What's the best statin to take?

[adssx]

I assume that the slight (and not statistically significant) increase of CRP concentration for CETP inhibitors is based on the trials of failed CETPi? Did they report CRP in obicetrapib trials?

@AnUser as you’re our lipid expert, do you have any thoughts on this by any chance: What's the best statin to take? - #317 by adssx ?

[AnUser]

HDL can be atherogenic at high levels iirc. If you substract HDL from total cholesterol you get the mass of all the atherogenic apoB particles, and it is also predictive in a different way, said as non-HDL-c. So amount of apoB particles matter but also the mass of them. I haven’t seen such 3D graph iirc but it would be interesting to see. HDL doesn’t do anything for ASCVD as there have been numerous CETPi that have failed and they pretty much only raised HDL. The only one with some effect decreased LDL as well but they didn’t bring it to market. The new CETPi decreases LDL by a lot too.

[adssx]

Thanks. Yes, I wonder whether “the lower the better” for ApoB could be correct as long as, for instance, your total cholesterol doesn’t go below a certain threshold (and isn’t too high either). Anyway, the obicetrapib and obicetrapib/ezetimibe trials might indirectly answer this question. Can’t wait to have the results.

[L_H]

On the HDL point. This gives a good overview on how and when hdl is antiatherogenic. I’d love to see something more recent

The metabolism and anti-atherogenic properties of HDL - PMC.

" The best known of these is their ability to remove cholesterol from cells, such as macrophages in the artery wall, in the first step of the reverse cholesterol transport pathway (5). HDL also inhibit LDL oxidation (6), promote endothelial repair (7), improve endothelial function (8), have anti-thrombotic and anti-inflammatory properties (8, 9), and inhibit the binding of monocytes to the endothelium (10). In addition to preventing atherosclerotic lesion progression, HDL also promote lesion regression in animals"

[adssx]

Gilles Lambert, co-author of this 2009 (!) paper published this in 2023: HDL as a Treatment Target: Should We Abandon This Idea?

High-density lipoproteins (HDL) have long been regarded as an antiatherogenic […] Unfortunately, neither increasing HDL with drugs nor direct infusions of reconstituted HDL have convincedly proven to be positive strategies for cardiovascular health, raising the question of whether we should abandon the idea of considering HDL as a treatment target. […] The results of two large clinical trials, one testing the latest CETP inhibitor Obicetrapib and the other testing the infusion of patients post-acute coronary events with reconstituted HDL, are still awaited. If they prove negative, these trials will seal the fate of HDL as a direct therapeutic target. However, using HDL as a therapeutic agent still holds promise if we manage to optimize their beneficial properties for not only ASCVD but also outside the cardiovascular field.

Lambert’s 2009 paper is also cited in this 2023 Iranian paper: HDL-cholesterol concentration and its association with coronary artery calcification: a systematic review and meta-analysis

According to this analysis of observational studies, high HDL-C levels were not found to predict protection against CAC. These results suggest HDL quality rather than HDL quantity is important for certain aspects of atherogenesis and CAC.
Interestingly, some observational clinical studies have indicated an association between different HDL subfractions and CAC. […] In a cross-sectional study, HDL-P and medium size HDL-P were protective against CAC (OR: 0.42 (0.22, 0.79), 0.002 and 0.36 (0.19, 0.69), 0.006, respectively), while large HDL-P and average size HDL-P were not (OR: 0.77(0.33, 1.83), 0.29 and 0.72(0.35, 1.48), 0.58, respectively).
HDL size is also a determinant of the anti-atherogenic properties of HDL. […] In another cross-sectional of Healthy Women Study, large HDL was inversely associated with CAC, but small HDL was not.
Thus, there is a controversy between the results of HDL particles and subfractions with CAC. This is probably due to the absence of a unique gold standard to measure the functional and physical characteristics of HDL subfractions among studies. Lack of standard and easily applicable methods to analyze and detect HDL particles and subfractions, limits their clinical usefulness for the assessment of cardiovascular risk. Therefore, further studies are needed to fully understand the impact of HDL subfractions and HDL-C in atherosclerotic CVD risk stratification in para clinics and different populations

[L_H]

Yes that’s very interesting, quality not quantity may be the critical thing.
It got me wondering whether there are any MR studies on this. There are genetics associated with higher hdl, so you’d expect to see some papers.

