较高的低密度脂蛋白胆固醇与较长的寿命有关？

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@scta123

he is not willing to prescribe me even the most benign of lipid lowering meds Ezetimibe saying that he sees no benefits of doing so and pointed out several side effects that in his opinion are not worth it.

What are the potential side effects of ezetimibe? It seems to have interesting properties, especially in men:

• Unraveling Potential Sex‐Specific Effects of Cardiovascular Medications on Longevity Using Mendelian Randomization 2023
• Ezetimibe increases resistance to oxidative stress and extends lifespan mimicking dietary restriction in Caenorhabditis elegans 2023
• Effect of moderate-intensity statin with ezetimibe combination vs. high-intensity statin therapy according to sex in patients with atherosclerosis 2023

[scta123]

@adssx

What are the potential side effects of ezetimibe?

I forgot… he showed me some research papers, but the side effects that he is most concerned were to do with pancreas and liver toxicity and gallbladder.

[L_H]

@adssx

What that does not mean and what are still open questions to me:

• Is ApoB the most important risk factor for CVD? (vs insulin resistance, BP, etc.)
• Does extremely low ApoB (30 mg/dL?) lower your risk of ASCVD near 0?
• Are there negative side effects of low ApoB? (e.g. for NDDs such as Parkinson’s) Is there a tradeoff?
• Should we lower ApoB at all costs?
• Are statins the best way to reduce ApoB? (vs bempedoic acid/ezetimibe, PCSK9i, CETPi, etc.)

Really like this list. I would also add the dlightly different:

• Do any negative side effects on longevity of using particular drugs (or supplements) outweigh the cvd benefits of lowering apoB to extremely low levels

[L_H]

@RapAdmin

Lets just agree that going below 60 or 70 mg/dl range is of debatable benefit. Getting to the 70 to 80 range is likely a good thing, I think most people and most cardiologists would agree (if you are above 100).

Yes!
(More characters)

[cl-user]

@Neo

I for instance spend massive efforts on optimizing all aspects of cardiovascular and other health including BP and inflammation

I think most people find it non intuitive that all those various papers are just averages so indeed if the only biomarker you know about a person is its LDL you can compute that, on average, a higher LDL is correlated with an higher CVD risk but that correlation is rather weak and the confidence interval is huge especially for high LDL.

We have to remind ourselves that most people are not well metabolically. For instance LDL obsessed people always point out that the all cause mortality is up for low LDL because a lot of very sick people have low LDL. That’s probably true but they also never say that the very same argument is equally true for high LDL. People who are metabolically unwell have high LDL (and TG and low HDL, etc.) and this also increases the all cause mortality.

This begs the question of how an individual can position himself on that curve which is where the multidimensionality curse comes into play. As soon as there more than one dimension rather than just one like LDL, it’s pretty easy to be an outlier and fall outside of the simple statistics.

For instance let’s take a few other biomarkers like HDL, TG, BP and HbA1C and let’s say we managed to be in the optimal 10% for each one. Let’s also assume they are not correlated for now so that we can compute the probabilities.

The probability of having 2 of those in the optimal 10% will be 1%. This alone positions you outside if the 95% confidence interval. 3 markers in the top 10% will be 0.1% and 4 markers will be 0.01%.
Now how many studies will work on a 0.01% subpopulation? Not a lot and certainly not the large LDL ones.

There are a few though, like the one on LMHR (Lean Mass Hyper Responders) who exclusively looked at people who have LDL > 200, HDL > 80, TG < 70. I don’t remember the statistics but it’s something like less than 0.01% of the population. These people have less plaque than a matched standard cohort and some of them have no plaque with an LDL of 500+.

Obviously that does not tell anything about risk vs LDL for the 99.99+% of the remaining population and this does not change that, on average, high LDL is bad for 95% of the population as shown by a lot of studies .

Now there are other subpopulations that have been studied which might be of interest here, like centenarians (results here) and, on that subgroup, normal to higher LDL is better than low LDL.
BTW on that subgroup low glucose is better though.

