Rapamycin and risk of cardiovascular disease

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#650

From my understanding, beyond addressing nutritional deficiency and lifestyle modification with potentially PCSK9 inhibition etc early to avoid pre-atherosclerosis/early stage - there are no AFAIK proven ways to “reverse” CAC over a population once atherosclerosis has passed a certain point to a later stage. I am aware of a few genetic targets that may reverse late stage. There is a lot of BS and magical thinking out there even by some professionals (not in this forum so far it seems) when it comes to certain ideologies - so I have been wary.

In fact, I was under the impression larger pools of evidence suggest statins may increase CAC:

“The findings of recent studies with larger sample sizes also suggest that statins promote vascular calcification. Henein et al. reported an annual CAC score increase of 30% at the age of 50 and 21.5% at the age of 70 by statin therapy. These findings were consistent with our present results”

https://www.nature.com/articles/s41514-018-0026-2

That’s partly why I started relatively lower doses of rapamycin as early as I’m comfortable doing after looking at the data and I’ve always eaten a nutritionally complete diet with lifestyle modifications and as many potential natural PCSK9 inhibitors as I can that I am comfortable taking in sufficient amounts that theoretically have a shot at the target. Figured throwing a bunch of darts might hit the target enough to do something. I am also waiting to sign up for oral PCSK9 inhibitors to hit phase 2 personally.

Heart disease is a top 5 killer in the 30s, especially among men. You can still get a regular heart attack and atherosclerosis without HCM, infections (ie COVID), or any weird heart stuff as a literal master athlete with decent diet.

But I have always had full lifestyle modification down by learning from Okinawan centenarian men who seem to have no ED with low rates of heart attack (>80% less!)

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#651

The study seems to contradict his personal experience. Perhaps it was just an individual effect for some reason.

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#652

This guy gives a good summary of the literature

Might be that a baseline CAC is very predictive and then follow the other risk factors. We’ve spoken of oxLDL before.

#653

I’m sorry the reference you cite is a little confusing to me.

“However, the findings of recent studies with large sample sizes suggested that statins promote coronary vascular calcification.7,8 In contrast, other studies demonstrated that statins protect against coronary vascular calcification.9,10,11 The extent of LDL-cholesterol (LDL-C)-lowering effects may modulate coronary vascular calcification.”

So the question is: Should we take statins to lower the increased levels we see with taking rapamycin?
If people are taking a statin, should they add a PCSK9 inhibitor such as Alirocumab?
Could a PCSK9 inhibitor such as Alirocumab replace a statin for lowering LDL?
Is there a PCSK9 inhibitor that can be taken orally?

#654

The specific article content you linked seems alright.

As far as the source and source bias go for the general audience - I would beware “Chris Kresser, Licensed Acupuncturist” of the “Kesser Institute” has a history of magic thinking anti-vax:

BTW, I’ve literally been to Beijing to learn about traditional Chinese medicine and acupuncture. I can also play Xiangqi at a fairly high level. So I’ve given it enough chances to see whether it has legs. There are some possibilities but I find most acupuncturists here in the US are busy writing articles about “mainstream medicine” vs “alternative medicine”, and aren’t actually aware of it or trying to contribute to science or “experimental medicine”.

I find these types of acupuncturists (and the like) folks often end up being an indirect money grab and not actual evidence-based but an attempt to sell something akin to penis enlargement pills. It’s easy to mix science and BS to make BS look real. It’s hard to debunk such BS because it takes 10x the effort.

“CAGR of 22.03% from 2021 to 2028” is more profitable than Big Pharma.

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#655

Further confusing me as a layman is this:

“The probability of statins that ranked first in reducing the risk of cardiovascular (CV) events was 60.6%, and the probability of PCSK9 inhibitor was 37.1%, while no significant difference of efficacy in reducing CV events was observed between the 2 agents (odds ratios [OR] 0.98, 95% CI 0.87–1.11). Statin ranked first in reducing all-cause and CV death. Compared with placebo, statins were associated with reduced risks of all-cause (OR 0.90, 95% CI 0.85–0.96) and CV death (OR 0.83, 95% CI 0.75–0.91) while PCSK9 inhibitors and ezetimibe were not.”

Statins also raise HDL levels, which most studies I have looked at are a good thing.

