Rapamycin and risk of cardiovascular disease

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#1359

I tend to avoid supplements out of an abundance of caution - unless the evidence starts being particularly compelling and preferably I can easily find USP grade or at the very least NSF certified - but I don’t see much against your suggestion either.

The big ones I see particularly compelling data on would be creatine monohydrate, taurine, and fish oil (assumption is very high quality and mixed tocopherols) on top of anything that cannot be easily obtained from diet to avoid nutritional deficiencies ie Vitamin D3 2,000 IU due to lack of sunlight exposure, magnesium or zinc. Vitamin K2 MK-7 is a maybe, but that can be easily patched with natto. Beta-alanine + bicarbonate (perhaps a rough 25/75 mix of potassium and sodium bicarbonate) is also a maybe with increased carnitine levels, particularly assuming one is at least semi-athletic.

Perhaps an alternative would be adding certain types of citrus peels to meals after careful processing.

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#1360

I mean there are a lot of things where that mindset can apply.

I do think the LDL hypothesis is particularly compelling but it’s not actually close to completely proven. It could be the case that certain types of LDL are relatively low harm, benign or even beneficial. Just as some people in Italy had “low HDL” where LDL levels were essentially not of consequence. Based on these “influencers”, they would be at high risk of death. But they’re not. I don’t see it mentioned here. So is that bias too?

We clearly do not know everything. I suggest you read the newest edition of Therapeutic Lipidology cover to cover at the very least to find out where the knowledge gaps are. Many here that are relying on “influencers” is more biased IMO. They have a tendency to make it seem like there are few to no knowledge gaps.

You’ll start realizing it’s not a done deal. Nobody should invest without fully understanding the investment, rather than hearsay. If you really want to prove investment skill in health related matters, I suggest trying your hand at biotech stocks (the ones where it is only one clinical trial riding on the stock price) to see how good you actually are empirically - talk is cheap. I find almost always people (including physicians btw) investing in biotech are terribly overconfident, but I can’t rule out you’re some biotech superstar. If you size your position based on your confidence level correctly, you should in theory be a a multi millionaire very soon. That could also increase your longevity more so.

My investments are based on my confidence level and I constantly reassess to see if I’m being overconfident or not. I also have a few buds who play devil’s advocate. I go through the strongest arguments of both sides and take care to avoid influencers that have incentives to bias me in their own direction. For my health, I find cutting my confidence levels in half tends to yield better results in the long run after new studies come out challenging my previous beliefs in the opposite direction.

If you have “pattern A” and LDL-P <1000 with lifestyle factors alone, do you really need a statin if you’re “healthy”? You’re welcome to run the numbers in the 30 year model on theoretical absolute risk reduction. I find it not particularly compelling as a potential benefit if you’re already at some of the lowest levels, unless you have another risk i.e. a family history of early ASCVD event.

Also, as I’ve mentioned, an intermittent dose of low-dose statin on top of pharmacogenetics with low-dose ezetimibe probably cuts this theoretical risk if you’re right about the LDL hypothesis while minimizing the potential risks of being wrong.

Why take the full dose? There aren’t necessarily many compelling arguments here for a full dose for “healthy” people even if you’re right.

If you have read through at least lipidology textbooks, research, and attended a few lipidology conferences to talk to the speakers - you’ll see what I mean. I’m not a lipidologist, but I can tell you lipidology gets weirder and more complex, the more you look deeply into it.

A natural bias towards interventionism is strong in most people. But the only easy gamble is diet since you can’t decide to never eat. So it’s easier to justify if the evidence is merely pointing me in one direction assuming a compound is within what a subpopulation could obtain from diet and they’re “safe” and in the clear. The only epi evidence I’ve seen so far is Okinawans and certain long-living Chinese subpopulations taking dietary lovastatin at low doses. So I think intermittent very low-dose statin is not necessarily a bad idea - especially if you’re borderline for ASCVD risks. However, I still look into any potential individual genetic-related risks with any intervention which would preferably call for “clean” drugs over “dirty” drugs. It could be that statins could harm some people and be beneficial in others.

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#1361

I would argue it is safe because of the safety data of reducing lipoproteins below the 20th percentile in short term RCT studies and PCSK9 genetic studies long term. The downside risk is low because of that evidence, and the upside is reducing risk of ASCVD developing at a later date. However 20th percentile isn’t terrible. The traditional Okinawan and Chinese diets are very low in SFA as far as I know so the LDL would be low to start with. If you added dietary statins on top of that and soy products it seems likely to me you would be in a similar territory as a low dose pharma statins. So it suggest to me certain amount of people of those populations would have very low LDL or apoB levels.