Note that there are other subpopulations like people with FH for instance where it has been shown that high LDL is indeed strongly correlated with bad outcomes. But again high LDL by itself is not FH.

Hopefully that thread will continue to discuss the nuances of a complex topic rather than turn into yet another LDL good/bad caricature.

[cl-user]

[Replying to myself here ]
I think It’s interesting to look at an extract of the Centenarian study for total cholesterol (TC) and glucose relative to the current discussion.

As you can see the probability of becoming centenarian is maximum for the 4th (3.1%) and 5th (3.0%) TC quintiles even though it’s not statistically significant. The only statistically significant finding is that the lowest TC quintile has the lowest probability of becoming centenarian.
Basically the only bad TC is the lowest and all the other TC values are statistically indistinguishable.

Now for the glucose it’s the opposite. Only the highest glucose quintile is really bad and the other values are statistically similar even though there is an insignificant trend toward lower is better.

Again that study is on a specific sub-population and the findings do not apply to other categories but as it’s a category we would like to be in it’s an interesting one.

[adssx]

@scta123

he showed me some research papers, but the side effects that he is most concerned were to do with pancreas and liver toxicity and gallbladder.

I quickly checked and couldn’t find much:

Ezetimibe and pancreas: Drug Induced Acute Pancreatitis Secondary to Ezetimibe

Drug induced acute pancreatitis (DIAP) is a rare clinical entity with incidence of <2% in general population. Most cases are typically mild and have excellent prognosis but prompt diagnosis and cessation of offending drug is important to avoid adverse outcomes.

Ezetimibe and liver toxicity: Couldn’t find anything

Ezetimibe and gallbladder: many papers saying that ezetimibe prevents gallstones.

[scta123]

@adssx

Ezetimibe and liver toxicity: Couldn’t find anything

Just googled it and I found this:

Although very rare, ezetimibe-associated liver injury is a potentially serious complication.

With hepatic inflammation due to ezetimibe, discontinue treatment and consider systemic steroids and anti-inflammatory agents, with weekly monitoring of liver function tests (ALT, AST, ALP, total bilirubin).

@adssx

many papers saying that ezetimibe prevents gallstones

But can cause cholecystitis as well.

[adssx]

@scta123

Although very rare, ezetimibe-associated liver injury is a potentially serious complication.

I can’t find data on the frequency. It seems extremely rare. So much that it might not be relevant at all.

@scta123

But can cause cholecystitis as well.

What are sources about that? In Google Scholar I could only find:

• Effect of ezetimibe on the prevalence of cholelithiasis - PMC
• https://www.sciencedirect.com/science/article/abs/pii/S0039606007002668

[Neo]

@cl-user

those various papers are just averages so indeed if the only biomarker you know about a person is its LDL you can compute that, on average, a higher LDL is correlated with an higher CVD risk but that correlation is rather weak

For me it is about triangulating between data and mechanistic understanding. The latter part is a very key part of my approach - even if the data, data, data is crucial, and mechanistic understanding in isolation is seldom good enough to make decisions based on.

We know with very high confidence that Apo B is *causal in increasing CVD. (More so than most relationships in medicine). So when I and my doctors and making decision about my CVD risk reduction protocol we are bringing to bear both “averages” data from clinical trials and Mendelian Randomization studies AND mechanistic understanding and then making triangulated decisions for me in my context with all the N=1 data we have for me.

[Neo]

Do we know what the centenarians had as lipid levels when they were young and middle age? Seems that would be more interesting to know than what their levels are when they are very old (as we know that Apo B goes up with age).

We also need to know mechanistically that non low lipids (at old age) are helping them become old vs that they are becoming old despite

Otherwise we are just back in associations and correlations and not causation.

Don’t know details, but I’ve heard that centenarians have better reverse cholesterol transport than “normal” population - if so they may be genetically less sensitive to higher lipid levels.

