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The LDL Paradox: Higher LDL-Cholesterol is Associated with Greater Longevity of Creative Commons Attribution 4.0 International License

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  • International Society For Vascular Surgery

Abstract

Objective: In a previous review of 19 follow-up studies, we found that elderly people with high Low-Density-Lipoprotein 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 promote 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.
The LDL Paradox: Higher LDL-Cholesterol is
Associated with Greater Longevity
1
MedDocs Publishers
Received: Oct 22, 2020
Accepted: Dec 01, 2020
Published Online: Dec 04, 2020
Journal: Annals of Epidemiology and Public health
Publisher: MedDocs Publishers LLC
Online edion: hp://meddocsonline.org/
Copyright: © Ravnskov U (2020). This Arcle is
distributed under the terms of Creave Commons
Aribuon 4.0 Internaonal License
*Corresponding Author(s): Ue Ravnskov
Independent researcher, Magle Stora Kyrkogata 9,
22350 Lund, Sweden.
Tel: +46-702580416; Email: uravnskov@gmail.com
Cite this arcle: Ravnskov U, de Lorgeril M, Diamond DM, Hama R, Hamazaki T, et al. The LDL paradox: Higher LDL-
Cholesterol is Associated with Greater Longevity. A Epidemiol Public Health. 2020; 3(1): 1040.
Annals of Epidemiology & Public Health
Open Access | Research Arcle
ISSN: 2639-4391
Ravnskov U1*; de Lorgeril M2; Diamond DM3; Hama R4; Hamazaki T5; Hammarskjöld B6; Harcombe Z7; Kendrick M8; Langsjoen P9;
McCully KS10; Sultan S11; Sundberg R12
1Independent researcher, Magle Stora Kyrkogata 9, Sweden.
2Laboratoire Coeur et Nutrion, TIMC-CNRS, Universite Grenoble-Alpes. Faculte de Medecine, France.
3Departments of Psychology, University of South Florida, US.
4Japan Instute of Pharmacovigilance Director, Japan.
5Toyama University Professor emeritus, Japan.
6Stromstad Academy, Ostervala, Sweden.
7Independent researcher, UK.
8East Cheshire Trust, Maccleseld District General Hospital, UK.
9Cardiologist, independent researcher, USA.
10Pathology and Laboratory Medicine Service, Veterans Aairs Boston Healthcare System, USA.
11Department of Vascular & Endovascular Surgery, Naonal University of Ireland, Ireland.
12Independent researcher, Sweden.
Abstract
Objecve: 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 paents 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 aer the publicaon of our study
and where LDL-C has been invesgated as a risk factor for
all-cause and/or Cardiovascular (CVD) mortality in people
and paents of all ages. We included studies of individu-
als without stan treatment and studies where the authors
have adjusted for such treatment.
Results: We idened 19 follow-up studies including 20
cohorts of more than six million paents or healthy peo-
ple. 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 stan treatment or not. CVD mortal-
ity was measured in nine cohorts. In two of them, it was
inversely associated with LDL-C; in ve of them, it was not
Keywords: LDL-Cholesterol; Cardiovascular; Mortality; Follow-
up; Stan treatment; Infecon.
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We restricted our analysis to studies where the authors had
excluded individuals on lipid-lowering treatment, or where they
had adjusted the results for such treatment. The studies required
an inial assessment of LDL-C, the age of the parcipants, the
length of the observaon me, and informaon about all-cause
and/or cardiovascular mortality at the end of follow-up.
Results
We idened 394 studies by using PubMed and four studies
from the reference lists of some of the studies. Based on the ab-
stracts we excluded 202 irrelevant studies. Among the 192 full
papers, we excluded 175 studies that did not sasfy our meth-
ods. Thus, we idened a total of 19 relevant studies including
20 cohorts with 6,357,729 paents or healthy individuals (Fig-
ure 1 and Table).
The associaon between LDL-C and CVD mortality was re-
corded in nine studies (ten cohorts). In one of the studies [6]
CVD mortality was associated with LDL-C among those with
diabetes (n= 1210) but not among those without diabetes (n=
915). In the study that included two cohorts [13], the associaon
was mirror J-shaped in one of them which only included young
people (n= 347,971); in the other one, which included all ages,
the associaon was inverse (n= 182,943). No associaon or an
inverse associaon was found in the other studies (n= 36,129)
[2,6-8,12,14]. With one excepon [7], all of the menoned stud-
ies included young and/or middle-aged individual. The associa-
on between LDL-C and total mortality was recorded in 19 of the
20 cohorts (Table 1). In the study without informaon about to-
tal mortality, the associaon between LDL-C and non-CVD mor-
tality was inverse with no associaon between LDL-C and CVD
mortality (n= 5,518) [3]. In a Korean study which only included
people below the age of 39 years, the associaon was weakly
U-shaped (n= 5,688,055) [18]. In a study of American Indians,
the associaon was U-shaped among those with diabetes (n=
1210) and inversely associated among those without diabetes
(n= 915) [6].
