#7

From what I remember, hyperabsorbers are about 20% of the untreated population. It’s a small group, so if the positive effect were limited to them, then we wouldn’t see the great results above.

However, note that statins increase absorption:

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So, are all statin users hyperabsorbers?

I’ve seen papers about statins being useless in hyperabsorbers, but I don’t know if papers looked at the opposite.

Ezetimibe has nothing to do with omega 3 so I don’t understand your question:

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But here we do have the signal. So what’s your point?

It could be specific to statins and ezetimibe here given the synergies between statins (that block synthesis but unfortunately increase absorption) and ezetimibe (that do the opposite).

However, the difference in LDL-C reduction is minor (and not even clinically significant) between statin monotherapy and the combo (and one paper notes “Although LDL-C reduction >50% was associated with reduced risk of all-cause mortality (p=0.027), this could not fully explain the overall cardiovascular benefit of HI statin-ezetimibe”). So it might be more than just this synergistic effect on cholesterol levels, and, as you say, another example of “general principle of lower dose combination therapies being better than (higher dose) mono therapies”. For instance, how much of the positive effect is just driven by the higher risk of diabetes at high-dose statin?

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#8

I’m not sure about that. Think Peter Attia (perhaps on one of his episodes with Dayspring actually, but not sure) suggested that people re-test their absorber/producer status once on a medical protocol to see if it could be either improved in by tweaking how much they are hitting absorption vs production

Also with regards to this balancing both - not sure if one perhaps can swap in other meds that decrease production for example BA vs a statins - into the frame work and pair with Ezetimibe.

Not sure if you are saying that testing for cholesterol balance (degree of absorber vs producer) for optimal N=1 and “precision medicine” may not be helpful?

#9

Would love to see more evidence on that black and white “nothing to do with” statement from you (and not just another black and white statement in a tweet by something who often is too black and white on twitter, perhaps to drive his followers up or something).

The last I saw the jury is still out, with some support that at least for ALA it does impact it negatively. So N=1 / precision medicine where there is a simple test to check Omega 3 index (which probably is with checking for any health optimizer even if not on Ezetimibe) still seems like something a longevity optimizer on Ezetimibe may want to consider.

See for example:

A randomized trial of the effects of ezetimibe on the absorption of omega-3 fatty acids in cardiac disease patients: A pilot study

Conclusion: Ezetimibe therapy inhibited the absorption of omega-3 fatty acids. Patients receiving ezetimibe therapy may not receive the expected cardiovascular benefits from dietary supplementation with omega-3 fatty acids.

I have read all or most refereed articles reporting clinical research or metanalysis, including the one you posted. The scant research is suggestive of the belief that ezetimibe will not substantially block and adsorption of at least some forms of omega-3 under some conditions but it does not exhaust even the omega-3 questions or close all doubts as to its validity. Beyond that, it says little and we know little. Specifically, we know almost nothing about a large number of related dietary substances that may be blocked (partially or wholly) by this drug. To name a few: pro-resolving mediators, omega-7, astaxanthin, lutein.

Conclusion: Ezetimibe therapy inhibits the absorption of omega-‐3 fatty acids. Patients receiving ezetimibe therapy will not receive the expected cardiovascular benefits from dietary supplementation with omega-‐3 fatty acids.

The Effects of Ezetimibe on Omega-‐3 Fatty Acid Absorption in the Prevention

No interactions were found between ezetimibe and Fish Oil. However, this does not necessarily mean no interactions exist.

https://www.drugs.com › ezetimibe-…Ezetimibe and Fish Oil Interactions - Drugs.com

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#10

Thought some of the papers did not show all cause mortality and just wanted to help ensure people new to reading study results did not see that as signal of no all cause mortality reduction in those cases

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#11

I just started min dose statin + ezetimibe and i took a complete omega 3 test right before including ala. I will take it again in a few months along with the 99$ test to make sure i dont have too low desmeratol for brain health.

