Zero cardiovascular risk

[mccoy]

This topics relates to chapter 7 of peter's Attia book 'Outlive', discussed in another thread.

Now, the proposed strategy is to eradicate the main cause of atherosclerosis (hence, cardiovascular disease), by taking back the blood ApoB levels to the physiological levels of babies, specifically, to 20-30 mg/dL. This strategy of course involves the use of cholesterol lowering drugs, like statins and more (typically, two kinds of drugs).

My question:

Would you guys with an already optimal lipids panel (by conventional definitions) contemplate the adoption of Peter's Attia strategy to decrease the atherosclerotic risk to zero, by taking cholesterol lowering drugs?

Can you come up with significant drawbacks or pitfalls to this strategy? Knowing that the potential side-effects of statins can be avoided by choosing other drugs?

 

 

Edited April 22, 2023 by mccoy

[Guest]

That's the distribution of causes of death by age group in the US (from the cdc):

Given it's enormous share in causes of death among the (very) old, it seems reasonable to emphasize prevention. It's not just about longevity, but also quality of life - which tends to take a sharp downturn with advanced ASCVD (certainly after your first hearth attack or stroke).

 

The current data-situation supports the notion, that very low levels of APOB-bearing particles will stop the progression of ASCVD - or even reverse it (albeit very slowly). Now how aggressive you'll need to be depends on your personal risk. However, advanced age generally is the most prevalent risk. So there is a point to try to lower "elevated" APOB by medical means if necessary, if you're older than, say, 50. Where "elevated" could mean anything above 60/70 mg/dl.

However, not all drugs are the same. For example ezetimibe/zetia is successful in lowering LDL/APOB - but no study was able to find an effect on mortality. This could be a hint, that there are unaccounted for side effects. That not a new thing: the first fibrates on the market where hailed for lowering LDL. But long-term analysis demonstrated that they increased mortality. And there is indeed a large-scale ex-post cohort analysis in South Korea, that shows increased mortality with ezetimibe,

Long story short: you only should consider LDL-lowering drugs, that are proven to lower all-cause mortality.

Statins - for better or worse - are part of that category. And for the vast majority of people they are the best option, because PCSK9-inhibitors are damn expensive and require a doctors consultation every 14 days. Also one of the 2 inhibitors on the market has somewhat unclear data on all-cause mortality.

[Guest]

To supplement my comment - here are the results of the most recent meta analysis of the effects of ezetimibe and PCSK9 inhibitors:

https://hospitalhealthcare.com/clinical/cardiovascular/meta-analysis-finds-pcsk9-inhibitors-and-ezetimibe-combined-with-statins-reduce-non-fatal-mi-and-stroke-in-high-risk-patients-but-not-death/

and the underlying study in the BMJ:

https://boris.unibe.ch/169782/1/bmj-2021-069116.full.pdf

 

Ezetimibie cannot be universally recommended. The data on mortality (cardiovascular or all-cause) is pretty clear: there is no benefit. Note: this is also true comparing patients taking ezetimibe monotherapy vs. placebo patients taking nothing else - i.e. not even statins. Why is there no benefit? We don't really know, as there hasn't been sufficient collection of data by the drug maker. It could be, that it's simply too weak an effect. Or it could be negative side effects that increase the risk of ASCVD or some other cause of death through some other mechanisms.

PSCK9 inhibitors are a little more complicated. Evolocumab has confusing data on mortality at best. Alirocumab on the other hand got data for a clear benefit on all-cause mortality. As the meta analysis is combining both drugs, the net result is "no benefit" for mortality in their study. Interestingly Peter Attia commented as to injecting Alirocumab.

That leaves statins, fibrates and bile acid sequestrians. Of which statins by far have the best data for effects and least side effects. This is not to say that they don't have side effects. Just that lowering you LDL by 50 mg using statins is much easier and a  much more pleasant experience than trying the same with fibrates and bile acid drugs.

[mccoy]

Thanks Guest for your insights, I spoke with one medical doctor who raised questions about the availability of PCSK9 inhibitors, here they may be available only to those with serious cholesterol problems (probably high Lp(a) by inherited genes). I'm going to ask the local pharmacy because, if this is so, it would be the end of it as a potential general preventive measure in Italy, whatever the literature reports are.

