LDL-C does
not cause cardiovascular disease: a comprehensive review of the current
literature
Uffe Ravnskov,Michel de Lorgeril,David M Diamond,Rokuro Hama,Tomohito Hamazaki,Björn Hammarskjöld, show all
ORIGINALLY POSTED AT https://www.tandfonline.com/doi/full/10.1080/17512433.2018.1519391
Pages 959-970 |
Received 11 Jan 2018, Accepted 31 Aug 2018, Accepted author version posted
online: 10 Sep 2018, Published online: 11 Oct 2018
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ABSTRACT
Introduction:
For half a century, a high level of total cholesterol (TC) or low-density
lipoprotein cholesterol (LDL-C) has been considered to be the major cause of
atherosclerosis and cardiovascular disease (CVD), and statin treatment has been
widely promoted for cardiovascular prevention. However, there is an increasing
understanding that the mechanisms are more complicated and that statin
treatment, in particular when used as primary prevention, is of doubtful
benefit.
Areas covered: The authors of three large reviews recently published by
statin advocates have attempted to validate the current dogma. This article
delineates the serious errors in these three reviews as well as other obvious
falsifications of the cholesterol hypothesis.
Expert commentary: Our search for falsifications of the cholesterol hypothesis
confirms that it is unable to satisfy any of the Bradford Hill criteria for
causality and that the conclusions of the authors of the three reviews are
based on misleading statistics, exclusion of unsuccessful trials and by
ignoring numerous contradictory observations.
KEYWORDS: Atherosclerosis, cardiovascular, cholesterol lowering, coronary heart disease, exposure–response, mortality, statin
1. Introduction
According to the British-Austrian philosopher Karl Popper, a
theory in the empirical sciences can never be proven, but it can be shown to be
false. If it cannot be falsified, it is not a scientific hypothesis. In the
following, we have followed Popper’s principle to see whether it is possible to
falsify the cholesterol hypothesis. We have also assessed whether the
conclusions from three recent reviews by its supporters [1–3] are based on an accurate and comprehensive
review of the research on lipids and cardiovascular disease (CVD).
2. Does high total cholesterol cause atherosclerosis?
2.1. No association between total cholesterol and degree of
atherosclerosis
If high total cholesterol (TC) causes atherosclerosis, people
with high TC should have more atherosclerosis than people with low TC. In 1936,
Landé and Sperry found that corrected for age, unselected people with low TC
were just as atherosclerotic as people with high TC [4]. Since then, their seminal observation has
been confirmed in at least a dozen studies [5]. A weak association between TC and degree
of atherosclerosis has been found in some studies [5], but the authors only studied patients
admitted to a hospital and may, therefore, have included patients with familial
hypercholesterolemia (FH). As the percentage of such patients in a cardiology
department is much higher than in the general population, a bias may have been
introduced. In accordance, the positive association between TC and degree of
atherosclerosis noted in the study by Solberg et al. disappeared when those
with TC above 350 mg/l (9 mmol/l) were excluded [5,6].
2.2. No exposure–response
If high TC were the major cause of atherosclerosis, there should
be exposure–response in cholesterol-lowering drug trials; for example, the
arteries of those whose lipid values are lowered the most should benefit the
most. However, in a review of 16 angiographic cholesterol-lowering trials,
where the authors had calculated exposure–response, this correlation was only
present in one of them, and in that trial, the only treatment was exercise [5].
3. Does high TC cause CVD?
3.1. An idea supported by fraudulent reviews of the literature
If high TC was the major cause of CVD, people with high TC
should have a higher risk of dying from CVD. The hypothesis that high TC causes
CVD was introduced in the 1960s by the authors of the Framingham Heart Study.
However, in their 30-year follow-up study published in 1987 [7], the authors reported that ‘For
each 1 mg/dl drop in TC per year, there was an eleven percent increase in
coronary and total mortality’. Three years later, the American Heart
Association and the U.S. National Heart, Lung and Blood Institute published a
joint summary [8] concluding, ‘a one percent reduction in
an individual’s TC results in an approximate two percent reduction in CHD risk’.
