DR. WEEKS’ COMMENT:
“Observational studies have shown that among the 13 million American survivors of cancer higher blood lipid levels are associated with better survival .”
Got cancer? Well, guess what? Yup: high cholesterol is good for you.
Got chronic kidney disease? High cholesterol is good for you!
Got COPD – chronic obstructive pulmonary disease? Yes: High cholesterol is good for you!
Got congestive heart failure? High cholesterol is good for you and can save your life!
Needing dialysis? High cholesterol is good for you and prolongs life!
How about if you are over 70? Yup. You guessed it: High cholesterol is good for you! The older you are, the more benefit you get from high cholesterol.
We have taught this to patients for years but have been thwarted by drug companies seducing doctors with research grants while pushing cholesterol lowering drugs – all the while knowing full well that anti-oxidants (inexpensive vitamins which prevent the damage (oxidation) to healthy cholesterol are the best solution. I will always remember what Dr. Alan Tisdale a great mentor at medical school taught me on evening while on call at the university hospital: “What you have to understand, Brad, is that the dumbest body is smarter than the smartest doctor!” He knew that the body makes magnificent efforts to self-correct. Cholesterol, after all is what our stress hormones and sex hormones are made from. It is like money in the bank – great potential to be drawn down as needed. Cholesterol only becomes problematic when it is oxidized – a fault it shares with, let me see, ALL of our biochemical substances!
Ask your doctor if he or she knows that high cholesterol is good for people with all these problems.
Bring a copy of this post to your next appointment!
Lipids in aging and chronic illness: impact on survival
Csaba P. Kovesdy1,2, Kamyar Kalantar-Zadeh3,4
1Division of Nephrology,
2Department of Medicine,
Division of Nephrology and Hypertension, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA
17 December 2007
Arch Med Sci 2007; 3, 4A: S74-S80
Hypercholesterolemia has been implicated as a risk factor for atherosclerosis
by numerous observational studies in the general population. Observational
studies in patients suffering from various chronic illnesses and in individuals
with advanced age have indicated an inverse association between cholesterol
level and mortality, suggesting that the classical
not apply to these groups. It is yet unclear what the reasons for these
paradoxically inverse associations are. We present a summary of the descriptive
studies that have examined the association between cholesterol levels and
outcomes in a variety of patient groups. The various possible mechanisms behind
the observed “lipid paradox” and the potential implications of reverse
epidemiology of hypercholesterolemia in clinical medicine and public health are
Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of
morbidity and mortality in the general population . Our current
knowledge on the risk factors that are instrumental in the initiation and
propagation of ASCVD was originally established by the
[2-6] and later corroborated by other observational studies. These studies
have established a strong association between risk factors such as
hypercholesterolemia, obesity, hypertension, and diabetes mellitus, and
ASCVD-related outcomes. The early association studies were soon followed
by randomized controlled trials aimed at correcting some of these risk
factors, and which ultimately established a causal link between the risk
factors and the subsequent outcomes [7-10]. These studies have had an
immense impact on clinical practice, since they established therapeutic
paradigms that promised to prolong the lives of large masses with
interventions that were safe and easy to implement.
Hypercholesterolemia is one the best examples to indicate how
knowledge gained from observational studies and subsequent
interventional trials was successfully transplanted into mass-therapeutic
interventions with a population-wide impact. The success of cholesterol
lowering therapy for primary, secondary and tertiary prevention has inevitably led to a desire to extend these beneficial treatments to as many patients as possible. This desire appeared especially warranted in the case of patients with a higher burden of ASCVD, where interventions based on the now widely accepted cholesterol-ASCVD paradigm should have reaped the most benefit.
It came, however, as a surprise that a number of observational studies in several distinct populations with a high ASCVD burden, such as individuals with
chronic heart failure or end-stage kidney failure, failed to show the classical association between higher cholesterol and worse outcomes that we came to expect, and indicated that higher cholesterol was paradoxically associated with better outcomes [11-16]. Questions still abound about the meaning of these studies and their therapeutic relevance. We present an overview of the cholesterol-ASCVD relationship in various patient populations that display a reversal of the classical
Populations with an inverse association between cholesterol level and mortality
Almost 20 million Americans suffer from chronic
kidney disease (CKD), of whom 400,000 individuals
have end-stage (stage 5) CKD and need
maintenance dialysis . Dialysis is a life-saving
procedure, but the yearly mortality rate in patients
undergoing maintenance dialysis is about 20%,
which is worse then what is seen in many cancers,
and is mainly a result of cardiovascular causes .