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#12

I don’t understand your point. Yes, it’s great to test the Omega 3 Index and EPA and DHA fractions (by the way: what do you think about this: Omega 3 makes me depressed: why? - #23 by adssx ?). But how does this relates to ezetimibe? (even if would decrease significantly DPA + EHA absorption, you’d just have to increase supplementation, no? Or do you mean someone with a low omega-3 index shouldn’t take ezetimibe?)

And I can’t find papers showing that ezetimibe impacts EPA or DHA but I found two articles showing the opposite (no effect): Interaction among Omega 3, Ezetimibe and HDL - #23 by adssx

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#13

The effect of statins on absorption seems quite complex: Association between cholesterol synthesis/absorption markers and effects of cholesterol lowering by atorvastatin among patients with high risk of coronary heart disease 2013

The effect of cholesterol lowering by atorvastatin was significantly associated with baseline lathosterol levels but modified bidirectionally by baseline campesterol levels. In patients with the highest baseline campesterol levels, atorvastatin treatment decreased cholesterol absorption by 46.1%, which enhanced the effect of LDL-C lowering. Atorvastatin treatment increased cholesterol absorption by 52.3% in those with the lowest baseline campesterol levels, which attenuated the effect of LDL-C reduction.

They conclude:

Based on these findings, instead of high absorption before statin treatment, patients with low cholesterol absorption, especially in the setting of high cholesterol synthesis, may particularly need combination treatment of a statin and ezetimibe at the beginning of treatment.

If this is correct, then you can indeed test for cholesterol balance:

Conclusion: ezetimibe + statin for everyone and… precision medicine becomes useless? (I don’t know :man_shrugging: )

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#14

@Neo FYI. I have been taking ezetimibe for 2 years. My omega index is 10.3%. N=1. I eat a lot of fish (tuna/ salmon) and walnuts (ALA), and I take fish oil most days. I was worried about ezetimibe but not any longer.

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#15

@约瑟夫_拉维尔 Perfect, and must feel good to have that data vs just hoping that your index was good and living in darkness

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#16

I’m saying the need to measure in order to know whether and to have an estimate of how much to supplement and then to confirm if there supplement choice was working

Without testing people with either overshoot (too much might be bad for a fib, etc)

I’m not following why you ask that, I said

  1. Would the Eze combo results be even better if a person measured their Omega Index and optimized their actually Omega types and levels their body is experiencing (vs just guessing at what dose to take via food and supplements). This is also quite simple to test.

—

(Haven’t read the the depression thread yet so don’t have the full context to comment on they part)

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#17

One can do it a bit more calibrated if one really wants it’s not just Eze = yes/no and Statin = yes/no one can be low dose or high dose of either etc and the cholesterol balance tests can help an health optimizer work on that calibration (even if I understand the average patient may not want to deal with things at that level)

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#18

Putting aside the cost and time required (and therefore the therapeutic lag compared to early combined “keep it simple stupid” statin + ezetimibe intervention), given the complexity and the interplay between the two I don’t even know how you could do that. What would be the decision tree/algorithm? There might be an optimum, such an optimized algorithm might be discovered one day (:pray:), but as of today, my conclusion based on the literature is: ezetimibe + low-dose statin for everyone, with the exception of hyperabsorbers who can start with ezetimibe only (that’s my case: ezetimibe lowered my LDL and ApoB by 40%! So I didn’t need to add a statin). Alternatively, everyone can start with ezetimibe and if enough (most likely hyperabsorbers) stop there and if not add a low-dose statin. If ezetimibe + statin not enough: add BA or PCSK9i or one day obicetrapib?