Your comments would constitute a good question to pose to Dr Attia himself, also that article is based on high risk patients, what about a preventive scheme, would the reasoning be more or less valid?

And of course, if we are in the 5% individuals who suffer muscle soreness and elevated liver enzymes from statins, we would have little other choice other than ezetimibe and fibrates.

Edited April 24, 2023 by mccoy

[mccoy]

I read the linked article, and it turns out they have separated the group with lower risk. The conclusions seem to rule out the use of cholesterol lowering drugs other than statins even in patients with low risk. A really puzzling issue, why the additional drugs lower non fatal MI and stroke but not the fatal ones, or alternatively introduce other mortality risk factors.

Quote

 

The authors also found that among patients with low to moderate risk of cardiovascular disease, adding either a PCSK9 inhibitor provided no additional benefit over statin therapy alone. In other words, it was only patients with the highest cardiovascular risk who benefited from adding either ezetimibe or a PCSK9 inhibitor to their statin. Similar reductions, again only among high or very high risk individuals and a lack of mortality benefit, were observed in patients intolerant of statins.

The authors concluded that the benefits of adding PCSK9 inhibitors and ezetimibe were limited largely to patients only with a high or very high cardiovascular risk.

 

[mccoy]

I find it useful to report the conclusions in the BMJ paper itself. Actually, in the context of a preventive therapy for those with low risk, the results would deny the use of drugs other than statins.

Quote

All-cause and cardiovascular mortality When used as monotherapy or combined, ezetimibe or PCSK9 inhibitor therapy had no impact on all-cause and cardiovascular mortality (table 3).

Quote

Discussion Principal findings In this network meta-analysis of 83660 individuals receiving maximal statin therapy or intolerant to statin therapy, ezetimibe or PCSK9 inhibitor may reduce non-fatal myocardial infarction and stroke in adults at very high or high cardiovascular risk, but not in those with moderate and low cardiovascular risk. Adding ezetimibe or PCSK9 inhibitor to the background lipid-lowering therapy had no significant effect on all-cause or cardiovascular mortality. Thus, patients with the most significant cardiovascular risk may gain maximum benefits, whereas those with moderate to low cardiovascular risk achieve trivial absolute reductions in non-fatal myocardial infarction and stroke. Similarly, ezetimibe or PCSK9 inhibitors in statin-intolerant patients may reduce myocardial infarction and stroke among patients with very high and high cardiovascular risk. Overall, PCSK9 inhibitors seemed to have the highest absolute reductions in myocardial infarctions and strokes when added to background therapy, followed by ezetimibe.

[mccoy]

I've checked PCSK9 inhibitors at the local pharmacy. It turns out that in Italy they are not in commerce, they are apparently administered only in hospitals to individuals who have had MI, strokes or similar. 

[Ron Put]

As I posted elsewhere, I would take Attia with a large grain of salt, even if I find his shows informative on many topics.

Statins in healthy people may not be a solution, as they tinker with the body's ability to make cholesterol, and we all need that 🙂 There are questions about diminishing brain functionality, as well as potential insulin resistance and other issues, which for healthy people may not be worth the risks.

Was this, for example, posted already?

Long-Term Outcomes of Short-Term Statin Use in Healthy Adults: A Retrospective Cohort Study

"Conclusions: Short-term statin use for primary prevention in this healthy cohort was associated with an increased risk of long-term diabetes and diabetic complications without cardiovascular benefits. Further study using pragmatic studies and prospective observational studies appropriately equipped to eliminate unidentified confounders are urgently needed."

[Saul]

I agree that it's ridiculous for people with good lipid levels to take statins.

  --  Saul

 

[Guest]

@ Saul:

I guess this is hard to come to conclusion about without putting some numbers to it. What is a good lipid level? Conventional wisdom for people in primary prevention would say that anything below 100 mg/dl in LDL-C is "good". However, people like Peter Attia, Tom Dayspring and Allan Sniderman (the latter 2 are very well respected researchers, who almost single handily shaped the modern view on blood lipids over the past 40 years) make a reasonable point, that anyone is at high risk for ASCVD if someone is living long enough.

