Got cancer? Rx raise your total cholesterol…

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 [48].”

 

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, Salem Veterans Affairs Medical Center, Salem, VA, USA

2Department of Medicine, University of Virginia, Charlottesville, VA, USA

3Harold Simmons Center for Kidney Disease Research and Epidemiology,

 

Division of Nephrology and Hypertension, Los Angeles Biomedical Research Institute  at Harbor-UCLA Medical Center, Torrance, CA, USA

4David Geffen School of Medicine at UCLA, Los Angeles, 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 Framingham paradigm may

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

discussed.

 

Introduction

 

Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of

morbidity and mortality in the general population [1]. Our current

knowledge on the risk factors that are instrumental in the initiation and

propagation of ASCVD was originally established by the Framingham study

[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 Framingham cholesterol paradigm, the so-called “lipid paradox”, and discuss possible explanations for this phenomenon.

 

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 [17]. 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 [18].

Whereas patients on dialysis are indeed suffering

from a higher burden of the diseases linked to

cardiovascular morbidity and mortality in the

Framingham paradigm, observational studies that

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. [16] 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 [14]. 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 [13]. 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), [26] 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 “Framingham paradigm”.

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 [27]. 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 [30]. 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 [30].

 

Individuals with congestive heart failure (CHF)

currently number approximately 5 million in the USA

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 [32].

There are currently over 10 million octogenarians

and nonagenarians in the USA, and their proportion

is growing [36]. The incidence of cardiovascular

disease in the elderly is high [37]. 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 [42].

Cardiovascular mortality accounts for roughly 50%

of deaths in COPD patients, [42] 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 [43].

 

HIV infection and AIDS has been associated with

accelerated rates of atherosclerosis and

cardiovascular disease [44]. 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 [48].

 

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 [22]. 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 [20]. 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 USA die within 5 years after starting

dialysis, which is worse than the mortality of many

cancer patients [20]. 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

survival.

 

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

[53]. 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 [54]. 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 [55]. The altered cytokine

and neuroendocrine profiles of obesity could also

confer a relative survival advantage: increased

production of adiponectines [56] and soluble tumor

necrosis factor alfa receptors [57] 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 [58]. 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 [59]. 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, [60]

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 [61]. Weight loss may also be associated

with reduced skeletal muscle oxidative metabolism,

leading to a weakened anti-oxidant defense [62].

 

 

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 [63].

This so-called “endotoxin-lipoprotein” hypothesis

was originally introduced to explain the seemingly

protective role of hypercholesterolemia in cardiac

cachexia of CHF patients [64]. 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 [65]. 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

discussed above.

 

 

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

population of Framingham, MA more then 40 years

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 [70].

 

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Csaba P. Kovesdy, Kamyar Kalantar-Zadeh

 

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