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Mike41

LDL CHOLESTEROL AND LONGEVITY

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again we see lowest levels of ldl 84mg/dL we’re significantly associated with HIGHER mortality compared to men with moderately high levels of 117/ 137. The lower risk was about 40% if I’m reading this correctly. Thank you Al Pater for another study indicating that In males lower ldl may not be a goal we should be striving for. Personally my ldl is 105 but that Is with  using 40 mg of Crestor.
 

020 Aug 16;10(8):e036976. doi: 10.1136/bmjopen-2020-036976.PMID: 32801200https://bmjopen.bmj.com/content/bmjopen/10/8/e036976.full.pdfAbstractObjectives: To investigate the relationship between low-density lipoprotein cholesterol (LDL-C) and all-cause mortality among middle-aged and elderly Chinese population.Design: Prospective cohort study.Setting: This study used data from the China Health and Retirement Longitudinal Study.Participants: Middle-aged and elderly participants with complete data were enrolled for a 4-year follow-up of total mortality and plasma levels of LDL-C, including 4981 male respondents and 5529 female respondents.Results: During a 4-year follow-up, there were 305 and 219 deaths in men and women, respectively. Compared with the first quintile (Q1) of LDL-C, the adjusted HRs (95% CIs) were 0.818 (0.531 to 1.260) for Q2, 0.782 (0.507 to 1.208) for Q3, 0.605 (0.381 to 0.962) for Q4 and 0.803 (0.506 to 1.274) for Q5 in men. The results from restricted cubic spine (RCS) showed that when the 20th percentile of LDL-C levels (84 mg/dL) was used as the reference, a lower LDL-C concentration (<84 mg/dL) was associated with a higher 4-year all-cause mortality risk. By contrast, both quintile analysis and RCS analysis did not show a statistically significant association in women.Conclusions: Compared with moderately elevated LDL-C (eg, 117-137 mg/dL), a lower plasma level of LDL-C (eg, ≤84 mg/dL) was associated with an increased risk of 4-year all-cause mortality in middle-aged and elderly Chinese men. The results suggest the potential harmful effect of a quite low level of LDL-C on total mortality.Keywords: epidemiology; preventive medicine; public health; risk management

Edited by Mike41

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On 8/20/2020 at 7:36 AM, Mike41 said:

again we see lowest levels of ldl 84mg/dL we’re significantly associated with HIGHER mortality compared to men with moderately high levels of 117/ 137. The lower risk was about 40% if I’m reading this correctly. Thank you Al Pater for another study indicating that In males lower ldl may not be a goal we should be striving for. Personally my ldl is 105 but that Is with  using 40 mg of Crestor.

...

This has been discussed at length elsewhere on this forum, if I recall.  There are various causes for low LDL and it also depends on individual characteristics, but generally, in healthy populations, the preponderance of the evidence indicates that lower LDL is better.

LDL cholesterol: How low can you (safely) go?

A recent meta-analysis published in JAMA Cardiology suggests that it is both safe and effective to lower LDL below 70 mg/dL. The authors reviewed a large database of CVD patients with LDL levels averaging 70 mg/dL or less at the start of the studies. On average, there was a 20% drop in CVD risk seen for every 39 mg/dL drop in LDL cholesterol. In other words, a drop in LDL from 70 mg/dL down to 31 mg/dL was associated with 20% fewer CVD events such as heart attack or stroke.

The benefit was consistent regardless of the medications used to lower cholesterol. The JAMA Cardiology meta-analysis looked at studies in which LDL was lowered with a statin drug, which works by lowering LDL production in the liver, or with a different type of medication, including ezetimibe (Zetia), which interferes with absorption of LDL from the intestine, or PCSK9 inhibitors, newer injectable medicines that increase uptake of LDL from the bloodstream into the liver. The drop in CVD risk was in line with previous studies of patients who started with LDL levels around 130 mg/dL, and saw a drop in CVD events of about 22% for every 39 mg/dL drop in LDL.

