#1231

I think it tells us markers are just markers and we shouldn’t try and fix them but the underlying problem instead.

#1232

That is generally true - but there are some real problems with the classic evidence pyramid thinking.

I would emphasize that “lower-quality” evidence such as meticulously done N-of-1 crossover trials & Mendelian randomization can be very useful if carefully interpreted with a lot of contextual knowledge, while “high-quality” evidence can be useless or harmful.

Here’s an example:

Ivermectin in a meta-analysis was shown to be effective for COVID-19 treatment. This was later shown to be based on fraudulent data.

As for the case of LDL-P/apoB, my current opinion is LDL-P<1000 and LDL 70-90 (if not discordant) would be a reasonable treatment target for a lipidologist to consider, particularly if there are risk-enhancing factors, medication side effects are very carefully considered, and if it cannot be done through lifestyle alone.

Let’s say we compare LDL 55 vs LDL 70-90, assuming no discordance. What is the purported difference in absolute risk reduction on all-cause mortality over a few decades (let’s say 20-30 years) if your position happens to be correct? That should be more informative.

I suspect the difference would be clinically insignificant in a “healthy” individual with no risk factors (maybe a theoretical 1% or less absolute risk reduction) - while waiting for more information over the next 20 years is probably a better option.

That being said, many people will have varying opinions on this. My general rule is to cut my confidence level in half after a lot of research on any purported benefit (expert opinions alone can and very often are incorrect) - unless there are very, very good reasons and I fully understand the subject at hand. We can size a position based on confidence level of the benefits vs harms accordingly.

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#1233

In randomized controlled trials, lowering from 70 mg/dl median LDL-c show a reduction in events, both in statins and PCSK9, with no observed adverse effects. With a relative risk reduction equal to when the starting LDL-c was twice as high.

Because LDL-C–lowering therapies tend to produce the same relative percentage lowering of LDL-C regardless of starting levels, the absolute lowering of LDL-C and therefore the relative and absolute risk reductions will mathematically be a function of the baseline LDL-C. For example, in patients starting with an LDL-C level of 2.6 mmol/L (100 mg/dL), a 60% decrease in LDL-C (what a PCSK9 inhibitor typically achieves) should lower LDL-C by 1.6 mmol/L (60 mg/dL), reduce the relative risk of major vascular events by 31%, and, assuming a 5-year major vascular event rate of 25% in a secondary prevention population, yield an absolute risk reduction of 7.8%. If the same patients started with an LDL-C level of 1.8 mmol/L (70 mg/dL), LDL-C should be lowered by 1.1 mmol/L (42 mg/dL) and the relative risk of major vascular events by 23%, which would yield an absolute risk reduction of 5.8%.

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#1234

That’s quite a change in LDL and Tryglicerides --What was your RAPA dose and frequency?

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#1235

I started a 5 mg/weekly with GFJ and EVOO then titrated up to 20 mg-biweekly then went down again to 10 mg/weekly with just the EVOO. High doses gave me diarrhea which is the main reason I am now at 10 mg/weekly with EVOO. I am still a little concerned with my lipids because I have a BMI of ~22.5 and eat a quasi-Mediterranean diet.

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#1236

Thank you – was asking because all my lipid were pretty good (Triglycerides 56/ HDL 68 / LDL 116) before starting RAPA except my doctor wanted my LDL even lower and was trying to force compliance with a Statin (which I’m resisting)

@tongMD my LDL is obviously way above the 70 mg/dL you cite as a starting point for further reduction - but my HDL and Triglycerides are good . . . would you be worried if you were me and go on Statin with the possible sidde effects?

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#1237

Note your meta analysis is NOT in healthy individuals with low risk and no risk factors in the first place. Context is super important.

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#1238

I am not your doctor and I haven’t even seen you. Please don’t ask me whether you should go on a statin or not.

I’m certainly not going to be providing anything beyond general information and my nonexpert interpretation of the literature that should never be relied upon to make any sort of treatment decisions.

As mentioned, consider requesting a referral for a lipidologist.

I will mention there isn’t any human data to guide healthy individuals for long-term statin use (ie risk of tendinopathy), nor is HDL really a resolved issue. There is such a gross oversimplification on the immunological function of lipoproteins overall. AFAIK, Attia probably hasn’t mentioned it much at all. I don’t think he’s ever gone over statins, MMP, cartilage, and collagen. Or immunology much.

