Rapamycin and risk of cardiovascular disease

[Bicep]

When trying to find the truth, bias matters. It’s hard enough to figure out what’s going on without the blinders.

I thought for a long time that you must be working for somebody in Pharma trying to peddle more statins. Now I think you’ve just swallowed their line (and hook and sinker).

[Joseph_Lavelle]

Incentives matter. Human being cannot help it. But disregarding the best information available because there is a chance of bias influencing the overall results is not wise. And don’t forget that everybody has bias, even the people pointing out other people’s bias.

Still, people should be free to place their bets.

[scta123]

@AnUser

Yes, someone will surely get rich from generic statins costing $2.2 a month like for Rosuvastatin 5 mg…

Some will. And additionally Atorvastatin is considered one of the most successful selling drugs of all time.

[scta123]

@AnUser

Time * apoB count

This is simply a very reductive and simplistic understanding or wishful thinking.

[cl-user]

@AnUser

That is the consensus.

The full title of the article is Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, genetic, and therapeutic insights: a consensus statement from the European Atherosclerosis Society Consensus Panel

So it’s the consensus of the European Atherosclerosis Society Consensus Panel
which is not an official organism or anything like that. It’s just another forum: “EAS was founded in 1964 as a forum for researchers to share ideas about atherosclerosis research”
And guess who are the sponsors of that forum? (from their web site)

[Neo]

I invest a lot in very aggressively lowering my Apo B and Lp(a) including using the PCSK9 inhibitor repatha, even if very expensive and do diet strategies even if they take extra effort (and a lot of exercise).

But it seems like you may be approaching things here in a biased way - exactly along the lines of what you are telling others to not do…!?

With my highlights below:

@AnUser

That’s too lukewarm. Extremely low apoB will most likely going to prevent the formation of atherosclerosis. Any other hypothesis, which are unproven and are speculation, are totally unnecessary as this captures everything.

People who aren’t targeting optimal apoB levels without giving sound reasons not based on mechanistic speculation or assosciation studies, are probably doing so because they’re stuck in an ideological flywheel IMO. They’ve built their ideas too much and the momentum is taking them places where they wouldn’t go otherwise if they took a breath, relaxed, and considered the evidence once more.

Say that people kept Apo B ultra, ultra low, do you think that would enable their cardiovascular systems to become perpetual, infinite machines that would not still eventually break down for some other reason(s)?

Apo B is in my view probably a massive and huge part of the risk, but especially if we want to live ultra long (and probably in any case), we probably should be thinking about other ways - beyond achieving consistent very low Apo B - to as keep our cardiovascular systems young, healthy and rejuvenated.

@AnUser

@DeStrider

But maybe not completely…

This is typically used to justify above optimal apoB levels. It’s probably a way to cope.

Could it be that your Apo B is everything, as long as I have that under control I’m good black and white world view and in your words “Any other hypothesis, which are unproven and are speculation, are totally unnecessary as this captures everything” is your way of oversimplifying and precisely “coping”?

[Neo]

@AnUser i took the time to write the above because I hope it may help you reflect and see something about yourself and not just the flaws in us others here in the forum

You input and links and information that you bring to the forums are each often very valuable. It’s just that how it is mixed with such massive (over)confidence and black and white conclusions may make it risky for others to read and probably also to yourself.

[AnUser]

@Neo

Say that people kept Apo B ultra, ultra low, do you think that would enable their cardiovascular systems to become perpetual, infinite machines that would not still eventually break down for some other reason(s)?

I said atherosclerosis, that will not form according to Thomas Dayspring at ultra low apoB, Lp(a) aside. I think Lp(a) is important as well, but I don’t mention it, as it’s like telling a smoker it’s important to consider using an air purifier.

@Neo

Apo B is in my view probably a massive and huge part of the risk, but especially if we want to live ultra long (and probably in any case), we probably should be thinking about other ways - beyond achieving consistent very low Apo B - to as keep our cardiovascular systems young, healthy and rejuvenated.

I don’t mind, as I said, if someone already has atherosclerosis they should take care of inflammation as well.

@Neo

Could it be that your Apo B is everything, as long as I have that under control I’m good black and white world view and in your words “Any other hypothesis, which are unproven and are speculation, are totally unnecessary as this captures everything” is your way of oversimplifying and precisely “coping”?

