Higher LDL-Cholesterol is Associated with Greater Longevity?

Vlasko · February 23, 2024, 9:05pm

The LDL Paradox: Higher LDL-Cholesterol is Associated with Greater Longevity

Objective: In a previous review of 19 follow-up studies, we found that elderly people with high Low-Density-Lipo-protein Cholesterol (LDL-C) live just as long as or longer than people with low LDL-C. Since then, many similar follow-up studies including both patients and healthy people of all ages have been published. We have therefore provided here an update to our prior review.

Methods: We searched PubMed for cohort studies about this issue published after the publication of our study and where LDL-C has been investigated as a risk factor for all-cause and/or Cardiovascular (CVD) mortality in people and patients of all ages. We included studies of individuals without statin treatment and studies where the authors have adjusted for such treatment.

Results: We identified 19 follow-up studies including 20 cohorts of more than six million patients or healthy people. Total mortality was recorded in 18 of the cohorts. In eight of them, those with the highest LDL-C lived as long as those with normal LDL-C; in nine of them, they lived longer, whether they were on statin treatment or not. CVD mortality was measured in nine cohorts. In two of them, it was inversely associated with LDL-C; in five of them, it was not associated. In the study without information about total mortality, CVD mortality was not associated with LDL-C. In two cohorts, low LDL-C was significantly associated with total mortality. In two other cohorts, the association between LDL-C and total mortality was U-shaped. However, in the largest of them (n>5 million people below the age of 40), the mortality difference between those with the highest LDL-C and those with normal LDL-C was only 0.04%.

Conclusions: Our updated review of studies published since 2016 confirms that, overall, high levels of LDL-C are not associated with reduced lifespan. These findings are inconsistent with the consensus that high lifetime LDL levels promotes premature mortality. The widespread promotion of LDL-C reduction is not only unjustified, it may even worsen the health of the elderly because LDL-C contributes to immune functioning, including the elimination of harmful pathogens.

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Ravnskov U, de Lorgeril M, Diamond D, Hama R, Hamazaki T, Hammarskjöld B, et al. The LDL paradox - higher LDL cholesterol is associated with greater longevity. Ann Epidemiol Public Heal. (2020) 3:1040.
Full Text (PDF)

Vlasko · February 23, 2024, 9:11pm

Lack of an association or an inverse association between low-density-lipoprotein cholesterol and mortality in the elderly: a systematic review

Uffe Ravnskov et al. BMJ Open. 2016.

Abstract

Objective: It is well known that total cholesterol becomes less of a risk factor or not at all for all-cause and cardiovascular (CV) mortality with increasing age, but as little is known as to whether low-density lipoprotein cholesterol (LDL-C), one component of total cholesterol, is associated with mortality in the elderly, we decided to investigate this issue.

Setting, participants and outcome measures: We sought PubMed for cohort studies, where LDL-C had been investigated as a risk factor for all-cause and/or CV mortality in individuals ≥60 years from the general population.

Results: We identified 19 cohort studies including 30 cohorts with a total of 68 094 elderly people, where all-cause mortality was recorded in 28 cohorts and CV mortality in 9 cohorts. Inverse association between all-cause mortality and LDL-C was seen in 16 cohorts (in 14 with statistical significance) representing 92% of the number of participants, where this association was recorded. In the rest, no association was found. In two cohorts, CV mortality was highest in the lowest LDL-C quartile and with statistical significance; in seven cohorts, no association was found.

Conclusions: High LDL-C is inversely associated with mortality in most people over 60 years. This finding is inconsistent with the cholesterol hypothesis (ie, that cholesterol, particularly LDL-C, is inherently atherogenic). Since elderly people with high LDL-C live as long or longer than those with low LDL-C, our analysis provides reason to question the validity of the cholesterol hypothesis. Moreover, our study provides the rationale for a re-evaluation of guidelines recommending pharmacological reduction of LDL-C in the elderly as a component of cardiovascular disease prevention strategies.

