Low Levels of Low-Density Lipoprotein Cholesterol and Mortality Outcomes in Non-Statin Users

Ki-Chul Sung et al. J Clin Med. 2019.

Abstract

We aimed to test the association between low-density lipoprotein cholesterol (LDL-C) and cardiovascular disease (CVD), cancer, and all-cause mortality in non-statin users. A total of 347,971 subjects in Kangbuk Samsung Health Study (KSHS.57.4% men, mean follow up: 5.64 ± 3.27 years) were tested. To validate these associations, we analyzed data from another cohort (Korean genome and epidemiology study, KoGES, 182,943 subjects). All subjects treated with any lipid-lowering therapy and who died during the first 3 years of follow up were excluded. Five groups were defined according to baseline LDL-C concentration (<70, 70-99, 100-129, 130-159, ≥160 mg/dL). A total of 2028 deaths occurred during follow-up in KSHS. The lowest LDL-C group (LDL < 70 mg/dL) had a higher risk of all-cause mortality (HR 1.95, 1.55-2.47), CVD mortality (HR 2.02, 1.11-3.64), and cancer mortality (HR 2.06, 1.46-2.90) compared to the reference group (LDL 120-139 mg/dL). In the validation cohort, 2338 deaths occurred during follow-up. The lowest LDL-C group (LDL < 70 mg/dL) had a higher risk of all-cause mortality (HR 1.81, 1.44-2.28) compared to the reference group. Low levels of LDL-C concentration are strongly and independently associated with increased risk of cancer, CVD, and all-cause mortality. These findings suggest that more attention is needed for subjects with no statin-induced decrease in LDL-C concentrations.

PubMed Abstract

Full Text - Open Access

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Cells produce cholesterol starting with acetyl-CoA. Statins hold back the conversion of acetyl-CoA into cholesterol, but if there is an initial shortage of acetyl-CoA, the individual concerned will face considerable health problems. That is probably where this association comes from (viz a shortage of acetyl-CoA).

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Relationship of serum cholesterol levels in man infected with parasites has drawn the attention of various workers. Since it has been shown in-vitro studies that parasites like Giardia and Entamoeba can grown in lipid rich media in the absence of serum, it would be interesting to determinate the mechanism of lipid/cholesterol utilization. Recent studies have shown elevated levels of lipoproteins like high density lipoprotein (HDL), low density lipoprotein (LDL) and total cholesterol in patients suffering from parasitic infection (4). In human body cholesterol is synthesized in liver, which incidentally happens to be a major extraintestinal site of infection with Entamoeba histolytica . Keeping this in view, the following queries arise (i) is there any correlation between cases of amoebic liver abscess (ALA) with cholesterol synthesis in liver? (ii) in case of intestinal amoebiasis, what is the source of cholesterol? (iii) how do the amoebae utilize cholesterol in these two different areas (iv) what is the role of cholesterol in enhancing virulence and pathogenecity of E. histolytica (v) does cholesterol help in cyst formation?

Role of cholesterol in parasitic infections - PMC (nih.gov)

From this study I draw the conclusion that people who defend high cholesterol are controlled by the brain parasite Toxoplasma gondii.

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Association of lipoprotein levels with mortality in subjects aged 50 + without previous diabetes or cardiovascular disease: a population-based register study

Lise Bathum et al. Scand J Prim Health Care. 2013 Sep.

Abstract

Objective: This study aimed to investigate the association of lipoprotein and triglyceride levels with all-cause mortality in a population free from diabetes and cardiovascular disease (CVD) at baseline. The European Guidelines on cardiovascular disease prevention state that in general total cholesterol (TC) should be < 5 mmol/L (190 mg/dL) and low-density lipoprotein cholesterol (LDL-C) should be < 3 mmol/L (115 mg/dL).

Design: A population-based register study in the period 1999-2007 including 118,160 subjects aged 50+ without statin use at baseline. All-cause mortality was related to lipoprotein and triglyceride levels and adjusted for statin use after inclusion.