The authors fraudulently referred to the Framingham publication to support this
widely quoted false conclusion.
In two additional reviews written by authoritative supporters of
the cholesterol hypothesis [9,10], more misleading information was reported.
To see how these proponents explained results discordant with the cholesterol
hypothesis, quotations from 12 articles with such findings were searched for in
the three reviews [11]. Only two of the articles were quoted
correctly and only in one of the reviews. About half of the contradictory
articles were ignored. In the rest, statistically nonsignificant findings in
favor of the cholesterol hypothesis were inflated, and unsupportive results
were quoted as if they were supportive. Only one of the six randomized
cholesterol-lowering trials with a negative outcome was cited and only in one
of the reviews [11].
3.2. The association between TC and CVD is weak, absent or
inverse in many studies
During the years following the report of the Framingham Heart
Study, numerous studies revealed that high TC is not associated with future
CVD. with the strongest evidence of a lack of relation between TC and CVD in
elderly people. For instance, a review published in 2002 included references to
12 such studies [12]. A 2004 Austrian study [13] published 2004 including 67,413 men and
82,237 women who had been followed up for many years found that TC was weakly
associated with coronary heart disease (CHD) mortality for men, except for
those between age 50 and 64 years. For women, it was weakly associated
among those below the age of 50 years, and no association was present
after that age. No association was found between TC and mortality caused by
other CVDs, except that low TC was inversely associated with CVD mortality for
women above the age of 60 years.
In 2007, the Prospective Studies Collaboration [14], the writing committee of which included
the same authors as those for Collins et al. [1], published a meta-analysis including 61
prospective observational studies consisting of almost 900,000 adults, which
concluded that TC was associated with CHD mortality in all ages and both sexes.
We have not been able to obtain the original data [15]. However, the authors had ignored at least
a dozen studies, including the Austrian one, where no association or an inverse
association was noted, and in several studies, the number of participants
deviated from the number reported by the Prospective Studies Collaboration.
Today, the general opinion is that TC is not the most useful or
accurate predictor of CVD, and interest has increasingly focused on low-density
lipoprotein cholesterol (LDL-C).
4. Does high LDL-C cause atherosclerosis?
4.1. An idea based on selected patient groups
If LDL-C is atherogenic, people with high LDL-C should have more
atherosclerosis than those with low LDL-C. At least four studies have shown a
lack of an association between LDL-C and degree of atherosclerosis [5], and in a study of 304 women, no
association was found between LDL-C and coronary calcification [16]. One exception is a study of 1779 healthy
individuals without conventional risk factors for CVD [17]. Here, the authors found that LDL-C was
significantly higher among those with subclinical atherosclerosis (125.7
vs.117.4 mg/dl). However, association does not prove causation. Mental
stress, for instance, is able to raise cholesterol by 10–50% in the course of
half an hour [18,19], and mental stress may cause
atherosclerosis by mechanisms other than an increase in LDL-C; for instance,
via hypertension and increased platelet aggregation.
5. Does high LDL-C cause CVD?
5.1. LDL-C of patients with acute myocardial infarction is lower
than normal
If high LDL-C causes CVD, LDL-C of untreated patients with CVD
should be higher than normal. However, in a large American study [20] including almost 140,000 patients with
acute myocardial infarction (AMI), their LDL-C at the time of admission to
hospital was actually lower than normal. In another study with the same finding
[21], the authors decided to lower the
patients’ LDL-C even more, but at a follow-up 3 years later, total
mortality among those with LDL-C below 105 mg/dl (2 mmol/l) was twice
as high compared to those with a higher LDL-C, even after adjustment for
confounding variables (14.8% vs. 7.1%, p = 0.005).
It has been suggested that inverse causation explains the
inverse association between mortality and LDL-C; for example, that cancer and
infections lower LDL-C. A more likely explanation is that CVD may be caused by
infections and that LDL directly inactivates almost all types of microorganisms
and their toxic products [12,22,23]. Consistent with that finding is the observation
that healthy individuals with low LDL-C have a significantly increased risk of
both infectious diseases [23] and cancer [24]; the latter possibly because
microorganisms have been linked to almost 20% of all cancer types [25].
