Jump to content

Is High LDL-c Harmless in Otherwise Healthy People?


Recommended Posts

[Moderator's Note: I moved the first two posts in this thread from here, where they was off-topic. --Dean]

On 3/7/2021 at 5:26 AM, Dean Pomerleau said:

But I wonder just how generalizable and healthy your diet and lifestyle practices are long-term for people without your life threatening genetic condition.

 

I wonder the same thing about CR.  It often works wonders especially in the short term.  Some struggle to sustain success long term.  And there are cases of it spiraling into disaster typically attributed to bad luck, bad genes or bad execution.

I find it fairly compelling that a large and growing number of people (and mice too!) have found benefits with similar approaches to mine for numerous diseases such as MS, MD, ALS, SMA, CMT, Parkinson's, Alzheimer's and Huntington's as well as many forms of cancer.  And Virta Health and others have rapidly growing successful businesses treating common problems such as obesity, diabetes and heart disease using various forms of ketogenic diets as foundational aspects of their therapies.

It appears the most common pitfall of ketogenic diets, especially high saturated fat or animal based, is an extreme rise in LDL perhaps affecting 20 to 30% of those who stick with it long term.  I fall into this group as my LDL has already more than doubled and is rising, perhaps into the range of 500 to 800 if I sustain my current practices and trajectory.  But despite much looking I have yet to see compelling evidence high LDL is harmful in the context of good metabolic health (low BP, low bodyfat, high HDL, low triglycerides, low insulin, stable blood sugar w/ low HbA1C, normal thyroid, low inflammation, etc.).

Link to comment
Share on other sites

 

3 hours ago, Todd Allen said:

I wonder the same thing about CR.  It often works wonders especially in the short term.  Some struggle to sustain success long term.  And there are cases of it spiraling into disaster typically attributed to bad luck, bad genes or bad execution

Perfectly true. Hardcore CR should be attempted only with great care and is not recommended for people with risk factors for an eating disorder.

3 hours ago, Todd Allen said:

It appears the most common pitfall of ketogenic diets, especially high saturated fat or animal based, is an extreme rise in LDL perhaps affecting 20 to 30% of those who stick with it long term.  I fall into this group as my LDL has already more than doubled and is rising, perhaps into the range of 500 to 800 if I sustain my current practices and trajectory.  

Wow. Good luck with that.

3 hours ago, Todd Allen said:

But despite much looking I have yet to see compelling evidence high LDL is harmful in the context of good metabolic health (low BP, low bodyfat, high HDL, low triglycerides, low insulin, stable blood sugar w/ low HbA1C, normal thyroid, low inflammation, etc.).

The average person in this study's [1] cohort may not have had quite as favorable markers of metabolic health (besides LDL) as you do, but they were categorized as "low risk" for CVD based on such markers (their median estimated 10-year risk of developing (let alone dying from) CVD was only 1.3%) and they didn't have nearly as high LDL as you do (median LDL-C of 205 in the highest quintile).

Nevertheless those otherwise-low-CVD-risk people who were in the highest LDL quintiles died from CVD at a 50-80% higher rate during ~30 years of followup than folks with study participants with LDL less than 100. Here is the graph of CVD mortality stratified by LDL quintile:

Screenshot_20210308-153753_Chrome.jpg

You can certainly try to argue such a study doesn't apply to you, either because of your underlying disease (KD) and/or because you are metabolically healthier than those in the upper LDL quintiles in [1].

But I would consider that a stretch and would personally be very reluctant to take the chance that very high LDL is harmless in otherwise healthy people, especially given the additional evidence from:

  1. People with familial hypercholesterolemia (who are the only population I know of whose LDL approaches yours) who have a 22x higher risk of developing heart disease than people with LDL < 130 [2].
  2. Mendelian randomization studies (e.g. [3]) which have found that in otherwise well-matched populations, the lifetime risk of CVD in people with genetic mutations that modestly elevate their LDL is 50% higher per 38mg/dl increase in LDL.   

--Dean

-----------

[1] Circulation. 2018 Nov 20;138(21):2315-2325. doi: 

10.1161/CIRCULATIONAHA.118.034273.

Long-Term Association of Low-Density Lipoprotein Cholesterol With Cardiovascular 
Mortality in Individuals at Low 10-Year Risk of Atherosclerotic Cardiovascular 
Disease.

