Consistently lost in the wash of this debate is whether rapamycin can protect against CAD despite an increase in lipids. As I’ve pointed out numerous times, there’s considerable evidence that this is the case.
In a rabbit study, rapamycin resulted in zero plaque rupture and a decrease in plaque burden while increasing lipids. This was in contrast to a 56% incidence of plaque rupture in the control group. The mechanism seems to be an increase in the thickening and stability of the fibrous cap. A similar effect has been seen with gotu kola.
So again, is there evidence that the low risk person with elevated lipids from rapamycin needs to resort to statin therapy? If concerned , there’s statin alternatives. A good therapeutic target seems to be an ApoB to ApoA ratio < 0.8. I’m very close to that with just adding citrus bergamot at 1000 mg per day. I’m going to see if pantethine 600 mg is additive. Best of both worlds without the risk of diabetes or cognitive impairment.
I don’t know if I have to say this but obviously rabbit studies are near useless as well, except for one’s pet rabbit.
I find it unlikely that we will ever know whether rapamycin can offset the extreme risks from elevated apoB, or another mTOR inhibitor. In the meanwhile I don’t see the problem in trying to alleviate that with supplements as you do, or medications that lower apoB. If apoB goes down all is well.
You seem to be very confident that MR studies imply that any treatment that changes {LDL, APO-B} must correspondingly change [AS]CVD risk, even when, in the case of rapamycin, this is not supported by animal studies. Why are you so confident in this one line of evidence?
In the end Humans are not all the same, but studies on mammals are not IMO “near useless”. I am into n~8 biohacking studies with humans which are useful because we have some vague idea as to what happens with Homo Sapiens, but “near useless” is not a conclusion I agree with.
Because it is a different animal, you are not a rabbit, which is an entirely different complex system. What works in one tend to not work in another because there are so many different moving, causal parts.
Here’s some examples and a good article on this topic:
Approximately 100 vaccines have been shown effective against an HIV-like virus in animal models, however, none have prevented HIV in humans.
Likewise, up to one-thousand drugs have been shown effective for neuroprotection in animal models but none have been effective for humans.
Along the same lines, of twenty two drugs tested on animals and shown to be therapeutic in spinal cord injury, none were effective in humans.
The success of the animal model in basic research can also be questioned based on the fact that, according to one report, only 0.004% of basic research papers in leading journals led to a new class of drugs.
For example, in part because the targets derived from animal models are not predictive for humans, the percentage of new drugs in development, after initial evaluation, that ultimately make it to market is somewhere in the area of 0.0002%.
Mendelian randomization is done on humans, also with a study design that eliminates most confounders due to the natural randomization of gene variants. Those same gene variants that in many cases only do one thing, for example increase apoB a little.
Yes it’s comparing rapamycin and everolimus with tacrolimus which is not a mTOR inhibitor.
It’s not a good quality study, but mTOR inhibitors also had 12 times higher rate of dyslipidemia compared to tacrolimus, so association is consistent there at least.
I’d be crazy to me to not control lipids with rapa because of some crap animal studies, just my opinion. Hopefully the increase in apoB isn’t as atherogenic as without rapa, but I wouldn’t bet on it as lipids can be decreased so safely IMO.
Because it is a different animal, you are not a rabbit, which is an entirely different complex system. What works in one tend to not work in another because there are so many different moving, causal parts.
Yes, in general animal models don’t recapitulate the details of the corresponding human disease – although the situation is less bad than often suggested. I recall, however, that most of our experimental understanding of cholesterol metabolism and its relation to atherosclerosis comes from rabbits. Statins were developed in rabbits. To the extent we can say that cholesterol (in whatever form) causes CVD in any animal, we can say it for rabbits. So rabbit evidence is worth quite a lot.
Those same gene variants that in many cases only do one thing, for example increase apoB a little.
This is the crux. The studies I’ve seen usually use a GWAS or similar to find genetic regions of interest. They literally have no idea what those regions do. I’m not sure how reliable causal inference can be with such methodology. Some studies do use variation in known genes – which leads to better conclusions. For example, MR suggests that alterations in the mevalonate pathway affects CVD, which is good evidence for the utility of statins (at least to the extent they mimic the natural variation), but isn’t as directly applicable to rapamycin.
I don’t know the literature well enough to know how to interpret it in this situation though, which is why I asked.
Of course, the reason for increased cardiovascular events could be the fact that the mTor-inhibited groups failed to keep their lipids within the normally accepted bounds.
It would be nice to see a study (which I don’t think we are going to see anytime soon) that compares for instance; rapamycin users taking statins or some other lipid control measures vs those that don’t.
LDL-C works as an activator of toll-like receptor (TLR) pathways, which are implicated in many autoimmune and immune processes. TLRs are transmembrane receptors, which play a key role in both basic and adaptive immune responses. In several articles I picked up the inhibition or over activation might be problematic. In short what I picked up, very low LDL-C may lead to problems with immunity, too high leads to ASCVD. So is there an optimal level?
This is going to be a bit ironic, but one of the things they first tested in rabbits was whether dietary cholesterol would cause atherosclerosis and it did. It doesn’t in humans, or rather very rarely. It was an observational study of autopsies that first presented the idea of cholesterol deposits in arteries. Also an observational study was at the forefront:
“It might have never been possible to develop a statin were it not for the mid-century epidemic of CHD, the powerful epidemiological evidence linking it to elevated plasma cholesterol …” tobert2003.pdf (335.1 KB)
I don’t doubt that sometimes animal models work, I just don’t think this is evidence for that they do in this specific case.