5.2. Elderly people with high LDL-C live the longest
If high LDL-C was the major cause of atherosclerosis and CVD,
people with the highest LDL-C should have shorter lives than people with low
values. However, in a recent systematic review of 19 cohort studies including
more than 68,000 elderly people (>60 years of age), we found the
opposite [26]. In the largest cohort study [27], those with the highest LDL-C levels lived
even longer than those on statin treatment. In addition, numerous Japanese
studies have found that high LDL-C is not a risk factor for CHD mortality in
women of any age [28].
5.3. Mendelian randomization
An argument used in the three expert reviews [1–3] is based on Mendelian randomization, which
has shown that lower genetically determined LDL-C concentrations are associated
with lower all-cause mortality. But again, association does not mean causation.
Other genes in the same individual may have opposite effects, and as pointed
out by Burgess et al., ‘Power, linkage disequilibrium, pleiotropy, canalization
and population stratification have all been recognized as potential flaws in
the Mendelian randomization approach’ [29].
6. Does cholesterol-lowering treatment lower the risk of CVD?
6.1. No exposure–response in the statin trials
The strongest proof of causality is that a lowering or
elimination of the suspected causal factor is able to lower the incidence of
the disease in question. There have been small, but statistically significant,
benefits in coronary event outcomes from statin trials. However, are the
benefits of statin treatment produced by lowering LDL?
If high LDL-C were the major cause of CVD, the benefit from
statin treatment should be better the more LDL-C is lowered; for example, there
should be a systematic exposure–response relationship. The authors of the three
reviews [1–3] assert that statin trials have demonstrated
such dose–responses. As proof, they have compared the outcomes in various
trials with the degree of LDL-C lowering, and it is impossible to know whether
the greater effect of a trial using a higher statin dose may be caused by its
cholesterol-lowering effect or pleiotropic effects. True exposure–response is
based on a comparison between the degree of cholesterol lowering in each
patient in a single trial and the absolute reduction of their risk. True
exposure–response has only been calculated in three clinical statin trials, and
it was absent in all three [30–32]. Even a correctly calculated
exposure–response does not prove causality, because an innocent risk factor,
for instance, LDL-C, may change in the same direction as the real cause, but
the absence of exposure–response is a strong argument against causality.
Furthermore, in their calculation, Silverman et al. [2] compared the number of major vascular
events (MVEs) with the relative risk reduction (RRR). MVE is of dubious value
as a measure of benefit because it is defined very differently in various
trials [33]. Using RRR as a measure of benefit is also
highly misleading [34], as it inflates the appearance of the rate
of event reduction. For instance, in a trial where 2 of 100 participants in the
control group die but only 1 of 100 in the treatment group die, the absolute
risk reduction (ARR) is only a 1% benefit. However, if one reports the RRR,
then a 50% benefit can be reported, because one is 50% of two.
A preferred way to measure the therapeutic benefit of statin
treatment would be to compare the ARR per year of CVD mortality, CHD mortality,
and total mortality of each trial with the degree of LDL-C lowering, as we have
done in Table 1 and Figures 1 and 2. These data are from the 26 statin trials
included in the meta-analysis by Silverman et al. [35–59] and from 11 trials that they excluded [60–69]. As seen from Figures 1 and 2, there was a weak, positive association in
the included trials, whereas the association was inverse in the ignored trials.
Table 1. Mortality in the statin
trials included in the meta-analysis by Silverman et al. [2] and in 11 statin trials they have ignored
and where the authors have reported coronary and/or total mortality. The
figures for LDL-C lowering are the approximate mean differences between the
treatment group and the control group. Among the ignored trials only the EXCEL
trials [60,61] were primary preventive.
Figure 1. The association between degree of LDL-C lowering
and the absolute risk reduction of CHD mortality (%/year) in 21 statin trials,
where CHD mortality was recorded and which were included in the study by
Silverman et al. and in 8 ignored statin trials. ARR is associated with degree
of LDL-C lowering in the included trials (y = 0.16x − 0.018)
but inversely associated in the ignored trials (y = 0.08x + 0.062).
