Rapamycin and risk of cardiovascular disease

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#1585

Your mindset appears to be that lower LDL is always better in all contexts. But the epi study shows that may not always be true. Certainly, as you say, correlational work of that sort has its limits.

(Although the “sick patient” bias should not be a major confounder - that happens more if you are measuring LDL when people arrive at the hospital; these measurements are years before death in most cases. But nevertheless, we can’t say for sure - agreed.)

But can’t say for sure is true in both directions - we can’t say that lower LDL is helpful in all contexts. We lack data.

You say that you aren’t saying that “everyone should be on a statin.” But when I read everything you write - with the exception of that sentence - it seems like your logic dictates that they should be. Probably this is just due to my misunderstanding. But I guess it would clarify your position if you mentioned a few examples where you don’t believe a person should be on a statin.

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#1586

Those levels look great. Sadly ApoB doesn’t get lumped in with a standard cholesterol test you have to order it separately

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#1587

Thanks. That’s what I wanted to know. I was hoping I could coax the data on ApoB out of the standard cholesterol data, but I guess not. :frowning:

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#1588

Simple – I’m not saying everyone should be on a statin because there are multiple ways of lowering LDL/apoB other than statins. Statins have potential side effects, so as with any intervention there should be a cost/risk/benefit analysis.

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#1589

It’s easy to order ApoB if you just ask next time you get a lipid panel order from your healthcare provider. Probably even better would be direct measure of LDL particles via NMR Lipoprofile, although it’s more expensive too.

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#1590

FWIW

NMR LipoProfile® With Lipids and Insulin Resistance Markers
(With Graph)

For LabCorp Test:123638
In the US $125.00 is amount billed to insurance in the NYC area.(as of 03/04/2023, spoke to LabCorp CS to get estimate test cost)

Compare the cost, verify the test code as LabCorp has same test name with different options/parameters/measurements.

Review PDF below for testing parameters

NMR LipoProfile Assay Options Table.pdf (40.5 KB)

One test cost $63.00{was on 03/05/2023 on web site] selfpay through Marek, I did not verify which one.

Shop around for the cost, as there are many places offering direct self testing services.

Review

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#1591

I want to argue about things were there isn’t great expertise. But it’s true this is a “do your own research” website. I hope no one does major changes without consulting with their doctor.

We’ve already debated that LDL “paradox”, which btw is the same for being overweight, where it is associated with lower all cause mortality.

Higher lipids and being overweight (rather than normal weight) is associated with lower all cause mortality.

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#1592

In the short term, a few years, we do have the data. There is a meta analysis of randomized controlled trials of statins in this thread that do show a decrease in all cause mortality depending on decrease of LDL. Even in people without preexisting heart disease.

Who knows the long term effects on ACM? Or long term effects of anything on ACM? Unless your association study is controlling for parasitic infections, liver disease, absorption issues, you are far from knowing sure. And even then there might be something you’re not controlling for.

In your study, those who took statins (lipid lowering medications) the association with all cause mortality was weaker. Which makes the authors conclude that it is not a causal relationship and I quote

“Hence it would be incorrect to use our data as an argument against the use of lipid lowering treatment in the prevention of atherosclerotic cardiovascular disease and mortality.”

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#1594

Regarding the highlighted part: I’ve not argued against this. I’ve said we lack data - which we do.

Statins are prescribed to prevent CVD under certain conditions that vary somewhat depending on the country but generally amount to (1) secondary prevention - for which their benefit is clearly established, and (2) primary prevention - in the event risk calculators show a risk greater than X over Y years.

Example language for (2) from 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease.

“Statin therapy is first-line treatment for primary prevention of ASCVD in patients with elevated low-density lipoprotein cholesterol levels (≥190 mg/dL), those with diabetes mellitus, who are 40 to 75 years of age, and those determined to be at sufficient ASCVD risk after a clinician–patient risk discussion.”

There are other criteria commonly used to prescribe. For instance, you can use a calculator, and typically if the 10 year risk is > 7.5%, a statin is recommended.
https://tools.acc.org/ASCVD-Risk-Estimator-Plus/#!/calculate/estimate/
You might note that statin therapy is not indicated in all cases, and may not be indicated in a person with an LDL of 140 who is otherwise in good health (non-smoker, not diabetic, no hypertension, etc.).

