#1276

Historically - for those who are interested - here’s the original controversy with JUPITER (a lot of back and forth since, of course):

https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/416101

Quote:

" Conclusion The results of the trial do not support the use of statin treatment for primary prevention of cardiovascular diseases and raise troubling questions concerning the role of commercial sponsors."

#1277

I don’t know why you would pick that quote. Just because “why not, I’m feeling like doing it” ?

Just to be very clear about what CronosTempi is quoting and thereby given a falsified impression about the current consensus: it’s outdated and no lipidologist would agree with that statement

Jupiter had an extended open label phase of 4 years under the same clinical controlled conditions - the final results of JUPITER being published AFTER the article CronosTempi posted was written. There is no debate here. The remarkable thing is indeed, that people with normal (not high) LDL benefited in ACM from cutting their LDL by about half.

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#1278

But the PCSK9 inhibitor trial I linked on the very same post did go below 50 mg/dl. Maybe you are misreading what I was writing (I was not limiting my argument do statins, but arguing about low LDL in general) or you are actually not reading what I’m posting.

The final results for JUPITER (4 years in controlled open label) were published AFTER your linked article was published. It would be prudent if you are quoting articles written from 2013 onward.

And just to be clear: the argument for low LDL is not resting on rosuvastatin/JUPITER alone. Even pravastatin (a rather weak statin) showed lower ACM in it’s major trial designed to test for that.

You said, quote: “the RCTs often don’t show lower all cause mortality the lower the LDL (down to 50mg/dl and below). They show fewer cardiovascular deaths but not lower ACMortality”

That’s just plain wrong.

Also I was under the impression, that you are making an argument against Low LDL, thereby referencing the observational trials reporting a U-shaped relationsip. If that is not the case I apologize for the misunderstanding. So… what’s you hypothesis?

I was making a general argument for low LDL. The evidence for that is overwhelming. So just that I understand you correctly: you are in favor of low LDL - just not about aiming for 50 or below 50? If you want it specifically for below 50mg/dl - look at the PCSK9i trials. ODYSEE lowered ACM in addition to high dose statin, by targeting and achieving sub 50 mg/dl.

I see: now you are narrowing down my and your statement specifically to the below 50 mg/dl part. So you agree that low LDL in general is prudent? As for below 50mg/dl - these are the trials for PCSK9i.

I would agree that there is no strong evidence, that the general population should aim for below 50 mg/dl. Depending on the trial, ASCVD plaque regression was seen by aiming at 70mg/dl-80mg/dl - though lower levels lead to better outcomes. So if you can keep at, let’s say, 60 mg/dl for decades from early age on, that should be sufficient.

Tom Dayspring would argue, that newborns and small kids, and some hunter-gatherer tribes naturally have LDL in the range 20-40 mg/dl. And kids have a high demand for cholesterol to begin with (cell membranes). If there would a problem at very low level - why are there still kids?

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#1279

Wow, Guest, put the guns down, I don’t have an “agenda” :slight_smile: Like I said, I posted the study to give a historical context for those who are interested in how the controversy regarding JUPITER evolved. It is quite helpful to understand that context, because we keep hearing the same or similar arguments recycled repeatedly, so if anyone is interested in the back story it’s right here in an encapsulated form. I picked that quote for the simplest reason of any - it’s a “conclusion”, which puts forth the case, and if anyone is interested they can read it… what other part should I have posted? Lays out the claim, go read the argument. This doesn’t mean I’m endorsing this or somehow “giving a falsified impression”. It’s a strictly historical context for those interested in the controversy… which I stated up front. Hope that’s clear!

FWIW, I’m on atorvastatin 10mg/day and am on my own initiative switching to a more powerful 4mg/day pitavastatin, so I’m hardly anti-statin. I think they are great drugs (unless you are genetically unlucky and can’t tolerate them), as much for CVD as for pleiotropic benefits. There are side effects, as with almost all drugs, but for most people the trade offs are worth it.

At the same time, I think it’s worth being aware of all counterarguments and the historical context of the controversies otherwise you may be puzzled as to how some arguments emerged. Let’s always stay intellectually engaged, and it’s good to hear out anyone who has a coherent argument for or against. Peace!

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#1280

If you read those 1200 posts you will discover, that there is quite some LDL-skeptism in general and statin-skeptism in particular. Despite the high quality evidence that is established science.

There is no need to pick a 14 year old quote that makes it seem, as if rosuvastatin is a failed drug - given that it does not represent the scientific consensus of 2024 at all.