There is some evidence to even suggest some subtypes of HDL are atherogenic. We really don’t know as much as Attia claims.

We can see here biglycan which is a proteoglycan that attracts apoB and apoE is in 100% of lesions - but apoE is present in almost 100% of lesions, apoA1 in 100%, and apoB, the supposed initiator, according to Attia, is only present in 90%. If you understand the basics of lipidology and assume Attia’s non-expert hypothesis was flawless, it should be 100% apoB - not 90%.

Now this does not mean anyone should stop a statin if they are indicated for one by their doctor or that apoB is irrelevant. I mentioned the weekly dosing with increased “hepatoselectivity” as an option to reduce risk of myopathy (or potential cognitive risks by avoiding specific statins that may significantly cross BBB) in those where it is indicated by their doctor to talk with their doctor about the benefits vs risks in statin switching - particularly those with risk enhancing factors for atherosclerosis.

It just means the mechanism isn’t as clear as purported and there’s a lot of real gaps. It’s easy to sell a vastly simplified story - “do something” in healthy people and pay me 6 figures per patient as VIP medicine, which has documented risks of its own. If there isn’t a big risk we are reducing - why trade one potential small benefit for several potential risks? There are other options that can be tried first. And even then Attia seems to have been off statins himself - I wonder why since he doesn’t appear to have explained it despite his “faith” in statins. Now if there was better evidence in the context I’m looking for or I’m indicated for it - I’d seriously consider taking a statin. I’m not claiming statins are super harmful drugs either - they’re relatively “safe” overall assuming perfect conditions and usage.

Seems to me that many people can potentially lower LDL from say 100-130 to 70-90 with say 12-15g 100% psyllium husk from food (especially if you have low soluble fiber intake), 5 grams of 100% cocoa bits from food, and/or “perfect” lifestyle factors alone - if you’re aiming for some target. If you’re not discordant - there probably isn’t significant potential benefit in absolute risk reduction from a target of 70-90 through daily combined statins/ezetimibe to say a target 55 in “healthy” people (55 may be a more reasonable target in certain high risk patients with history) with no risk factors. When Attia claims statins are so-called “compound interest” as an investment, that doesn’t take into account other systemic risks. If his position turns out to be true - why not take the route of “compound interest” with the lowest potential risks?

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#1240

I’m not sure if risk is the most important thing for the healthy, but prevention, preventing ascvd from developing in the first place. Most people (90%+) have a positive CAC at between age 70-90. I think that a very low LDL over a long time might prevent CAC from turning positive at that age. If an LDL is healthy at 30-40 mg/dl we don’t know, but it is for neonatals, and in short term studies, and it does lower risk in those who are unhealthy and at high risk without any observed side effects. So you’ll have to consider this being an ‘ascvd mechanism’. And of course studies are done on those who are unhealthy or at high risk, because without any events you can’t find an effect. I don’t know if you can use mendelian randomization to study very low ldl levels.

On the surface, a target LDL level of less than 70 mg/dl may appear markedly low, but its cogency can be supported by a physiological rationale that we are born with an LDL level of 30–40 mg/dl, and, at that time, the development of the brain is at its peak. The safety of low LDL level has been supported by Ray et al. They reported that the reduction of LDL levels to as low as that of a neonate is safe as well as beneficial in reducing the risk of angina, MI, or cerebrovascular disorder and total mortality [19]. These might be the levels to which humans are inherently adapted, and the levels ventured to be achieved [14]. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5937425/

1 Like
#1241

How relevant is this to your situation? How many people age 70-90 had no risk factors and “perfect” lifestyle factors in the first place when say 30-50s? Long time second-hand smoke exposure counts as a risk factor. They probably did not have “perfect” lifestyle factors.

“An important accomplishment of the second half of the 20th century has been the reduction of smoking prevalence among persons aged greater than or equal to 18 years from 42.4% in 1965 to 24.7% in 1997”

https://www.cdc.gov/mmwr/preview/mmwrhtml/mm4843a2.htm

The Japanese have a >50% CAC score of 0 in age 65-75 (as far as I could find to compare US vs Japan data) for those with zero main risk factors (smoking, diabetes, hypertension, dyslipidemia) - not even detailed risk stratification using newest in depth criteria. That’s without adjusting for “perfect” lifestyle factors - which I suspect will put that number in much higher proportion for CAC = 0.

