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Annals of Epidemiology & Public Health

Open Access | Research Article

The LDL Paradox: Higher LDL-Cholesterol is

Associated with Greater Longevity
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
1
Independent researcher, Magle Stora Kyrkogata 9, Sweden.
2
Laboratoire Coeur et Nutrition, TIMC-CNRS, Universite Grenoble-Alpes. Faculte de Medecine, France.
3
Departments of Psychology, University of South Florida, US.
4
Japan Institute of Pharmacovigilance Director, Japan.
5
Toyama University Professor emeritus, Japan.
6
Stromstad Academy, Ostervala, Sweden.
7
Independent researcher, UK.
8
East Cheshire Trust, Macclesfield District General Hospital, UK.
9
Cardiologist, independent researcher, USA.
10
Pathology and Laboratory Medicine Service, Veterans Affairs Boston Healthcare System, USA.
11
Department of Vascular & Endovascular Surgery, National University of Ireland, Ireland.
12
Independent researcher, Sweden.

*Corresponding Author(s): Uffe Ravnskov Abstract

Independent researcher, Magle Stora Kyrkogata 9, Objective: In a previous review of 19 follow-up studies,
22350 Lund, Sweden. we found that elderly people with high Low-Density-Lipo-
Tel: +46-702580416; Email: [email protected] 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
Received: Oct 22, 2020 here an update to our prior review.
Accepted: Dec 01, 2020
Methods: We searched PubMed for cohort studies
Published Online: Dec 04, 2020 about this issue published after the publication of our study
Journal: Annals of Epidemiology and Public health and where LDL-C has been investigated as a risk factor for
Publisher: MedDocs Publishers LLC all-cause and/or Cardiovascular (CVD) mortality in people
and patients of all ages. We included studies of individu-
Online edition: http://meddocsonline.org/
als without statin treatment and studies where the authors
Copyright: © Ravnskov U (2020). This Article is have adjusted for such treatment.
distributed under the terms of Creative Commons
Attribution 4.0 International License Results: We identified 19 follow-up studies including 20
cohorts of more than six million patients or healthy peo-
ple. Total mortality was recorded in 18 of the cohorts. In
Keywords: LDL-Cholesterol; Cardiovascular; Mortality; Follow- eight of them, those with the highest LDL-C lived as long as
up; Statin treatment; Infection. those with normal LDL-C; in nine of them, they lived longer,
whether they were on statin treatment or not. CVD mortal-
ity was measured in nine cohorts. In two of them, it was
inversely associated with LDL-C; in five of them, it was not

Cite this article: 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.

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We restricted our analysis to studies where the authors had