See the graph from the CDC that I posted earlier.

There is good data out off large randomized placebo controlled clinical trials and genetic cohort studies demonstrating, that APO-B/LDL-C levels substantially below 100mg/dl confer additional benefit for cardiovascular mortality and all-cause mortality. Up to a point where the progress of ASCVD can be virtually stopped.

How to get to those low levels is someones personal journey. But drugs can reasonably play a part in that. It is prudent to be skeptical about a particular drug, of course. Even among the same class of drugs, there can be large variations. Alirocumab has much more convincing data than the other PCSK9-inhibitor on the market - Evolocumab. The first fibrates increased mortality - whereas modern fibrates do the opposite. There was a statin called Lipobay in the early 2000s that had 20-80 times the rate of serious side effects than it's competitors - Bayer Pharma deceived the public about that, got sued for billions and had to pull it from the market. And ezetimibe has no effect on mortality, not even cardiovascular, despite lowering LDL - which can make you question what kind of long-term side effects lurk in the background.

But don't throw out the baby with the bathwater. Modern statins - particularly the high-potency ones Atorvastatin and Rosuvastatin - have long term data showing decreased all-cause mortality. And in proportion to the level of LDL-lowering. We are talking about 5 years of clinical trials and up to 15 years of well collected follow-up data, i.e. 20 years of total observation. So if Alirocumab is not possible to acquire and you prefer to not spend your days and nights on the toilet thanks to bile acid drugs - statins are an option that can be considered.

 

@ Ron Put:

That study is certainly not up to date. Just last year a major review in the UK found, that the diabetes risk of statins is negligible if you compare it with the ASCVD-benefit of statins. That's the reason diabetic patients routinely get statin prescriptions as part of their treatment.

[mccoy]

I've been pondering the issue for a while, listening to other opinions and so on. A dose of baby statin (5 mg crestor) could grant a reduction of 30-40% in cholesterol values, without significant side effects. The most known effect, myalgia, is controversial and often results equal to the placebo group in randomized trials.

Statin-induced myalgia and myositis: an update on pathogenesis and clinical recommendations

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6019601/

 

 

[mccoy]

I have heard about the mechanism which could cause side effects, such as a reduced peripheral synthesis of cholesterol, potentially deleterious in the muscles and in the brain. Also, an inhibition of Coq10 (which is part of the same cascade upon which the HMG CoA reductase acts) with negative consequences on mitochondrial functionality.

Fact is that such effects are dose-dependent, are associated to individual (genetic) propensities and could even be caused even by supplements such as fermented red rice, which has an active compound very similar to lovastatin (monacolin-K).

Bottom line, statins are reliable and powerful, they should be avoided by particular individuals such as those carrying ApoE4 alleles and so at risk of dementia, whereas muscle symptoms could be decreased by assuming supplemental Coq10 or by ceasing the statin-based therapy.

A drug not mentioned in previous posts is bempedoic acid, which has not effect on peripheral tissues but only in the liver, together with ezetimibe it can be as powerful as statins. Of course these two are not their potential collateral effects.

But everything has apparently its own risk, even fresh fruit, one of the healthiest food groups, can have the side effects of elevating blood glucose in individuals with some intolerance.

 

[mccoy]

I was almost forgetting the original concept: zero cardiovascular risk. I've been pondering more and it sounds even more promising. This procedure would entail to pose oneself within the 1st or 2nd percentile of the population, in terms of ApoB, LDL or non-HDL cholesterol, which would mean very low values of ApoB and LDL-C and less than 100 mg/dL TC. Probaly, even within the 5th percentile would avoid atherosclerotic processes.

For example, I'm almost 63. Atherosclerotic risk is cumulative and appears to be based on a long temporal horizon, such as 30 years, as proposed by Allan Snidermann and others. If I began my zero-CVD risk scheme presently, then I would theoretically be able to hit 93 years with no further accumulation of plaques, maybe even a reduction of those accumulated so far. Minimizing the probability of strokes and heart attacks beyond one's fifties would not be a trivial thing. Besides, that would let me free to concentrate on other causes of disease and death, such as cancer, dementia, metabolic dysfunction.