“There is some evidence that the statin effects on HDL reduce progression of atherosclerosis and risk of cardiovascular disease independently of reductions in LDL”.
Effects of Statins on High-Density Lipoproteins: A Potential Contribution to Cardiovascular Benefit - PMC.

It seems to be, that the preponderance of evidence still favors statins in reducing all-cause mortality by reducing cholesterol levels.

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#656

Agreed that the author is an acupuncturist but his references remain valid as do many of his key points regarding CAC.

I’m certainly not an anti vaxer but I’m glad there are those out there willing to question their overall value. It’s how science should work. We shouldn’t all be in lockstep over Any device or therapeutic out there but rather critically questioning everything, including vaccines.

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#657

If you throw out studies sponsored by the pharmaceutical companies then the absolute risk reduction by statins on primary prevention is about 0.8%.
Furthermore, many clinicians and researchers now believe that the primary beneficial mechanism is anti inflammatory. Do we need statins to lower inflammation?

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#658

First I am not advocating or recommending statins to anyone.

As I have posted before, I am not a big fan of pharmaceutical companies, but I cannot automatically dismiss their findings. If a crooked liar tells the truth sometimes, it’s still the truth.

I don’t feel like I have a dog in the race.

I take bergamot extract, omega-3s, fiber, plant sterols, etc., etc., maintain a BMI of less than 24, currently 22, and exercise regularly.

My doctor prescribed a statin for me years ago near the age of my requirement. Because of my job at the time, I just didn’t have the fortitude to get regular exercise and I became overweight.

If you feel the need to immediately lower your LDL, statins are much faster than any health food supplement I have ever tried.

For years before I started taking rapamycin I was able to keep my LDL and other lipids in the very good range without taking a statin. I have posted my charts on this forum before.
My cholesterol kept rising the longer I took rapamycin. So I will be taking atorvastatin again because it works very well for me and I have never had any problems with it. It will lower my cholesterol back into the good range in less than a month. Then I will start rapamycin again.

Maybe, it’s my age, particular genetics, etc, but rapamycin has certainly raised my bad lipids and lowered my HDL.

Mayo Clinic says:
“While dietary supplements can help, you might also need prescription medications to get your cholesterol numbers to a safe level”

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#659

Fair enough.
I too think that statins have their place in certain circumstances, just not every circumstance. For secondary prevention I think the evidence in their favor is rather clear.

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#660

Well, I guess I will have to rethink healthy HDL levels, though mine have never been over 60
Looks like a probable U-shaped curve.
Perhaps it is not relevant at all unless it’s way out of range.
It’s not one of the biomarkers included in the epigenetic age calculator based on Dr. Morgan Levine.

Peter Attia

@PeterAttiaMD

Jul 23

I think it is fair to say HDL-C is a less-than-helpful biomarker once you know apoB. I will doing a dedicated HDL podcast in a few weeks (released about 6 weeks later).


@JohnKastelein

Jul 24

Replying to @Drlipid @society_eas and 2 others

This U shaped relationship is “ discovered “ by scientists and Journals with a short memory … it was reported 4 decades ago and then as now it is explained by residual confounding … Am adressing this in a new analysis of the Epidemiology as well as the Trial data …,

@ProfKausikRay

Jul 24

in prospective studies for incident ASCVD, with > 3 million person years of FU &>25k events, it’s flat not U shaped from our ERFC paper in 2009. MR & trial data could help put this uncertainty to bed. pains me when I see referrals using ratios of TC/HDLc

Mike Lustgarten, PhD

@mike_lustgarten

Jul 23

Replying to @Drlipid @society_eas and 2 others

All-cause mortality risk increases for HDL > 58 in men, > 75 in women in a meta-analysis of 24 studies:

youtube.comHDL: What’s Optimal For Minimizing Disease Risk And Maximizing…

Join us on Patreon!https://www.patreon.com/MichaelLustgartenPhDCronometer Discount Link: https://shareasale.com/r.cfm?b=1390137&u=3266601&m=61121&urllink=&af…

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#661

HDL anti inflammatory capacity may be more important than HDL itself and seems to be an independent risk factor to evaluate.

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#662

The issue of elevated lipids on rapamycin and CVD diseases is still an open debate. Both Dr G and Dr B recommend a statin if your lipids dsyregulate, but is this simply a standard of care default advisement, since neither truly knows the answer or risk? Neither are cardiologists, and Dr B’s research is mostly mice? So how can he make this massive translation prediction?