Results: All-cause mortality was lower in the groups with TC or LDL-C above the recommended levels. Compared with subjects with TC < 5 mmol/L, adjusted hazard ratios for the group aged 60-70 years ranged from 0.68 (95% confidence interval (CI) 0.61-0.77) for TC 5-5.99 mmol/L to 0.67 (95% CI 0.59-0.75) for TC 6-7.99 mmol/L and 1.02 (95% CI 0.68-1.53) for TC ≥ 8 mmol/L in males and from 0.57 (95% CI 0.48-0.67) to 0.59 (95% CI 0.50-0.68) and 1.02 (95%j CI: 0.77-1.37) in females. For triglycerides, ratios comparednn with the group < 1 mmol/L in the females agedb 60-70 years ranged from 1.04 (95% CI 0.88-1.23) to 1.35 (95% CI 1.10-1.66) and 1.25 (95% CI 1.05-1.48) for triglycerides 1-1.39 mmol/L, 1.4-1.69 mmol/L, and ≥ 1.7 mmol/L, respectively. Statin treatment after inclusion provided a survival benefit.

Conclusion: These associations indicate that high lipoprotein levels do not seem to be definitely harmful in the general population. However, high triglyceride levels in females are associated with decreased survival.

From the Full Text:

The most striking finding was that compared with the reference levels, high TC, HDL-C, or LDL-C levels were associated with lower mortality in the elderly and this was the case for even very high levels. The finding that high TC or LDL-C levels were associated with a lower mortality is contrary to the general assumption that there is a higher mortality among subjects with high lipoprotein levels. Our findings could seem controversial. However, most studies performed in older adults show an inverse association between TC and mortality and a recent study demonstrated an inverse association between TC and non-cardiovascular mortality in a population free of CVD and statin use at baseline. These findings were significant from the age of 65 years and were largely due to an inverse association with non-HDL-C. Our study demonstrates the same significant inverse association between high levels of TC and its subfractions and mortality in all age groups from as early as 50 years.

PubMed Abstract

Full Text - Open Access

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This is the data (per the corresponding author):


https://biobank.ndph.ox.ac.uk/ukb/field.cgi?id=30640

But I’m not clear on what you’re objecting to. Is ‘suggest’ too speculative? Given the linearity of the trend, seems like a reasonable speculation.

Low and High-Density Lipoprotein Cholesterol and 10-Year Mortality in Community-Dwelling Older Adults: The Shanghai Aging Study

Wanqing Wu et al. Front Med (Lausanne). 2022.

Abstract

Background: The relationship between serum cholesterol and mortality remains disputed. This study aimed to examine the association of low and high-density lipoprotein cholesterol (LDL-C and HDL-C) with all-cause mortality among community-dwelling older adults in the Shanghai Aging Study.

Methods: We followed 3,239 participants free of lipid-lowering agents for a median of 10 years. Levels of LDL-C and HDL-C were measured at baseline using fasting blood samples. Survival status was confirmed by the local mortality surveillance system. The associations between the levels of LDL-C, HDL-C, and all-cause mortality were assessed by Cox proportional hazards models.

Results: The increment of LDL-C concentration was related to a lower risk of mortality (p for trend < 0.05). Using the highest quintile of LDL-C (≥4.10 mmol/L) as a reference, the lowest quintile of LDL-C (<2.61 mmol/L) was associated with the highest risk of mortality, after adjusting for confounders (HR 1.67; 95% CI 1.26-2.21), exclusion of death within the first 2 years of follow-up (HR 1.57; 95% CI 1.17-2.11), and exclusion of functionally impaired participants (HR 1.46; 95% CI 1.07-2.00). A U-shape relationship was found between HDL-C level and the mortality risk. Using the third quintile of HDL-C (1.21-1.39 mmol/L) as a reference, HR (95% CI) was 1.46 (1.09-1.95) for the lowest quintile (<1.09 mmol/L) and 1.45 (1.07-1.96) for the highest quintile (≥1.61 mmol/L) of HDL-C, after adjusting for confounders; and 1.57 (1.15-2.15) for the lowest quintile and 1.45 (1.04-2.01) for the highest quintile of HDL-C, after exclusion of death within the first 2 years of follow-up; and 1.55 (1.11-2.16) for the lowest quintile and 1.42 (1.00–2.02) for the highest quintile of HDL-C, after exclusion of functionally impaired participants.