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Ravnskov U, Diamond DM, Hama R, Hamazaki T, Hammarskjöld B, Hynes N, Kendrick M, Langsjoen PH, Malhotra A, Mascitelli L, McCully KS, Ogushi Y, Okuyama H, Rosch PJ, Schersten T, Sultan S, Sundberg R. Lack of an association or an inverse association between low-density-lipoprotein cholesterol and mortality in the elderly: a systematic review. BMJ Open. 2016 Jun 12;6(6):e010401. doi: 10.1136/bmjopen-2015-010401. PMID: 27292972; PMCID: PMC4908872.
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Virilius · February 23, 2024, 9:11pm

Observational trials show an U-curve for cholesterol levels because cancer patients have low cholesterol due to the cancer “eating up” all the apoB particles and sugar. In intervention trials, we can consistedly see a decrease in primary endpoints and strokes as well as lower all-cause mortality and reduced plaque volume, especially with stronger medication such as rosuvastatin or atorvastatin.

AlexKChen · February 23, 2024, 9:14pm

LDL cholesterol has a very slight negative (non-significant) correlation with epigenetic age from what I’ve seen. Also a very slight negative correlation with some proteomic clocks that someone from the Wyss-Corey lab used on their paper

You still have to look at the ApoE levels and the particle sizes, not all LDL particle sizes are equal.

It’s possible that (as with the case of low hemoglobin a1c), low LDL is a symptom of something else that is concerning (I think someone hypothesized this). Low albumin?

That said, what about longitudinal studies where you’ve done the proper Mendelian randomization? I think people who genetically have very low LDL cholesterol (eg genetically PCKS9i) tend to have few ill effects? [but idk if a very comprehensive mortality analysis of them has been done]

anon16510610 · February 23, 2024, 9:16pm

Vlasko · February 23, 2024, 9:22pm

Associations between Serum Levels of Cholesterol and Survival to Age 90 in Postmenopausal Women

Adam X Maihofer et al. J Am Geriatr Soc. 2020 Feb.

Abstract

Objectives: Although elevated lipid levels predict increased risk of coronary heart disease and death in middle-aged women and men, evidence is mixed if lipid levels measured in later life predict survival to very old ages. We examined lipid levels and survival to age 90 with or without intact mobility in a large cohort of older women.

Design: Prospective cohort.

Setting: Laboratory collection at a Women’s Health Initiative (WHI) center and longitudinal follow-up via mail.

Participants: Women aged 68 to 81 years at baseline.

Measurements: Serum high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol were collected at baseline. Participant survival status and self-reported mobility was compared across lipid levels.

Results: HDL and LDL levels were not associated with survival to age 90 after adjustment for cardiovascular risk factors (HDL: quartile (Q) 2: odds ratio [OR] = 1.14 [95% confidence interval [CI] = .94-1.38]; Q3 OR = 1.08 [95% CI = .88-1.33]; Q4 OR = 1.09 [95% CI = .88-1.35]; LDL: Q2 OR = 1.07 [95% CI = .88-1.31]; Q3 OR = 1.27 [95% CI = 1.04-1.55]; Q4 OR = 1.07 [95% CI = .88-1.31]). Similarly, no associations were observed between HDL and LDL levels and survival to age 90 with mobility disability. High HDL was not associated with survival to age 90 with intact mobility after adjustment for other cardiovascular risk factors. Compared with the lowest LDL quartile, the three upper LDL quartiles were associated with greater odds of survival to age 90 with intact mobility (LDL: Q2 OR = 1.31 [95% CI = .99-1.74]; Q3 OR = 1.43 [95% CI = 1.07-1.92]; Q4 OR = 1.35 [95% CI = 1.01-1.80]; P = .05).

Conclusion: Neither higher HDL nor lower LDL levels predicted survival to age 90, but higher LDL predicted healthy survival. These findings suggest the need for reevaluation of healthy LDL levels in older women.

