In this very recent study we see that many people, even those with extremely high LDL’s as in familial hypercholesterolemia, do not develop plaque and do not have cardiac events. Even within family members there is a significant discrepancy.
The authors concluded that this is because there are many modifiable risk factors beyond LDL cholesterol even in this group with LDL’s > 190.
CAC scores as well as emerging other technologies will be able to tell us who needs a plethora of meds to control their cholesterol levels.
Well, only 10 to 15% of smokers develop lung cancer so CVD isn’t the only disease with multiple modifiable causal variables. But yes, I’m totally on board with screenings assessing both calcified and (especially) non-calcified soft plaque burden. A few points: they should have used apoB, not LDL cholesterol, as the marker; the study found that those with high LDL and soft plaques had a high event rate even without calcified plaques, so it’s critical to be able to look at more than just calcium, and finally the authors mention that their follow up was only 4 years and that the findings should not discourage lowering of LDL with inexpensive meds such as statins in high-LDL patients, but rather to help stratify whether or not such patients need even more aggressive LDL lowering with more expensive meds such as PCSK9 inhibitors, etc.
All that being said, directly viewing plaque burden (or lack thereof) with safe and readily available imaging methods is the way to go, and I’m excited for the future of the field! Not only will it make it easier to stratify risk, it will also make it easier to do studies assessing reversibility of plaques.
Costs me $100 USD for a CT coronary calcium to tell me pretty much everything about my totality of interventions as they relate to CVD risk.
How many people do you know who have had a CT coronary calcium scan?
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I would say not many.
I have a guy 40 years old with a brother and father both with a heart attack in their 40’s. I’ve been trying to get him screened for 2 years.
Most people, especially men, aren’t proactive with their health and only react when something happens.
I would surmise that rapamycin users are an exception.
As I suspected. I know of no one.
We are “Healthy user bias” confounders.
No idea – I’ve never asked. What I’m not clear on is whether the newer CTs can pick up soft plaque. Apparently they only used CT in this study, yet they report on soft plaque, so if that’s the case then this tech has come a long way since my last scan 10 years ago.
Maybe, I have asked this before. Why do you think my doctors, including my cardiologist, don’t give a damn about a CT coronary calcium scan and my insurance won’t pay for it anyway?
I know many Youtube doctors recommend it.
Isn’t it odd though that even in symptomatic patients, meaning chest pain believed to be cardiac in nature, and LDL ‘s as high as 154, only a little over a half had any plaque at all, calcified or non calcified? In those with extremely high levels over 190 , most likely representing familial hypercholesterolemia that they’ve had over most of not all of their life, only 64% have any plaque?
I mean shouldn’t practically all of them at least have plaque?
I realize that ApoB is the flavor of the month but LDL is still strongly looked upon by almost all physicians as a major risk.
The telling conclusion is that LDL should be viewed along with other risks.
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I don’t really know since multiple studies have shown it to have excellent prognostic value even out to 10-15 years.
When I had mine done my Hopkins cardiologist who ordered it called and said, “ go ahead and exercise because you’re not having a heart attack over the next 10 years, and probably never”.
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I’d consider LDL particles (or Lp(a), for that matter) to be “necessary but not sufficient” for CVD. Clearly other genetic/nutritional/behavioral factors can partially and even fully prevent plaque buildup that would otherwise occur in the presence of high LDL.
ApoB isn’t just the flavor of the month. The research showing that particle # is critical, not the amount of cholesterol on the particles as a whole, has been building for years if not decades. Just because most medical providers are still only measuring LDL (and not ApoB or Lpa) because they don’t know any better doesn’t mean it’s the right thing to do. Old habits die hard.
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So there must be a study showing primary prevention of cardiac events even in those with no other risk factors except an increase in ApoB levels. I guess that’s anything above 100?
I don’t know, but if there isn’t one yet, you can choose to keep waiting but I’ll go with where the overwhelming evidence points, which is that ApoB is a better marker of risk:
Apolipoprotein B Particles and Cardiovascular Disease.
Recent Mendelian randomization study:
https://www.thelancet.com/journals/lanhl/article/PIIS2666-7568(21)00086-6/fulltext
“Higher apoB shortens lifespan, increases risks of heart disease and stroke, and in multivariable analyses that account for LDL cholesterol, increases risk of diabetes.”
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Agreed that ApoB is a good add on, not totally convinced that it should completely replace HDL and triglycerides. If I’ve had a heart attack or multiple risk factors I’d want it under 90. In general I’d like it under 130 if no risk factors.
But the question still remains, what do we do about the modest to moderate increase that may occur secondary to rapamycin.
Do we consider other risk factors?
Does it just depend on a certain cut off number?