Suggesting lower LDL may not always be indicated is NOT an argument against the use of lipid lowering treatments in the prevention of ASCVD & mortality *** in populations for which they are currently indicated. ****

It is an argument that they may not be indicated for the entire population. This argument is consistent with the standard of care established by our leading cardiology groups (the ACC & etc.). I see you like to suggest others shouldn’t do their own research but instead should rely on the experts. Actually this is the consensus position of the experts.

Regarding the all-cause data: you can’t do a meta analysis of a population that wasn’t studied in the underlying RCTs. If you have an RCT that shows they gave statins to a large population irrespective of their starting CVD risk and this showed an ACM benefit, please do share it. I don’t think such a study has been done?

If that study hasn’t been done, the studies you are quoting are merely demonstrating that statins benefit the people for whom they are typically prescribed - those at elevated risk of CVD. It doesn’t show more than that. I certainly agree with that, which is why I take Rosuvastatin myself.

If that study hasn’t been done, you are making an error in generalizing from a patient population for which statins are indicated to a patient population for which, till now, they have not been prescribed. It could turn out that that extrapolation is accurate; it may turn out otherwise. We won’t know for sure until we do the study.

And you are very much doing your own research if you are listening to Peter Attia on this subject when he is deviating from the established medical consensus. I personally have no arguments against doing one’s own research. But you apparently do. Although you are on this site. And trying to get your LDL down to ~30? Weird.

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#1595

It’s a heuristic not a natural law. It would never make sense to never do your own research. You’re making large claims like statins may harm people overall more than they help who don’t have very high risk for CVD at around 140 mg/dl LDL. Using association studies to do so, in which the authors themselves say to not to do that because those on cholesterol lowering medication had a weaker association, thus not probably finding causality.

You can find the discussion about the meta analysis of rcts here:

#1596

I agree - and I even believe this to a large extent with myself and my own research. I love science and biology, but I’m not a scientist or a biologist, and while I’ve read almost every paper on rapamycin out there, I also know that I’m missing a lot in terms of background and perspective when I’m reading these papers, so I’m never too confident in my own opinions in this area… I think we all have to have a lot of humility when it comes medical and science opinions… be curious, not opinionated. And, when push comes to shove, I have to default to the experts as they have spent their lives studying the topic. Of course… there is still the problem of what experts to listen to, and thats a whole other area of problematic discourse.

I was talking to a friend who is a cardiologist out of Stanford Medical School and Cleveland clinic… his opinion was its impossible for lay people to judge who is a good doctor or not, who is a good cardiologist or not… people default to simplistic heuristics like “did I get good service, was the doctor nice and respectful”… which have zero predictive ability in terms of medical outcomes. Its all extremely complex, and frequently we oversimplify for the sake of having to make a decision…

These discussions are good, and educational, and they move us forward in terms of understanding, but I suspect we shouldn’t get too confident that any of us is “right” at any given time. with luck, maybe we are close to being right for our own bodies for some of the time… thats probably the best we can hope for.

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#1597

You misunderstood the meaning of what the study authors said. In any event, how the authors chose to interpret or position the data they gathered is of less interest than the actual data they gathered.

Regarding the RCTs, I repeat myself: If you have an RCT that shows they gave statins to a large population irrespective of their starting CVD risk and this showed an ACM benefit, please do share it.

If that study hasn’t been done, you are making an error in generalizing with such confidence from a patient population for which statins are indicated to a patient population for which, till now, they have not been prescribed. It could turn out that that extrapolation is accurate; it may turn out otherwise.

It is fine to have an opinion and believe the overall body of evidence suggests a particular answer is likely. What I am reading from your tone is that you are convinced the answer is unquestionably clear.

I am trying to remain more humble in my opinions than that. I am aware that expert opinion is divided on this subject at this time; medical practice is not to uniformly reduce LDL via statins regardless of starting LDL level & risk factors, and there is definitely a possibility that doing so will harm more than it benefits.

If & when it becomes clear that is not the case, perhaps we will add statins to the water supply, or do something along the lines of adding the Vitamin D directly to the milk. We are not there yet in my opinion. If I am reading you correctly, you are convinced that we are.