In this study, there was no increased risk of adverse outcomes (including muscle aches, liver dysfunction, new onset of diabetes, cancer, and bleeding strokes), even when LDL was lowered to as low as 20 mg/dL. Although statin medications themselves have been linked to side effects, especially at high doses, it appears that extremely low LDL concentrations are not responsible for side effects.

In other words, lowering LDL beyond our previous target of 70 mg/dL appears to be not only safe but beneficial, in patients with CVD.

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Right. Let us note however, that the JAMA study referenced in that article only examines certain outcomes such as cancer, diabetes etc. What it does not do is examine all-cause mortality which is the gold standard. If you can show that low or v. low LDL has no negative, or indeed only positive outcome in all-cause mortality, then it would be a slam dunk. It's looking good for low LDL, but not 100% conclusive.

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19 hours ago, TomBAvoider said:

Right. Let us note however, that the JAMA study referenced in that article only examines certain outcomes such as cancer, diabetes etc. What it does not do is examine all-cause mortality which is the gold standard. If you can show that low or v. low LDL has no negative, or indeed only positive outcome in all-cause mortality, then it would be a slam dunk. It's looking good for low LDL, but not 100% conclusive.

My original point exactly. All cause mortality. Accordingly PCSK9 inhibitors, which lower ldl significantly lower cardiovascular mortality in heart disease patients But overall mortality is increased. Again heart disease patients we are talking about so anybody’s guess where that would leave those without heart disease, logically it would have seriously worse effects on them. Right?

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LDL-C is an important component in our overall health but it is just that, a component.  Mortality/morbidity is the sum of the whole and the interaction between all the components.  The study does not address what the other lipid components were, such HDL, triglycerides, LDL particle number or size, Apo B level, or how the study participants achieved such low LDL levels or other health problems or medications. My ears would perk up after reading this study if my LDL were so low and I wasn't taking any lipid lowering medications and even more concerning would be why didn't my doctor who ordered this test didn't discuss it with me.

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On 9/13/2020 at 10:01 AM, jlanzy said:

The study does not address what the other lipid components were, such HDL, triglycerides

https://bmjopen.bmj.com/content/bmjopen/10/8/e036976.full.pdf

"Adjusted for age, smoking, drinking, BMI, living alone status, household income, educational level, rural residence, ADL disability, hand grip strength, HDL-C, triglyceride, haemoglobin, hypertension, HBS/diabetes, history of stroke, cancer, heart disease, lung disease, liver disease, kidney disease, digestive disease, asthma, arthritis, psychological problem and memory problem."

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On 9/14/2020 at 1:04 PM, AlPater said:

https://bmjopen.bmj.com/content/bmjopen/10/8/e036976.full.pdf

"Adjusted for age, smoking, drinking, BMI, living alone status, household income, educational level, rural residence, ADL disability, hand grip strength, HDL-C, triglyceride, haemoglobin, hypertension, HBS/diabetes, history of stroke, cancer, heart disease, lung disease, liver disease, kidney disease, digestive disease, asthma, arthritis, psychological problem and memory problem."

It would now be interesting to see this study done with Caucasians to see if the same mortality exists for very low LDL-C.  I suspect that it would be difficult to find a statistically significant Caucasian  study population whose LDL-C were so low without lipid lowering interventions.

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in light of covid I thought this excerpt may be relevant from AL Paters article. Emphasis on maybe!

 

Several explanations for the unfavourable effects of low
LDL-C levels may be proposed.  LDL-C has been suggested
to play an important role in host defense against both bacterial and viral pathogens
Indeed, many animal and
laboratory experiments have shown that LDL could bind
to and inactivate a broad range of microorganisms and
their toxic products.
This hypothesis may be further
supported by the recent finding that LDL-C was associated
with reduced infectious mortality based on the data from
37 250 patients in the international Monitoring Dialysis
many cancer types are caused by viruses.
We reviewed nine cohort studies including more than 140
000 individuals followed for 10–30 years and found that
LDL-C may have the potential to protect against cancer as many cancers are caused by viruses.
In addition, it has been proposed that
low cholesterol was associated with cancer. cholesterol-lowering experiments on rodents have 
found to possess significantly lower cancer mortality. Therefore, lower LDL-C may contribute to a higher risk of death from infection and cancer, which in turn results in increased all-cause mortality.
This study demonstrated that middle-aged and elderly Chinese men with very low LDL-C had an increased risk of all-cause mortality, which calls for special attention to be paid to the possible harmful effect of a very low level of LDL-C. 