In a Korean study of non-stan users [14], which in-
cluded two cohorts, the associaon was mirror J-shaped in one
of them, which included only young people (n= 347,971). In the
other cohort, where the mean age was 53 years (n= 182,943)
the associaon was inverse. In one study [20] the associaon
was U-shaped (n= 4,485). No associa on or an inverse associa-= 4,485). No associaon or an inverse associa-
on was found in the other studies (n= 319,578), eight of which
included young and/or middle-aged people [2,4-12,14-17,19].
associated. In the study without informaon about total
mortality, CVD mortality was not associated with LDL-C. In
two cohorts, low LDL-C was signicantly associated with to-
tal mortality. In two other cohorts, the associaon 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 dierence 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 conrms that, overall, high levels of LDL-C are
not associated with reduced lifespan. These ndings are in-
consistent with the consensus that high lifeme LDL levels
promotes premature mortality. The widespread promoon
of LDL-C reducon is not only unjused, it may even wors-
en the health of the elderly because LDL-C contributes to
immune funconing, including the eliminaon of harmful
pathogens.
Introducon
Strengths and limitaons of this study
This is a systemac review of cohort studies where LDL-C
has been analyzed as a risk factor for all-cause and/or cardio-
vascular mortality.
Studies may not have been included here in which there
was an evaluaon of LDL-C as a risk factor for mortality but it
was not menoned in the tle or in the abstract.
▪ Studies may not have been included here because we have
only searched PubMed and only included papers in English.
Objecve
In a previous review of 19 studies, where the authors had
followed 30 cohorts including more than 68,000 elderly people
aer having measured their LDL-C, we found that in the studies
represenng more than 90% of the parcipants, those with the
highest LDL-C lived the longest; none of the studies found the
opposite [1]. In nine of the cohorts, the authors had recorded
cardiovascular (CVD) mortality as well and found that in two of
the studies, mortality was the highest in the lowest LDL-C quar-
le, a result that was stascally signicant. In seven cohorts,
no associaon was found.
Aer the publicaon of our review, many similar studies have
been published. As our ndings contradict the general consen-
sus about the impact of LDL-C on cardiovascular and overall
health, we felt it was important to review these addional stud-
ies in detail.
Methods
We have performed two systemac searches on PubMed af-
ter papers published between May 2016 and July 2020 where
the authors have followed paents or healthy people for some
years aer having measured their LDL-C. In one of our searches
we used the following keywords: “follow-up AND LDL-choles-
terol AND mortality NOT trial”; in the other one we used: “LDL-
cholesterol AND mortality AND (stan OR lipid-lowering) NOT
trial.” We also retrieved the references in the relevant publica-
ons.
Figure 1: Flow chart.
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Figure 2: The associaon between TC measured in 2009 and
total mortality per 1,000 during 2010 for men age 15-60 years
in 181 countries according to WHO´s Global Health Observatory
data repository.
Figure 3: The associaon between TC measured in 2009 and
total mortality per 1,000 during 2010 for women age 15-60 years
in 181 countries according to WHO´s Global Health Observatory
data repository.
Authors Parcipants and country n
Age Follow-up Result
(years) (years) Total mortality CVD mortality
Park et al., [2] Paents on peritoneal dialysis. Korea 749 Mean 59.6 10 Inverse Inverse
Ghasemzadeh et al., [3] Community-dwelling people. Iran 5,518 Mean 54 11.9 NIaNS
Bendzala et al., [4] Paents with hypertension. Slovakia 473 >60 10 NS NI
Orozco-Beltran et al., [5] High-risk community-dwelling people.