There are tons of influencers out there whose claim to fame is to be contrarian on this topic by cherry picking papers and not discussing different standards of scientific evidence. There is no need to feed this fire and confuse people (most of which are not familiar with the literature).

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#1281
#1282

That’s actually plain right. It should be uncontroversial. The overwhelming majority of RCTs either don’t go to <51 mg/dl or don’t show all cause mortality benefits from that level.
Jupiter doesn’t go that low in the intervention group and so can’t tell us anything about 50mg/dl and below.
The other trial you quote, ODYSEE, the treatment group is at mean 66mg/dl at 48 months of treatment. And it doesn’t look at all cause mortality.

If you can think any RCTs that show an All Cause Mortality benefit from below 51mg/dl I’d be really interested. But I can’t think of any at all for primary prevention.

The mean LDL in the treatment arm is above 50 for the majority of the treatment duration. So no, it doesn’t tell us anything about sub 50 levels. And its not looking at All Cause Mortality

The hunter gatherer data shows LDL levels above 50 in adults, not below.
Small children do naturally have very low LDL but I struggle to understand how that is good support for adults targeting those levels. There could be myriad developmental reasons why children don’t need as much LDL.

The RCTs don’t support lowering below the 50 to 70 range. And so, as i stated above, my hypothesis is: LDL has a function, and therefore any natural mutations which lead to extremely low LDL in adults may have compensatory adaptations. Therefore we can’t rely on Mendelian Randomization studies to suggest targeting below 50 mg/dl.
In short: “the lower the better” isn’t supported by the evidence. But targeting 50 to 70 is.

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#1283

Here’s the Mayo Clinic’s opinion:

Summary: We just don’t know if low LDL (below 40) is bad. However, there may be a link to hemorrhagic stroke.

I think it’s best to stay between 40-70 for LDL and ApoB. The Mayo Clinic agrees.

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#1284

Let’s be precise about the semantics - down to 50 means areas above 50 as well, but lower than the conventional approaches in the guidelines (that is: below 100, or for the most recent guidelines below 70). If that is our point of disagreement - fine, let’s be precise about that.

For ODYSEE - the on-treatment group started at 38 mg/dl after initiation and had a final measure of 53 mg/dl as their last value at 48 months - being below 50 for vast majority of the time. You are referencing the intention-to-treat population - which is not the same as the population actually being treated for 48 months (or not treated to target). The sub-analysis actually showed, that those on-treatment with an initial level of down to 30 mg/dl had the lowest ACM.

So even for “below 50 mg/dl” there is RCT data!

BUT: I would agree that there is no convincing reason to go to the trouble to target below 50 mg/dl IF YOU START EARLY IN LIFE. However: if you’re 60 and just starting to get an LDL of 130 mg/dl under control, this benefit-to-risk ratio is in favor of below 50.

As for children: relative to their body-weight (and hence LDL-pool available at a given concentration) children have a higher demand for cholesterol than adults - due to their growing body. It’s a major part of cell membranes and the brain tissue. If there would be a problem regarding their LDL, we would know about it.

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#1285

i think that’s where you’ve misunderstood, getting your LDL “down to 50 and below” means equal to or less than 50.
I’m not sure how it can mean “above 50”?

ODYSEE didn’t find statistical significance for “all cause death”. That’s spelled out on page 36 of the Supplementary Appendix

I’d be really interested in studies showing this. But I’m still not sure why we should use child ldl levels as a target for adults. The logic seems shaky.

I’m not sure what RCTs support that for all cause mortality. I genuinely am interested so please do share them. I’m just not convinced any exist.

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#1286

Here’s another often overlooked health benefit of lowering your LDL\ApoB to the 40-70 range.

You don’t stress much about having a heart attack or stroke. The number 1 killer is relegated to the dustbin in your mind (and rightfully so).

Reduced stress and anxiety is great for health and lifespan and, in a virtuous loop, reduces your chance of heart attack and stroke. :wink:

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#1287

I too have listened to every Dayspring interview and researched the topic thoroughly. I was very fortunate (I believe) to have my GP 15 years ago (at 38) recognize I was overweight, unhealthy, and not likely (at that time) to be able to meaningfully address my high cholesterol so she put me on Lipitor. Love it or hate it, I’m now fit, healthy, intervening in many ways for longevity and have a 0 calcium score and no measurable plaque on a CT angiogram. I’ve now added Zetia (I tested as a hyper absorber) and target <50 for ApoB. The science makes sense to me and at a minimum I think everyone should aim for that. If you truly want to reduce existing plaque, I wouldn’t wait, get on a PCSK9 and whatever else it takes to drop ApoB below 50, preferably to ~30. You won’t impact the calcium score much I suspect but you can slowly pull the cholesterol from soft plaques and reduce your overall ascvd risk. Good luck!

