#9

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).

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#10

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.”

===
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.
Full Text

#11

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:

  1. Lack of a published protocol
  2. Searching of only one database
  3. Nonuniform application of inclusion/exclusion criteria
  4. A lack of critical appraisal of the methods used in the included studies
  5. No indication of the quality or uncertainty of the included data
  6. Issues with the accuracy of data extraction, and,
  7. 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

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#12

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.

2 Likes
#13

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.

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#14

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.

1 Like
心血管健康
#15

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.

3 Likes
#16

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.

7 Likes
#17

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.”

===
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.

1 Like
#18

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?

7 Likes
#19

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.

12 Likes
#20

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.”

===
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.

1 Like
#21

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

9 Likes
#22

Low-density lipoprotein cholesterol and all-cause mortality: findings from the China health and retirement longitudinal study.

Liang Zhou et al. BMJ Open. 2020.

Abstract

Objectives: 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 theZhou L, Wu Y, Yu S, Shen Y, Ke C. Low-density lipoprotein cholesterol and all-cause mortality: findings from the China health and retirement longitudinal study. BMJ Open. 2020 Aug 16;10(8):e036976. doi: 10.1136/bmjopen-2020-036976. PMID: 32801200; PMCID: PMC7430481. 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.

===
Zhou L, Wu Y, Yu S, Shen Y, Ke C. Low-density lipoprotein cholesterol and all-cause mortality: findings from the China health and retirement longitudinal study. BMJ Open. 2020 Aug 16;10(8):e036976. doi: 10.1136/bmjopen-2020-036976. PMID: 32801200; PMCID: PMC7430481.
Full Text

1 Like
#23

I think this bot is malfunctioning.

4 Likes
#24

Relations of Change in Plasma Levels of LDL‐C, Non‐HDL‐C and apoB With Risk Reduction From Statin Therapy: A Meta‐Analysis of Randomized Trials | Journal of the American Heart Association (ahajournals.org)

Europe PMC

9789241565349-eng.pdf (who.int)

Long-term secondary prevention of cardiovascular disease with a Mediterranean diet and a low-fat diet (CORDIOPREV): a randomised controlled trial - PubMed (nih.gov)

Effect of cutting down on the saturated fat we eat on our risk of heart disease | Cochrane

Dietary intake of total, animal, and plant proteins and risk of all cause, cardiovascular, and cancer mortality: systematic review and dose-response meta-analysis of prospective cohort studies - PMC (nih.gov)

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#25

When Russians send their spammers they are not sending their best.

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#26

I think it goes without saying that the prevailing wisdom or common belief is that LDL-C should be kept in a certain range or at least below a certain threshold to reduce the risk of adverse health outcomes. However, there really isn’t a scientific consensus, either, which may come as a surprise to most people. More like a prevailing majority stance. My intent here was to show that there is a significant number of researchers with statistical findings that contradict mainstream thought and call into question the current criteria used to determine when initiation of cholesterol-lowering therapy may be prudent. And this includes articles and studies in the BMJ. If nothing else, these studies (and more that I haven’t included here) raise concerns over the current reference ranges that are relied on by physicians to make decisions on pharmacological intervention.

2 Likes
心血管健康
#27

We have direct evidence from intervention trials which trump any and all observational trials that lowering LDL-C lowers mortality.
Why do you ignore the pyramide of evidence? Why do you keep citing fringe papers? This just screams agenda.

2 Likes
#28

So there isn’t a scientific consensus, but there is mainstream thought? Even though you seem to contradict yourself, I can assure you outside of CIS, there is a medical consensus on the matter. Just look up ACC guidelines for America or ESC in Europe. With over 50,000 cardiology members for the former and 100,000 for the latter. But it doesn’t matter since your papers have been debunked by the other posts in this thread.

1 Like