associated. In the study without information about total
excluded individuals on lipid-lowering treatment, or where they
mortality, CVD mortality was not associated with LDL-C. In
had adjusted the results for such treatment. The studies required
two cohorts, low LDL-C was significantly associated with to-
an initial assessment of LDL-C, the age of the participants, the
tal mortality. In two other cohorts, the association between
length of the observation time, and information about all-cause
LDL-C and total mortality was U-shaped. However, in the
and/or cardiovascular mortality at the end of follow-up.
largest of them (n>5 million people below the age of 40),
the mortality difference between those with the highest Results
LDL-C and those with normal LDL-C was only 0.04%.
We identified 394 studies by using PubMed and four studies
Conclusions: Our updated review of studies published from the reference lists of some of the studies. Based on the ab-
since 2016 confirms that, overall, high levels of LDL-C are stracts we excluded 202 irrelevant studies. Among the 192 full
not associated with reduced lifespan. These findings are in- papers, we excluded 175 studies that did not satisfy our meth-
consistent with the consensus that high lifetime LDL levels ods. Thus, we identified a total of 19 relevant studies including
promotes premature mortality. The widespread promotion 20 cohorts with 6,357,729 patients or healthy individuals (Fig-
of LDL-C reduction is not only unjustified, it may even wors- ure 1 and Table).
en the health of the elderly because LDL-C contributes to
immune functioning, including the elimination of harmful The association between LDL-C and CVD mortality was re-
pathogens. 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=
Introduction 915). In the study that included two cohorts [13], the association
was mirror J-shaped in one of them which only included young
Strengths and limitations of this study
people (n= 347,971); in the other one, which included all ages,
▪ This is a systematic review of cohort studies where LDL-C the association was inverse (n= 182,943). No association or an
has been analyzed as a risk factor for all-cause and/or cardio- inverse association was found in the other studies (n= 36,129)
vascular mortality. [2,6-8,12,14]. With one exception [7], all of the mentioned stud-
ies included young and/or middle-aged individual. The associa-
▪ Studies may not have been included here in which there tion between LDL-C and total mortality was recorded in 19 of the
was an evaluation of LDL-C as a risk factor for mortality but it 20 cohorts (Table 1). In the study without information about to-
was not mentioned in the title or in the abstract. tal mortality, the association between LDL-C and non-CVD mor-
▪ Studies may not have been included here because we have tality was inverse with no association between LDL-C and CVD
only searched PubMed and only included papers in English. mortality (n= 5,518) [3]. In a Korean study which only included
people below the age of 39 years, the association was weakly
Objective U-shaped (n= 5,688,055) [18]. In a study of American Indians,
the association was U-shaped among those with diabetes (n=
In a previous review of 19 studies, where the authors had
1210) and inversely associated among those without diabetes
followed 30 cohorts including more than 68,000 elderly people
(n= 915) [6]. In a Korean study of non-statin users [14], which in-
after having measured their LDL-C, we found that in the studies
cluded two cohorts, the association was mirror J-shaped in one
representing more than 90% of the participants, those with the
of them, which included only young people (n= 347,971). In the
highest LDL-C lived the longest; none of the studies found the
other cohort, where the mean age was 53 years (n= 182,943)
opposite [1]. In nine of the cohorts, the authors had recorded
the association was inverse. In one study [20] the association
cardiovascular (CVD) mortality as well and found that in two of
was U-shaped (n�����������������������������������������������
= 4,485). No association or an inverse associa-
the studies, mortality was the highest in the lowest LDL-C quar-
tion was found in the other studies (n= 319,578), eight of which
tile, a result that was statistically significant. In seven cohorts,
included young and/or middle-aged people [2,4-12,14-17,19].
no association was found.
After the publication of our review, many similar studies have
been published. As our findings contradict the general consen-
sus about the impact of LDL-C on cardiovascular and overall
health, we felt it was important to review these additional stud-
ies in detail.
Methods
We have performed two systematic searches on PubMed af-
ter papers published between May 2016 and July 2020 where
the authors have followed patients or healthy people for some
years after 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 (statin OR lipid-lowering) NOT
trial.” We also retrieved the references in the relevant publica-
tions.

Figure 1: Flow chart.

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Figure 2: The association between TC measured in 2009 and Figure 3: The association between TC measured in 2009 and
total mortality per 1,000 during 2010 for men age 15-60 years total mortality per 1,000 during 2010 for women age 15-60 years
in 181 countries according to WHO´s Global Health Observatory in 181 countries according to WHO´s Global Health Observatory
data repository. data repository.

Table 1: The association between LDL-C and total and/or CVD mortality in 19 follow-up studies (20 cohorts) of 6,357,729 patients and
healthy people.

Age Follow-up Result

Authors Participants and country n
(years) (years) Total mortality CVD mortality
Park et al., [2] Patients 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 NIa
NS
Bendzala et al., [4] Patients with hypertension. Slovakia 473 >60 10 NS NI
High-risk community-dwelling people.
Orozco-Beltran et al., [5] 51,462 >30 3.2 Inverse NI
Spain
Tanamas et al., [6] Indians. USA 2,125 >40 10.1 Inverseb NSc
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] Patients 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] Patients with acute CVD. Italy 589 58-74 20 Inverse NS
Non-statin users. Korea
Significantly higher in the lowest LDL-C
Sung et al., [13] Cohort 1 (KSHS) 347,971 Mean 39.6 5.6
quintile than in the 3rd quintile
Cohort 2 (KGES) 182,943 Mean 53 8.6
Hospitalized patients with MI or heart
Yousufuddin et al., [14] 23,397 >18 <20 Inverse Inverse
failure. USA
Dégano et al., [15] CVD patients. Spain 27,400 Mean 74.8 3 Inverse NI
Community-dwelling people without
Maihofer et al., [16] 3,567 68-91 ­5 NS NI
statin treatment. USA
Sittiwet et al., [17] Community-dwelling men. Finland 398 ≥75 3 NS NI
Weakly U-
Lee et al., [18] Community-dwelling people. Korea 5,688,055 20-39 7.1 NI
shapedd
Zhou et al., [19] Community-dwelling people, China 10,510 ≥45 4 NSe NI
Kobayashi et al., [20] Dyslipidemic patients without CVD. Korea 4,485 Mean 58.4 5.3 U-shaped NI
6,357,729
NI: No information. NS: Not significant. MI: Myocardial infarction. a: No information about total mortality, but the association 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 quartile 2 and 3; 0.3% and 0.31% died in quartile 1 and 4. e: Highest mortality in the first LDL-C quintile of men.