So be it. Good luck.

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#1598

Your cardiologist friend is absolutely right. Doctors don’t get sued because they’re less competent than someone else, it’s because they’re rude or dismissive. The layperson really has no means to assess the competency of a doctor. They don’t know enough to do so.

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#1599

That sounds like a practically impossible trial, if you are not basing study participants on CVD risk as you won’t get any CVD events to establish statistical significance.

I am agnostic about statins, it is the LDL lowering that is causing the effect not the statins themselves (although statins do have other beneficial effects). As shown in the meta analysis showing a larger decrease in ACM with a larger decrease in LDL. And genetic, mendelian randomization studies and ASCVD risk.

#1600

You are missing the point, it seems.

If we have a study showing that lowering blood sugar in diabetics leads to increases in all-cause mortality, that would be … unsurprising. Furthermore, “a larger decrease in ACM with a larger decrease in” blood sugar would be anticipated (although it might not work out that way, for various reasons).

One of the hallmarks of that disease is that the blood sugars are elevated above normal levels.

From this we should not conclude that lowering the average blood sugar in a population of lean and seemingly healthy people with a fasting blood sugar in the 90’s is beneficial, let alone conclude that “a larger decrease in ACM with a larger decrease in” blood sugar is likely for this population.

Similarly, a study showing that lowering LDL in people at high risk for CVD leads to increases in all-cause mortality would be … unsurprising. One of the risk factors for the disease is LDL. Furthermore, “a larger decrease in ACM with a larger decrease in” LDL would be anticipated.

However, from this we should not conclude that lowering the LDL in people at low risk for CVD would necessarily be beneficial. It doesn’t mean it won’t be; it just means we are extrapolating beyond the data we have.

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#1601

It’s not extrapolating from the randomized controlled trials without any data, the genetic and mendelian randomization studies fill in the gaps (duration). Where lifelong decreases in LDL have massive, compounding decreases in ASCVD causal risk.

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#1602

Hello! Reductions in LDL are associated with reductions in CVD risk. This is agreed.

The question is are reductions in LDL below some level associated with reductions in ACM risk?

#1603

What else do you think is causing the decrease in ACM? There was a statistically significant decrease in cardiovascular mortality in the same study, depending on degree of LDL reduction.

#1604

To your point. I discussed this in the doctor’s thread.

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#1605

I scanned this. Thank you.

CONCLUSIONS

The present meta-analysis confirms that LDL-C–lowering therapy statistically reduces mortality. The meta-regressions and meta-analyses by subgroups indicate that LDL-C lowering may not be beneficial for all-cause and CV mortality end points in trials with more than 50% LDL-C reduction and in trials with low baseline LDL-C levels. By contrast, the reduction in MI risk was consistent across all analyses. However, annual NNTs were overall relatively high, and trials enrolling patients with high baseline LDL-C levels reported the most benefit from LDL-C–lowering therapy especially for MI. Achieving lower LDL-C goals did not further increase risk reduction consistently. Uncovering subgroups of patients who derive the most benefits from LDL-C levels reduction remains clinically relevant.

I’ll highlight a couple sentences here, which are consistent with my earlier comments:

  • The meta-regressions and meta-analyses by subgroups indicate that LDL-C lowering may not be beneficial for all-cause and CV mortality end points […] in trials with low baseline LDL-C levels.

As per my lowering blood sugar hypothetical, if your starting point is already low, it may not help. If your starting point is high, it likely will. Not surprising, right?

  • By contrast, the reduction in MI risk was consistent across all analyses.

As noted before. Lowering LDL always reduces CVD risk. It doesn’t always reduce ACM risk (or at least, we don’t know if it does).

  • However, annual NNTs were overall relatively high, and trials enrolling patients with high baseline LDL-C levels reported the most benefit from LDL-C–lowering therapy especially for MI.

Not surprising. Those at highest risk of disease benefit the most from medicine that reduces the risk of disease .

  • Achieving lower LDL-C goals did not further increase risk reduction consistently.

Exactly.

Final point: the people in the RCTs that this meta analysis uses as input were at high risk of CVD. That is a particular population of patients. Statins have shown benefits for that group. This doesn’t constitute convincing evidence that lowering LDL will benefit those who are not at high risk of CVD.

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