 

[Ron Put]

On 4/22/2023 at 2:19 PM, mccoy said:

Would you guys with an already optimal lipids panel (by conventional definitions) contemplate the adoption of Peter's Attia strategy to decrease the atherosclerotic risk to zero, by taking cholesterol lowering drugs?

I most certainly would not.

Attia has an agenda, as well as biases, that I disagree with, even though I regularly listen to him. Same for Dayspring.

Both dismiss nutrition by erecting straw men arguments, without adequately addressing the evidence supporting nutrition. Instead, they focus on pharmaceuticals to remedy what is more often than not caused by poor nutrition (including high-fat and high-protein diets). Dayspring claims that you could eat 20 eggs a day without any adverse effects in many of his appearances, yet has never addresses the fundamental contradiction that saturated fat is very likely to cause long-term detrimental effects, and that some dietary cholesterol is absorbed by virtually anyone, even the genetically lucky ones.

Dietary cholesterol and (primarily) animal fat will increase your LDL-C, and yes, will also increase your chance of an adverse event. Even the genetically luckiest have a reduced absorption of up to 40%, but first they are a small minority, and also even they can have increased cholesterol if eating 20 eggs a day. For most of us, the less dietary cholesterol and to a large extent, fat intake, the better.

mccoy, I checked a few of my genetic markers for LDL and no, I am not lucky at all. In my case, I attribute my relatively low lipids on diets, and to a lesser extent to exercise. Diet has by far the largest effect, for example eliminating olive oil dropped my cholesterol by about 30 points, based on my tests. Adding fats increases my numbers.

[mccoy]

I heard many experts in the field and they all agree that, as a rule, diet and lifestyle cannot solve serious cases of hypercholesterolemia. Also, as a rule, diet and lifestyle cannot bring cholesterol values down to neonatal values. That seems reasonable. Nobody said that diet and lifestyle have no use, Peter Attia and Tom Daysprings are the first ones to underline that some people who follow very high-fat ketogenic diets exhibit stratospheric LDL values, which are not acceptable, and this can be worked out by eliminating saturated fats.

Dr. Esselstyn senior clearly stated that some individuals who followed his very low fat diet could not take TC below 200 mg/dL, and that they needed statins. It is a known fact that diet and lifestyle alone cannot abate cholesterol below a certain measure.

Also, Tom Dayspring clearly stated that dietary cholesterol usually does not govern serum cholesterol, but this is not true in people who are hyper adsorbers. The example about 20 eggs is used probably to pinpoint the fact that absorption of dietary cholesterol has an upper daily threshold, more than that goes to waste. I've listened to about 15 or 20 podcasts from Daysprings and he surely does not reason the extreme way you construed.

Also, I would encourage you to read the book from Peter Attia, you'll understand his skepticism about nutrition. It is mainly driven by the confusion and disagreement present in the scientific literature. This aspect has also been explained by Jinny Messina in his interview I posted in another thread. Bias often rules supreme in nutritional studies. I noticed that pretty soon, and myself am pretty skeptic about all that is written on nutrition articles. Unfortunately, we should refer to unbiased or neutral nutritionists or other specific experts who know the literature well and are able to discern the truth from the claims. 

To go back to the OP, zero CVD: is it worth to individuals who already have low cholesterol levels to pursue this goal which necessarily entails the considerate and moderate use of pharmaceutical drugs? The concept has been clearly expressed by Dayspring, Sniderman, Attia. LDL particles are subject to random impacts against the arterial walls. The lesser the number of particles, the lesser the probability of impacts, the lesser the probability of plaque occurrence. Near to zero particles = near to zero atherosclerotic risk, to be projected on a 30-years temporal horizon. Is it worth for us to have no more buildup of plaques in 30 years from now? 

 

Edited June 8, 2023 by mccoy

[Saul]

2 hours ago, Ron Put said:

I most certainly would not.

Attia has an agenda, as well as biases, that I disagree with, even though I regularly listen to him. Same for Dayspring.