Abdullah SM(1)(2), Defina LF(3), Leonard D(3), Barlow CE(3), Radford NB(4), 
Willis BL(3), Rohatgi A(1), McGuire DK(1), de Lemos JA(1), Grundy SM(1)(2), 
Berry JD(1), Khera A(1).

Author information:
(1)Department of Internal Medicine, University of Texas Southwestern Medical 
Center, Dallas (S.M.A., A.R., D.K.M., J.A.D., S.M.G., J.D.B., A.K.).
(2)Veteran's Affairs North Texas Medical Center, Dallas (S.M.A., S.M.G.).
(3)The Cooper Institute, Dallas, TX (L.F.D., D.L., C.E.B., B.L.W.).
(4)The Cooper Clinic, Dallas, TX (N.B.R.).

BACKGROUND: The associations of low-density lipoprotein cholesterol (LDL-C) with 

cardiovascular disease (CVD) and coronary heart disease mortality in an 
exclusively low estimated 10-year risk group are not well delineated. We sought 
to determine the long-term associations of various LDL-C and non-high-density 
lipoprotein cholesterol (HDL-C) thresholds and CVD and coronary heart disease 
mortality in a large, low 10-year risk cohort.
METHODS: The study sample included participants of the CCLS (Cooper Center 
Longitudinal Study) without a history of CVD or diabetes mellitus and defined as 
low risk (<7.5%) for 10-year atherosclerotic CVD events
at baseline based on 
Pooled Cohort Risk Assessment Equations. The associations of fasting LDL-C and 
non-HDL-C with CVD mortality were tested with Cox proportional hazards models.
RESULTS: In 36 375 participants (72% men, median age 42) followed for a median 
of 26.8 years
, 1086 CVD and 598 coronary heart disease deaths occurred. Compared 
with LDL-C <100 mg/dL, LDL-C categories 100 to 129 mg/dL, 130 to 159 mg/dL, 160 
to 189.9 mg/dL, and ≥190 mg/dL were associated with a significantly higher risk 
of CVD death, with hazard ratios of 1.4 (95% CI, 1.1-1.7), 1.3 (95% CI, 
1.1-1.6), 1.9 (95% CI, 1.5-2.4), and 1.7 (95% CI, 1.3-2.3),
and mean reductions 
in years free of CVD death of 1.8, 1.1, 4.3, and 3.9, respectively. After 
adjustment for atherosclerotic CVD risk factors, LDL-C categories 160 to 189 
mg/dL and ≥190 mg/dL remained independently associated with CVD mortality, with 
hazard ratios of 1.7 (95% CI, 1.4-2.2) and 1.5 (95% CI, 1.2-2.1), respectively. 
In multivariable-adjusted models using non-HDL-C <130 mg/dL as the reference, 
non-HDL-C 160 to 189 mg/dL, 190 to 219 mg/dL, and ≥220 mg/dL were significantly 
associated with CVD death, with hazard ratios of 1.3 (95% CI, 1.1-1.6), 1.8 (95% 
CI, 1.4-2.2), and 1.5 (95% CI, 1.2-2.0), respectively. Restricting the cohort to 
those with 10-year risk <5% did not diminish the associations of LDL-C and 
non-HDL-C with CVD mortality.

CONCLUSIONS: In a low 10-year risk cohort with long-term follow-up, LDL-C and 
non-HDL-C ≥160 mg/dL were independently associated with a 50% to 80% increased 
relative risk of CVD mortality. These findings may have implications for future 
cholesterol treatment paradigms
.

DOI: 10.1161/CIRCULATIONAHA.118.034273
PMID: 30571575 [Indexed for MEDLINE]

-----------------

[2] J Am Coll Cardiol. 2016 Jun 7;67(22):2578-89. doi: 10.1016/j.jacc.2016.03.520. 

Epub 2016 Apr 3.

Diagnostic Yield and Clinical Utility of Sequencing Familial 
Hypercholesterolemia Genes in Patients With Severe Hypercholesterolemia.

Khera AV(1), Won HH(2), Peloso GM(3), Lawson KS(4), Bartz TM(5), Deng X(6), van 
Leeuwen EM(7), Natarajan P(1), Emdin CA(8), Bick AG(8), Morrison AC(4), Brody 
JA(9), Gupta N(8), Nomura A(10), Kessler T(11), Duga S(12), Bis JC(9), van Duijn 
CM(7), Cupples LA(6), Psaty B(13), Rader DJ(14), Danesh J(15), Schunkert H(11), 
McPherson R(16), Farrall M(17), Watkins H(17), Lander E(8), Wilson JG(18), 
Correa A(19), Boerwinkle E(4), Merlini PA(20), Ardissino D(21), Saleheen D(22), 
Gabriel S(8), Kathiresan S(23).