Squares: included trials; triangles: ignored trials.
Figure 2. The association between degree of LDL-C lowering
and the absolute risk reduction of total mortality (%/year) in 26 statin
trials, where total mortality was recorded and which were included in the study
by Silverman et al. and in 11 ignored trials. ARR is weakly associated with
degree of LDL-C lowering in the included trials (y = 0.28x + 0.06)
but inversely associated in the excluded trials (y = −0.49x − 0.81).
Symbols: see Figure 1.
According to Ference et al. [3], the most compelling clinical evidence for
causality is provided by ‘the presence of more than 30 randomized
cholesterol-lowering trials that consistently demonstrate that reducing LDL-C
reduces the risk of CVD events proportional to the absolute reduction in LDL-C’.
As previously noted, this is not true exposure–response. Furthermore, in
their Figure 5(a), that illustrates the association,
the authors have only included data from 12 of the 30 trials they refer to. If
all of the trials in Table 1 are included, as we have done in Figure 3, there is no association between
LDL-C lowering and coronary event rate.
Figure 3. The association between the absolute 5-year risk
reduction (ARR) and the degree of LDL-C lowering in 12 trials included in Table
4A in the article by Ference et al. (r = 2.59) and from 21
trials they have ignored or excluded (r = −0.1).
White symbols: trials included in the analysis by Ference et
al.; black symbols: excluded or ignored trials; squares: primary-preventive
trials; round symbols: secondary-preventive trials; stippled line: regression
line for the included trials; full line: regression line for all trials.
Figure 4. The association between the absolute risk
reduction of CHD mortality in 21 statin trials included in the study by
Silverman et al. and in 7 ignored trials and the year where the trial protocols
were published. The vertical line indicates the year where the new trial
regulations were introduced. Symbols: see Figure 1.
Figure 5. The association between the absolute risk
reduction of total mortality in 26 statin trials included in the study by
Silverman et al. and in 11 ignored trials and the year where the trial
protocols were published. The vertical line indicates the year where the new
trial regulations were introduced. Symbols: see Figure 1.
Ference et al. [3] claim that short-term follow-up
(2 years or less) may be unable to demonstrate an association. We have,
therefore, calculated the regression coefficients after having excluded such
trials, but they do not differ much (included trials: r = +2.59
vs. +3.39; excluded trials: r = −0.1 vs. +0.15).
6.2. The benefit of statin treatment is exaggerated
Collins et al. [1] also used the RRR to quantify the benefit
from statin treatment. They claimed that lowering LDL-C by 2 mmol/L will
cause an RRR of MVE of about 45%/year, and here, they refer to the
meta-analysis performed by the Cholesterol Treatment Trialists [70]. But according to Figures 3 and 4 in that article, the ARR of MVE was
only 0.8% (1% for men and 0.2% for women), and the ARR of total mortality was
0.4% (both sexes).
According to the meta-analysis by Silverman et al. [2], reducing LDL-C lowers the risk of MVE in
the primary and secondary prevention trials by 0.35 and 1.0%/year/mmol/l
reduction of LDL-C, respectively. However, as mentioned, they excluded at least
11 unsuccessful statin trials in which MVE was reported. One of the reasons for
the exclusion of a subset of trials may be that they considered trials with
fewer than 50 events as unreliable, but in all of the excluded trials, the
number of events was higher.
Moreover, neither Collins et al. [1] nor Silverman et al. [2] mentioned that in four statin trials, where
a high-degree lowering of LDL-C was compared with a low-degree lowering, no
significant difference with respect to the number of MVEs was obtained,
although LDL-C was lowered by 0.4–1 mmol/L more in the high-dose groups [53,55,56,61].
Furthermore, the most important outcome – an increase of life
expectancy – has never been mentioned in any cholesterol-lowering trial, but as
calculated recently by Kristensen et al., statin treatment does not prolong
lifespan by more than an average of a few days [71].
