#2013

People sometimes fall into the trap that anything other than a RCT is worthless. That’s not true. If it were, then you wouldn’t have it published in one of the most prestigious heart journals , Circulation.

The observation that 40% of those studied in their 50’s have no plaque despite very high LDL levels is a piece of the puzzle. Not meant to be the final say, but it has value and shouldn’t be merely discarded. It would be meaningful to know how and why that group is protected.

1 Like
#2014

Higher levels of inflammation can lead to more susceptibility to plaque forming but without intervention, disease progression is only delayed.

1 Like
#2016

I forget the name of the book that publishes the pictures of artery disease in people who have died young. None of them had calcified plaque, but all had significant blockage. How were they measuring the plaque in the people studied in their 50s?

#2017

Plaque was determined by both coronary calcium scores and CCTA.

#2018

Here is what Alan Sniderman says (also talking to Peter) on the same topic.

We can’t make the disease go away (talking about damage to arteries). We can modify the effects of the disease or the consequences, but when we talk about LDL cholesterol and ApoB, the levels are so low now [with the current treatments], but you still have an artery that’s destroyed and so you are going to have a substantial number of events.

Earlier they talked about people with that had normal lipid levels dying at an early age and a family history of the same. They said there’s a lot we don’t know. And that’s correct. You can’t read a few studies or watch a few videos and become an expert.

3 Likes
#2019

Totally out of context, what he meant with that is that it’s too late to lower lipids in many cases. In this case I am advocating in trying to avoid the artery being destroyed, while others are waiting for it to happen before they try to lower lipids and events. Alan Sniderman is agreeing with me, naturally because I partly learned that from him.

And guess what conclusion they came to people with normal lipids level having a family history of dying young from the disease? Lower apoB, and earlier of course. I went back to the podcast to double check it.

I specifically cited Thomas Dayspring because he said exactly what I paraphrased. I didn’t avoid to cite Allan because he somehow is ‘disproving’ what I say, which he never did as you see. Lol.

#2020

The latest “Arrow” from Eades has a couple very interesting sections which taught me things. In the first he links to a doctor from Australia who talks about heart disease. She explains small dense LDL in a way I have never heard. It sounds like I should look again at AGE’s. Important:

https://michaeleades.substack.com/i/135379346/cholesterol-low-carb-cac-and-statins

#2021

Another one from the same “Arrow” was an explanation of Mendelian Randomization. I am actually pretty good at math, and have also had college level statistics that I understood. I’ve read quite a bit about MR, and still have failed to get a grip on what exactly is going on there. This guy is a fantastic explainer and I now know that I really, really didn’t understand what was going on there. I’m going to read it again, but thought I’d share that as well:

https://michaeleades.substack.com/i/135379346/mendelian-randomization

#2022

This short video is probably the clearest and the simplest explanation of mendelian randomisation I’ve heard. For those who prefer watching and listening to reading.

2 Likes
#2023

Michael Leades thinks RCT’s doesn’t show the LDL reduction lowers heart disease, while MR does and it confuses him. We even have metas of RCT’s showing statins decreasing all-cause mortality dependent on the LDL decrease. He didn’t question if he’s read the literature wrong or missed something. “He’s going to look into the MR results” at a later date. I’m guessing he’s going to do some mental gymnastics like other people with motivated reasoning, but I might be wrong. Just to fit the data to the conclusion he wants.

#2024

As a farmer I am always (yearly) trying to figure out what seed to buy. Trust me it matters. The difference is huge. If you look at trials done by farmers and touted by particular brands, they always show their brand is best. Stuff done by universities should be best, but there are ways to cheat, and they do. Money is really great at messing up objective trials.

University trials on medical stuff is very similar I’m sure. The pharma companies pay for the research. Universities are not rich, and reputation is for sale. I’m very cynical at this point. It doesn’t need to be a conspiracy and they may not be doing it on purpose.

I’m pretty agnostic still and just watching the show.

3 Likes
#2025

The only way to navigate these waters is to be able to understand, and read the methodology behind the research. If the paper methodology is sound, it’s a good heuristic to assume the result is as well regardless of the source of funding. Another important part is replication, meaning other labs can repeat the results.

There is lots of supplement studies with 1 study on 20 people touting it to be great, and so everyone “should” buy it. It’s not only in agriculture. If it’s repeated over and over, by different researchers, that’s very interesting. Common sense should separate the wheat from the chaff.