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Maihofer AX, Shadyab AH, Wild RA, LaCroix AZ. Associations between Serum Levels of Cholesterol and Survival to Age 90 in Postmenopausal Women. J Am Geriatr Soc. 2020 Feb;68(2):288-296. doi: 10.1111/jgs.16306. Epub 2020 Jan 13. PMID: 31930739.
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Vlasko · February 23, 2024, 9:28pm

Cholesterol and all-cause mortality in elderly people from the Honolulu Heart Program: a cohort study

I J Schatz et al. Lancet. 2001.

Abstract

Background: A generally held belief is that cholesterol concentrations should be kept low to lessen the risk of cardiovascular disease. However, studies of the relation between serum cholesterol and all-cause mortality in elderly people have shown contrasting results. To investigate these discrepancies, we did a longitudinal assessment of changes in both lipid and serum cholesterol concentrations over 20 years, and compared them with mortality.

Methods: Lipid and serum cholesterol concentrations were measured in 3572 Japanese/American men (aged 71-93 years) as part of the Honolulu Heart Program. We compared changes in these concentrations over 20 years with all-cause mortality using three different Cox proportional hazards models.

Findings: Mean cholesterol fell significantly with increasing age. Age-adjusted mortality rates were 68.3, 48.9, 41.1, and 43.3 for the first to fourth quartiles of cholesterol concentrations, respectively. Relative risks for mortality were 0.72 (95% CI 0.60-0.87), 0.60 (0.49-0.74), and 0.65 (0.53-0.80), in the second, third, and fourth quartiles, respectively, with quartile 1 as reference. A Cox proportional hazard model assessed changes in cholesterol concentrations between examinations three and four. Only the group with low cholesterol concentration at both examinations had a significant association with mortality (risk ratio 1.64, 95% CI 1.13-2.36).

Interpretation: We have been unable to explain our results. These data cast doubt on the scientific justification for lowering cholesterol to very low concentrations (<4.65 mmol/L) in elderly people.

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Schatz IJ, Masaki K, Yano K, Chen R, Rodriguez BL, Curb JD. Cholesterol and all-cause mortality in elderly people from the Honolulu Heart Program: a cohort study. Lancet. 2001 Aug 4;358(9279):351-5. doi: 10.1016/S0140-6736(01)05553-2. PMID: 11502313.
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scta123 · February 23, 2024, 9:35pm

Intervention trials typically involve studying people who are already affected by ASCVD.
Some studies have suggested that in certain populations, such as older adults or those with chronic diseases like heart failure or kidney disease, higher LDL cholesterol levels may be associated with better outcomes. This phenomenon is not yet fully understood and requires further investigation. However, it’s essential to approach these findings with caution.
In some individuals, the efficiency of their apoA-1, which supports HDL reverse cholesterol transport, may mitigate the impact of LDL cholesterol levels on cardiovascular health. However, the effectiveness of apoA-1 varies among people. Currently, there isn’t a specific test to directly measure the efficiency of apoA-1. So better watch LDL-C (apoB).

Vlasko · February 23, 2024, 9:37pm

Total cholesterol and all-cause mortality by sex and age: a prospective cohort study among 12.8 million adults

Sang-Wook Yi et al. Sci Rep. 2019.

Abstract

It is unclear whether associations between total cholesterol (TC) levels and all-cause mortality and the optimal TC ranges for lowest mortality vary by sex and age. 12,815,006 Korean adults underwent routine health examinations during 2001-2004, and were followed until 2013. During follow-up, 694,423 individuals died. U-curve associations were found. In the TC ranges of 50-199 and 200-449 mg/dL, each 39 mg/dL (1 mmol/L) increase in TC was associated with 23% lower (95% CI:23%,24%) and 7% higher (6%,7%) mortality, respectively. In the age groups of 18-34, 35-44, 45-54, 55-64, 65-74, and 75-99 years, each 1 mmol/L higher TC increased mortality by 14%, 13%, 8%, 7%, 6%, and 3%, respectively (P < 0.001 for each age group), for TC ≥ 200 mg/dL, while the corresponding TC changes decreased mortality by 13%, 27%, 34%, 31%, 20%, and 13%, respectively, in the range < 200 mg/dL (P < 0.001 for each age group). TC had U-curve associations with mortality in each age-sex group. TC levels associated with lowest mortality were 210-249 mg/dL, except for men aged 18-34 years (180-219 mg/dL) and women aged 18-34 years (160-199 mg/dL) and 35-44 years (180-219 mg/dL). The inverse associations for TC < 200 mg/dL were stronger than the positive associations in the upper range.