6.3. The benefit from statin treatment has been questioned
For some years, many researchers have questioned the results
from statin trials because they have been denied access to the primary data. In
2004–2005, health authorities in Europe and the United States introduced New
Clinical Trial Regulations, which specified that all trial data had to be made
public. Since 2005, claims of benefit from statin trials have virtually
disappeared [72], see Figures 4 and 5.
6.4. Adverse effects from statin treatment
According to Collins et al. [1], adverse effects from statin treatment are
extremely rare, and the incidence of statin adverse effects can only be
obtained from randomized controlled trials. However, many drug-related adverse
effects in other therapy areas have only emerged from observational studies and
post-marketing surveillance. Furthermore, most statin trials have included a
run-in period, where participants received the drug for a few weeks, after
which those who suffered adverse effects or who were unwilling to continue were
excluded. The results from two trials without a run-in period [55,64] and where a high statin dose was compared
with a low dose demonstrated that this is an effective way to minimize the
number of reported side effects; in SAGE [64], serious side effects were recorded in
more than 20% in both groups, and in IDEAL [55], the number was almost 50%.
According to Collins et al. [1], myopathy occurs in only 0.01% of treated
individuals per year, but in most statin trials, myopathy is only recorded if
creatine kinase is more than 10 times higher than normal. However, in a study
by Phillips et al. [73], microscopic examinations of muscle
biopsies from statin-treated patients with muscular symptoms and normal
creatine kinase levels showed signs of myopathy. When patients stopped
treatment, their symptoms disappeared, and repeated biopsies showed resolution
of the pathological changes.
To reject the frequent occurrence of muscular problems with the
argument that muscle symptoms are nocebo effects is also invalid. In a study of
22 statin-treated professional athletes [74], the authors reported that 17 (77%) of the
athletes terminated treatment because of muscular symptoms, which disappeared a
few days or weeks after drug withdrawal. The explanation for statin-induced
adverse muscle effects is probably that statin treatment not only blocks the
production of cholesterol but also blocks the production of several other
important molecules, for instance, coenzyme Q10, which is indispensable for
energy production. As most energy is produced in the muscle cells, including
those of the heart, the extensive use of statin treatment may explain the
epidemics of heart failure that have been observed in many countries [75].
Furthermore, case–control and cross-sectional studies have shown
that statin use is observed significantly more often among patients with
cataracts [76], hearing loss [77], suicidal ideation [78], peripheral neuropathy [79], depression [80], Parkinson’s disease [81], interstitial cystitis [82], herpes zoster [83], impotency [84], cognitive impairments [85–88], and diabetes [89,90]. In some of these studies, the side
effects disappeared with discontinuation of the statins and worsened with
rechallenge [74,84,85]. As cholesterol is a vital substance for
the renewal of all cells, and since statins also block the production of other
molecules necessary for normal cell function [75], it is not surprising that statin
treatment may result in side effects from many different organs.
According to Collins et al., statin treatment protects against
cancer. However, in three trials, cancer occurred significantly more often in
the treatment groups [24], and there is much evidence that low
cholesterol predisposes to cancer. For instance, several experiments on rodents
with lipid-lowering drugs produced cancer [91], and in nine human cohort studies, cancer
rates were inversely associated with cholesterol levels measured in healthy
people 10 to more than 30 years earlier [24]. Therefore, case–control studies in which
the incidence of cancer in statin-treated patients was lower than in controls
are invalid because many untreated individuals have low cholesterol, and those
on statins have lived most of their lives with high cholesterol that may have
provided protection from developing cancer.
The reported incidence of most of the above-mentioned side
effects may be relatively small, but taken together, the total number can
become substantial, in particular in patients who continue statin treatment for
many years.
6.5. Does treatment with proprotein convertase subtilisin–kexin
type 9 inhibitors improve the outcome?