Is the rapamycin protective in and of itself?
Does the lipid elevation indicate that rapamycin is working? Like a biomarker.
These important questions are still unanswered but I continue to believe that rapamycin is protective via multiple mechanisms.
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From everything I’ve seen in recent years, measuring/treating HDL cholesterol is a waste. It has correlations but no apparent causation. Supplements like niacin that raise HDL are worthless, and the CETP drugs that raise HDL bombed as well (although one of them might be making a comeback, but not because it raises HDL). I’d consider ApoB, Lp(a) and TG to be the “big 3” that give by far the simplest, easiest, clearest picture of lipid risk.
In a person taking rapamycin who experiences significantly elevated ApoB and/or TG (no idea what if anything rapa does to Lpa), I’d get baseline coronary calcium CT and then treat the lipid elevations with diet modification and if necessary a quality low risk supplement such as amla or citrus bergamot and follow lipids carefully. If one has no risk factors, zero plaque and chooses to let the lipids go without treatment, I’d at least get a follow up scan within a few years or so.
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I’d say HDL is more U shaped than worthless. Sweet spot seems to be 40-60.
At what level of ApoB and or triglycerides would you intervene if secondary to rapamycin?
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I wouldn’t intervene, since I practice dermatology and don’t prescribe rapamycin. 
But, how about 100 for each? Somewhat subjective based on other risk factors, calcium score, personal medical history, family history, etc. 75 nmol/L for Lp(a), since that’s when risk apparently starts going up, regardless of whether Lp(a) is worsened by rapamycin or not.
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Here’s something else to consider. I’ve been arguing that we need to tread carefully with a drug like rapamycin that has been shown to improve both health and lifespan even when a side effect appears deleterious like increased lipids.
Rapamycin is not the only drug associated with elevated lipids, clozapine, a semi-miraculous drug for schizophrenia, is also known for this side effect. Clozapine is , like rapamycin, hydrophobic and mixes very poorly with water.
Here’s a study showing that the increase in lipids controls the clinical response to the drug. This is particularly true for elevated triglycerides which assist with the absorption, pharmacokinetics, and distribution of the drug ,as well as driving it across the blood brain barrier. It would seem that lipid elevation is directly correlated with clinical responses to the drug, and those treated with statins to address this issue experienced clinical relapse.
Could this also be the case with rapamycin? Could this explain why some of us have a significant and robust response especially early on in the course? Do those with no symptomatic improvements also have no lipid elevation?
It’s worth considering before tinkering too much with the drug.
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The study
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Protective effect of lycopene on serum cholesterol and blood pressure: Meta-analyses of intervention trials
Our meta-analysis suggests that lycopene taken in doses ≥25 mg daily is effective in reducing LDL cholesterol by about 10% which is comparable to the effect of low doses of statins in patient with slightly elevated cholesterol levels.
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The study is associational at best, very weak at true underlying mechanistic pathways. But it was way back in 2007.
“this study highlights the possibility that clozapine’s pharmacological and thus therapeutic activity is associated with serum lipids” They didn’t look at anything related to mTOR, purely conjecture mechanism pathways such as the drug hitching a ride along the VLDL highway and crossing the BBB.
Compare to this paper, which actually proves Rapamcyin dysregulates trigyclerides.
Fast forward 2021:
Mechanistic/mammalian target of rapamycin and side effects of antipsychotics: insights into mechanisms and implications for therapy
https://www.nature.com/articles/s41398-021-01778-w.pdf
“In two previous studies, enhanced mTOR activity disrupted hepatic lipid homeostasis by regulating the expression of sterol regulatory element-binding protein-1c (SREBP-1c) transcription factor. Congruent with this report, other studies found that olanzapine significantly increased SREBP-1c expression, which was suppressed by inhibiting mTORC1 activity with rapamycin. These studies suggest that olanzapine simultaneously activates the mTOR and AMPK pathways that may mediate metabolic complications, and provide evidence that the hepatic mTOR signaling pathway has a central role in the pathogenesis of antipsychotic drug-induced metabolic side effects. In conclusion, multiple lines of evidence indicate that hepatic mTOR signaling is a critical pathway in the antipsychotic-induced glucose and lipid metabolism, which may contribute to weight gain, MetS and other complications”
I haven’t looked too deep, and perhaps they weren’t looking and/or was of inconsequential concern, but in the hundreds of studies of chronic rapamycin dosing cohorts (vast majority cancer, years+ on Rapamycin, lipids dysregulation very common), was CVD NEVER a secondary endpoint finding? Surely this would be a signal outcome? Maybe the data dosen’t even exist.
Does Dr Green ask his patients for CT cardio scan before/after? Given the number of patients he has, this would be some amazing data.
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