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Discussion of them inherit as well [45]. This observation could explain why
LDL-C in FH people with and without CVD is almost the same,
The role of infections and people with FH live on average just as long as other people
If high LDL-C is the main cause of CVD, people with low and [46,47]. Furthermore, FH people with the lowest LDL-C become
normal levels should live longer than people with high levels just as atherosclerotic as those with the highest values [48-53];
because CVD is the most common cause of death in most coun- an observation that is valid for non-FH people as well [54]. A
tries. However, as we have shown, many follow-up studies from strong argument is also a study of ten young patients (age 3-32
around the world have shown that people with high LDL-C live years) with homozygous FH [55]. Six of them had signs and
just as long as or longer than other people. This strongly sug- symptoms of coronary heart disease, but all of them were free
gests that the cholesterol hypothesis is invalid; a fact that has from ischemic brain lesions and had a normal cerebral blood
been demonstrated in many other ways [21]. For example, the flow. FH may even protect against infections because in the 19th
WHO´s Global Health Observatory data repository from 2010 century where infectious diseases was the commonest cause of
has shown that people in countries with the highest cholesterol death, those with FH lived longer than the general population
live the longest (Figure 2 and 3). [56].

We would therefore suggest that lowering LDL-C may not The role of diabetes
be necessary. A proposal that is further strengthened by the In one of the studies mentioned in table 1 there was a U-
fact that independent researchers have documented that sta- shaped or a linear association between TC and/or LDL-C and
tin treatment has many significant adverse effects [21,22]. Of total and CVD mortality among those with diabetes, but no as-
further importance is the fact that many studies have shown sociations between those without diabetes [6]. This study in-
that low cholesterol is associated with increased mortality from cluded only American Indians and the finding may therefore
infections [23], probably because LDL-C partakes in the immune have a genetic explanation, because several studies have shown
system by adhering to and inactivating many microorganisms that LDL-C is not associated with mortality among diabetics
and their toxic product [24]. This fact is not widely recognised, [57-62]. Furthermore, in a systematic review of high quality,
but it has been documented by more than a dozen research double-blind cholesterol-lowering trials, the authors found that
groups [25]. such treatment is unable to reduce mortality and cardiovascular
Why high cholesterol may appear as a risk factor complications in type-2 diabetics [63].