A new cholesterol-lowering drug has recently been introduced. It
is an antibody that inhibits proprotein convertase subtilisin–kexin type 9
(PCSK-9), which lowers LDL-C by approximately 60%. In FOURIER, the largest and
longest PCSK-9 inhibitor trial, evolocumab was compared with placebo in more
than 27,000 statin-treated patients with CVD [92]. The trial was stopped after
2.2 years because the number of MVE was reduced with statistical
significance (9.8% vs. 11.3%). However, both CVD mortality and total mortality
had increased, although not with statistical significance. A relevant question
is, therefore, why the trial, the sponsor of which (Amgen) was responsible for
data collection, was ended after only 2.2 years. Furthermore, this trial
is yet another proof that there is no exposure–response between LDL-C and total
or CVD mortality.
7. Does FH prove that high LDL-C causes CVD?
7.1. A low percentage of FH individuals die prematurely
For many years, it has been assumed that high LDL-C was the
cause of the increased risk of CVD and premature deaths in individuals with FH,
and this argument was used by Collins et al. [1] and Ference et al. [2] as well. However, many observations are in
conflict with this hypothesis.
For instance, according to the Simon Broome registry, only a
small percentage of FH individuals die at an early age, and the mortality among
the elderly does not differ from the mortality of the general population
despite their high LDL-C [93].
In a study by Mundal et al., 4688 individuals aged
0–92 years with FH were followed up for 18 years [94]. During that time, 113 died, whereas the
expected number in the general population was 133. The mortality benefit cannot
have been due to lipid-lowering treatment because there was no significant
difference between the number on such treatment among those who died and those
above the age of 18 years who survived (88.2% vs. 89.1%).
7.2. No LDL-C difference between FH individuals with and without
CVD
If high LDL-C causes premature CVD in FH, the LDL-C of those
with CVD should be higher compared to others, but at least six studies of
untreated FH individuals have shown no significant differences in LDL-C or age
[95–100]. It has also been shown that FH relatives
without FH may have shorter lives than the general population [101]. Most likely, a small subset of FH
individuals and their relatives inherit CVD risk factors that are more
important than high LDL-C on CVD outcomes.
8. Has CVD mortality decreased after the introduction of statin
treatment?
For decades, a decrease in CVD mortality has been observed in
many countries, and the presumed reason for the decrease is the increasing use
of statin treatment. However, this interpretation is highly questionable [72]. In a Swedish study including 289 of the
290 municipalities, no association was found between statin use and the change
in mortality from AMI [102]. Also, the American National Health and
Nutrition Examination Survey [103] found that during the period 1999–2006,
the number of AMI and strokes increased from 3.4% to 3.7% and from 2.0% to
2.9%, respectively. During the same period, mean LDL-C level decreased from
126.1 to 114.8 mg/dl, and the self-reported use of lipid-lowering drugs
increased from 8% to 13.4%. Furthermore, statin utilization in 12 European
countries between 2000 and 2012 was not associated with reduced CHD mortality
or its rate of change over the years [104].
9. Conclusion
The idea that high cholesterol levels in the blood are the main
cause of CVD is impossible because people with low levels become just as
atherosclerotic as people with high levels and their risk of suffering from CVD
is the same or higher. The cholesterol hypothesis has been kept alive for
decades by reviewers who have used misleading statistics, excluded the results
from unsuccessful trials and ignored numerous contradictory observations.
10. Expert commentary
In our analysis of three major reviews [1–3], that claim the cholesterol hypothesis is
indisputable and that statin treatment is an effective and safe way to lower
the risk of CVD, we have found that their statements are invalid, compromised
by misleading statistics, excluding unsuccessful trials, minimizing the side
effects of cholesterol lowering, and ignoring contradictory observations from
independent investigators.
The usual argument in support of the lipid hypothesis is that
numerous studies of young and middle-aged people have shown that high TC or
LDL-C predict future CVD. This is correct, but association is not the same as
causation. Few authors have adjusted for other CVD-promoting factors such as
mental stress, coagulation factors, inflammation, infections, and endothelial
sensitivity, all of which are closely related to LDL receptor abnormalities [105]. For instance, mental stress can raise TC
[17,18] possibly because cholesterol is necessary
for the production of cortisol and other steroid stress hormones, and mental
stress may cause CVD by an increased production of epinephrine and
norepinephrine, which contribute to hypertension and hypercoagulation. The
reason why high TC is a risk factor only for young and middle-aged people may
be that mental stress is more common among working people than among retired
senior citizens.