#1362

Yeah but they’re not eating i.e. tofuyo every day. It’s intermittent. PCSK9 studies are different than taking statins - which increase PCSK9 somewhat.

What I’m asking is what is the estimated absolute risk reduction for ASCVD event over 30 years from say LDL-P 900 to lower amounts based on your proposed dose? You can use 30 year validated Framingham model to see yourself what the theoretical risk reduction is, assuming LDL hypothesis is correct.

Plug in the numbers.

It’s a very low actual benefit if assumptions are true. Just like when people say red meat causes colon cancer - if you avoid processed red meat and eat regular red meat - the absolute risk increase is perhaps +1% with no clear certainty (above a certain limit of red meat per day). So really it’s not significant yet people still consider the advice as some gospel. No guideline says never eat red meat because there isn’t actually proof. There is only evidence for limiting red meat.

I’m not sure trading a small potential benefit for several potential harms (depending on the statin dose and other factors) is particularly worthwhile. The larger the potential absolute benefit and lower the potential absolute harms - the more it actually makes sense. And that’s assuming you’re right about what is not proven but still by expert consensus a hypothesis, even if it is compelling.

#1363

I was thinking of a longer time horizon than 30 years. Reducing apoB from 80 mg/dl (20th percentile) to below 60 mg/dl (5th percentile) or to 30 mg/dl should have an effect equal to from higher amounts as the relationship is log linear everywhere else. Of course it might be the same difference as a return of 5.5% vs. 6%. It won’t even be a very big effect at 30 years even, but 40 or longer. It is arresting a serious cause of ASCVD. If you believe higher than 20 th percentile apoB is bad even for 30 or 40 year olds you are agreeing with Peter Attia anyway. I don’t know if the framingham model is compounding the effect.

#1364

30 years is the longest we have in terms of validated models. So it makes no sense to really use 40 or 50 years since we have no idea. For example, slightly elevated blood pressure can be benign and potentially beneficial for older adults. You don’t know that anything necessarily is always bad when your entire body’s physiology changes in 40 years.

Peter Attia is an “influencer” and he makes 6 figures per patient per year. He endorses statins yet he doesn’t take statins anymore. You’re welcome to explain to me why if statins are universally great and he’s such a great supporter why he doesn’t take them? Or maybe he has the incentive bias to push toward intervention?

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#1365

In april last year he was taking a PCSK9 inhibitor and a statin. I don’t think he’s changed since then. Unless this is a misleading transcript.

Peter takes a PCSK9 inhibitor and a statin and he can basically eradicate it

To be honest I don’t solely think in time horizons, but this is a completely different way of approaching the problem. I’m more interested in what’s causing ASCVD and I think apoB and non-HDL-c in a too large of amount is it, and over time. While we’re talking about Peter, it is also the difference between medicine 2.0 and medicine 3.0. Medicine 2.0 is 10 year risk calculators.

#1366

Perhaps I’m mistaken then on what he takes - I’m not quite sure since I don’t follow him much. Here’s my source which is second-hand:

“5. Atorvastatin & ezetimibe
Peter Attia claims he no longer takes these drugs.”

#1367

That’s from an older video. He doesn’t use atorvastatin in his practice because of the higher chance it can pass the BBB than other statins.

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#1368

Or maybe he’s selling you “medicine 3.0” and has an incentive bias to push an intervention. Otherwise, how would you justify charging so much per patient? Doing something different will lead to more money. I have been using 30 year risk but even the validation is in an limited setting

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#1369

I’m aware of it passing the BBB btw - note I mentioned rosuvastatin previously as a general pick. So if he’s so good - why did he pick atorvastatin in the first place?

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#1370

I think we’re venturing off-topic a bit. You might be right. Peter’s book on longevity is coming out on the 28th of March. His arguments are probably going to be written in more detail there. With sources for lower apoB, hopefully.

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#1371

I’ve identified 15 population studies associating low LDL with increased all cause mortality.
There’s at least 11 randomized studies showing no benefits of statins without underlying CVD.
There’s evidence that very low LDL may inhibit immune function and lead to infections.
You confuse relative with absolute risk. The absolute risk reduction in total mortality in primary prevention with statins approaches zero.
Your fallback tends to be, “ Peter Attia says so”. He’s a smart guy, but all of us are wrong. Frequently. No one knows the consequences of extreme lowering of LDL or ApoB over many decades. We just don’t know.
We do know from Mendelian studies that statins can cause cognitive dysfunction. All of us have seen muscle and joint pains. There’s even a diabetes risk.
We thought for multiple decades that low serotonin was the cause of depression and raising it was the principal mechanism of SSRI’s. This was gospel. We now know that we wrong all along , and that includes doctors who are much more prestigious than Attia.
As Tong says, lipidology is extremely complex, and so is CAD, and cardiac events.
It could be that if we reduced ApoB to near zero starting at a young age that CAD would cease to exist and it would buy us approximately another 3 years of life ( per Richard Miller).
But we certainly don’t know that.