All I’ve found so far relates to infection, not cvd.

“Mendelian randomization using genetic variants associated with HDL-C as an instrumental variable was consistent with a causal relationship between elevated HDL-C and reduced risk of infectious hospitalizations”

https://www.ahajournals.org/doi/10.1161/ATVBAHA.119.313381#:~:text=Mendelian%20randomization%20using%20genetic%20variants,method%2C%20P%3D0.001).

[L_H]

Found a recentish paper

https://www.metabolismjournal.com/article/S0026-0495(20)30215-8/fulltext

Results
Genetically determined HDL cholesterol and apolipoprotein A-I levels were not associated with CAD.
HDL mean diameter (β = 0.27 [95%CI = 0.19; 0.35]), cholesterol levels in very large HDLs (β = 0.29 [95%CI = 0.17; 0.40]), and triglyceride content in very large HDLs (β = 0.14 [95%CI = 0.040; 0.25]) were directly associated with CAD risk, whereas the cholesterol content in medium-sized HDLs (β = −0.076 [95%CI = -0.10; −0.052]) was inversely related to this risk.

[Neo]

@L_H @scta123 you’ve both in the past asked for my perspective / why I weigh going after Apo B in an aggressive way. This paper hits many of those reasons so I thought I’d share it.

There is urgent need to treat atherosclerotic cardiovascular disease risk earlier, more intensively, and with greater precision: A review of current practice and recommendations for improved effectiveness

The relationship between low-density lipoprotein cholesterol (LDL-C) and risk for ASCVD is one of the most highly established and investigated issues in the entirety of modern medicine. Elevated LDL-C is a necessary condition for atherogenesis induction. Basic scientific investigation, prospective longitudinal cohorts, and randomized clinical trials have all validated this association. Yet despite the enormous number of clinical trials which support the need for reducing the burden of atherogenic lipoprotein in blood, the percentage of high and very high-risk patients who achieve risk stratified LDL-C target reductions is low and has remained low for the last thirty years. Atherosclerosis is a preventable disease. As clinicians, the time has come for us to take primordial and primary prevention more serously. Despite a plethora of therapeutic approaches, the large majority of patients at risk for ASCVD are poorly or inadequately treated, leaving them vulnerable to disease progression, acute cardiovascular events, and poor aging due to loss of function in multiple visceral organs. Herein we discuss the need to greatly intensify efforts to reduce risk, decrease disease burden, and provide more comprehensive and earlier risk assessment to optimally prevent ASCVD and its complications. Evidence is presented to support that treatment should aim for far lower goals in cholesterol management, should take into account many more factors than commonly employed today and should begin significantly earlier in life.

https://www.sciencedirect.com/science/article/pii/S2666667722000551

Can be paired with this figure that Tom Dayspring recently tweeted

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@Neo

There is urgent need to treat atherosclerotic cardiovascular disease risk earlier, more intensively, and with greater precision: A review of current practice and recommendations for improved effectiveness

Interesting paper; thanks for sharing. I like their recommendations:

We recommend:

• Progression of atherosclerosis seems unlikely when all these conditions are met:
  • LDL-C in all previous years never exceeds 85 mg/dl
  • Non-HDL-C is below 100 mg/dl
  • There are no significant enhancing factors
  • The patient is fit and follows a healthy lifestyle (such as the AHA Seven Healthy Habits)
  • Medications would not be indicated for these patients unless they develop plaque, but of course continued healthy lifestyle is vital.
  • These patients should be evaluated yearly to estimate risk if and when it develops.
• Treatment to reduce or at least halt progression of intimal changes is indicated when one or a combination of the following exists:
  • Patients have LDL-C consistently greater than 100 mg/dl or non-HDL-C > 110 mg/dl.
  • Plaque
  • Significant enhancing factors
  • Established ASCVD.
• Studies have shown that reversal of plaque begins when LDL-C falls below approximately 60–80 mg/dl and treatment is begun before significant scarring and calcification occurs.
• Thus, getting LDL-C below 40 mg/dl seems the most effective goal for patients in the category of more advanced atherosclerosis.
• Very advanced disease or very high risk would benefit from lowering LDL-C < 20 mg/dl.