It is important to emphasize that LDL participates in the immune
system by adhering to and inactivating all kinds of microorganisms and their
toxic products and that many observations and experiments have incriminated
infections as a possible causal factor of CVD [21–23], and our results indicate that there may
be better methods than cholesterol lowering to prevent atherosclerosis and CVD.
11. Five-year view
Statin treatment is prescribed for perpetual use, but very few
trials have continued for more than a few years. In the longest follow-up study
(20 years) [106], the authors claimed that pravastatin
used as primary prevention reduced the risk of CHD by 27% and the risk of major
adverse cardiovascular events by 25%. However, these figures represented RRR;
the ARR was only a few percentage points. A more serious bias is the statement,
mentioned only in a supplement, that the authors did not know how many of the
participants had used pravastatin during the 20 years of follow-up after
the trial [107]. A relevant goal for future research
would be to encourage independent investigators to compare the health status of
those who have taken statins for many years with the status of untreated
individuals with the same risk factors who have lived just as long.
The lipid hypothesis has been perpetuated by the authors who
have ignored the results from trials with a negative outcome, who have misused
statistics, and who have ignored all contradictions documented by independent
researchers. The increased risk of CVD in people with FH has been a primary
argument in support of the lipid hypothesis. Surprisingly, several studies of
untreated people with FH have shown that LDL-C does not differ significantly
between those with and without CVD [95–100] and that elderly people with FH live just
as long as elderly people from the general population despite their high LDL-C
[93,94]. FH individuals with significant CVD may
have inherited other, more important risk factors than a high LDL-C.
Despite the fact that LDL-C is routinely referred to as the ‘bad
cholesterol’, we have shown that high LDL-C levels appear to be unrelated to the
risk of CVD, both in FH individuals and in the general population and that the
benefit from the use of cholesterol-lowering drugs is questionable. Therefore,
a systematic search for other CVD risk factors is an important topic for future
research.
Key issues
·
The hypothesis that
high TC or LDL-C causes atherosclerosis and CVD has been shown to be false by
numerous observations and experiments.
·
The fact that high
LDL-C is beneficial in terms of overall lifespan has been ignored by
researchers who support the lipid hypothesis.
·
The assertion that
statin treatment is beneficial has been kept alive by individuals who have
ignored the results from trials with negative outcomes and by using deceptive
statistics.
·
That statin treatment
has many serious side effects has been minimized by individuals who have used a
misleading trial design and have ignored reports from independent researchers.
·
That high LDL-C is the
cause of CVD in FH is questionable because LDL-C does not differ between
untreated FH individuals with and without CVD.
·
Millions of people all
over the world, including many with no history of heart disease, are taking
statins, and PCSK-9 inhibitors to lower LDL-C further are now being promoted,
despite unproven benefits and serious side effects.
·
We suggest that
clinicians should abandon the use of statins and PCSK-9 inhibitors and instead
identify and target the actual causes of CVD.
Acknowledgments
The WVI board had approved sponsorship for the open access. This
is a charitable organisation and not for profit.
Declaration of Interest
U Ravnskov, M de Lorgeril, R Hama, M Kendrick, H Okuyama and R
Sundberg has published books with criticism of the cholesterol hypothesis. PJ
Rosch has edited a book with criticism of the cholesterol hypothesis. KS
Mccully has a US patent for a homocysteine-lowering protocol. The authors have
no other relevant affiliations or financial involvement with any organization
or entity with a financial interest in or financial conflict with the subject
matter or materials discussed in the manuscript apart from those disclosed.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or
other relationships to disclose.
Correction Statement
This article has been republished with minor changes. These
changes do not impact the academic content of the article.
References
Papers of special note have been highlighted as either of
interest (•) or of considerable interest (••) to readers.
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Funding: This paper was funded by Western Vascular Institute.
Funding: This paper was funded by Western Vascular Institute.
