Rapamycin and risk of cardiovascular disease

[Davin8r]

@rivasp12

The initial premise of this post was that rapamycin should be protective against atherosclerosis, and possibly even reverse it, even in the presence of a lipid elevation.

This is great, but I’d hypothesize an even greater decrease in plaque with the addition of lipid-lowering therapy, or at least addition or adjustment of dose of existing lipid therapy to nullify the increased lipids from the rapa.

[rivasp12]

There were members of both groups on statins. There was no indication in the results that the statin/ rapamycin participants had a better response than the rapamycin only .

[Davin8r]

They were already on statins. They didn’t increase the dose or change meds to compensate for the increase in lipids. Your premise is “don’t bother”, while mine is “do both”. While a statin wouldn’t be my first choice if lipid elevation is relatively mild (prefer a supplement and/or ezetimibe, for instance), I still think risk/reward is still in favor of safely keeping lipids controlled, especially since we know there’s no downside to lowering LDL/ApoB.

[rivasp12]

The use of lipid lowering drugs is to negate a risk factor. In this study , the group on rapamycin had an actual reversal of atherosclerosis despite elevated cholesterol values. There’s no need to subject patients to medication side effects when you have reversal of a disease process without the medication.
It’s possible that statins would augment the effect, but that should have shown up in the study if the effect was significant.

[Davin8r]

Statin dosages weren’t adjusted to keep lipids at pre-sirolimus levels (because this would have been a confounding variable), so any effect of statins would not have shown up in this study. You’d need a 3rd group that got both sirolimus and additional lipid control.

[Davin8r]

Wait a minute! LOL. Look at Table 1. LDL decreased nearly 30 mg/dL in the sirolimus group over the course of the study, but only decreased by 14 mg/dL in the control group. The difference between groups wasn’t statistically significant, but the sirolimus group did have a statistically significant increase in HDL (also perplexing). TG also weren’t raised by sirolimus, which seems contrary to previous findings.

Since we know sirolimus doesn’t typically lower LDL or raise HDL, it looks like there was some confounding going on. Not sure what to think of this study or how useful it is. Seems like one could just as easily conclude that lowering LDL and increasing HDL caused a decrease in cIMT(?)

[rivasp12]

Yeah, sure, it was the extra 16 point LDL drop that caused atherosclerosis reversal over 1 year and had nothing to do with the fact that they were the group on rapamycin. In that case we don’t need more than a modest LDL drop to get reversal of atherosclerosis. Of coupon studies have actual demonstrated this.

[rivasp12]

Correction: of course no study has demonstrated this.

[Davin8r]

We need an explanation for those lipid numbers, otherwise drawing any conclusions from this study seems premature. Maybe the patients’ statin dosages actually were being adjusted in the background, and that’s why LDL/HDL went in the opposite direction of what was expected and TG didn’t change from rapamycin therapy (?). Or maybe the prednisone and tacrolimus these patients were also taking had an effect on the lipids? The Cellcept in the control group? Multiple potential confounders here.

The hypothesis that “rapamycin therapy causes LDL elevation but that this doesn’t matter due to the overpowering anti-atherogenic effect of rapamycin”, doesn’t seem adequately answered by this study because LDL was apparently not elevated by the rapa in the first place.

[rivasp12]

In this study of post heart transplant patients,both the rapamycin and the controls received pravastatin. Per figure 2 the LDL levels were virtually identical out to two years. Only the rapamycin group prevented the progression of CAD.

[rivasp12]

Study here

Sirolimus in De Novo Heart Transplant Recipients Reduces Acute Rejection and...

[Davin8r]

Ok so if rapamycin doesn’t even increase LDL in the first place, that pulls the rug out from the underlying hypothesis of this thread doesn’t it? If you don’t see an increase in LDL after starting rapa, then why even ask if you should treat it?

[rivasp12]

Being a smart guy, you’re well aware that elevated lipids can be a side effect of rapamycin usage.
I’m attempting to reassure them that studies show that such increases are often transient and that rapamycin, in and of itself, is able to reverse atherosclerosis so that interventions, such as statin therapy, may not be necessary with its own attendant side effects.

[Agetron]

rapamycin, in and of itself, is able to reverse atherosclerosis…

Can it slow… maybe stop atherosclerosis , but reverse it? I don’t know… I think it might reverse it. At 64 years… my Coronary Calcium Scan shows no calcium at all zero. My diet… heavy in whole milk and steak… my LDL-C 176. Always high… I think rapamycin kicked up an extra 20 points.