Whereas patients on dialysis are indeed suffering
from a higher burden of the diseases linked to
cardiovascular morbidity and mortality in the
attempted to establish a link between classical risk
factors such as obesity, hypertension and
hypercholesterolemia, and cardiovascular outcomes
have indicated a reversal of the expected relationship
[16, 19-21]. These apparently counterintuitive
associations or survival paradoxes have been
referred to as “reverse epidemiology” [22, 23].
Several studies indicate that low, rather than
high, serum total cholesterol and LDL are associated
with poor survival in dialysis patients [11-13, 15].
Recently Kilpatrick et al.  showed that the
“cholesterol paradox” is universal across subgroups
of dialysis patients except for African Americans, in
whom higher LDL was associated with worse
survival, a so-called “paradox within paradox”. In
an attempt to explain the inverse association
between cholesterol level and mortality in patients
on dialysis Liu et al. showed that higher total
cholesterol was, in fact, associated with increased
mortality in a subset of patients without evidence
of inflammation and malnutrition, while patients
with such evidence retained the inverse association
that was the characteristic of their overall patient
cohort . A similar interaction was described by
Iseki et al. who showed higher mortality with higher
total cholesterol only in dialysis patients with serum
albumin levels higher than 4.5 g/dl . These
results implied that lower total cholesterol was in
fact a surrogate marker of inflammation and/or
malnutrition, hence therapy directed toward
lowering cholesterol should not be withheld,
especially given the additional, potentially beneficial
non-lipid-related effects of statins, the most widely
used cholesterol-lowering drugs [24, 25]. Based on
this it came as a surprise that the only completed
clinical trial aimed at improving outcomes through
lipid lowering with a statin in diabetic patients on
dialysis, Die Deutsche Diabetes Dialyse Studie (the
4D Study),  did not show a significant reduction
in the composite outcome of death from cardiac
causes, non-fatal myocardial infarction and stroke.
The latter finding puzzled those who were
contending that the reverse epidemiology of
cholesterol would be an exclusively statistical
phenomenon without any biological plausibility.
Until recently it was believed that the
counterintuitive phenomenon of reverse
epidemiology is restricted to dialysis patients and
that the vast number of individuals with moderate
degrees of CKD (stages 3 and 4) who are not on
dialysis would follow the “
However, even CKD in its earlier stages is
considered a strong and independent predictor of
cardiovascular mortality, [21, 27-29] with death
being far more common than progression towards
end-stage in CKD . Supporting the idea that the
cholesterol paradox seen in ESRD can also be
detected in patients with earlier stages of CKD,
a cohort study in 986 men with CKD stages 1 to
5 not on dialysis showed an inverse association
between lipids and survival . Exploring the
confounding effect of co-morbid conditions and the
malnutrition-inflammation complex this study found
the inverse association between cholesterol and
mortality attenuated, but not reversed after
multivariable adjustments .
Individuals with congestive heart failure (CHF)
currently number approximately 5 million in the
and show striking similarities to CKD patients. Both
patient populations have a high prevalence of
comorbid conditions, a high hospitalization rate,
a low self-reported quality of life, and an excessively
high mortality risk, mostly due to cardiovascular
causes [18, 31]. CHF patients with hypercholesterolemia
have also displayed lower mortality[32-35] and lower serum cholesterol is associated with higher death risk in these patients .
There are currently over 10 million octogenarians
and nonagenarians in the
is growing . The incidence of cardiovascular
disease in the elderly is high . A reversal of the
traditional relationship between cardiovascular risk
factors and survival outcomes has also been
observed in these populations. Although not
regarded as a universal finding, but several studies
have indicated that low, rather than high total and
LDL cholesterol levels have been associated with
increased mortality in the elderly [37-41].
Chronic obstructive pulmonary disease (COPD)
affects approximately 16 million Americans and is
the fourth leading cause of death worldwide .