Spain 51,462 >30 3.2 Inverse NI
Tanamas et al., [6] Indians. USA 2,125 >40 10.1 InversebNSc
Zuliani et al., [7] Community-dwelling people. Italy 1,044 >64 9 Inverse NS
Harari et al., [8] Male workers. Israel 4,832 42.1 22 NS NS
Charach et al., [9] Paents with heart failure. Israel 305 70.3 20 Inverse NI
Montesanto et al., [10] Community-dwelling people. Italy 255 >90 5.3-8.6 NS NI
Penson et al., [11] High-risk individuals. USA 6,136 >45 10-13 NS NI
Berton et al., [12] Paents with acute CVD. Italy 589 58-74 20 Inverse NS
Sung et al., [13]
Non-stan users. Korea
Cohort 1 (KSHS) 347,971 Mean 39.6 5.6 Signicantly higher in the lowest LDL-C
quinle than in the 3rd quinle
Cohort 2 (KGES) 182,943 Mean 53 8.6
Yousufuddin et al., [14] Hospitalized paents with MI or heart
failure. USA 23,397 >18 <20 Inverse Inverse
Dégano et al., [15] CVD paents. Spain 27,400 Mean 74.8 3 Inverse NI
Maihofer et al., [16] Community-dwelling people without
stan treatment. USA 3,567 68-91 5 NS NI
Siwet et al., [17] Community-dwelling men. Finland 398 ≥75 3NS NI
Lee et al., [18] Community-dwelling people. Korea 5,688,055 20-39 7.1 Weakly U-
shapeddNI
Zhou et al., [19] Community-dwelling people, China 10,510 ≥45 4NSeNI
Kobayashi et al., [20] Dyslipidemic paents without CVD. Korea 4,485 Mean 58.4 5.3 U-shaped NI
6,357,729
NI: No informaon. NS: Not signicant. MI: Myocardial infarcon. a: No informaon about total mortality, but the associaon between LDL-C and
non-CVD mortality was inverse. b: U-shaped among those with diabetes mellitus. c: Associated among those with diabetes mellitus. d: 0.27%
died in quarle 2 and 3; 0.3% and 0.31% died in quarle 1 and 4. e: Highest mortality in the rst LDL-C quinle of men.
Table 1: The associaon between LDL-C and total and/or CVD mortality in 19 follow-up studies (20 cohorts) of 6,357,729 paents and
healthy people.
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Discussion
The role of infecons
If high LDL-C is the main cause of CVD, people with low and
normal levels should live longer than people with high levels
because CVD is the most common cause of death in most coun-
tries. However, as we have shown, many follow-up studies from
around the world have shown that people with high LDL-C live
just as long as or longer than other people. This strongly sug-
gests that the cholesterol hypothesis is invalid; a fact that has
been demonstrated in many other ways [21]. For example, the
WHO´s Global Health Observatory data repository from 2010
has shown that people in countries with the highest cholesterol
live the longest (Figure 2 and 3).
We would therefore suggest that lowering LDL-C may not
be necessary. A proposal that is further strengthened by the
fact that independent researchers have documented that sta-
n treatment has many signicant adverse eects [21,22]. Of
further importance is the fact that many studies have shown
that low cholesterol is associated with increased mortality from
infecons [23], probably because LDL-C partakes in the immune
system by adhering to and inacvang many microorganisms
and their toxic product [24]. This fact is not widely recognised,
but it has been documented by more than a dozen research
groups [25].
Why high cholesterol may appear as a risk factor
A relevant queson is why many previous studies have shown
that high TC or high LDL-C are associated with CVD. A possible
explanaon is that stress Can considerably increase both TC and
LDL-C considerably [26] and stress can increase the risk of CVD
by other ways than by raising cholesterol [27,28]. Most of the
early follow-up studies only included young and middle-aged
people, and this group is likely to be more stressed than those
who have reached rerement age. In support of this hypoth-
esis, two of the four cohorts in our review where there was a
posive associaon between mortality and LDL-C included only
young and middle-aged individuals [13,18]. In all of the cohorts
that were restricted to an older populaon, those with high
LDL-C lived just as long or, in most cohorts, longer than those
with low LDL-C. This observaon is in accord with sixteen stud-
ies published before our review in BMJ Open [1] which have
shown that elderly people with high TC live the longest [29-43].
Furthermore, in a prospecve cohort study by the UK Biobank
including more than half a million healthy Brish people age 49-
69 years, TC was not associated with CVD mortality (risk rao
0.98; 0.89 to 1.08) [44].
The role of familial hypercholesterolemia
In the study by Sung et al., [13] CVD mortality among those
with the highest LDL-C was higher than among those with nor-
mal LDL-C, but the dierence was not stascally signicant.