[scta123]

@Neo

Apo B is *causal in increasing CVD

Does it have a strong prediction value as well?

[Neo]

@scta123

strong prediction value as well?

As mentioned before - I’m aiming at seeing if I can give it a shot to live healthily to 100-120 and perhaps beyond.

In that context my best estimate is that lower Apo B will decrease my risks of CVD in the later decades.

(If/as I experience any negatives or as new data and mechanistic understanding comes out I might/likely will calibrate along the way).

Not sure what is new here, so will engage less as long as it feels like just back in versions of past conversations here on the forum being rehashed.

[cl-user]

@scta123

Does it [APOB] have a strong prediction value as well?

Nope: The causal effect is 0.464 (Model-averaged causal effect 0.392). Better than any other coronary artery disease (CAD) predictor they looked at though.

ApoB remained the highest ranking individual model (model posterior probability 0.455) and the risk factor with the strongest marginal evidence[…]
No alternative risk factor had similar strength of evidence, suggesting that ApoB is indeed the most important risk factor and not just a representative of a group of highly correlated lipoprotein measures with similar evidence. On exclusion of ApoB, the top risk factors were triglycerides content in small HDL particles (marginal inclusion probability 0.461, FDR <0.05) and LDL cholesterol (marginal inclusion probability 0.417, FDR <0.05). Yet, the evidence for these two lipoprotein measures is much weaker compared to the evidence for ApoB in the main analysis.

From: High-throughput multivariable Mendelian randomization analysis prioritizes apolipoprotein B as key lipid risk factor for coronary artery disease

They have some interesting takeaways:

ApoB has been shown to be a superior measure to LDL-cholesterol in the prediction of CAD risk and in prediction of coronary artery calcification. From a clinical perspective, statins target LDL-cholesterol levels rather than ApoB, suggesting that greater benefit might be obtained from lipid-lowering drugs that target lipoprotein particle number. When analyzing data from UK Biobank only, there was also some evidence for triglyceride content measures as an additional risk factor.

[Neo]

Thanks for valuable share.

@cl-user

Nope: The causal effect is 0.464

That seems like a very strong relationship for something in medicine?

From what you quoted above, it seems to me to be a “yes, relatively strong”

Edit: that seems be inline with (or weaker than) what the authors feel and state themselves:

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Also, this centenarian study only looked at total cholesterol. Until we have a study looking at apoB and HDL (or maybe even HDL quality and subtypes as suggested above) we cannot conclude much. (The CETP inhibitor trial results will be very interesting and will hopefully help us improve our mechanistic understanding…)

[cl-user]

@adssx

Until we have a study looking at apoB and HDL (or maybe even HDL quality and subtypes as suggested above) we cannot conclude much

Here it is. This one is particularly interesting because it has CVD and all cause mortalities.
It is consistent with all the similar studies:

• High TC is only bad below 60 and good after 60.
• High APOB is bad below 60 and don’t care after 60.
• Very high APOB is very bad below 60 and slightly bad after 60.
• Very low TC and APOB are always bad or trending bad.
• High TG is always bad.
• Low APOA1 (HDL) is always bad.

From The association of apolipoproteins with later‐life all‐cause and cardiovascular mortality: a population‐based study stratified by age

[DeStrider]

However if we expect to have longer lifespans than regular folks, we may want to keep ApoB and TG lower for longer.

[cl-user]

it’s not what the plots show.
Very low TC is always bad for all cause mortality for all age groups.
Very low TC is trending bad for CVD mortality for all age groups though not statistically significant.
So if you have a too low TC you die sooner.

For APOB there is no significant effect for very low, low or medium levels.
Very low APOB is trending bad though not statistically significant.
High and very high APOB is bad.
So keep your APOB low of medium. Extremes are bad.

In all cases TG is bad and low HDL (APOA1) is bad.

[L_H]

@cl-user

Very low TC is always bad for all cause mortality for all age groups.

I think we can only say that very low TC is associated with por all cause mortality. It may or may not be bad.