Cardiovascular mortality accounts for roughly 50%
of deaths in COPD patients,  but the relationship
between cholesterol and mortality is reversed in
these patients too. While studies examining
cholesterol and outcomes in COPD are sparse, one
large study found a trend towards lower risks of
hospitalizations and death in men with COPD who
had higher cholesterol levels .
HIV infection and AIDS has been associated with
accelerated rates of atherosclerosis and
cardiovascular disease . The association
between classical risk factors of CVD and outcomes
in HIV and AIDS is complex, since highly active
antiretroviral therapy can be associated with
changes in body composition including lipodystrophy,
and may induce an atherogenic lipid
profile [44, 45]. Nevertheless, low BMI, weight loss,
and low total cholesterol have all been associated
with poor prognosis in AIDS populations [46, 47].
Observational studies have shown that among the
13 million American survivors of cancer higher blood
lipid levels are associated with better survival .
Pathophysiology of lipid paradox
Several hypotheses have been advanced to
explain the lipid paradox in such chronic disease
states as CHF and CKD that are associated with
wasting (Figure 1).
Survival advantages that exist in hypercholesterolemic
individuals with chronic disease
states may, in the short-term, outweigh the harmful
long-term effects of these risk factors in causing
cardiovascular disease and death . Dialysis
patients may not live long enough to die of the
adverse effects of high cholesterol, because they
are more likely to die from consequences of
undernutrition . The time discrepancy or
differential between these two sets of competing
risk factors can explain why the treatment of
hypercholesterolemia may be practically irrelevant
in individuals with chronic disease states and high
rate of short-term death, in whom long-term survival is quite low. Currently 2/3 of all dialysis
patients in the
dialysis, which is worse than the mortality of many
cancer patients . Similar to dialysis patients, the
short-term mortality in most populations with
chronic disease states is excessively high as a result
of their protein-energy wasting conditions. Such
individuals will not live long enough to die of
consequences of hyperlipidemia, which need years
to decades to exert their deleterious impact on
Under uremic circumstances the metabolism of
atherogenic lipoproteins such as LDL, IDL and HDL
is altered, and is characterized by lowered catabolic
rates along with decreased production rates
[49-52]. This results in an overall longer half life in
spite of net “normal” plasma concentrations. The
modification of these lipoproteins by inflammation,
oxidation, carbamylation and glycation is more
pronounced (due in part to the longer residence
time and to the effect of the uremic milieu), which
can then lead to an enhanced atherogenic potential
. The plasma level of these lipids may not be
a good measure of their atherogenic potential; hence
the term dyslipidemia (rather than hyperlipidemia)
may be a more appropriate term to use in patients
with CKD. Illustrating this concept, a recent study
showed that a higher pro-inflammatory to antiinflammatory
HDL ratio was associated with
increased death risk in dialysis patients . While
the altered lipoprotein metabolism clearly adds an
additional layer of complexity to this issue, it does
not explain the linear inverse association between
the traditional lipid levels and mortality in patients
with CKD, and it also does not explain the same
association in patient groups with other chronic
diseases who have normal kidney function.
With cholesterol level being a surrogate marker
of nutritional status, physiologic mechanisms linked
to the individual’s nutritional status could provide
additional explanations for the better survival seen
with higher cholesterol levels. Several hypotheses
exist about how obesity might be beneficial in the
short term. Obesity may be associated with a more
stable hemodynamic status, and it may mitigate
stress responses and heightened sympathetic and
renin-angiotensin activity . The altered cytokine
and neuroendocrine profiles of obesity could also
confer a relative survival advantage: increased
production of adiponectines  and soluble tumor
necrosis factor alfa receptors  by adipose tissue
may neutralize the adverse effects of tumor
necrosis factor alfa. Higher catabolic rate in cachexia
may lead to generation of excessive amounts of
toxic metabolites; these can be more effectively
sequestered when abundant adipose tissue is
present . Indeed weight loss and reduction in
adipose tissue reserve is associated with the
imminent release of, and significant increase in
circulating lipophilic hexachlorobenzene and other
chlorinated hydrocarbons . A recent study in
dialysis patients showed that obese patients had
a relatively smaller proportion of the so-called “high
metabolic rate compartment” and viscera, 
whereas patients with a lower body mass or BMI
had a higher proportion of these urea generating
compartments relative to their body size. These
findings may provide an explanation as to why loss
of body fat has recently been found to be
associated with increased death risk in dialysis
patients . Weight loss may also be associated
with reduced skeletal muscle oxidative metabolism,
leading to a weakened anti-oxidant defense .