[L_H]

Thank you, really useful to have one paper that looks at all this. I can see we may suffer from confirmation bias but looking at the recommendations, I feel reassured that my 60ish apoB is well in the recommended zone. I particularly liked:
“* Studies have shown that reversal of plaque begins when LDL-C falls below approximately 60–80 mg/dl and treatment is begun before significant scarring and calcification occurs.”

Where I disagree with the author is when they draw safety conclusions from 2 studies that only ran for 19 and 33 months respectively. “There is no apparent clinically significant harm from lowering LDL to even the very lowest levels (< 10 mg/dL)”.

Something I thought very interesting (and perhaps a little disingenous by the author):
" Based on the log-linear relationship of LDL-C to the hazard ratio for an acute ASCVD event, the LDL-C level where no excess risk occurs is approximately 38 mg/dL or 1 mmol/L [[64]] This value is consistent with the LDL-C levels observed among hunter-gatherer populations [[65]"

Of the 2 papers referenced for this quote - one doesn’t mention LDL at all. And the other actually states:
“Evidence from hunter-gatherer populations while
they were still following their indigenous lifestyles showed
no evidence for atherosclerosis, even in individuals living
into the seventh and eighth decades of life (15,16). These
populations had total cholesterol levels of 100 to 150 mg/dl
with estimated LDL cholesterol levels of about 50 to 75
mg/dl.”

One final thought - if our goal is to avoid atherosclerosis for say, 200 years in case other interventions allow for a super-normal lifespan, then simply reducing apoB to say, 35 ng/dl from 80 ng/dl won’t do that. It just reduces the annual risk by a further finite %. Which means that it increases the average expected age before atherosclerosis ‘sets in’. If, on average, at 80 ng/dl you’ll probably have atherosclerosis by age 100, then reducing it to 35 ng/dl will say, change that age to 115 or 120 years on average. And if we eat MacDonalds every day then that average won’t mean much - we might expect to suffer from cvd much much younger. BUT if we reduce oxidation and inflammation aswell as maintaining a low apoB, then there’s evidence that this could be avoiding and reversing atherosclerosis altogether. We know there are several cofactors for cvd, and at a policy level it makes sense to target something we have measures of and drugs for. But at an individual level - it makes sense to target all the cofactors because we can’t eliminate one of them (apo B) to zero.

[Neo]

@adssx

There are no significant enhancing factors*

It’s just that for me aging is the number one such factor - and I’m shooting for a healthy 120-140 years at least

Basically their figure below captures the concept - at some point almost everyone would hit the horizontal line (perhaps even with aggressive actions)

[AnUser]

What is the baseline statistical likelihood to reach above 100 years old, 110, 120 years, etc?

[Neo]

@L_H

if our goal is to avoid atherosclerosis for say, 200 years in case other interventions allow for a super-normal lifespan, then simply reducing apoB to say, 35 ng/dl from 80 ng/dl won’t do that. It just reduces the annual risk by a further finite %. Which means that it increases the average expected age before atherosclerosis ‘sets in’. If, on average, at 80 ng/dl you’ll probably have atherosclerosis by age 100, then reducing it to 35 ng/dl will say, change that age to 115 or 120 years on average.

Agree - for me that means that every extra 5-10 ng/dl matters

@L_H

at an individual level - it makes sense to target all the cofactors because we can’t eliminate one of them (apo B) to zero.

Agree. And aggressively. Aggressive on inflammation, aggressive on avoiding AGEs and glycation, aggressive on Lp(a) if one is not optimal on it, and aggressive on Apo B.

(And in general no stuff like McDonalds).