GWAS is actually superior to any other method like candidate genes, as candidate genes tend to not replicate in GWAS which is odd if they actually did have the effect as expected. Of course there are certain genes with large effects like in PCSK9 but they do not explain all of the genetic variation when it comes to heritable apoB levels.
It is actually possible to know what these genes do. They are ‘associated’, with the trait in question, like higher apoB, with a very low p-value, GWAS has much lower p-value requirements than for regular studies, p-value 5×10^−8. It is possible to figure out the mechanism of a gene, and even do drug repurposing, simply by matching genes with those in a database:
Genes that were identified by transcriptome wide analysis, molecular mapping QTL, and gene-set analysis were filtered on the consolidated druggable gene list from drug databases.
Does that answer you question that we can know what the genes do? There also are some analysis that can be used in Mendelian randomization to reduce pleiotropy - like MR-egger, but they’re way over my head.
I think it’s exactly that. Rapamycin would be indirectly atherogenic via apoB. Maybe that’s why people who take daily Rapa hasn’t in observational studies been shown to live longer than the general population. Since only a 24 mg/dl increase reduces chance to live to 90th percentile lifespan by 60%. Granted, these were lifelong increases in apoB causing such an effect, so it depends on when starting rapamycin.
@AnUser just asking for a friend I am not looking for medical advice, just hypothetical less abstract point of view. What would you do in this case:
AGE 48
TC 181
LDL-C 112
HDL-C 58
nonHDL-C 123
ApoB 84
TG 44
BP 115/75
BMI 21.5
BF 11%
CR 15%
FAMILY HISTORY no ASCVD / no cancer
SMOKE no
ALCOHOL no
MEDICINES Rapamycin 6mg/week, acarbose
SUPPLEMENTS none
I would try everything to lower apoB to below 60 mg/dl, and to around 30 mg/dl if it was somewhat easy. You seem to have a good diet and/or good genes, so it shouldn’t be too difficult to do so. It isn’t surprising that there is no family history of ASCVD if your apoB is 84 right now even with 6 mg rapa a week. You might be protected already if your apoB was below 60 for decades as that will delay ASCVD by a lot.
How would your strategy look like? Supplements? Medicines? (I don’t think “my friend” would be willing to introduce any dietary changes, but would you?)
Unfortunately I have no previous ApoB numbers, but my friend who is cardiologist said they use a calculator to asses ApoB levels from cholesterol levels too sometimes if measurements are not available. So I might do that for years back if I find my blood tests.
Trial and error, if someone mentions a supplement you can try to find some randomized controlled trials (meta analysis) showing it lowers LDL, which will probably lower apoB too. And if it lowers your apoB, that’s good and you found the solution. I prefer medications because I think they have lower risk as there is more data, FDA approval, etc. Of course certain supplements like psylium husk and oat beta glucans are risk free, but they don’t really move lipids by a lot either. So it is personal preference and what you believe is best.
I have rosuvastatin and ezetimibe which I personally am going to test. I did take rosuvastatin for some time but I have to make my own capsules with a pestle and mortar for my, right now, lower dosage. It is slightly annoying to make the capsules. So I haven’t been testing, my apoB was 55 last time I checked and that was only from berberine 500 mg + using canola oil in cooking for 1 yr. I stopped berberine because I think I got some side effects with my joints, they felt a bit weird.
You have to directly measure apoB, otherwise you could do LDL particle count or LDL, those are proxies for apoB.
Yes, I understand. Well my GP is not willing to hear me about medicines, my husband (MD) thinks I am crazy, my friend (top local) cardiologist thinks there is no need to go lower…
Btw what was your ApoB before berberine and canola oil? Do you take rapamycin? How much chage did you experience in ApoB levels if any?
I have rsuvastatin and ezetimbe too, but I am not willing to start ATM ( I forced my husband to get me prescription together with empaglifozin and it has been in my medicine cabinet ever since… for emergency only ). Statins open too many questions, ezetimbe seems like a good solution, but I am still a bit annoyed at starting another medicine… I checked some supplements and niacin and bergamote seem most promising. Lysine + vitamin C seems ridiculous, but since I take lysine (EAA drink before workouts) I might add some vitamin C too. Probably can’t hurt. And I also have mixed feelings at preventing something that probably does not pose a serious threat, seems more like OCD (or at least in that direction) to me. Will have my eyes open and my mind not opposed to lowering ApoB…
It is good at getting some seemingly opposing view from time to time and seems you do take your research seriously, so all input in passionately “defending” your position gives a great insight.
I am not looking for medical advice, just hypothetical less abstract point of view. What would you do in this case:
). Statins open too many questions, ezetimbe seems like a good solution, but I am still a bit annoyed at starting another medicine… I checked some supplements and niacin and bergamote seem most promising. Lysine + vitamin C seems ridiculous, but since I take lysine (EAA drink before workouts) I might add some vitamin C too. Probably can’t hurt. And I also have mixed feelings at preventing something that probably does not pose a serious threat, seems more like OCD (or at least in that direction) to me. Will have my eyes open and my mind not opposed to lowering ApoB…