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Well, there's also the known effect of cholesterol dropping when the person is on a downward health slope. I remember reading an interview with a doctor who said that he often hears from patient relatives that the cholesterol numbers have significantly improved in the sick relative, and that is celebrated by the relatives whereas to the doctor that is the signal that things have turned for the worse and death is now the likely outcome. In other words, it's possible that the casuality is reversed - not low cholesterol leading to early mortality, but an underlying disease process that will result in early mortailty leads to low cholesterol. If this is true, then we should see the following: LIFELONG low cholesterol, i.e. not as a result of a possible disease process, should lead to at least a normal lifespan - and this is true, at least in those families in Italy where a genetic variant results in superlow LDL, those families are characterized by a virtual absence of CVD and longer than average lifespans. Also, medication designed to lower cholesterol should not result in a shorter lifespan, because the lower cholesterol is not caused by an underlying disease process. Here it's a more difficult situation, because frequently the initiation of cholesterol lowering medication is prompted by CVD problems, which in turn impacts lifespan. And the picture is indeed mixed. There doesn't seem to be much evidence that statins shorten lives, and little evidence that they cause cancer in humans (possibly might even lower cancer incidence). On the other hand, PCSK9 inhibitors have come in for some concerning stats, where perhaps folks on those medications are doing worse longevity-wise, it's too early to say authoritatively. That leaves two final cases. One, lifestyle interventions, diet and exercise which lead to lower cholesterol - given the effects of this, it's hard to expect a negative impact on health and longevity. That leaves the last case - where cholesterol is lowered in someone for no discernable reason and it represents a change (unlike lifelong low cholesterol) - I don't find it surprising that somone like that might have some hidden underlying health problems that result in early mortality. But I would not necessarily chalk that up to the effect of the cholesterol being lowered, but the effect of whatever it was that lowered the cholesterol as a side effect. YMMV.

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Tom summarizes my thoughts on the subject, exactly.

There are studies that show that reduction in weight among obese people increases mortality.  Reduction in alcohol consumption in heavy drinkers also increases mortality.  I'd guess that if I search, I'll find something that says that reduction in smoking results in increased mortality too.  These all have an explanation, of course....

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On this subject, we have now the recent P.Attia's podcast with Tom Dayspring as a host.

 

I've listened to it twice. Amongst the finest details and minutiae of lipidology, I think I've grabbed the following important points, which are relevant to the atherogenic risk, which governs CV disease:

  1. LDL cholesterol concentration remains the most representative single factor of this risk. LDLp is more significant than the LDL-C usually measured, and APOB is recently adopted as the most significant metrics.
  2. The lower the LDL or APOB, the better. There is not a recognized optimum, very low values are OK since in the body we have 3 main pools of cholesterol: brain, peripheral cells and plasma, and the latter, the one we measure, is the smaller in total quantity. Hence, a great reduction in serum cholesterol will not by any means compromise the total cholesterol pool in the body.
  3. HDL cholesterol as a single metrics is not very significant. The higher the better has not been proven to benefit
  4. Non-HDL cholesterol is a good proxy for APOB cholesterol in 70 to 80% or people, whereas in diabetics it can exhibit poor correlation.
  5. Fancy measurements of cholesterol, with all types of particles fractions and so on are unnecessary and essentially a waste of money.
  6. Lp(a) protein constitutes a genetic risk factor, but we only need to measure it once in our life. If we are carriers of the gene which elevates this protein, we just need to lower APOB with lifestyle or pharmaceutical interventions.

The above points # 1 and 2 strongly deny the narrative of many supporters of the paleo and low carb dietary models: Tom Dayspring is one of the top living lipidologists. A high LDL is a scientifically recognized, significant atherogenic factor. Especially so if measured in terms of APOB essays. And a low APOB/LDL is not at all bad. Non-HDL cholesterol is often a good metrics for atherogenic risk, but it fails in people with diabetes and other conditions (20-30% of the population).