No not really. I would be happy to talk about other hypothesis, but it’s pointless when people are for example coping by figuring out ‘other things’, while their apoB is above optimal, which unlike the ‘other things’ have good evidence behind them.

Once the discussion levels up, more interesting avenues is available. Once the nearly-useless filters of ‘industry funding’, ‘big pharma bad’, etc, are gone, the discussion can move from gossip to something very good IMO. Big pharma is the reason why they have the medicines they do. Rapamycin would never come to market. Everolimus would never be studied by Novartis for its effect on immunosenescence, giving more confidence for many people about rapamycin effect in humans. I don’t care about ‘big pharma’ ‘small pharma’, or whatever else, only of the evidence and clinical trials, etc.

@Neo

It’s just that how it is mixed with such massive (over)confidence and black and white conclusions may make it risky for others to read and probably also to yourself.

It’s based on very good evidence, if apoB reduction was seen as important, it would capture most of the value as I said earlier for those who don’t have atherosclerosis already, based on the MR studies where longer term treatment compounds gains up to 80% reduction or more. In the PCSK9 loss-of-function studies the only person who got ASCVD was an overweight smoker with a very high Lp(a).

[AnUser]

@Neo

Say that people kept Apo B ultra, ultra low, do you think that would enable their cardiovascular systems to become perpetual, infinite machines that would not still eventually break down for some other reason(s)?

Without keeping apoB ultra low, it’s not going to happen for sure. It’s not only very significant but necessary of any strategy to prevent ASCVD or the effects of it. Based on randomized controlled trials and genetic studies of course.

[Paiva]

Whats the number suggested for “ultra low for APOb” ?

[AnUser]

20-30 mg/dl “If you want to live to 100 -Peter Attia”. 30-40 mg/dl, Thomas Dayspring.

Physiologic levels we are born with up to around ~5 years old. High brain development at that time.

[Paiva]

Thanks for sharing. Too hard to reach 20-30 mg/dc. Mine is now 60mg/dc. Mybe i need to change my combo ( ezetimibe-pitavastatina-bergamot-bempedoic acid. I will try pcsk9 inhibitor to see what happens…

[cl-user]

As usual it’s not that simplistic and extreme reduction of LDL is a sure way to die earlier of other causes (all causes mortality).
BTW note that the confidence intervals for very high LDL levels are very wide, showing that LDL alone an only a weak predictor.
As usual if you care about your lipids get a Lp(a) test and a NMR lipid panel and don’t focus only on the estimated LDL of the standard panel.

[DeStrider]

@cl-user Very informative charts! Where did you find them?

[scta123]

@AnUser

20-30 mg/dl “If you want to live to 100 -Peter Attia”. 30-40 mg/dl, Thomas Dayspring.

Can I say this is “hallucination”?

[AnUser]

@cl-user

As usual it’s not that simplistic and extreme reduction of LDL is a sure way to die earlier of other causes (all causes mortality).

Correlation isn’t causation, typically this is because there is another disease lowering the LDL and at the same time increasing all cause mortality. It might be parasitic infection, cancer, fraility, etc.

[cl-user]

Very low LDL being bad for the all cause mortality is a very common finding. For instance it was one of the findings of the centenarians study above in that thread.
I will dig out the study from which I took that plot but in the mean time here is another one.
Association between low density lipoprotein cholesterol and all-cause mortality

[AnUser]

Very low LDL being bad for the all cause mortality is a very common finding.

It’s not bad for all cause mortality since it’s merely a correlational study, if you want to assess causality or find them you have to use a randomized controlled trial or a mendelian randomization study.
Generally there is a reduction of cardiovascular events with lowering to very low levels in clinical trials.

[scta123]

LDL-C is not correlated very strongly with ASCVD. Other risk factors have much higher correlation which makes you think that lDL-C on its own is rather benign and probably becomes detrimental only when paired/grouped woth other risk factors. At least Dutch guidelines @Arhu shared yesterday makes you think that that there is some merit in this thought. Would Thomas Dayspring or PA state the same if it weren’t for entertainment purposes on twitter or podcasts?

[AnUser]

Why do you think correlation is very important? I believe when there is randomized controlled trials, genetic studies, these are able to assess causality, and thus whatever they say it’s more important to take into account.