Conclusions: We found an inverse association of LDL-C and a U-shape relationship of HDL-C with long-term all-cause mortality in a cohort with community-dwelling older Chinese adults. Levels of LDL-C and HDL-C are suggested to be managed properly in late life.

From the full text:

”Our finding is consistent with previous studies where an inverse association of LDL-C with all-cause mortality was found among older adults. […]
High LDL-C might not be a risk indicator at old age and thus be used to identify older adults at risk and start cardiovascular disease management. Instead, those with low LDL-C in late life might warrant further attention. An adjustment of diet may help to increase their level of LDL-C and avoid extra risk of all-cause mortality."

PubMed Abstract

Full Text - Open Access

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I didn’t object to anything.

Yes that’s a speculation and we should be aware that it is nothing more than this. The curve below 0.7 mg/dL could go back up (the dreaded U shaped curve), be flat or continue to go down.

(By the way, I recently joined the “lower the better” team for LDL/ApoB and CVD (I didn’t have an opinion before) but come on, we should avoid defending hypotheses as facts and promoting theses in a religious way. We’re all trying to find the truth and to make the best possible decisions for ourselves, given the available evidence. It’s a common quest. It shouldn’t be a fight.)

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Of course…

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Best post in this thread (for me).

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I’m curious what made you change your mind. I think LDL by itself is really a rather useless marker. It is poorly correlated with CVD and people need to take a lot of other factors in consideration to asses a meaningful CVD risk.

I mean it’s like body weight. Nobody would take only that marker to assess somebody’s health even though (like LDL) it’s somewhat correlated with bad outcomes. There is also a U shape curve and plenty of other factors that need to be looked at. BMI which uses weight and height is a little bit better and then you can get a DEXA scan that will give an incredibly better assessment of the health.
I really don’t get why most people obsess solely on LDL instead of doing an NMR lipid panel + BP + inflammation, etc. to have a much better picture.

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When it comes to this topic I’ll take the side of
cardiologists, doctors, experienced medical professionals with decades of experience, hospitals, scientific research from solid Western sources, etc… that say high LDL is bad.

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Association between hypercholesterolemia and mortality risk among patients referred for cardiac imaging test: Evidence of a “cholesterol paradox?”

Alan Rozanski et al. Prog Cardiovasc Dis. 2022 Sep-Oct.

Abstract

Aim: Some observational studies have observed a lower, rather than higher, mortality rate in association with hypercholesterolemia during follow-up of patients after cardiac stress testing. We aim to assess the relationship of hypercholesterolemia and other CAD risk factors to mortality across a wide spectrum of patients referred for various cardiac tests.

Methods and results: We identified four cardiac cohorts: 64,357 patients undergoing coronary artery calcium (CAC) scanning, 10,814 patients undergoing coronary CT angiography (CCTA), 31,411 patients without known CAD undergoing stress/rest single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI), and 5051 patients with known CAD undergoing stress/rest SPECT-MPI. Each cohort was followed for all-cause mortality using risk-adjusted Cox models. We pooled the hazard ratios between cohorts with a random effects model. Baseline risk varied markedly among cohorts, from an annualized mortality rate of 0.31%/year in CAC patients to 3.63%/year among SPECT-MPI patients with known CAD. Hypertension, diabetes, and smoking were each associated with increased mortality in each patient cohort (pooled hazard ratio[95% CI]: 1.38[1.33-1.44], 1.88[1.76-2.00], and 1.67[1.48-1.86], respectively). By contrast, hypercholesterolemia was associated with decreased rather than increased mortality (pooled hazard ratio[95% CI]: 0.71[0.58-0.84]). Analysis of serum lipids among 7744 patients undergoing CAC or CCTA scanning revealed an inverse relationship between LDL cholesterol and mortality.

Conclusions: Among a broad spectrum of patients referred for a variety of cardiac tests and ranging from low to high clinical risk, hypercholesterolemia was not associated with increased mortality risk. Our findings suggest that hypercholesterolemia may be sensitive to confounding by other clinical factors and post-test treatment changes in patient populations.