The above considerations mostly confirm what Luigi Fontana writes in his latest book, which we discussed.

I don't know if those of you guys who listened to this podcast have taken home more important considerations. To date, I think these are the most authoritative, well-explained, conceptually reasonable considerations I've heard. They've been very useful in dissipating some of the confusion existing on the issue.

Edited by mccoy

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Yeah, I listened to this while exercising (which is when I listen to medically-oriented podcasts), and as usual Tom Dayspring delivers. It's worth going back a couple of years to the long series of podcasts he did with Peter Attia about cholesterol. Very educational. 

The thing that always amazes me is how far the average doctor or even specialist, such as a cardiologist is from the current research. Unless the doctor continues to educate themeselves, they're soon out of touch, and they can only rely on what they learned at school. What's worse, that what's being taught at med school is also frequently badly outdated and the schools for some reason don't feel motivated to update their curriculum. 

I know this for a fact, because even in casual conversations with GP doctors, you realize they know very little about cholesterol and what they know is out of date by decades.

One note on HDL from the podcast. We don't know much about the function of HDL and as explained in the podcast we're unlikely to learn much going forward, because there is no financial incentive to investigate. There doesn't appear to be much value to be extracted from the HDL number in the standard tests we all take. In very, very rough outlines, for part of the population, higher HDL is a marker for lower number of the very harmful particles, but that's not even true for a substantial minority. It's also possible to have zero CVD problems with low HDL, though that depends on many other factors. As usual, it's all complicated.

It's a very good episode, though, if you want to learn more about cholesterol.

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On 9/23/2020 at 2:43 AM, mccoy said:

On this subject, we have now the recent P.Attia's podcast with Tom Dayspring as a host.

Thanks, mccoy!

I just listened to it and it was very illuminating. I may have missed it, but I noticed that the apoB/apoA-1 ratio was not mentioned. To my knowledge, this is an even stronger predictor than apoB alone:

The apoB/apoA‐I ratio: a strong, new risk factor for cardiovascular disease and a target for lipid‐lowering therapy – a review of the evidence

I have recently checked my apoB and apoA-1 I am still at a relatively good spot (64 and 132, respectively)

I also checked my lipoprotein (a), which I guess I have to do once only.

Do others here check these values?  Especially for apoB and apoA-1, have you noticed a significant improvement on CR?

Finally, they did not touch on Methylmalonic Acid, which is another significant factor that increases with age.  I had mine checked as well (134) and wondering if others here have done it periodically and if long-term CR has a significant effect?

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Ron, the podcast was not very clear about the ApoB suggested range. Could you check please from your lab reports the following data and report here:

  • ApoB normal range
  • LDLp, LDL-C normal range

Also, from what I grasped from the podcast,  ApoB is about the same as LDL cholesterol (but a more reliable parameter of the atherogenic risk) and ApoA1 is about the same as HDL cholesterol, so we might guess that the ratio ApoB/ApoA1 is about the same as LDL/HDL. If the parameter has not been mentioned, probably they do not believe it's a significant one. Methylmalonic acid, ditto.

I would presume that the suggestions to decrease atherogenic risk would be to remain within the lower deciles of ApoB lab range (below the median). Then, they proceed to examine further risk factors and parameters, but lipids, especially so ApoB, is the governing parameter as far as I understood. HDL=ApoA1 would be best within the upper deciles, whereas they don't speak much about triglycerides, but here we all know the lower deciles are best.

My last consideration: at this point, we might say that the lower the ApoB-LDL, the best, but at least in my case there is a practical optimization to pursue. That is, I cannot bend all my energies and resources, dietetically speaking, to lowering ApoB as much as I can, since this would entail to eat so few fats that I should renounce the nutrients in nuts for example or other healthy fats, and eat lots of carbs, which would probably increase my blood sugar, which would constitute a risk factor for CVD. Also, I do not tolerate many starches. So, at the end, it's all an individual optimization strategy. Low ApopB/LDL is very good, whereas very low ApopB/LDL, not necessarily so, considering our overall individual balance and requirements.

Edited by mccoy

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