From the full text:

“Inverse associations in the range <200 mg/dL were more than 3-fold stronger than positive associations for cholesterol levels ≥200 mg/dL, except for the youngest adults. Positive associations in the upper TC range were strongest for youngest adults and weakened with advancing age. TC levels <200 mg/dL may not necessarily be a sign of good health.”

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Yi SW, Yi JJ, Ohrr H. Total cholesterol and all-cause mortality by sex and age: a prospective cohort study among 12.8 million adults. Sci Rep. 2019 Feb 7;9(1):1596. doi: 10.1038/s41598-018-38461-y. PMID: 30733566; PMCID: PMC6367420.
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RapAdmin · February 23, 2024, 9:38pm

Yes - reviewing PeerPub commentary on this paper suggests its really not something people should put much value in. I recommend everyone get a PeerPub account so you can see the commentary on research papers like these.

Important methodological flaws limit the findings from the paper by Ravnskov and colleagues

We performed a post-publication critical appraisal of this paper and found a number of methodological flaws not least:

Lack of a published protocol

Searching of only one database

Nonuniform application of inclusion/exclusion criteria

A lack of critical appraisal of the methods used in the included studies

No indication of the quality or uncertainty of the included data

Issues with the accuracy of data extraction, and,

A lack of controlling for confounding due to the effect of lipid-lowering treatment and HDL-C levels presenting major bias and more likely underpinning the majority of the observed inverse associations.

Based on the above-identified flaws in the paper by Ravnskov and colleagues we concluded: “Given that the authors failed to account for significant confounding as well as the methodological weaknesses of both the review and its included studies, the results of this review have limited validity and should be interpreted with caution. At this time it would not be responsible, or evidence-based, for policy decisions to be made based on the results of this study”.

Our full appraisal can be found on our website here: Home - 2020 - The Centre for Evidence-Based Medicine

Elderly patients with CV risk factors do benefit from pharmacologic reduction of LDL-C by suffering fewer heart attacks, strokes and probably reduced mortality. Seniors should not discontinue statin therapy due to this study, which is based on lower quality data than the treatment guidelines are based on.

This comment has been published as an online letter by BMJ Open. [4]

References

1: Ravnskov U, et al. Lack of an association or an inverse association between low-density-lipoprotein cholesterol and mortality in the elderly: a systematic review. BMJ Open. 2016 Jun 12;6(6):e010401. doi:10.1136/bmjopen-2015-010401. PubMed PMID: 27292972.

2: Hannan EL. Randomized clinical trials and observational studies: guidelines for assessing respective strengths and limitations. JACC Cardiovasc Interv. 2008 Jun;1(3):211-7. doi:0.1016/j.jcin.2008.01.008. Review. PubMed PMID: 19463302.

3: Savarese G, et al. Benefits of statins in elderly subjects without established cardiovascular disease: a meta-analysis. J Am Coll Cardiol. 2013 Dec 3;62(22):2090-9.doi:10.1016/j.jacc.2013.07.069. Epub 2013 Aug 28. PubMed PMID: 23954343.

4: Keller DL, Statins do prevent heart attacks and strokes in the elderly. BMJ Open, published online on June 21, 2016 at the following URL: http://bmjopen.bmj.com/content/6/6/e010401.long/reply#bmjopen_el_9817

Virilius · February 23, 2024, 9:40pm

The JUPITER trial specifically looked at people at risk without ASCVD.

Some studies have suggested that in certain populations, such as older adults or those with chronic diseases like heart failure or kidney disease, higher LDL cholesterol levels may be associated with better outcomes.