Both dismiss nutrition by erecting straw men arguments, without adequately addressing the evidence supporting nutrition. Instead, they focus on pharmaceuticals to remedy what is more often than not caused by poor nutrition (including high-fat and high-protein diets). Dayspring claims that you could eat 20 eggs a day without any adverse effects in many of his appearances, yet has never addresses the fundamental contradiction that saturated fat is very likely to cause long-term detrimental effects, and that some dietary cholesterol is absorbed by virtually anyone, even the genetically lucky ones.

Dietary cholesterol and (primarily) animal fat will increase your LDL-C, and yes, will also increase your chance of an adverse event. Even the genetically luckiest have a reduced absorption of up to 40%, but first they are a small minority, and also even they can have increased cholesterol if eating 20 eggs a day. For most of us, the less dietary cholesterol and to a large extent, fat intake, the better.

mccoy, I checked a few of my genetic markers for LDL and no, I am not lucky at all. In my case, I attribute my relatively low lipids on diets, and to a lesser extent to exercise. Diet has by far the largest effect, for example eliminating olive oil dropped my cholesterol by about 30 points, based on my tests. Adding fats increases my numbers.

I agree with Ron; I ignore Attia dogma.

(And my lipids have been excellent since starting CR, about 30 years ago.  (As a child, they were good, but not outstanding.  CR did that.))

[mccoy]

6 hours ago, Saul said:

And my lipids have been excellent since starting CR,

How do you translate the qualitative attribute 'excellent' to quantitative terms? You may not be in the 'less than 5th percentile' subgroup which would grant near immunity from atherosclerosis.

 

6 hours ago, Saul said:

agree with Ron; I ignore Attia dogma.

By definition, Attia seems everything but dogmatic

[IgorF]

A few cents, I am not deeply sure I understand all I want but some digging in different directions brings me these conclusions that I will try to investugate more

- RBC could be a big part of the puzzle, they form a huge percentage of body mass, thus they increased substantially in the paleolitic -> agricultural -> industrial transition; they "are out of scope" by the most texts novadays because it is less convenient to speak about them in the lipid topics, but that is like discussing any big topic with 50% cutoff

- junk food invention + modern lifestyle is a separate thing, it is an addition/extension that forms a newer phenotype that should be analyzed on its own and not mixed with several tens of generations which were not completely but adopted to calories increase

- developed human body has no ways to get into neonatal chole level, the freakiest data I saw is posted here by Alan Pater (https://www.crsociety.org/topic/11215-latest-bloodwork/?do=findComment&comment=41488) he had very low TC paired with very low RBC, perhaps in the times of his hardest CR experiments, the regimen definitely not suitable for longterm mass usage

- dietary modifiers like chole intake, fats etc - is true and could be significant in overall figures, the data is huge for 20 century and a plethora of dietary regimens and lifestyle, actually it was the first guess thus investigated a lot

- there is no easy way to see in the bloodwork snapshots correlation between RBC and TC - it seems body "guesses" about the future energy guarantees and moves in the strictly (both intra- and inter-species RBC range) defined ranges. Generally RBCs are regulated by satisfactory delivery of oxygen to the tissues, so other factors can modify (e.g. trainings on high altitudes and other forms of mild hypoxia), it is hard to say what mechanism of homeostasys (RBC or chole) leads/wins but seems RBC has higher prio

- RBC can vary chole in their membranes in some range, up to membranes become rigid and cells will have real problems to change their shape moving to the thinnest areas (causing tissue hypoxias), so on one hand they act as a sunk buffer for chole to some degree, but abundance of chole higher than some level causes harm independently of LDL atherosclerosys way

- so far, despite the diapasons of RBCs are relatively rigid, their lifetime, membrane chole and the diapason itself could vary serum chole due to constant exchange happening, seems not directly with LDLs but somehow should be tightly interconnected because RBCs are very important and we know they are very specialized and due to this do not produce own chole

- farmaceutical interventions discussed are generally for already bad cases, it is really hard to answer on personal strategies on the topic, I think for those with low chole and no other known factors the best thing to do is to USG regularly carotid arterie and all other things and do less often some more deep (and unwanted due to radiation) scans to see if the personal risk model is changing with time towards the universal risk model

 

PS:

I suddenly dropped after 5-6 weeks into "mild CR" phenotype and my TC dropped to 143 from usual 150-160 while my RBCs are also moved slightly down - 4.1 (4.6-6), also low Hgb, Hct, neutrophils. I did no reticulocites test this time but I suspect they are also on the low end - my body switches to prolonged use of RBCs due to energy shortage  and this also reflected with similar % of TC shift without any other changes in my diet/regimen.