From the full text:

  • Patients with hypercholesterolemia had higher survival compared to patients without hypercholesterolemia.[…] Hypercholesterolemia was associated with a 28% risk reduction for ACM in pooled analysis.*

PubMed Abstract

Full Text - Science Direct

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OR

2.) Health influencers, clickbait, snake oil salesmen, random folks with no cardiovascular training or experience, and paper mills saying high LDL is good.

A comment a bit too derisive of the opposing view. The greats were never derisive of each other. (Thinking of the Einstein- Niels Bohr debate. Justice Antonin Scalia and Justice Ruth Bader Ginsburg were good friends. Their families even took vacations together.) But debates nowadays are too strident.

The studies Vlasko and others posted are from scientists, not influencers. But since you prefer youtube videos, here are some “influencers” who are also MDs.

Below is an org that is made up of MDs and scientists.

Among the members are:

Davies, Hywel; MA, DM (Oxon), FRCP (Lond), FACP, FACC. Previously Assoc. Professor, University of Colorado; Chief of Cardiology, Denver VA Hospital; Senior Lecturer and Hon. Consultant physician at Guy’s Hospital, London, UK. Present address: Rue de Condémines 9, CH-1950 Sion, Switzerland.

Kjellevand, Tor Ole; MD, Consultant, Department of Cardiology, Rikshospitalet, University Hospital. 0027 Oslo, Norway.

Mascitelli, Luca; MD, specialist in Cardiology and Sports Medicine; Lieutenant Colonel, Chief of Sanitary Service, Comando Brigata alpina “Julia”, Italian Army, 8 Via S. Agostino, Udine 33100, Italy.

and the late great Fred Kummerow.

Throughout his career, which began in the 1940s, Kummerow challenged orthodoxy in science. His dogged determination to bring to light findings that contradicted popular notions about diet and health sometimes cost him friends and research funds. He argued, for example, that dietary sources of cholesterol like meat and eggs had no influence on heart disease unless they were prepared in a manner that oxidized the cholesterol.

Kummerow’s early work on heart disease led him to realize, decades before anyone else, that artificial trans fats in food were clogging arteries and interfering with blood flow dynamics. His earliest research on trans fats dates to 1957.

Kummerow’s efforts to remove trans fats from foods began in 1968, when he urged the American Heart Association to ask the Institute of Shortening and Edible Oils to have its members reduce the amount of trans fatty acids in shortenings and margarines, replacing them with essential fatty acids such as linoleic acid. The industry reluctantly agreed. That change coincided with a steady decrease in coronary heart disease mortality after 1968, a decline Kummerow saw as additional evidence that trans fats endanger the heart. (Heart disease rates had been climbing before that.)

In 2009, when he was 94, Kummerow filed a citizen’s petition with the U.S. Food and Drug Administration requesting that it “ban partially hydrogenated fat from the American diet.” His 3,000-word petition documented the science linking trans fats in food to inflammation, an increase of LDL cholesterol, a buildup of plaque and an increased risk of blood clots in the coronary arteries.

“Everybody should read my petition because it will scare the hell out of them,” he said at the time.

When the FDA failed to respond to his petition for four years – the law requires a response within 180 days – Kummerow, then 98, filed a lawsuit to force the agency to make a determination on his petition. Three months later, the FDA announced a “tentative determination” that trans fatty acids “are not generally recognized as safe for any use in food.”

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Sorry for being derisive, but for me saying high LDL is good is like telling me black is white. I’m just not buying it.

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I’m not sure that is what is happening on this forum though - do you feel that generally in the case?

I for instance spend massive efforts on optimizing all aspects of cardiovascular and other health including BP and inflammation, I frequently do full NMR panels - a well as whole range of other cardiovascular disease relevant markers, I’ve done a lot of heart imaging including MRI, ultrasound and a CAC and stress tests

and importantly focus a lot on optimizing diet, exercise, stress and sleep

And - not or - I care a lot about lowering Apo B.

I think many if not most of the people working towards lower Apo B is better on this forum are similar. They are going to great lengths to optimize many other aspects of cardiovascular health (and health and longevity in general).