So maybe it does reverse it. Or, I have the right genetics.

[DeStrider]

Thank you all for your lively debate. This is one of the biggest issues facing Rapa users, so it’s really important to analyze this issue from as many different angles as possible.

And, I enjoyed the debate. Thanks guys.

[Davin8r]

@rivasp12

…rapamycin, in and of itself, is able to reverse atherosclerosis so that interventions, such as statin therapy, may not be necessary with its own attendant side effects.

I hope this is true, and it’s exciting to see that there’s at least a small number of small human clinical studies showing some anti-atherosclerotic potential of rapamycin. I just don’t believe that the studies mentioned so far suggest that one can ignore lipid increases from rapa (after all, one study showed lowered LDL after rapa and one study showed no change, so the hypothesis could not even be tested). Also, these studies also aren’t generalizable to non-transplant patients who aren’t on multiple immunosuppressive drugs and who are only taking the drug once weekly instead of every day.

Again, it’s exciting to see that rapa likely has an anti-atherogenic effect, but I don’t see why safely controlling lipids isn’t a good thing. The corollary would be “I eat lots of broccoli and meditate every day, so I don’t need to bother to exercise”. Atherosclerosis has multi-factorial causation, so IMO it makes sense to address it from all sides. You don’t even need a statin or a supplement to reverse the lipid elevation from rapa. Even a few smart dietary changes could likely do it.

[rivasp12]

Davin8
Here’s an opinion piece that you’ll enjoy and it supports some of your thinking. We should discuss at some point.

There Is Urgent Need to Treat Atherosclerotic Cardiovascular Disease Risk...

[MAC]

@rivasp12

Re " Effect of sirolimus on carotid atherosclerosis in kidney transplant recipients: data derived from a prospective randomized controlled trial"

Although a positive (cIMT) small trial signal, I don’t think anywhere sufficient to answer this question definitively…certainly in the context of LIFELONG taking. Why didn’t they evaluate other CVD markers…VO2, CAC? They would not have been so onerous of tests at only 6 and 12 month intervals? They could have really done a better more fundamental physiological study.

An interesting observation from the study:

“In this study, cIMT was decreased in all patients (both groups) because of the transplant effect, which has already been observed in previous studies that compared cIMT before and after transplantation [19]. The reduction of cIMT may be one of the factors responsible for declining cardiovascular risk after kidney transplantation. In this study we also observed a class effect in which the sirolimus group had a greater reduction in cIMT; this was also seen in a model adjusted for principal factors associated with variability of cIMT”

But yet renal transplant patients have massively increased absolute CVD risk? So how to reconcile this short term cIMT improvement with very poor CVD outcome? We have some studies that show sirolimus + renal transplants have CVD lowering hazard ratios. So does this allow us to tease out a true sirolimus effect?

I found the comparative and changes in lipids very interesting (unusual?). Generally, positive or insignificant change, in both groups as well?

The paper references a cautionary note:

" Another point to consider in the pathophysiology of atherogenesis related to mTORI use is the time of exposure and the dose of these medications. The mTORI preferentially inhibit the
mTORC1 pathway, which is responsible for the major beneficial effects, including the anti-atherosclerotic responses. The inhibition of mTORC2, which was rapalog-insensitive, is related to increased insulin resistance and may be responsible for some serious undesired effects. Long-term treatment with mTORI may inhibit mTORC2 and may be responsible for the development of mTORC1 resistance, thus reversing its beneficial role in atherosclerosis [25]. This may explain the absence of effect on atherosclerosis in clinical trials with a long time of exposure to mTORI [15]"

Reference 15:

https://doi.org/10.1016/j.transproceed.2016.03.005

The study involved a group of 24 recipients treated with mTORi (mTORi group) and a group of 20 recipients treated with immunosuppressive regimen based on CNI (CNI group). [Carotid atherosclerosis was evaluated by measurement of the intima media thickness (IMT) of the common and internal carotid artery walls and detection of carotid plaques by a high-resolution
ultrasonography. The study was performed 3–24 years after transplantation. The mTORi group showed higher level of total cholesterol (242 vs 201 mg/dL), low-density lipoprotein cholesterol (140 vs 116 mg/dL), and triglycerides (226 vs 168 mg/dL). Post transplant diabetes developed in 34% of mTORi group compared with 25% in the CNI group. The mean of IMT (left and right) of common and internal carotid arteries was similar in both groups. Carotid plaques were detected in 46% of patients from the mTORi group and 25% from CNI group.The presence of carotid plaques combined with an IMT of >0.9 mm were associated with male gender, mTORi treatment and cardiovascular events. The incidence of coronary heart disease in mTORi group than in CNI group (53% vs 20%)

