Is cholesterol all there is to heart disease? Do people with high cholesterol but slow progression of heart disease disprove medical science?

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As a follow-up to the podcast discussion with Dave Feldman, I am musing a bit offline about what exactly his LHMR study would show even if atherosclerosis did not progress in his subjects much.

Because we already know that other factors besides LDL also modify risk.

Here is an interesting calculator that David Nunan (@dnunan79) sent me me: chd.bestsciencemedicine.com/calc2.html.

Now, based on it and using Framingham data, here is what would happen to risk if total cholesterol is 8 mmol/L (310 mg/dl), HDL is high, in a 74-year-old female who is 74 and physically active.

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7% chance of having a cardiovascular event.

Just one-in-thirteen!

Same exact risk factors but 45 years old instead of 74 years old?

Just 2%, or 1-in-50.

Yes, maxed-out total cholesterol but just a 2% chance of having an event at age 45.

Now let’s look at the same exact risk factors but as a 74-year-old male.

Not great, but still only a 15% 10-year risk of heart attack.

What about a 45-year-old male?

Less than 4% chance. With maxed-out cholesterol.

Now here’s what happens if in a 74-year-old male, keeping the same total cholesterol and HDL cholesterol, keep the same age, BUT get a) untreated hypertension, b) diabetes, and c) add a father with heart disease.

Suddenly you go from 7% to 100%!

Now here’s what happens if you keep all those same risk factors and reduce cholesterol from 310 to 77.

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Your risk of heart disease drops from certain to about 56%.

Nothing changes except cholesterol. Big drop in risk, but this drop is clearly not everything, and a lot of residual risk remains.

Now here’s what happens when you go low cholesterol, high physical activity, and take away all those other risk factors as well.

Risk down to less than 3% over ten years! In a 74-year-old.

Basically, non-HDL cholesterol (which roughly approximates LDL cholesterol if I am not mistaken) here accounts for about a doubling of whatever one’s baseline risk is.

That’s either massive or modest, depending on your point of view. So, according to Framingham, if you were like Dave’s population of interest and got everything dialed in except LDL cholesterol (in other words, if you were a 45-year-old, male lean mass hyperresponder practicing a healthy lifestyle on a ketogenic diet), what would we expect?

We would expect a very low rate of cardiovascular disease progression.

In other words, the model predicted by Dave Feldman in his LMHR project is the exact same as the one predicted by Framingham.

Only if we saw dramatically high rate of progression of atherosclerosis among LMHRs or a dramatically low rate would we be surprised. And for Dave’s study, we would not expect a sufficiently large sample size or methodologically rigorous design to detect a reduction to an already very low risk.

Despite this, these patients would still be about three times as bad off with respect to heart disease than if they had lower cholesterol.

As a reminder, here is the same risk profile as above except with low instead of high cholesterol:

So having very high cholesterol is roughly three times as bad as having low cholesterol while having a healthy lifestyle. But this three-fold elevation still does not result in an extremely high absolute risk.

As a side note, let’s also take a look at the role of diabetes vs. total cholesterol. Here is perfect everything, age 74, female, physical activity, etc., except for diabetes.

4.4% risk of cardiovascular event in the next 10 years.

Now here is perfect everything, age 74, female, physical activity, etc., except for 310 mg/dl total cholesterol (and no diabetes).

7.1% risk of cardiovascular event in the next 10 years.

So having high cholesterol is clearly worse than having diabetes according to our current knowledge. But they are somewhat comparable.

However, contrary to what Aseem Malhotra says, having high lipids is in fact somewhat worse than having diabetes.

But what if we add high lipids and diabetes together and take away physical activity?

Suddenly risk jumps to 18%.

In other words, all of these risk factors are synergistic. They work together to increase risk of cardiovascular disease.

It’s not one or the other. Insulin resistance or cholesterol or smoking or hypertension or age or sex.

All are important.

Statins are thought to be a great drug not because they are the cure-all of cardiovascular disease (they are not), but because they reduce a major risk factor in a safe way.

The same cannot be said about inflammatory cytokines, which, when blocked in the CANTOS trial, caused an increase in sepsis.

We use statins by reason of historical accident: not because LDL is everything, but because as a species we found a way to reduce a major risk factor and haven’t been able to do the same with the other risk factors to the same degree.

Reducing LDL does not solve the problem of cardiovascular disease. It just causes a substantial reduction in risk. But really reducing risk requires an attack on several fronts. None of these can be neglected if we want to minimize risk of deadly and debilitating heart attacks.

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1 Comment

  1. It is estimated by some that CVD events would be reduced to close to 0 with a LDL level between 50-70 and total serum-c below 140.

    No extra LDL roaming around, no chance of it being oxidized and turned into plaques.

    Ironically, these numbers come from a paper authored by Cordain and Vogel (among others) !

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