But those associations are once again polluted by cofounding factors such as cancer. Remove cancer and the U-curve turns into a straight linear curve.

In some individuals, the efficiency of their apoA-1, which supports HDL reverse cholesterol transport, may mitigate the impact of LDL cholesterol levels on cardiovascular health.

It could, but there is no reason why you couldn’t increase HDL while decreasing LDL-C.

AnUser · February 23, 2024, 9:52pm

You are writing with outdated knowledge.
Of course higher LDL implies a worse biological age since it increases with aging.

Why does ApoE levels matter?

No particle size do not matter afaik. Only amount of particles (apoB).

All of these association studies are reverse causation. There are lots of diseases that decrease LDL.

Yes… it is reverse causation.
If you genetically increase apoB you live much shorter.

I see no point in addressing any of these studies posted by @Vlasko they are all so pathetically methodologically flawed it is no point in even considering them.

Vlasko · February 23, 2024, 9:53pm

This is just the first in a series of papers that I’m posting. And I’m not necessarily endorsing this view. But I wanted to raise awareness that there are a number of studies with similar findings.

AnUser · February 23, 2024, 10:00pm

Stop wasting people’s time and stick with mendelian randomization studies and RCT’s.
If you don’t understand the severe flaws in the type of studies you are posting, and leave it unmentioned, do not post them.

Dr.Bart · February 23, 2024, 10:04pm

Infants and small children have extremely low levels of LDL and there is no evidence that affects them adversely in any way, especially when faced with growth and development when substrate is very much needed.

Vlasko · February 23, 2024, 10:08pm

A nonlinear association of total cholesterol with all-cause and cause-specific mortality

Guo-Dong He et al. Nutr Metab (Lond). 2021.

Abstract

Background: The link between total cholesterol (TC) and all-cause and specific mortality has not been elucidated. Herein, we aimed to evaluate the effect of TC levels on all-cause, cardiovascular disease (CVD), and cancer mortality.

Methods: All data analyzed were obtained from the National Health and Nutrition Examination Survey 1999-2014. The relationship between levels of TC and mortality was determined through Cox proportional hazard regression analysis coupled with multivariable adjustments. Two-piecewise linear regression models and Cox models with penalized splines were applied to explore nonlinear and irregular shape relationships. Kaplan-Meier survival curve and subgroup analyses were conducted.

Results: The sample studied comprised 14,662 men and 16,025 women, categorized as 25,429 adults aged 18-65 and 5,258 adults over 65 years old. A total of 2,570 deaths were recorded. All-cause, cardiovascular, and cancer mortality showed U-curve associations after adjusting for confounding variables in the restricted cubic spline analysis. Hazard ratios (HRs) of all-cause and cancer mortality were particularly negatively related to TC levels in the lower range < 200 mg/dL, especially in the range < 120 mg/dL (HR 1.97; 95% CI 1.38, 2.83, HR 2.39; 95% CI 1.21, 4.71, respectively). However, the HRs of cardiovascular disease mortality in the range < 120 mg/dL were the lowest (HR 0.60; 95% CI 0.15, 2.42). In the upper range, a TC range of ≥ 280 mg/dL was correlated with mortality as a result of CVD and cancer (HR 1.31; 95% CI 0.87, 1.97 and HR 1.22; 95% CI 0.82, 1.79). The lowest cumulative survival rate of all-cause mortality was recorded in the lowest TC-level group, while the lowest cumulative survival rate of CVD mortality was recorded in the highest TC-level group.

Conclusions: A nonlinear association of TC level with all-cause, cancer, and CVD mortality in the American population was observed, suggesting that too low or too high serum total cholesterol levels might correlate with adverse outcomes.

From the full text:

“Our findings indicated that TC levels might be a critical risk factor in the general population, and TC levels < 200 mg/dL might not be indicative of good health.”

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He GD, Liu XC, Liu L, Yu YL, Chen CL, Huang JY, Lo K, Huang YQ, Feng YQ. A nonlinear association of total cholesterol with all-cause and cause-specific mortality. Nutr Metab (Lond). 2021 Mar 10;18(1):25. doi: 10.1186/s12986-021-00548-1. PMID: 33691735; PMCID: PMC7945313.