Neonatal physiology is very different. For example, heart rate of 140, RR 45, and BP 75/45 is “normal” for neonates. That would warrant a trip to the ER for an adult.

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#1242

I don’t think staying at 70 - 90 mg/dl will be enough to prevent ASCVD since there is a decrease in risk for those who are unhealthy and who are at high risk when lowering even from that. Meaning it is a factor to consider because there is a causal mechanism. I don’t think you can mitigate this with other factors since it is such a strong factor when all other factors are excluded - in genetic studies and rcts.

#1243

Do you understand why the other risk factors matter in calculating risk? Let’s assume your hypothesis is correct - what is the absolute risk reduction in healthy people?

As an example, let’s generously assume everything you assert is absolutely correct with no flaws, if you have a 30-year risk of <10% of ASCVD risk at LDL 100-130, what is the difference in absolute risk reduction for lowering LDL to 40-55 vs LDL 70-90? (You can calculate this with Framingham data)

An intervention reducing risk from 30% to 25% is very different than say 5% to 4%. And that’s generously assuming that the effect would be the same if one has say T2D & HTN - which it probably isn’t.

Meanwhile, we can wait for more data to better refine our approach or newly approved treatments that might even reverse atherosclerosis (or similar) in 30 years. This could very well decrease all-cause mortality far more as a better bet.

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#1244

You’re ignoring several of the most important considerations.

  1. Benefit / risk always must be considered.
  2. Primary prevention differs from secondary.
  3. The presence of other risk factors
  4. Absolute vs relative risk.
  5. Total mortality risks.
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#1245

If you had to bet, based on current information, what LDL level would be appropriate to develop no ASCVD and live to 90 healthily? If all else is equal, obviously.

Would you say 70 - 90 mg/dl?
Or 40-55?

#1246

Having an LDL at say 55 with no discordance and statins doesn’t mean the 30-year ASCVD risk is 0%. I would revise your assumptions.

Arguably, within 30 years there may be a proven treatment to reverse atherosclerosis. Waiting for more data isn’t necessary a bad thing when you can afford to.

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#1247

Would you guys be saying the same thing about blood pressure to your patients? “Don’t worry about controlling BP if your current CVD risk is low because there will probably be treatments to reverse all the sequelae of hypertension 30 years from now”(?). Seems like primary prevention is a lot easier than secondary. Why not prevent plaque from ever building up in the first place by safely keeping ApoB low now rather than accept the risk over the next few decades and gambling on reversal?

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#1248

I found this an interesting article about atherosclerosis.

Mummies reveal that clogged arteries plagued the ancient world

Clogged arteries are seen as the quintessential symptom of an unhealthy modern lifestyle. But the condition was common across the ancient world, even among active hunter–gatherers with no access to junk food, a study of mummies has found.

“There’s a belief that if we go back in time, everything’s going to be OK,” says cardiologist Greg Thomas of the University of California, Irvine, a senior member of the study team. “But these mummies still have coronary artery disease.” The paper is published in the current issue of The Lancet 1.

https://www.nature.com/articles/nature.2013.12568

This shows all signs of being a long genes not being sufficiently expressed problem. Hence if you can get the long genes to express (and I think you can) then it should do something.

However, I have also that my LDL-C bounces around quite a bit. Sometimes it is under the UK threshold of 3 (mmol/L) and sometimes over and varies in a range of about 25%. Hence I have not really bothered about it that much.

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#1249

I mean, you could say that about everything humans have done but were wrong about. Bloodletting and burning witches made sense “in a way,” too.

99.9% of “traditional Chinese medicine” is complete bunk, just like most “traditional” or “holistic” medicine.

And while I’m offending people . . . you can toss 100% of acupuncture and 95% of “chiropractic medicine” into that same bin, too.

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#1251

In the west, we treated syphilis by infecting the patients with malaria. So I’m not sure we can cast stones.

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#1252

We can look at your example of treating BP and “AT1R disruption” as an example.

What’s the difference in absolute risk reduction for “treating” BP to 120/80 vs 110/70 vs 100/60 for someone that is prehypertensive?

If treating someone who is 120-130/80-90 with let’s say an ARB like telmisartan 20 mg to roughly 110/70 already potentially reduces a big risk over 30 years, why should I treat to 100/60 for some not very significant potential additional risk reduction while risking multiple potential side effects, unless I am highly (or even moderately) certain there is real significant absolute risk reduction in all-cause mortality?