If you have High LDL Cholesterol In Midlife This Is How You Should Think About It.
What you need to know about high LDL cholesterol.
If you have high LDL cholesterol and are unsure what that means for your risk of heart disease, this article is for you.
Over the course of your lifetime, your LDL cholesterol will slowly increase.
This isn't the case for everyone, but for the majority of people, it will.
The reason it increases is multifactorial.
Lifestyle certainly plays a role, but your genetics drive about 50% of that change1.
By midlife, the average male and female will see a significant rise in their LDL cholesterol.
Compared to birth, your LDL cholesterol will have risen 2 to 3 fold2.
For males, LDL cholesterol starts to rise in the mid-twenties. This rise happens about ten years later, in the mid-30s for females.
This 10-year phase shift in LDL cholesterol level rise is thought to explain why females tend to develop heart disease about ten years later than males.
By age 65, most people will have an LDL cholesterol level between 3.5 to 4 mmol (135 to 155 mg/dl).
What Matters Is Cumulative Exposure.
It is not your absolute LDL cholesterol level at any given time that matters most.
What matters is how long your LDL cholesterol level has been elevated.
This is known as your cumulative LDL exposure.
Just like cigarette smoking, the risk of lung cancer does not arise from having smoked 40 cigarettes in one day but more so from the total number smoked over a lifetime.
In smoking, this is known as ‘pack years’.
This represents the cumulative cigarette exposure over time.
The same concept applies to LDL cholesterol.
A higher cumulative LDL cholesterol exposure equals a higher likelihood of plaque in the coronary arteries, known as atherosclerosis.
But remember, heart disease or atherosclerosis does not kill people.
Heart attacks kill people.
A heart attack occurs when plaque in your coronary artery ruptures and causes a clot to form, which stops blood flow to the heart muscle, causing it to die.
But the more plaque you have, the higher the risk of a heart attack.
In simple terms.
Higher Cumulative LDL-C exposure = More Plaque = More Risk Of An Event.
But this works in reverse.
A lower risk of an event is driven by less plaque, which is driven by less cumulative LDL cholesterol exposure over time3.
This is why it matters far more to your risk of an event if you have had high LDL-C from a very early age (Higher cumulative exposure) compared to suddenly developing higher LDL-C later in life.
But LDL-C is not the only driver of risk.
Other factors, such as high blood pressure, smoking, insulin resistance, etc., act as force multipliers for the risk of an event.
Think of having high LDL cholesterol like speeding and the risk of a car crash.
Speeding will certainly increase your risk of an event, but it doesn’t guarantee it.
Now add being intoxicated into the mix.
It, again, doesn't guarantee that you will have a car crash, but your odds have risen dramatically.
The added risk factors, such as high blood pressure, play an important role because they result in more LDL-C particles being retained in the artery wall, causing plaque to form.
If you take an average LDL cholesterol exposure and add one or more of these risk factors, your risk of an event such as a heart attack or stroke increases dramatically.
But the opposite also holds true.
If you can achieve ideal control of these risk factors, your risk significantly decreases.
It never goes to zero.
But it drops—a lot.
So here is what you need to ask yourself if you are in midlife and your doctor has told you that you have high LDL cholesterol.
How long has it been high, and for how long WILL it likely be high? i.e. Are you only in your 20s?
Do you have any other risk factors that can act as a force multiplier of risk, e.g. High blood pressure, insulin resistance, excess weight, inactivity, smoking, etc?
What do these mean for my lifetime risk of an event, and do you want to lower that risk using lifestyle interventions, medications, or both?
If you are young, have multiple decades of remaining life years, and have added risk factors, your risk of an event is likely to be high.
So also, is the potential for benefit by aggressively addressing any high LDL-C or other risk factors.
Let’s end with an example.
Take a 45-year-old female with an LDL-C of 4.0 mmol (155 mg/dl) who is overweight with a systolic blood pressure of 134 mmHg and has a family history of heart disease.
This is not an unusual patient to see in clinical practice.
Based on these inputs their risk of a heart attack by age 50 is 0.8%.
Not exactly that concerning on first pass.
But let’s model out the same person’s risk to age 80.
That same person, untreated, now has a risk of a heart attack of 32%.
Now, we have a risk that seems worrying.
This illustrates the illusion of safety that shorter-term, e.g. 10-year risk models provide and highlights the importance of lifetime risk estimation.
But now let’s do what is necessary (Lifestyle or medications) to lower this same person’s LDL-C by 2.0 mmol/l (77 mg/dl) and systolic blood pressure to less than 120 mmHg.
Their risk of a heart attack at age 50 has gone from 0.8% to 0.5%.
Not exactly anything to write home about.
Hence, the inertia to aggressively treat such a person if only considering near-term risk.
But what about the impact on lifetime cardiovascular risk?
This now goes from 32% to 7.9%.
A huge reduction in risk.
Cummulative exposure to risk needs to be thought of as not only the time that has passed but also the potential time that will pass.
This is why cumulative exposure to all risk factors and estimation of lifetime risk and benefit is crucial to providing excellent cardiovascular care.
As I have grown fond of saying:
“Ten-year cardiovascular risk estimates are only useful for those looking to live another ten years”.
If your time horizon of risk extends beyond the next ten years, then you need to start thinking about cumulative risk but also cumulative benefit.
And of all the risk factors we can control, LDL cholesterol is the easiest to modify.
The next step is yours.
Common and rare gene variants affecting plasma LDL cholesterol. Clin Biochem Rev. 2008 Feb;29(1):11-26.
Sex differences in lipids: A life course approach. Atherosclerosis. 2023 Nov;384:117270.
The LDL cumulative exposure hypothesis: evidence and practical applications. Nat Rev Cardiol (2024).
Again Paddy, fantastic quick read, layman’s terminology, great advice and understanding provided. I have taken a lot (positive) from this article in how I manage my life and medication a year and a half on from my stenting. Never felt fitter and healthier as that blood supply to the heart muscle was obviously volume depleted before but now gives me much more VO2 max. Thanks Paddy.
There is the LDL theory of heart disease. There is another theory which notes an absence of LDL in plaque and suggests that only oxidized LDL may matter for heart disease. There are also important negative side effects connected with statin drugs. I knew one of the developers of statin drugs-- he was very disappointed in how they actually turned out. I think it is important to note that much remains unsettled here.