CVD mortality was in fact highest among those with the low-
est LDL-C and with stascal signicance. Furthermore, the
number who died among those with high LDL-C included less
than 0.1% of the parcipants. In the large study of Lee et al.,
[18] where the associaon between LDL-C and total mortal-
ity was J-shaped, the dierence between the mortality among
those with normal LDL-C and those with the highest values was
only 0.04%. Most likely, some of those with the highest LDL-C
in these studies may have had Familial Hypercholesterolemia
(FH), and there is much evidence that the cause of CVD in FH
is not high LDL-C but elevated coagulaon factors, which a few
of them inherit as well [45]. This observaon could explain why
LDL-C in FH people with and without CVD is almost the same,
and people with FH live on average just as long as other people
[46,47]. Furthermore, FH people with the lowest LDL-C become
just as atheroscleroc as those with the highest values [48-53];
an observaon that is valid for non-FH people as well [54]. A
strong argument is also a study of ten young paents (age 3-32
years) with homozygous FH [55]. Six of them had signs and
symptoms of coronary heart disease, but all of them were free
from ischemic brain lesions and had a normal cerebral blood
ow. FH may even protect against infecons because in the 19th
century where infecous diseases was the commonest cause of
death, those with FH lived longer than the general populaon
[56].
The role of diabetes
In one of the studies menoned in table 1 there was a U-
shaped or a linear associaon between TC and/or LDL-C and
total and CVD mortality among those with diabetes, but no as-
sociaons between those without diabetes [6]. This study in-
cluded only American Indians and the nding may therefore
have a genec explanaon, because several studies have shown
that LDL-C is not associated with mortality among diabecs
[57-62]. Furthermore, in a systemac review of high quality,
double-blind cholesterol-lowering trials, the authors found that
such treatment is unable to reduce mortality and cardiovascular
complicaons in type-2 diabecs [63].
The role of low LDL-C
Reverse causality has been suggested as an explanaon of
the higher mortality associated with low cholesterol meaning
that various diseases, for instance cancer and infecons may
lower the content of cholesterol in the blood. It is true that low
cholesterol is associated with cancer, but the explanaon is
most likely that low cholesterol predisposes to cancer, because
several follow-up studies of healthy youths have shown that
the risk of cancer 10-40 years later in life is signicantly greater
among those with low TC [64]. Also, in three stans trials there
was an increased risk of cancer in the treatment arm [64]. Ad-
dionally, in several case-control studies the risk of cancer was
signicantly increased among those who were or had been
treated with stans [64].
An apparent contradicon is that in several cohort studies,
stan-treated paents suered less oen from cancer, but in
these studies, the authors have compared the stan-treated pa-
ents with non-treated people from the general populaon. As
untreated people are likely to have lower cholesterol than sta-
n-treated paents, and as a majority of stan-treated paents
stop the treatment [65], these  ndings are seriously biased, be-[65], these  ndings are seriously biased, be-, these ndings are seriously biased, be-
cause the authors did not invesgate whether the paents had
connued with their stan-treatment. It is therefore impossible
to know whether the benet was due to stan treatment or to
their high LDL-C.
The role of the drug industry
Although dozens of books and medical reviews wrien by
independent sciensts have documented a lack of evidence for
the cholesterol campaign [21], the main reason for the persist-
ence of the cholesterol hypothesis may be industry inuence.
Even those who write the guidelines are supported by the
drug industry. For instance, in the new European guidelines for
chronic coronary syndromes [66], dyslipidaemia [67] and dia-coronary syndromes [66], dyslipidaemia [67] and dia-
betes, [68] the 150 pages long lists of the many authors and re- the 150 pages long lists of the many authors and re-
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viewers’ nancial conicts show that almost all of them have
been supported by the drug industry; some of them by more
than a dozen drug companies. Furthermore, these guidelines
have more than 500 references, but none of the contradictory
studies menoned above are menoned.
As suggested by Moynihan et al., [69] all medical journals,
advocacy groups and medical associaons should “move away
from nancial relaonships with companies selling healthcare
products and reforms to bind professional accreditaon to edu-
caon free of industry support”.
Conclusion
The hypothesis that high LDL-C is the major cause of CVD,
the most common cause of death in most countries, is unlikely
because follow-up studies of more than half a million of pa-
ents and healthy people have shown that those with the high-
est LDL-C live just as long or longer than those with low LDL-C.
Contributors: UR performed the paper search and wrote the
rst dra of the manuscript. All authors have read the reviewed
papers and made improvements of the content and the word-
ing of the manuscript. The gures are constructed by Zoe Har-
combe and are based on data from WHO.
Compeng interests: TH has received speaker fees from Nis-
sui Pharmaceucal and Nippon Suisan Kaisha. KSM has a US
patent for a homocysteine-lowering protocol. RH, HO, RS and
UR have wrien books with cricism of the cholesterol hypoth-
esis.
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... Of interest, an opposite outcome was achieved by other authors, both in a recently published review concerning a number of studies published since 2016, 17 and in a prospective cohort study, 18 where high levels of LDL were not associated with reduced lifespan, but with greater longevity. ...
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