BACKGROUND: Approximately 7% of American adults have severe hypercholesterolemia 

(untreated low-density lipoprotein [LDL] cholesterol ≥190 mg/dl), which may be 
due to familial hypercholesterolemia (FH). Lifelong LDL cholesterol elevations 
in FH mutation carriers may confer coronary artery disease (CAD) risk beyond 
that captured by a single LDL cholesterol measurement.
OBJECTIVES: This study assessed the prevalence of an FH mutation among those 
with severe hypercholesterolemia and determined whether CAD risk varies 
according to mutation status beyond the observed LDL cholesterol level.
METHODS: Three genes causative for FH (LDLR, APOB, and PCSK9) were sequenced in 
26,025 participants from 7 case-control studies (5,540 CAD case subjects, 8,577 
CAD-free control subjects) and 5 prospective cohort studies (11,908 
participants). FH mutations included loss-of-function variants in LDLR, missense 
mutations in LDLR predicted to be damaging, and variants linked to FH in 
ClinVar, a clinical genetics database.
RESULTS: Among 20,485 CAD-free control and prospective cohort participants, 
1,386 (6.7%) had LDL cholesterol ≥190 mg/dl; of these, only 24 (1.7%) carried an 
FH mutation. Within any stratum of observed LDL cholesterol, risk of CAD was 
higher among FH mutation carriers than noncarriers. Compared with a reference 
group with LDL cholesterol <130 mg/dl and no mutation, participants with LDL 
cholesterol ≥190 mg/dl and no FH mutation had a 6-fold higher risk for CAD (odds 
ratio: 6.0; 95% confidence interval: 5.2 to 6.9), whereas those with both LDL 
cholesterol ≥190 mg/dl and an FH mutation demonstrated a 22-fold increased risk 
(odds ratio: 22.3; 95% confidence interval: 10.7 to 53.2).
In an analysis of 
participants with serial lipid measurements over many years, FH mutation 
carriers had higher cumulative exposure to LDL cholesterol than noncarriers.
CONCLUSIONS: Among participants with LDL cholesterol ≥190 mg/dl, gene sequencing 
identified an FH mutation in <2%. However, for any observed LDL cholesterol, FH 
mutation carriers had substantially increased risk for CAD.

Copyright © 2016 American College of Cardiology Foundation. Published by 
Elsevier Inc. All rights reserved.

DOI: 10.1016/j.jacc.2016.03.520
PMCID: PMC5405769
PMID: 27050191 [Indexed for MEDLINE]

-------------

[3] Sci Rep. 2020 Jun 8;10(1):9208. doi: 10.1038/s41598-020-66027-4.

In-depth Mendelian randomization analysis of causal factors for coronary artery 
disease.

Tan YD(1), Xiao P(1), Guda C(2).

Author information:
(1)Department of Genetics, Cell Biology & Anatomy in Nebraska University Medical 
Center, Omaha, NE, 68198, USA.
(2)Department of Genetics, Cell Biology & Anatomy in Nebraska University Medical 
Center, Omaha, NE, 68198, USA. babu.guda@unmc.edu.