Higher concentrations of lipoproteins may confer
a survival advantage in chronic disease states, since
lipoproteins (including circulating cholesterol
molecules) can actively bind and neutralize
circulating endotoxins, hence attenuating the
propensity of the endotoxins to cause inflammation,
accelerated atherosclerosis and poor outcomes .
This so-called “endotoxin-lipoprotein” hypothesis
was originally introduced to explain the seemingly
protective role of hypercholesterolemia in cardiac
cachexia of CHF patients . Hence, it is possible
that higher circulating cholesterol levels play
a protective role against the deleterious effect of
endotoxins that may be more frequently absorbed
from leaky guts in the setting of edematous states
such as in dialysis or heart failure patients [62, 63].
It is possible that lower cholesterol is not the
cause but merely a consequence of conditions that
lead to poor outcomes in patients with chronic
disease states who exhibit a paradoxical risk factor
profile. Reverse causation is a known possible
source of bias in epidemiologic studies that examine
associations without a clear distinction for the
direction of the causal pathway . While it is
plausible to attribute the association between low
cholesterol and higher mortality to reverse causation,
this fails to explain why high cholesterol is
associated with better outcomes in the populations
Out of approximately 300 million Americans only
10 to 11 million (5 percent) are older than 80 years.
Reaching such an advanced age could be viewed
as a ’’survival selection’’, and there is a possibility
that affected individuals are genetically protected
against the ravages of cardiovascular disease and
other fatal conditions. A similar explanation can be
used for dialysis patients who represent the 5%
survivors of the entire spectrum of CKD, as are CHF
patients who are the survivors of a large population
with cardiovascular disease [20, 66]. Hence, geriatric
populations or dialysis or CHF patients could be
genetically and/or phenotypically dissimilar to their
peers who did not survive. The “survival selection”
hypothesis, however, cannot explain the survival
paradoxes observed in other chronic disease states
such as rheumatoid arthritis or in patients with
earlier stages of CKD, nor can it explain why the
described paradoxical associations reverse and
become yet again “conventional” in dialysis or CHF
patients after successful kidney or heart
transplantation [18, 67].
Clinical and public health implications of
“Reverse Epidemiology” for lipid management
In today’s environment of ever growing patient
numbers, shorter doctor visit times, institutional
and regulatory pressures to implement population-
wide ‘’standardized’’ interventions, and aggressive
pharmaceutical marketing campaigns, it is not
surprising that a one size fits all type of approach
to cholesterol management appears very enticing.
It is still unclear how this approach will be affected
by the evidence amassed in the above cited
observational studies. The field of reverse
epidemiology is still in its infancy, and up to this
point it has generated more questions than
answers. The biologic plausibility of the inverse
associations between cholesterol level and mortality
still needs to be elucidated. Therapeutic targets
need to be clarified by designing randomized
controlled trials specifically targeting the affected
patient populations. We caution against dismissing
all the observational data purely because they
contradict established paradigms.
To date there are tens of millions of patients who
display high morbidity and mortality from chronic
disease states, and whose disease courses and
outcomes appear to be different then that of the
ago. While there are no clear answers yet to guide
therapy in these patients, the realization of what we
don’t know is a very important step in scientific
discovery. Today the field of reverse epidemiology is
where conventional epidemiology was 40 years ago.
Time will tell how it will evolve; at least the questions
surrounding the role of cholesterol may soon have
a more definitive answer, once the results of ongoing
randomized controlled trials in affected patient
populations will become available [68, 69]. For the
time being we cannot advocate a change in current
clinical practices, given the lack of prospective
studies testing the role of cholesterol in patients
with chronic illnesses. Changing our current practice
pattern could take 40 or more years, but we may
one day prescribe cholesterol-raising medications to
certain patients. After all, paradigm shifts can lead
to scientific revolutions .
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