If statins truly impart their efficacy via reduced inflammation, and lipids are simply an association, then how do we rationalize the conundrum that rapamycin ALSO lowers inflammation, yet lipids are elevated? Can both statin and rapamycin both be anti-atherosclerotic, yet one decreases lipids, and the other increases?

Rapamycin alters liver expression, which isn’t an inflammatory pathway? So is the “benevolent” argument that the LDR receptor and TG processing are blunted, releasing lipids and allowing higher circulating TG, but that they DO NO HARM because of the vasculatory anti-inflammatory protection afforded by rapamycin?

Rapamycin is generally anti-inflammatory, so does this trump atherosclerosis in the presence of increased lipids? I don’t think there is sufficient longitudinal data in cancer/transplant patients to draw CVD risk conclusions…not sufficient time lapse, nor monitoring of say CAC?

Having lipids traffic through the circulatory at higher levels and higher duration, is only allowing for greater and greater oxidation. The fact that TG/HDL is greatly elevated on rapamycin means smaller particle size and higher count. You combine smaller particle size with greater oxidation risk…preponderance of greater CVD risk via > oxLDL.

At time of writing, I’m NOT convinced the rise in lipids is benevolent.

Certainly, if you’re like Agetron with a CAC of zero at 64, he’s got major runway to proceed on course, whilst monitoring CAC. For someone with a much higher score…harder decision? Stay on course, track CAC?

Systemic application of sirolimus prevents neointima formation not via a
direct anti-proliferative effect but via its anti-inflammatory properties
https://sci-hub.se/https://doi.org/10.1016/j.ijcard.2017.03.052

Background: Systemic treatment with sirolimus, as used for immunosuppression in transplant
patients, results in markedly low rates of in-stent restenosis. Since the underlying mechanisms
remain obscure, we aimed to determine the molecular and cellular effects of systemic sirolimus
treatment on vascular remodeling processes.

Conclusion: Our findings show that systemic sirolimus treatment effectively prevents SMC and
EC proliferation in vivo without directly affecting these cells. Instead, sirolimus prevents
neointima formation and re-endothelialization by attenuating the inflammatory response after
injury with secondary effects on SMC and EC proliferation. Thus, despite a similar net effect, the mechanisms of systemic sirolimus treatment are largely different from the local effects achieved
after application of sirolimus-eluting stents

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#663

There are studies, such as this one suggesting that rapamycin dosages matter.

And the presence or absence of other risks always matter. Most rapamycin users for longevity purposes are probably healthy in general with few, if any, other risk factors. Just a guess.

Also, I suspect that the lipid elevations from weekly rapamycin are modest in the majority of patients. There’s always exceptions. Dosing does matter when it comes to side effects from any drug.

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#664

Does is the poison.

So are you sort of agreeing that it’s NOT benevolent in terms of pathological/mechanistic CVD, but yet, with the right person, dose and risk factors, not an “actual” event or longevity risk? Namely, like any other drug…risk/reward?

#665

I agree, “” At time of writing, I’m NOT convinced the rise in lipids is benevolent."

Yes, the supposition of some members of the forum, seems to be:
Rapamycin extends life so the rise in lipids must not be a bad thing.

My thinking is more in line with: If we keep our lipids low maybe rapamycin will extend our lives even longer.

Of course, at this stage, it is only supposition and opinion.

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#666

"
These results suggest that RAPA interferes with TG metabolism by altering the insulin signaling pathway, inducing increased secretion of very low density lipoprotein and promoting deposition of TG in the aorta"
These were also daily doses. And a preliminary paper.

#667

Yes. I would say so. There’s so many factors to consider and weigh. I also think that rapamycin is protective beyond its anti inflammatory component. It inhibits intimal smooth muscle proliferation and foam cell formation. That’s a pretty big deal.
I’m also impressed by the lipid lowering effects of multiple natural supplements which I prefer because I’ve encountered so many patients complaining of muscle aches, fatigue, and mental foggyness on statins. So I’m biased.

#668

I’d 100% agree if medications were side effect free. They’re not so it’s a risk/ benefit decision. For me, all too often, the risk is greater.

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#669

One other thing . On this site we only have very limited data to consider but Alan Green has 1000 patients on rapamycin. Many, if not most of them, are aware of their lipids. This could be extremely informative and would be an actual human study. It wouldn’t be a perfect study obviously, but it would be more than what we presently have, by far.

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