regularly: Aim for at least 150 minutes of moderate aerobic activity weekly. This has minimal effect on LDL cholesterol, but does improve cardiovascular outcomes.
• Maintain a Healthy Weight: Weight loss improves LDL and HDL cholesterol levels.

2. Medications

For patients unable to achieve target LDL levels through lifestyle changes, medications are often necessary:

• Statins: The gold standard for reducing LDL cholesterol by inhibiting cholesterol production in the liver.
• Ezetimibe: Works by reducing cholesterol absorption in the intestines.
• PCSK9 Inhibitors: Monoclonal antibodies that dramatically lower LDL by increasing liver uptake of cholesterol.
• Bempedoic Acid: A newer option that reduces LDL levels in statin-intolerant patients.

3. Advanced Therapies

• Lipoprotein Apheresis: For individuals with extremely high LDL levels resistant to traditional therapies.
• Inclisiran: A cutting-edge RNA-based PCSK9 therapy that targets LDL cholesterol with an injection every 6 months.

The Link Between LDL Cholesterol and Cardiovascular Disease

Dr. Dayspring often stresses that there is no "safe" level of high LDL cholesterol. The relationship between LDL-C and ASCVD risk is linear: the lower the LDL cholesterol, the lower the risk of cardiovascular events. Recent clinical trials like the FOURIER and ODYSSEY Outcomes studies confirm the benefits of aggressive LDL lowering, even in high-risk populations.

Myths About LDL Cholesterol

1. “Diet Alone Can Control LDL.”
   While diet is crucial, many people require medication to reach optimal LDL targets.

2. “LDL Cholesterol Doesn’t Matter if HDL is High.”
   High HDL cholesterol does not negate the risks associated with elevated LDL levels. There is no evidence that having high HDL is protective nor beneficial. See other posts and parts of my cholesterol book.

3. “You Can’t Have Too Low LDL Levels.”
   Extremely low LDL levels (e.g., <20 mg/dL) are safe and reduce cardiovascular risk without adverse effects. See the FOURIER and FOURIER OLE trials as well as many others.

LDL Cholesterol: A Modern Approach

Today, the focus is not only on lowering LDL cholesterol but also on addressing its subtypes and associated risk factors. Personalized medicine, guided by advanced lipid testing and tailored therapies, allows for more precise cardiovascular risk management.

We need to treat cholesterol earlier, more aggressively, and to much lower numbers than current guidelines and targets. Drs. Michael Shapiro, Peter Toth, and Michael Makeover emphasized this in their most recent paper. It's a brilliant article and I highly recommend everyone read it in it's entirety.

Study:
https://www.sciencedirect.com/science/article/pii/S2666667722000551 

Final Thoughts

LDL cholesterol is a cornerstone of cardiovascular risk assessment and management. As myself, and others like Dr. Prof Kausik Ray and Dr. Thomas Dayspring, frequently assert, controlling LDL levels is one of the most effective strategies for preventing ASCVD. Through a combination of lifestyle changes, pharmacological interventions, and advanced therapies, patients can achieve healthier LDL levels and significantly reduce their risk of heart disease. We can completely eliminate heart disease if we choose to do so. Which is why I wrote the book and blog!

Takeaway: Know your LDL cholesterol numbers, aim for personalized targets, and work closely with your healthcare provider to protect your heart health.

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This post is a chapter from my new Cholesterol Book. If you want updates on when that book will be ready for purchase, click on my updates link and sign up to receive updates:

https://dralo.net/cholesterol