People tend to be tribal in their thinking. Hence even policy viewpoints can depend on the tribe that people associate with rather than people associating with a political tribe because they agree with the policies.
People tend to disassociate with a tribe when the leaders of the tribe do things that they dislike normally because it causes them problems (or people close to them).
Sadly, but not surprisingly necessarily, this goes as far as scientific views.
Science is a buzzword. Evidence is not.
All I can say is that when my father wasnât lowering his LDL, his arterial plaque scores kept going up at a normal level.
When he started LLT with statins and BA and Ezetemibe, his arterial plaque froze in itâs tracks. There are the influencers and then thereâs the data. Iâll go with the data every time.
If you want to halt arteriosclerosis, lower your ApoB and LDL below 55.
We do know that ezetimibe inhibits dietary cholesterol uptake in the intestine and disposes of it fecally. So ezetimibe lowers LDL-C lipid levels in the blood. But what happens when you give ezetimibe to vegetarians who get very little dietary cholesterol? Does it mean since ezetimibe doesnât have any dietary cholesterol to inhibit the absorption of, it therefore will not lower lipid blood levels? That is the question explored in this study - an oldie (2006!), but goodie - and I like this study a lot, it was very well designed and quite decisive in its findings, which we can have a high degree of confidence in. The bottom line, regardless of your dietary cholesterol intake, ezetimibe works as intended.
The lipid-lowering effect of ezetimibe in pure vegetarians
https://www.jlr.org/article/S0022-2275(20)43275-4/fulltext
" Results of previous studies have shown that ezetimibe (10 mg/day) reduces LDL cholesterol in patients with mild hypercholesterolemia on a normal-cholesterol diet (dietary intake of 200â500 mg/day) by 16â22%. However, the LDL cholesterol-lowering effect of ezetimibe in subjects with an extremely low dietary cholesterol intake (vegetarians) has not been studied. We conducted a randomized, double-blind, placebo-controlled, two-phase crossover study in 18 healthy pure vegetarians to assess the effect of ezetimibe (10 mg/day) on plasma lipids, cholesterol absorption, and its synthesis. Treatment periods lasted 2 weeks each, with an intervening 2 week washout period. Fractional cholesterol absorption was determined using the continuous dual stable isotope feeding method. Mean dietary cholesterol intake in the pure vegetarians was extremely low and averaged 29.4 Âą 16.8 and 31.4 Âą 14.4 mg/day during the placebo and ezetimibe administration phases, respectively. Fractional cholesterol absorption during the placebo phase was 48.2 Âą 8.2% and was decreased by 58% during ezetimibe treatment to 20.2 Âą 6.2% (P < 0.001). This change in intestinal cholesterol absorption was followed by a significant reduction in LDL cholesterol of 17.3%. In individuals with extremely low dietary cholesterol intake, treatment with ezetimibe (10 mg/day) leads to a significant reduction of cholesterol absorption and a clinically relevant decrease of plasma LDL cholesterol, comparable to that of subjects with a normal dietary cholesterol intake. Thus, the lipid-lowering effect of ezetimibe is mediated mainly through a reduction of the absorption of endogenous (biliary) cholesterol."
Meanwhile for those worried about oxidized dietary cholesterol, they can rest easy that ezetimibe works as intended as another old ezetimibe study demonstrates.
Ezetimibe inhibits the incorporation of dietary oxidized cholesterol into lipoproteins
https://www.jlr.org/article/S0022-2275(20)43392-9/fulltext
âOxidized cholesterol is present in significant quantities in the typical Western diet. When ingested, oxidized cholesterol is absorbed by the small intestine and incorporated into both chylomicrons and LDL, resulting in LDL that is more susceptible to further oxidation. Feeding studies in animal models and epidemiological studies in humans have suggested that oxidized cholesterol in the diet increases the development of atherosclerosis. In this study, we determined the effect of ezetimibe, a drug that inhibits small intestinal absorption of cholesterol, on the levels of oxidized cholesterol in the serum after a test meal containing oxidized cholesterol. We demonstrate that ezetimibe, 10 mg per day for 1 month, markedly reduced the levels (50% decrease) of oxidized cholesterol in the serum after feeding a test meal containing either Îą-epoxy cholesterol or 7-keto cholesterol, two of the predominant oxidized cholesterols found in the diet. Moreover, the decrease in oxidized cholesterol in the serum was attributable to a decrease in the incorporation of dietary oxidized cholesterol into both chylomicrons and LDL. Because there was no decrease in postprandial triglyceride levels, we conclude that this decrease in oxidized cholesterol levels in the serum is attributable to decreased absorption and not to enhanced clearance. Whether this decrease in oxidized cholesterol absorption prevents or delays the development of atherosclerosis remains to be determined.â
As the resident vegan, Iâll share that I put off taking EZ for a minute thinking there was nothing for it to do⌠but lo and behold, my numbers went down after starting⌠so, my n=1 shows the study was correct 
I then discovered most of the cholesterol EZ blocks comes from your own bile, not your food.