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#19

@adssx Personally I’ll simply do the home cholesterol balance test now and then and use that to eg help calibrate whether to be on 3, 5 or 10 mg of the Ezemibe

The cholesterol balance test will also help me decide on how much to bring on any statin at all (assuming I’m continuing with my PCSK9), with regards to not having demosterol go too low since that might have a negative risk profile for neurological

I’m not saying that cholesterol balance test will answer all questions, but combined with detailed lipid panels (I like NMR + Apo A/B + Lp(a)) and a other testing I feel it has begun to help me calibrate in on exact protocols and since lipid management is something expect to be doing for many decades, perhaps the majority of my entire life, it feels like one of the areas that I want to keep calibrating and now and then optimizing as my body might (will?!) change (to some extent is picked up by this and other tests)

Again this approach is not something I’m arguing the average patient should do, but for someone that is devoting to help optimizing it feel like a simple, relatively low cost way to get some extra data that might help a bit more.

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#20

Everyone is in their own unique situation. Statins, like most meds have side effects, and if you are vulnerable (f. ex. PD), it may make sense to avoid them if you can get your lipids to goal by other means. But every statin has its own profile, so it pays to take that into consideration. The other aspect, is that statins have extensive pleiotropic effects. If you are interested in those “positive side effects”, you have to consider the balance of benefits/negatives, that are relevant to your situation. Statins have been studied extensively - that’s a big plus in my book, because I can have more confidence in knowing what I’m getting and making adecision about the overall effects; often people spring for some med or supplement based on fewer sides but that’s because it has been less studied, not because it is better. I have made an assesment that in my case, a statin makes sense, because I like the “positive” side effects. YMMV.

Throw in “pleiotropic effects of statins” into pubmed, and read until the cows come home! I’m a fan.

To get you started:

https://www.sciencedirect.com/science/article/pii/S0925443920303161?via%3Dihub

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#21

A lot of papers here. Too many, almost. I have not gone through them, just scanned your post. Thank you for sharing.

My thoughts are:

  1. Eliminate any of these that are not RCTs. There is a place for other types of studies, but when we have RCTs, I tend to focus on those. I saw the word “associated” a lot, so I am guessing they are not all RCTs but I did not confirm.

  2. Ignore all that show obvious things such as Statin + Ezetimibe lowers LDL more than Statin alone. We know this already.

  3. Mostly ignore all that show obvious things such as S+E lowers CVD more than S alone. We basically know this already also - if LDL is lowered further, CVD risk declines. I think this is well established. The question we are interested in at this stage of knowledge is around all-cause mortality.

Again, I did not do the work, and I thank you for pulling this together. I am just noting my thought process is we want to examine RCTs that evaluate all-cause mortality at this point.

As a side note, I do take Rosuvastatin and Ezetimibe myself. But I do wonder to what degree this improves my mortality risk.

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#22

Which $99 test are you referring to that measures desmosterol?

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#23

As someone with an APOE4 allele, I don’t have that much interest in decreasing cholesterol synthesis anyway, if I can get away with other ways of keeping apoB and other markers optimal. For the reason of keeping the brain healthy if someone has that and can’t measure synthesis biomarkers. I’m thinking about trying ezetimibe monotherapy for that reason. I’m not touching high intensity statins until the STAREE and PREVENTABLE trials on high intensity atorvastatin reports results.

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#24

I don’t agree with this approach, and neither does Dr. Dayspring. The issue is those with ApoE4’s, die from all the usual stuff (e.g. #1 and #3 cause of death/disability being CAD, Stroke) and from neurocognitive decline.

The issue is making sure desmosterol is adequate while on a statin. If not, the statin needs to be diminished or replaced. Medications like bempodoic acid, ezetimibe or Repatha don’t seem to decrease cholesterol synthesis in the brain.

I have been requesting all my ApoE4 patients to get their desmosterol measured. This is available by self order on the EmpowerDx website as their $100 cholesterol panel includes this.

@GregordianKnot Here is the link https://empowerdxlab.com/products/product/cholesterol-dx-test

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#25

What do you do if you can’t measure desmosterol? It’s not available outside the U.S.

Ezetimibe, and PCSK9 inhibitors if necessary seems good in that scenario.

I would choose Praluent over Repatha as its trial showed an effect on all-cause mortality post hoc.

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#26

I agree with this, for folks APOE4, who cannot measure this, certainly manage one’s lipids, but don’t take statins due to this risk.

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