#2026

The development of polygenic scores, such as GPSMult, has provided valuable insights into the relationship between LDL-C levels, coronary plaque, and CAD risk. The GPSMult, developed by Khera et al. (2023), incorporates genome-wide association data across five ancestries for CAD and ten CAD risk factors. It demonstrated a strong association with prevalent CAD and outperformed previously published CAD polygenic scores across all ancestries [1].

In addition to genetic factors, the role of LDL-C lowering therapies has been studied extensively. The US Preventive Services Task Force (USPSTF) review found that statin therapy for primary prevention of CVD reduced the risk of all-cause mortality and CVD events consistently across different demographic and clinical populations [2].

However, the effectiveness of LDL-C lowering therapies may vary among individuals. The YELLOW-3 trial (NCT04710368) investigated the effect of PCSK9 inhibitors on coronary artery plaque stabilization in patients with high LDL-C levels despite statin therapy. The trial found that PCSK9 inhibitors failed to stabilize the fibrous cap in 20% of patients, suggesting that additional factors may be needed for effective treatment [3].

In conclusion, the combination of polygenic scores, such as GPSMult, and findings from studies like the YELLOW-3 trial and the USPSTF review, provide valuable insights into the relationship between LDL-C levels, coronary plaque, and CAD risk. However, more research is needed to fully understand the complex mechanisms underlying these associations and to develop personalized treatment strategies for individuals with high LDL-C but no plaque.

Sources:
[1] Khera, A. V., Chaffin, M., Zekavat, S. M., Collins, R. L., Roselli, C., Natarajan, P., … & Kathiresan, S. (2023). A polygenic score for coronary artery disease across multiple ancestries and its application to incident events. Nature Medicine, 29(2), 1793-1803. Link

[2] Chou, R., Dana, T., Blazina, I., Daeges, M., & Jeanne, T. L. (2016). Statins for prevention of cardiovascular disease in adults: evidence report and systematic review for the US Preventive Services Task Force. JAMA, 316(19), 2008-2024. Link

[3] ClinicalTrials.gov. (March 2023). Effect of Evolocumab on Coronary Artery Plaque Volume and Composition by CCTA and on Non-culprit Lesion FCT (YELLOW-3). Link

2 Likes
#2027

AnUser, no once again you are correct and completely incorrect. Again, you show the limits of a non-doctor who watches a few YouTube videos. If you listen to the podcast, he is saying that even if you have a CAC score of 0 the disease is still progressing. He says that no one has arteries that do not have arterial damage in today’s society.

He is not agreeing with your simplistic reasoning. Everyone would agree that if you start lowering lipid levels before age 30 then you will not have arterial disease and MI. But no one does that, and it is naïve to think that if you start dramatically lowering lipid levels late in life, you will not have cardiac events.

Thomas Dayspring does say this and it is good advice. It is certainly the advice I am following and I am hoping for the best just as he is. But even with statins and improved drugs, the deaths from cardiac events are still increasing.

1 Like
#2028

Which I don’t disagree with.

What does ‘no one’ mean? It’s probably not literal.

I don’t disagree with this either.

I see that I didn’t make myself clear, I meant it doesn’t develop with very long maintenance of physiologic apoB levels. I’m not sure I understand why ASCVD continues to develop if you drop apoB to physiologic levels even with CAC 0 but that would be an interesting question to ask.

#2029

I rarely disagree with anything you say. But you don’t know how much you don’t know. That is a blind spot.

1 Like
#2030

This article is a sobering reminder of how much we still don’t know. See the discussion section in particular.

“ the residual risk of CVD after optimal statin treatment remains at about 50%”

4 Likes
#2031

I don’t think so, but you’re free to tell me what my blind spot is.

#2032

After skimming over this article, the author is presenting a hypothesis of why cardiovascular diseases are not completely avoided with statin therapy (residual TRLs).

It is significant that many people using statin therapy still have a residual risk of developing ASCVD and cannot meet their target LDL-C targets

The remaining risk may very well be related to LDL levels remaining too high even with statins. But assuming the author’s hypothesis is correct, he is presenting ways to further decrease risk by eating healthier (less sugar and processed carbs) along with taking medications such as PCSK9 inhibitors, ezetimibe, niacin, fibrates and omega 3 which all lower triglycerides.

1 Like
#2033

I found it to be a very detailed and comprehensive review of the role of remnant cholesterol in the development of CVD. More complicated than LDL or ApoB alone.