Br,

Igor

Edited June 9, 2023 by IgorF

[mccoy]

Igor, my thought is less articulate and pretty down to basic aspects, mainly it revolves around this doubt: is it advantageous to abate cholesterol significantly (surely below the 5th percentile) by pharmaceutical drugs or is it overkill for those individual like ourselves who already have a cholesterol in the lower normal range with no additional risk factors.

The above besides the clinical controls you cite, since the advantage will manifest itself fully after about 30 years from the intervention

Edited June 9, 2023 by mccoy

[mccoy]

Lipid and lipoprotein reference values from 133,450 Dutch Lifelines participants: Age- and gender-specific baseline lipid values and percentiles

https://www.sciencedirect.com/science/article/pii/S1933287417303331

This article provides a statistical study, with percentiles, of a population representative of northern European Caucasian descent. It may be taken as representative of western caucasian males and females. Sorry if this post is limited to such a subgroup . The percentiles are stratified by age and gender, so we can cite them more precisely.

In the following figure we have from the 5th to the 95th percentiles and it is very interesting to notice that in males TC tends to plateau from about 50 to 70 years of age and then drop a little. In females the values are higher and tend to rise pretty steeply around menopausal age. The 5th percentile in men, we might say an optimal, very ideal location, hovers at 159 mg/dL. Lower percentiles in the same age group (50 to 70) are also cited:

TC 1st percentile: 135-139 mg/dL

TC 2.5th percentile: 147-151

[mccoy]

So, it is important to specify age when citing cholesterol percentiles (besides gender and ancestry).

These are the figures for calculated LDL-c percentiles (by the Friedewald formula), males.

1st: 65-71 mg/dL

2.5th: 75-80 mg/dL

5th: 85-87 mg/dL

Trigs, HDL , TC/HDL statistical values are also provided

[mccoy]

From the above figures, everyone of us can know where we are located in term of percentiles and decide about a strategy.

If we are naturally at the 1st percentile of LDL-C in our age group, then probably there should be no strategy, except to go on with the current lifestyle.

I find myself presently at about the 4th percentile of TC and at the 1st percentile of calculated LDL-C, so in my case, if the present values are confirmed, it would probably be overkill to take statins in absence of other risk factors and assuming these poor man's estimates of risk are representative of ApoB percentiles.

So, my considerations about myself: I'm going and wait a couple of weeks and repeat the analyses. If the values are confirmed, I may decide not to overkill, or I may decide a moderate overkill just to make sure (taking intermittent baby statins). If values are going to be higher, I'll have to think about itò

[Todd Allen]

17 minutes ago, mccoy said:

From the above figures, everyone of us can know where we are located in term of percentiles and decide about a strategy.

I don't think so.  I don't see total cholesterol of 600 mg/dL in the graphs.

[mccoy]

8 hours ago, Todd Allen said:

I don't think so.  I don't see total cholesterol of 600 mg/dL in the graphs.

Todd, you don't see it because you are an outlier. Such data constitute extreme values, located a little below the 100% percentile, which is the maximum value detected in a group or subgroup. The experts report even higher values,derived from homozygous FH (familiar hypercholesterolemia), up to about 1000 mg/dL TC. Such unlucky individuals exhibit values above the 90th or 95th  percentile from a young age and typically have some CV major events in their thirties, if not cured.

 

[Todd Allen]

15 hours ago, mccoy said:

Todd, you don't see it because you are an outlier. Such data constitute extreme values, located a little below the 100% percentile, which is the maximum value detected in a group or subgroup.

It's increasingly looking like most people could achieve cholesterol numbers similar to mine if they tried.  All that is needed is to get quite lean, be physically active and strictly limit dietary carbohydrates.  There isn't any data suggesting this is unhealthy.  Here is a paper on the need to study the phenomenon:  Elevated LDL-cholesterol levels among lean mass hyper-responders on low-carbohydrate ketogenic diets deserve urgent clinical attention and further research