A relevant question is why many previous studies have shown The role of low LDL-C
that high TC or high LDL-C are associated with CVD. A possible Reverse causality has been suggested as an explanation of
explanation is that stress Can considerably increase both TC and the higher mortality associated with low cholesterol meaning
LDL-C considerably [26] and stress can increase the risk of CVD that various diseases, for instance cancer and infections may
by other ways than by raising cholesterol [27,28]. Most of the lower the content of cholesterol in the blood. It is true that low
early follow-up studies only included young and middle-aged cholesterol is associated with cancer, but the explanation is
people, and this group is likely to be more stressed than those most likely that low cholesterol predisposes to cancer, because
who have reached retirement age. In support of this hypoth- several follow-up studies of healthy youths have shown that
esis, two of the four cohorts in our review where there was a the risk of cancer 10-40 years later in life is significantly greater
positive association between mortality and LDL-C included only among those with low TC [64]. Also, in three statins trials there
young and middle-aged individuals [13,18]. In all of the cohorts was an increased risk of cancer in the treatment arm [64]. Ad-
that were restricted to an older population, those with high ditionally, in several case-control studies the risk of cancer was
LDL-C lived just as long or, in most cohorts, longer than those significantly increased among those who were or had been
with low LDL-C. This observation is in accord with sixteen stud- treated with statins [64].
ies published before our review in BMJ Open [1] which have
shown that elderly people with high TC live the longest [29-43]. An apparent contradiction is that in several cohort studies,
Furthermore, in a prospective cohort study by the UK Biobank statin-treated patients suffered less often from cancer, but in
including more than half a million healthy British people age 49- these studies, the authors have compared the statin-treated pa-
69 years, TC was not associated with CVD mortality (risk ratio tients with non-treated people from the general population. As
0.98; 0.89 to 1.08) [44]. untreated people are likely to have lower cholesterol than sta-
tin-treated patients, and as a majority of statin-treated patients
The role of familial hypercholesterolemia stop the treatment ����������������������������������������������
[65]������������������������������������������
, these findings are seriously biased, be-
In the study by Sung et al., [13] CVD mortality among those cause the authors did not investigate whether the patients had
with the highest LDL-C was higher than among those with nor- continued with their statin-treatment. It is therefore impossible
mal LDL-C, but the difference was not statistically significant. to know whether the benefit was due to statin treatment or to
CVD mortality was in fact highest among those with the low- their high LDL-C.
est LDL-C and with statistical significance. Furthermore, the The role of the drug industry
number who died among those with high LDL-C included less
than 0.1% of the participants. In the large study of Lee et al., Although dozens of books and medical reviews written by
[18] where the association between LDL-C and total mortal- independent scientists have documented a lack of evidence for
ity was J-shaped, the difference between the mortality among the cholesterol campaign [21], the main reason for the persist-
those with normal LDL-C and those with the highest values was ence of the cholesterol hypothesis may be industry influence.
only 0.04%. Most likely, some of those with the highest LDL-C Even those who write the guidelines are supported by the
in these studies may have had Familial Hypercholesterolemia drug industry. For instance, in the new European guidelines for
(FH), and there is much evidence that the cause of CVD in FH chronic coronary
����������������������������������������������������
syndromes [66], dyslipidaemia [67] and dia-
is not high LDL-C but elevated coagulation factors, which a few betes, [68]�����������������������������������������������������
the 150 pages long lists of the many authors and re-
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viewers’ financial conflicts show that almost all of them have the survival of heart failure patients who maintained low LDL
been supported by the drug industry; some of them by more cholesterol levels. QJM. 2018; 111: 319-325.
than a dozen drug companies. Furthermore, these guidelines 10. Montesanto A, Pellegrino D, Geracitano S, Russa DL, Mari V, et
have more than 500 references, but none of the contradictory al. Cardiovascular risk profiling of long-lived people shows pe-
studies mentioned above are mentioned. culiar associations with mortality compared with younger indi-
viduals. Geriatr Gerontol Int. 2019; 19; 165-170.
As suggested by Moynihan et al., [69] all medical journals,
advocacy groups and medical associations should “move away 11. Penson PE, Long DL, Howard G, Toth PP, Muntner P, et al. As-
from financial relationships with companies selling healthcare sociations between cardiovascular disease, cancer, and very
products and reforms to bind professional accreditation to edu- low high-density lipoprotein cholesterol in the Reasons for Geo-
cation free of industry support”. graphical and Racial Differences in Stroke (REGARDS) study. Car-
diovasc Res. 2019; 115: 204-212.
Conclusion
12. Berton G, Cordiano K, Mahmoud HT, Bagato F, Cavuto F, et al.
The hypothesis that high LDL-C is the major cause of CVD, Plasma lipid levels during ASC: Association with 20 year mortal-
the most common cause of death in most countries, is unlikely ity: The ABC-5 study on heart disease. Eur J Prev Cardiol. 2019.
because follow-up studies of more than half a million of pa- doi.org/10.1177/2047487319873061
tients and healthy people have shown that those with the high- 13. Sung K-C, Huh JH, Ryu S, Lee JY, Scorlett E, et al. Low levels of
est LDL-C live just as long or longer than those with low LDL-C. low-density lipoprotein cholesterol and mortality outcomes in
non-statin users. J Clin Med. 2019; 8: 1571-1584.
Contributors: UR performed the paper search and wrote the
first draft of the manuscript. All authors have read the reviewed 14. Yousufuddin M, Takahashi PY, Major B, Ahmmad E, Al-Zubi H,
papers and made improvements of the content and the word- et al. Association between hyperlipidemia and mortality after
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combe and are based on data from WHO. heart failure: a propensity score matched cohort study and a
meta-analysis. BMJ Open. 2019; 9: e028638.
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