Virilius · February 23, 2024, 10:12pm

I can also spam thousends of intervention studies, Mendellian randomization and mechanistic studies showing the benefit of statins and PCSK9 inhibitors.
Look up the pyramide of evidence and stop relying on association studies to support your argument when there are many studies higher up the latter proving that lowering LDL-C indeed leads to lower mortality.
Besides, there are ZERO studies indicating that higher LDL-C decreasing plaque while there are many studies proving that purposely lowering LDL-C decreases plaque. Does plaque not matter to you?

RapAdmin · February 23, 2024, 10:17pm

I have friends / family members who are cardiologists out of Stanford Medical School / Cleveland Clinic. I don’t believe that there is much disagreement by them, or in the medical schools more generally, that lower APOB is better, at least down to the 50 to 100 level. Sure, there is discussion of how low is optimal, but thats a different issue than these papers are suggesting.

Yes - there will always be outliers in any research field. I’m not a cardiologist, so I personally go with what they suggest and what the expert consensus is.

Given that ASCVD is the number one killer of people in the USA, I’d be careful with contrarian approaches.

Vlasko · February 23, 2024, 10:25pm

Hit or miss: the new cholesterol targets

Robert DuBroff et al. BMJ Evid Based Med. 2021 Dec.

Abstract

Drug treatment to reduce cholesterol to new target levels is now recommended in four moderate- to high-risk patient populations: patients who have already sustained a cardiovascular event, adult diabetic patients, individuals with low density lipoprotein cholesterol levels ≥190 mg/dL and individuals with an estimated 10-year cardiovascular risk ≥7.5%. Achieving these cholesterol target levels did not confer any additional benefit in a systematic review of 35 randomised controlled trials. Recommending cholesterol lowering treatment based on estimated cardiovascular risk fails to identify many high-risk patients and may lead to unnecessary treatment of low-risk individuals. The negative results of numerous cholesterol lowering randomised controlled trials call into question the validity of using low density lipoprotein cholesterol as a surrogate target for the prevention of cardiovascular disease.

Coverage Article from the BMJ.
Excerpt:

"Because LDL cholesterol is considered essential for the development of cardiovascular disease, “it seems intuitive and logical to target [it],” say the researchers.
But they add: “Considering that dozens of [randomised controlled trials] of LDL-cholesterol reduction have failed to demonstrate a consistent benefit, we should question the validity of this theory.”
And they conclude: “In most fields of science the existence of contradictory evidence usually leads to a paradigm shift or modification of the theory in question, but in this case the contradictory evidence has been largely ignored, simply because it doesn’t fit the prevailing paradigm.”

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DuBroff R, Malhotra A, de Lorgeril M. Hit or miss: the new cholesterol targets. BMJ Evid Based Med. 2021 Dec;26(6):271-278. doi: 10.1136/bmjebm-2020-111413. Epub 2020 Aug 3. PMID: 32747335.

Virilius · February 23, 2024, 10:35pm

So study spamming it is then.

Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, genetic, and therapeutic insights: a consensus statement from the European Atherosclerosis Society Consensus Panel | European Heart Journal | Oxford Academic (oup.com)

Reduction in saturated fat intake for cardiovascular disease - Hooper, L - 2020 | Cochrane Library

Association Between Lowering LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic Interventions: A Systematic Review and Meta-analysis - PubMed (nih.gov)

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 - ScienceDirect

ATV.0000000000000164 (ahajournals.org)

Safety and efficacy of very low LDL-cholesterol intensive lowering: a meta-analysis and meta-regression of randomized trials - PubMed (nih.gov)

Effect of statin therapy on muscle symptoms: an individual participant data meta-analysis of large-scale, randomised, double-blind trials - The Lancet

Statins for the primary prevention of cardiovascular disease | Cochrane

Bempedoic Acid and Cardiovascular Outcomes in Statin-Intolerant Patients | NEJM