[Neo]

@L_H

hunter-gatherer populations

Think there were a lot of sucky things going on with our health when hunter-gathers

Other things you could triangulate with (from a Peter Podcast, have not looked at papers):

Now unfortunately, in the modern times, the apoB system is mostly a problem, not something we need ”‒ Dan Rader

Peter’s takeaway ‒ It’s not that we don’t need apoB, but if we could clear it more efficiently (like primates and other mammals) and walk around with 20 mg/dL (instead of 100 mg/dL), that would be the difference…

• Absent lifestyle things that raise apoB, it simply increases with aging

• Peter Libby has written eloquently about this‒ children and neonates have apoB concentrations similar to that of other animals

• As we age, the apoB concentration goes up; we are less efficient in clearing apoB from circulation

—

The latter points is one other reason why I want to keep Apo B aggressively low today, it might be become more difficult for me to keep that low if future decades

[Neo]

@AnUser

What is the baseline statistical likelihood to reach above 100 years old, 110, 120 years, etc?

With current methods I think 100 yrs relatively high for a person who does everything right, including early detection and then exponentially more difficult with 110 and 120 yrs

If the pace of scientific, medical and technological development of the last 1-2 decades continues each decade during our lives, the probability starts going up quite significantly

In the relatively likely scenario that the increase in the pace of scientific, medical and technological development of the last 1-2 decades continues the probabilities are even higher

For me even if there is just a 0.1% chance of reaching longevity escape velocity (my guesstimate is that it is much higher) and being able to experience the world of the next centuries and perhaps millennia and so much more life and adventure with family and friends (travel the solar system, experience incredible technological developments outside of medicine, etc, etc, etc) it’s worth investing effort, time and resources like crazy in health and longevity today and everyday

[L_H]

@Neo

for me that means that every extra 5-10 ng/dl matters

@L_H

at an individual level - it makes sense to target all the cofactors because we can’t eliminate one of them (apo B) to zero.

Agree. And aggressively. Aggressive on inflammation, aggressive on avoiding AGEs and glycation, aggressive on Lp(a) if one is not optimal on it, and aggressive on Apo B.

(And in general no stuff like McDonalds).

In terms of benefit. Given you current lipids, what do you calculate/estimate the impact of say a 10 ng/dl lowering of apob equates to in terms of your absolute risk of atherosclerosis by say 100 years old?

[Neo]

@L_H

calculate/estimate

I don’t think we really have this type of precision.

It’s just about making bets under uncertainty and trying to manage risk and reward as well as possible.

I can say that it is enough that I think it worth trying to add Eze to my overall approach and then evaluate and see how that feels and what happens with my bloodwork (including my Omega 3 Index numbers).

[L_H]

We don’t have precision but i think there is some value in estimating a ball park figure

My best guess is that being in the best 2% of apob + low inflammation, med diet, low dages etc. probably puts your 100 year old risk of atherosclerosis at below 0.5%

So another 10 mg/dl reduction for the next 50 years probably reduces this by less than 0.1%

So i guess the question is what is the risk to mortality of taking say ezetimibe for 50 years in order to achieve this?
That’s much harder to calculate but e.g if we have 10% lower ala absorption we could estimate an effect of that perhaps? Or maybe calculate the mortality risk impact of lowering muscle mass slightly. Or we could look at the kidney burden? Or the impact on brain function or immunity.

Given the things we can do that give a much higher mortality benefit and given that we really don’t (cant?) do everything, and that the side effects of any apob lowering medication are unknown, are there lower hanging fruit to focus on?

[AnUser]

How do you avoid Pascal’s mugging?

[Neo]

Adding Eze - test and evaluate - is not crowding out other “low hanging fruit” for me - so I think it’s more an “and” and not an “or”

As discussed before, my current medicines Repatha and soon Eze that I’ve been prescribed, are just my current decisions and not “50” year decisions. I will likely be making a lot of smaller and bigger changes over the next few years / decade not to mention over the next 50 years - as new data, testing, mechanistic understanding evolves