Conclusions

There was NO beneficial effect of immunosuppressive treatment with mTORi on carotid atherosclerosis in renal transplant patients.

What about larger, long term rapamycin HUMAN trials and CVD risk?

https://sci-hub.se/10.1034/j.1600-6143.2002.20610.x

“Lipid data from two large controlled studies of 1295 renal transplant patients were analyzed retrospectively. Sirolimus 2mg/day and 5mg/day were compared with placebo or azathioprine, and administered concomitantly with steroids and cyclosporine over 12months. Hypercholesterolemia and hypertriglyceridemia occurred in all treatment groups and were maximal at 2–3months. The sirolimus groups evidenced higher lipid levels than the controls, but the elevations diminished over time. At 1 year, the patients given sirolimus 2mg/day had a mean cholesterol level 17mg/dL greater and a mean triglyceride level 59mg/dL greater than the controls. Among the patients given sirolimus 5mg/day, mean cholesterol was 30mg/dL greater and mean triglycerides were 103mg/dL greater than the controls. Treatment with statins and fibrates was effective in reducing cholesterol and triglyceride levels, respectively, in the sirolimus-treated patients. The Framingham risk model predicted that the 17mg/dL elevation in cholesterol would increase the incidence of coronary heart disease (CHD) by 1.5 new cases per 1000 persons per year and CHD death by 0.7 events per 1000 persons per year. Lipid elevations observed in the sirolimus-treated patients were manageable, improved over time, and responded to lipid-lowering therapy. Based on the Framingham risk model, the CHD risks associated with these cholesterol elevations are small compared with the baseline risks of the transplant population.”

“The impact of sirolimus on major coronary risk factors was limited to an increase in the total serum cholesterol level”

In this study, they used classic lipid lowering interventions to mediate CVD risk, including the Sirolimus group, so we don’t have a clear cut sirolimus ONLY intervention. 48% of sirolimus 2mg/day were put on a statin. But again, RENAL transplant cohort, not healthy persons.

I don’t think this question is settled. Is there a subset of rapamycin users where there is an actual anti-atherolosclerotic long term benefit? And what would be this phenotype? Excellent physical and metabolic health, with LOW baseline lipids and glucose, ABSENT CVD?? But wait, is this phenotype going to even have lifespan lowering via CVD as baseline risk? So what is sirolimus overlay doing? This phenotype might be able to dose at higher levels for OTHER all cause mortality reducing effects?

Or someone with good markers and some level of CVD (say low risk CAC)…is this phenotype going to benefit the most over long term? Can this phenotype ride out some level of dyslipidemia, and does it matter if not fully transient??

[rivasp12]

So many questions and so few answers.
It is a shame that most of the humans on rapamycin have had many years of renal failure, or cardiac conditions, as well as many years of multiple cardiac risk factors. They’re not the perfect samples.

In general, people with no significant family history , and minimal to no other risk factors , are at low future cardiac risk. I don’t believe that rapamycin adds to that risk.

[MAC]

@rivasp12

In general, people with no significant family history , and minimal to no other risk factors , are at low future cardiac risk. I don’t believe that rapamycin adds to that risk.

We don’t know the answer to this. Otherwise @RapAdmin would have closed this thread.

Here’s the problem…if you’re on this site, you’ve got escapism fantasies, and that wish will only come true if you beat back ALL mortality pathways. Your probability of becoming a long lived individual goes up with higher Rapamycin doses, but yet you risk some degree of lipid, glucose, immuno, anemia, etc dysregulation, and some level of hopefully tolerable side effects. Is this hormesis, namely disrupting mTOR signalling, part of the longevity secret?

I believe it is, the central thesis.

So to achieve centenarian status on rapamcyin, you have no choice but to take some risk BUT you must be a biomarker hawk so you don’t short circuit yourself.