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#1288

Question, I have never measured the calcium score, so is it the same procedure CT scan for plaques to measure the calcium score also?

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#1289

To me this is not convincing - at all. You could argue that kids have very low testosterone levels also, and decide to keep your levels there. Or many other things.

I am NOT saying this is evidence against keeping your LDL low, I just think it is extremely low quality evidence in either direction.

The entire field of pediatrics exists because children are not just little adults.

#1290

I disagree. Many of the arguments against maintaining low levels of serum cholesterol say that it is harmful to adults. How could low levels be harmful if it doesn’t harm children? Especially since children are developing their brain and physiology while adults are simply maintaining it.

I think that since children spend a dozen years with low cholesterol levels, maintaining those same levels as an adult is not going to be harmful to an adult. Why would serum levels of cholesterol be dangerous to adults and not children?

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#1291

You know there’s the thing about eunuch longevity… :wink:

It’s a question if the side effects of low LDL could be equated in a similar manner like with low testosterone. I don’t think it has been established that low LDL have any side effects. We have trials for that. I’m not aware of any condition where you need to increase LDL levels, giving benefit, do you know? While I’m sure there are trials showing benefits of testosterone supplementation for those with low levels.

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#1292

@Thorin , @DeStrider @AnUser all your points are very interesting. I’ll also throw out there a hypothetical question- How about if perhaps maintaining the LDL at kid levels as adults it may trick our bodies to think we may need to start new processes, (i.e. start producing new T-Cells as an example), but the pushback I think is : if the answer to longevity would have been as simple as lowering and maintain LDL at a kid’s level then it would have been discovered long time ago. Most likely a very low LDL level at best helps with CVD but not much else beyond that.

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#1293

I view CVD, arteriosclerosis and events caused by those (heart attacks and strokes) as being the first longevity hurdle. Most people in the world (1 in 3) will die from this. 2 in 3 will have a heart attack or stroke. I don’t think you can even consider longevity without subduing the CVD monster through lowered LDL and ApoB (and inflammation). For those who die of CVD, they die, on average, 7.5 years earlier than expected. That’s why they say if CVD was cured, the average lifespan would increase by 2.5 years (1 in 3 * 7.5 years).

It also improves your healthspan when you have clear arteries and no strokes or heart attacks.

Finally, when people die at extreme old age in their sleep, it’s usually a cardiovascular event that kills them.

Keep a low ApoB/LDL before you even consider other interventions, or you are just wasting your time quite literally.

I take Bempedoic Acid, Ezetemibe and 5 mg Atorvastatin and have an ApoB and LDL of 48.

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#1294

Thats how I’d love to make the journey out of here LOL though at a very old age (hopefully)

Very good points. Reading your comments and comments from few others in these boards has absolutely convinced me job number one for longevity is to make sure ApoB and LDL are at lowest optimal levels. Will soon order supplies, I intend to initially start with Ezetemine and Atorvastatin(or may Pita) and see how it goes since my lipids have always been within normal range. If i need more help then might add the Bempedoic acid.

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#1295

When selecting a statin it is good to keep in mind pleiotropic benefits outside of its official indication of CVD. Also, it is good to individualize the statin (or any med), since everyone has unique vulnerablities. Atorvastatin is a very fine choice, has many proven benefits, and crucially has a ton of research and a long track record with a huge number of users. I am currently on 10mg/day atorvastatin and have tolerated it extremely well. Unfortunately, over the years, it has controlled my LDL less and less well. Last year I was back to 130’s, and this year we’ll see. If it comes back 160+ or whatever, I can probably get my PCP to bump my dose to 20mg/day if I fight really hard, beg and plead.

After a lot of research, I have decided to switch to 4mg pitavastatin, and since my PCP will refuse to prescribe it, I’m left to my own devices. I’ve ordered it from India and it has just arrived today. I intend to start taking it from November on, after detailed lipid tests. We’ll see if I tolerate it as well as atorvastatin and if it will give me better lipid numbers than my current statin. Everyone must do their own evaluation.

Pitavastatin is a newer statin and has a much shorter track record, less research and fewer users with less clinical data compared to atorvastatin, so for me it’s a bit of a gamble, though on paper I like what I see (remains to be verified by life!).

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