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Good call - Yes, we need to keep things respectful, even though we disagree here. There are always going to be disagreements, but we need to keep the tone of conversation a good one. Thanks!

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Yes - I’m having a tough time with it also. I see the papers that @Vlasko is posting, and they seem on the surface (i.e. quick read at the abstract level) to support this theory. But I also suspect that its probably not too hard to search on pubmed for “benefits of high LDL” and get a ton of papers, but that doesn’t necessarily mean that the preponderance of the high quality evidence is in support of this hypothesis. And I’m not so interested in this issue that I’ll dedicate the investment in time to probe deeply into the papers.

By the way Vlaskso, One thing I really like is how you’ve created these boxes with the links for the Pubmed abstract and the full text. How do you do this?

At a higher level I find this discussion really interesting because it highlights the always difficult balance between being open to new ideas, and at the same time not jumping too early to something. On the one hand, you don’t want to be like Pons and Fleishman hailing the discovery of “cold fusion” before the evidence is good. On the other hand, you don’t want to be so slow to change your thinking that you’re like the last doctor to adopt the germ theory of disease and finally start washing your hands after killing thousands of patients.

We face the same issue with rapamycin… and other longevity drugs, how much evidence is “enough”? At what point do you change your behavior? These are really hard questions, and everyone comes to them with different backgrounds, different biases and hopes and motivations.

When it comes to the issue of Cholesterol Levels - I’m happy to let the leading cardiologists and lipidologists guide my approach because I feel the area is so deeply researched that I have no hope of getting up to speed on all the relevant papers and making an informed decision myself.

And, I’d rather put my time into areas, like rapamycin research, or SGLT2 research, because the mainstream doctors are not deeply engaged in this reasearch, so I have to do it if I want to potentially take advantage of the benefits sooner rather than later.

Just my personal take on things. Others here have very different approaches which is fine - we all have to make our own path in this area.

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I like following this discussion and I have not tried hard to come to a personal view because my ApoB is OK and my LDL-C meanders around the threshold (there is an issue with blood samples metabolising and affecting LDL-C levels as well).

I can see a good mechanistic reason for low cholesterol in a cell being a problem and being symptomatic of a problem broader than cholesterol itself. Hence it would not surprise me if people with really low cholesterol in serum figures are such because they have some other issue.

Also I think atherosclerosis is also caused by the aging pathways as well as cholesterol. Hence if you fix other things then that is a good way to maintain good health without single mindedly going for lowering ApoB or LCL-C.

However, it is a useful debate to follow. I would recommend that people take the emotion out of it. It may be because I spent 25 years as an elected official (at City level and national level in the UK) that I am entirely happy if people disagree with me. In fact if I can work out why someone disagrees with me I might learn something that enables me to get closer to the truth.

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There is no sane doctor that would prescribe you medication to lower your LDL-C if your LDL-C is in the 70-100 mg/dl range.

LDL-C hypothesis is the concept that elevated LDL-C is a main risk factor in the development of atherosclerosis and consequently in cardiovascular diseases. It is just that.

Screenshot 2024-02-27 at 08.56.57
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I believe in casual role of LDL-C but LDL-C alone can not explain the complexity of ASCVD. Multiple studies have demonstrated that insulin resistance is a strong(er) predictor of ASCVD. The inflammatory processes that promote oxidative process of OxPL (OxLDL) are being further investigated. Lifestyle like smoking are again better predictors. Same with high BP.

And there is no data that the lower the better is true in healthy people. Even in people at high risk of ASCVD death the drastic LDL-C reduction only marginally reduces mortality. And we know from centenarian studies that LDL-C is not extremely low in this subgroup.

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@scta Yes, I understand your point. The people I know who are trying to reduce their LDL (myself included) have values that are considered high (over 100). Therefore, I feel that I need to reduce my LDL below 100 and I’m happy to do that.

I think of all the major diseases, atherosclerosis, and heart disease have the most research and we understand them well enough to handle them. I guess I’m channeling my inner Dr. Attia too much as he believes the lower the LDL the better.

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