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#1372

I suggest you take a look at the base failure rate.

To the layman, a highly plausible story “makes obvious sense” once they are explained over a blog/podcast.
This is made to feel so cutting-edge that clearly the medical establishment has not caught up. Peter Attia has a promising scientific story with plenty of “sciency” references (as I actually read through references if someone has a compelling enough extraordinary claim - I have seen he does make mistakes where he cited the opposite of what he was claiming - but perhaps it’s his editing team and human error). He’s not the only one.

There are plenty who actually conduct the trials. These are way deeper experts in their own field at the most cutting-edge “Medicine 4.0” as opposed to Peter Attia “Medicine 3.0” he’s selling.

97% of cancer drugs fail. These people are plenty smart folks with very compelling stories.

So if you have an amazing ability to pick apart what will succeed in clinical trials based on whatever the story is - you probably should make millions off that ability at least through picking biotech stocks. You don’t even have to be right all the time. Being right on confidence levels and sizing your position enough is sufficient. If Attia is so good at it - why does he need to charge so much money per patient and sell books etc? There aren’t any particular compelling reasons I can identify where the price vs value is justified.

It’s like charging forex/stocks signals or selling a promising book on forex/stocks to the average retail investor. It’s an excellent business model but usually not a great idea for the retail investor. Unfortunately, the retail investor rarely reads through say SEC filings, picking apart textbooks and references, and trade publications to actually fully understand their investments. To some extent, it is analogous.

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#1373

I think Sniderman puts this entire debate in context:

“We can only understand as individuals, there is no such thing as a group understanding”

I don’t think we are going to solve this debate. :rofl:

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#1374

I wonder if Attia has actually read say the ACC 2022 guidelines (which isn’t a 1-pager) and all. It repeatedly mentions apoB contrary to what he claims. Or if he actually reads through the CME material I go through, not just the research papers or conferences. Not all doctors actually just reads the 1 pager, nor are the guidelines really that short.

He’s probably talking about the “typical physician” who has limited bandwidth to read what is a lower priority as opposed to what is actually a higher priority reading that isn’t a “one-pager” when it comes to the “typical patient” - which can be fair. There are sizable amounts of cardiologists who do not put preventative at the top because they have other reading priorities for the immediate patients who have CHF and are about to die. There are preventative cardiology/lipidologist physicians out there that do make prevention a higher priority. Not surprisingly, Attia does not mention this.

Neither do I expect all doctors to know every single one of the rare diseases out there and nobody really should. Even if there is a 5% chance (cumulative incidence of all known rare diseases) you will encounter a patient with one. What really matters is being able to develop skills to figure out where to look, what to ask, and how to process the information you are getting. And of course communication skills so the patient understands what’s going on and all.

I have no issue with operating under uncertainty when we are trading potential benefits vs risk. It sort of depends on the physician on an individual level. I got my first COVID shot in a clinical trial in mid-2020 after interim data and being assured that original antigenic sin is unlikely, despite mRNA vaccines being relatively newer technology in a human clinical trial. Some may be more conservative and that can be a fair view.

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#1375

This is an interesting question. Looking at it simplistically I am awake at 7.34am in the morning in the UK without a hangover. I took dihydromyrecetin (1g), pantethine (2g) and melatonin (100mg) between when I started drinking and now (the melatonin during the night). I have in the past been a very heavy drinker, but my health is now better.

I accept that alcohol consumption has an impact on health that can be measured immediately using a fitbit and I see some effects in my weekly blood tests.

However, I think approaching it sensibly and not drinking every day enables at least the majority of damage to be repaired if not all of it. The biggest problem I have with drinking is I tend to eat more and I am currently aiming to reduce my weight.

#1377

Everyone makes their own decisions with the information that they have. I do not recommend that people drink alcohol for health reasons. I don’t mind if you take the view that people should not drink alcohol.

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#1379

That is potent (ic50) in the
Units of nanomolar range. The issue is how strongly HDAC is inhibited. My objective is to slow up HDAC rather than stop it.

#1380

Chronic inflammation as a risk factor for cardiovascular disease regardless of cholesterol levels.
It underlies most diseases of aging including cancer and AD.
Do what it takes to tame inflammation. Fortunately, rapamycin plays a role.

https://www.nature.com/articles/d41586-021-01453-6

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