Selecting a set of valid genetic variants is critical for Mendelian 
randomization (MR) to correctly infer risk factors causing a disease. We here 
developed a method for selecting genetic variants as valid instrumental 
variables for inferring risk factors causing coronary artery disease (CAD). 
Using this method, we selected two sets of single-nucleotide-polymorphism (SNP) 
genetic variants (SNP338 and SNP363) associated with each of the three potential 
risk factors for CAD including low density lipoprotein cholesterol (LDL-c), high 
density lipoprotein cholesterol (HDL-c) and triglycerides (TG) from two 
independent GWAS datasets. We performed in-depth multivariate MR (MVMR) analyses 
and the results from both datasets consistently showed that LDL-c was strongly 
associated with increased risk for CAD (β = 0.396,OR = 1.486 per 1 SD 
(equivalent to 38 mg/dL), 95CI = (1.38, 1.59) in SNP338; and β = 0.424, OR = 
1.528
per 1 SD, 95%CI = (1.42, 1.65) in SNP363)
; HDL-c was strongly associated 
with reduced risk for CAD (β = -0.315, OR = 0.729 per 1 SD (equivalent to 
16 mg/dL), 95CI = (0.68, 0.78) in SNP338; and β = -0.319, OR = 0.726 per 1 SD, 
95%CI = (0.66, 0.80), in SNP363). In case of TG, when using the full datasets, 
an increased risk for CAD (β = 0.184, OR = 1.2 per 1 SD (equivalent to 
89 mg/dL), 95%CI = (1.12, 1.28) in SNPP338; and β = 0.207, OR = 1.222 per 1 SD, 
95%CI = (1.10, 1.36) in SNP363) was observed, while using partial datasets that 
contain shared and unique SNPs showed that TG is not a risk factor for CAD. From 
these results, it can be inferred that TG itself is not a causal risk factor for 
CAD, but it's shown as a risk factor due to pleiotropic effects associated with 
LDL-c and HDL-c SNPs
. Large-scale simulation experiments without pleiotropic 
effects also corroborated these results.

DOI: 10.1038/s41598-020-66027-4
PMCID: PMC7280530
PMID: 32514076 [Indexed for MEDLINE]

Link to comment
Share on other sites

2 hours ago, Dean Pomerleau said:

The average person in this study's [1] cohort may not have had quite as favorable markers of metabolic health (besides LDL) as you do, but they were categorized as "low risk" for CVD based on such markers (their median estimated 10-year risk of developing (let alone dying from) CVD was only 1.3%) and they didn't have nearly as high LDL as you do (median LDL-C of 205 in the highest quintile).

Here's a table of baseline characteristics of people in the study:

LDL_CVD_baseline.jpg.735f8e63e0d964c33bcff002fb9673dc.jpg

This cohort has metabolic syndrome/insulin resistance which is no surprise as the majority of adults are prediabetic.  This cohort is merely borderline prediabetic so perhaps low risk by those with low standards.  The higher quintiles of LDL are older with higher rates of hypertension, higher BMI and slightly worse ranges on other markers and lower percentages of women all probably contributing to their increased mortality risk. So this doesn't well isolate the risk of elevated LDL in the unhealthy let alone speak to the risk of LDL in a healthy population.

 

Edited by Todd Allen
Link to comment
Share on other sites

  • 2 weeks later...

For men, [an HDL-c of] 50 - 59 seems to be optimal in terms of maximally reduced risk of death for all causes, with significantly increased mortality risk above 60. That data is in ~19 million subjects, see:
 

 

Edited by Dean Pomerleau
Added paranthetical clarification that Mike's video refers to optimal HDL-c, and not LDL-c.
Link to comment
Share on other sites

  • 9 months later...
  • 5 months later...

Yet another study identifying a large subset of those with extremely high LDL-C who are at low risk with respect to CVD.

Association of Coronary Plaque With Low-Density Lipoprotein Cholesterol Levels and Rates of Cardiovascular Disease Events Among Symptomatic Adults

Quote

Key Points

Question  What is the prevalence of coronary plaque, and is it associated with rates of cardiovascular events in patients with severely elevated low-density lipoprotein cholesterol (LDL-C) levels (≥190 mg/dL) who are universally considered to be at high risk?

Findings  In this cohort study of 23 143 symptomatic patients, absence of coronary artery calcium (CAC) and noncalcified plaque was a prevalent finding among those with severely elevated LDL-C levels. Across the LDL-C spectrum, absence of CAC was associated with low rates of atherosclerotic cardiovascular disease and death, with increasing rates in patients with greater CAC burden.

Meaning  These findings suggest that atherosclerosis burden, including assessment of CAC, can be used to individualize treatment intensity by identifying patients who are at low risk despite having severely elevated LDL-C levels.

 

Link to comment
Share on other sites

Join the conversation

You can post now and register later. If you have an account, sign in now to post with your account.
Note: Your post will require moderator approval before it will be visible.

Guest
Reply to this topic...

×   Pasted as rich text.   Paste as plain text instead

  Only 75 emoji are allowed.

×   Your link has been automatically embedded.   Display as a link instead

×   Your previous content has been restored.   Clear editor

×   You cannot paste images directly. Upload or insert images from URL.

Loading...
 Share

×
×
  • Create New...