Yes, by the time I learned about ezetimibe, that fact was already well-known, probably from studies like the one mentioned above.
2024 study with graphs of plaque on CTA over time. Average TPV (Total Plaque Volume) appears to increase linearly from year/age 45.
https://www.sciencedirect.com/science/article/pii/S1936878X23002346
OK, but did you know that the same thing applies to plant sterols 
? I would guess itâs logical. Undoubtedly it is a good thing in case of sitosterolemia. But is it also good in the absence of sitosterolemia, given that some have proposed - controversially - plant sterols as beneficial in CVD? Inquiring minds want to know. Any medication deserves a thorough establishment of all effects. A couple of papers (the EZE had a tiny # of subjects):
Ezetimibe Reduces Plant Sterol Accumulation and Favorably Increases Platelet Count in Sitosterolemia
A general look at phytosterols (review):
Phytosterols and Cardiovascular Disease
https://bpspubs.onlinelibrary.wiley.com/doi/epdf/10.1002/prp2.70329
AI summary:
Let us keep in mind that rapamycin appears to polarize M1/M2 in the opposite direction from GLP-1RA. And in a contest between the two, rapamycin takes precedence as itâs upstream of where GLP-1RA work here and affects the very mechanism of polarization leaving GLP-1RA nothing to work with. If you are taking both, be aware that it is rapamycin that will be dominant. In this context pulsed administration of rapamycin becomes interesting, as one could speculate that in the trough of zero, GLP-1RA could step in to again re-balance M1 and M2.
However, the interplay of GLP-1 and rapamycin - for that matter other anti-diabetics too, is quite complex and frequently counter-intuitive. When I research a drug for inclusion into my stack, I spend a huge amount of time and effort trying to map out the possible interactions, because that is really where the rubber hits the road. It makes little sense to look at the actions of a drug on paper - such as the quote above âpromotes M1 to M2 macrophage polarization, reduces pro-inflammatory cytokinesâ - if the other drugs in your stack completely abolish that effect, because you are counting on an effect that will be absent. You must then decide how to balance out these drugs by whatever means - dose, protocol, timing, or even inclusion.
Rapamycin and anti-diabetic drugs including GLP-1RA have a complex interplay in glucose control too. I have frequently noted in many threads that rapamycin definitely can be deleterious to pancreatic beta cells. This is a serious issue I have spent a lot of time on as someone who both takes rapamycin and has been pre-diabetic (for more than a decade).
Below is a paper that is super helpful in illuminating some of these issues, including the rapamycin and GLP-1 interplay, M1/M2 and other issues discussed. I didnât post it before as it doesnât fit neatly into any of the threads - rapamycin, glucose control, GLP-1 and anti-diabetics, pancreatic health. But because it focuses so much on the inflammatory aspect, I guess Iâll post it in this thread, even though it doesnât really fit perfectly. I would strongly urge anyone interested in understanding these issues to read the whole paper to really get a good grounding in the underlying physiology. Enjoy!
mTOR: A double-edged sword for diabetes
https://jlb.onlinelibrary.wiley.com/doi/full/10.1002/JLB.3MR0317-095RR
Thank you for sharingâthis is a very interesting paper.
The effect of rapamycin on β-cells and insulin resistance is a topic Iâm particularly interested in. It provides insights that complement other papers I have read regarding its impact on calcium uptake.
I asked Opus 5.5 (extra high mode) to reconcile these papers, specifically focusing on my context: glucose dysregulation, pulsed rather than chronic rapamycin, and non-T1DM.
Here it is:
Short answer: the review doesnât contradict the calcium idea, but it doesnât support it either. It is about how diabetes develops (immune cells and islet growth) and rests almost entirely on rodent and cell-culture work. The calcium paper youâre remembering (Lombardi 2017) is real. Its âcalciumâ finding is best read as one side of a mitochondrial defect in how β-cells link glucose metabolism to insulin release. A second group described the same defect from the Krebs-cycle side. The bigger issue for you is different: nothing yet shows that a β-cell mechanism causes your ~1-week CGM rise. And your protocol has a built-in confound that could produce the same signal without rapamycin. I also need to retract several things I told you in May.
| Review section | Relevance | Why |
|---|---|---|
| Immune half (NK, CD8, Th1/Th17, M1 cells destroying islets) | None | This describes autoimmune or inflammatory β-cell injury. Your GAD65, IA-2 and ZnT8 antibodies were all negative (2026-07-22) and hs-CRP is 0.44. Your NK count of 490 is a blood finding, not islet infiltration. |
| β-cell growth and mass (mTORC1 â cyclin D2) | Negligible | This is slow mass adaptation in rodents. It canât produce a reversible 1-week signal. |
| mTORC2 â β-cell toxicity (Barlow 2012, ref 122) | Possible, but needs prolonged exposure | Rapamycin inhibited mTORC1 acutely, but the toxicity tracked mTORC2 dissociation and loss of PKB (Akt) activity. Knocking down RICTOR to inactivate mTORC2 selectively reproduced the toxicity of chronic rapamycin. (C) |
| Liver glucose production (Houde 2010, ref 53) | A real candidate | In rats given 2 mg/kg/day for 15 days, the liver switched on its glucose-production (gluconeogenic) program and caused severe glucose intolerance, even though hepatic insulin signalling to Akt was preserved. Chronic dosing again, and apparently not via mTORC2. (C) |
The review also states that inhibiting mTOR promotes insulin resistance. That is the chronic picture. The one acute human study points the other way. With amino acids infused to switch on mTOR, rapamycin raised insulin-stimulated glucose uptake by 17% at meal-like insulin levels, with no effect at low insulin. (B: one clamp study in healthy volunteers.) You eat 1.6 g/kg of protein and take leucine during runs. An acute pulse is therefore more likely to help muscle insulin action than hurt it. Peripheral insulin resistance is the least likely acute driver for you.
Lombardi 2017 tested rat β-cell lines plus mouse and human islets at 25 nM for 24 h:
Shimodahira 2010 (cited in the review) used rat islets for 24 h:
These two findings likely describe one lesion. ι-KGDH is one of the mitochondrial enzymes that calcium switches on. So less mitochondrial Ca²⺠uptake (Lombardi) and lower ι-KGDH activity (Shimodahira) are plausibly the same defect seen from opposite ends. Calcium is a node in that loop, not necessarily its root. (C: this link is my synthesis; neither paper tested it.)
What the paper does not show:
Sources:
Calcium handling here is a huge area, and would take us way outside the remit of the subject matter of this thread, so Iâm not going to comment on it, other than to signal yet again that in my view the impact of rapamycin on pancreatic beta cells is complex and overall deleterious. However⌠it is complex, meaning you can find rapamycin on both sides of the issue (especially when you look at endoplasmic reticulum stress in beta cells). And because when it comes to discussing medical issues I have impulse control problems, I cannot restrain myself from posting some important papers (apologies - it has nothing to do directly with âcardiovascular health 2026â).
Glucose Amplifies Fatty Acid-Induced Endoplasmic Reticulum Stress in Pancreatic β-Cells via Activation of mTORC1
Autophagy plays a protective role in endoplasmic reticulum stress-mediated pancreatic β cell death
https://www.tandfonline.com/doi/full/10.4161/auto.21994
It is not for no reason that rapamycin coupled with glucose control agents results in superior health/longevity outcomes. Specifically, I believe it has to do with those agents which lower insulin demand, release and overall levels. Acarbose for example prevents the sharp bolus demand for insulin by eliminating glucose spikes. That leads to lower insulin demand and doesnât hammer beta cells as much. It is especially important to take an SGLT2i if you are on rapamycin, because you are dumping glucose which doesnât need to be handled by more insulin release. When taking rapamycin, you should adopt all measures to lessen stress on pancreatic beta cells.
CAUTION: Chinese paper
Lactoferrin influences atherosclerotic progression by modulating macrophagic AMPK/mTOR signaling-dependent autophagy
âThis study aimed to explore the role of lactoferrin (LTF) in atherosclerosis (AS) and its possible mechanisms. Human left coronary artery tissues were collected and divided into control (CON), coronary heart disease (CHD) and sudden coronary death (SCD) groups. Pathologic changes (including changes in the coronary plaque area, necrotic core, collagen fibers, and foam cell content) were observed. The LTF, P62, and 4-hydroxynonenal (4-HNE) expression levels were assessed. The ApoE â/â AS mouse model was established. The pathological changes and related protein levels were analyzed after autophagy inhibition. The foam cell model was constructed using an ox-LDL-induced human monocyte line, THP-1. The LTF, BECN1, LC3-II/I, AMP-activated protein kinase (AMPK)/the mammalian target of rapamycin (mTOR) pathway proteins, B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), and 4-HNE expressions were then detected after silencing of LTF or BECN1. Plaque stability was significantly lower in the SCD group compared to the non-SCD group (p < 0.05). LTF, P62 and 4-HNE levels in plaques increased as plaque stability decreased, and LTF was significantly correlated with plaque progression and autophagy levels. Autophagy inhibition by U0126 leads to the worsening of aortic luminal stenosis, increased necrotic core and foam cell deposits, decreased autophagosomes, reduced LTF expression, and upregulated P62 expression in AS mice. It was further demonstrated that LTF expression correlates with autophagy. LTF expression was increased in ox-LDL-treated THP-1 cells, and silencing BECN1 and/or LTF increased mTOR phosphorylation and 4-HNE levels, inhibited BECN1 and LC3 II expression and AMPK activation, and simultaneously decreased the Bcl-2/Bax ratio. LTF might alleviate AS pathology through accelerating the AMPK/mTOR pathway, and suggested that LTF may be a potential predictive molecule for AS.â
