American
College of Cardiology Foundation | Journal of the American College of
Cardiology | Optimal low-density lipoprotein is 50 to 70 mg/dlLower is
better and physiologically normal
J Am Coll Cardiol. 2004;43(11):2142-2146. doi:10.1016/j.jacc.2004.03.046
Abstract
The
normal low-density lipoprotein (LDL) cholesterol range is 50 to 70
mg/dl for native hunter-gatherers, healthy human neonates, free-living
primates, and other wild mammals (all of whom do not develop
atherosclerosis). Randomized trial data suggest atherosclerosis
progression and coronary heart disease events are minimized when LDL is
lowered to <70 mg/dl. No major safety concerns have surfaced in
studies that lowered LDL to this range of 50 to 70 mg/dl. The current
guidelines setting the target LDL at 100 to 115 mg/dl may lead to
substantial undertreatment in high-risk individuals.
| CHD |
coronary heart disease
|
| LDL |
low density lipoprotein
|
| NCEP-ATP-III |
Natural Cholesterol Education Program-Adult Treatment Panel-III
|
According
to the National Cholesterol Education Program-Adult Treatment
Panel-III (NCEP-ATP-III), the target low-density lipoprotein (LDL)
level for patients with established coronary disease or coronary heart
disease (CHD) risk equivalents (such as diabetes, peripheral or
cerebral vascular disease, or predicted 10-year CHD risk of >20%) is
<100 mg/dl (1). The European guidelines set the LDL target at <115 mg/dl (2).
Accumulating data from multiple lines of evidence consistently
demonstrate that the physiologically normal LDL level and the thresholds
for atherosclerosis development and CHD events are approximately 50 to
70 mg/dl.
Atherosclerosis
development is a complex process influenced by a myriad of risk
factors, although the LDL level is among the most important. In an
atherogenic millieu, oxidized LDL infiltrates the intima where it
stimulates inflammation, endothelial dysfunction, and eventually
atherosclerosis. Although it is true that very high LDL levels (>200
mg/dl) are strongly associated with CHD risk, atherosclerosis is not
uncommon even in those with relatively “normal” LDL levels (90 to 130
mg/dl) (3- 4). Moreover, the 10% of the population with the highest LDL levels account for only 20% of the CHD events (3).
Thus, focusing treatment only on those with very high cholesterol
levels will ignore 80% of the people destined to suffer a CHD event (4).
The mega-trials using statin therapy have demonstrated remarkable
reductions in CHD events and in all-cause mortality among patients with
baseline LDL levels generally from 120 to 180 mg/dl and on-treatment
values between 100 and 140 mg/dl (5- 11).
Whereas cardiovascular events were reduced by 25% in these studies,
approximately three out of four CHD events occurred despite the statin
therapy. This 25% reduction in LDL represents only partial treatment,
and more robust reductions appear to provide more impressive
improvements in prognosis (12).
The average total cholesterol level in American adults today is 208 mg/dl (corresponding to an LDL of approximately 130 mg/dl) (13). In this case, average is not normal because atherosclerosis is present in up to 40% to 50% of women and men by age 50 (14).
Atherosclerosis is endemic in our population in part because the
average person's LDL level is approximately twice the normal physiologic
level (Figure 1).
Figure 1
Total
cholesterol levels for hunter-gatherers, wild primates, and wild
mammals, generally range from about 70 to 140 mg/dl (corresponding to
low-density lipoprotein levels of about 35 to 70 mg/dl 24- 25). The mean cholesterol levels of modern Westernized humans are almost twice these normal values (13).
We
live in a world very different from that for which we are genetically
adapted. Profound changes in our environment began with the
introduction of agriculture and animal husbandry 10,000 years ago, too
recent on an evolutionary time scale for the human genome to adjust. As
a result of this ever-worsening discordance between our ancient
genetically determined biology and the nutritional, cultural, and
activity patterns in modern populations, many of the so-called diseases
of civilization, including atherosclerosis, have emerged. Evidence
from hunter-gatherer populations while they were still following their
indigenous lifestyles showed no evidence for atherosclerosis, even in
individuals living into the seventh and eighth decades of life (15- 16).
These populations had total cholesterol levels of 100 to 150 mg/dl
with estimated LDL cholesterol levels of about 50 to 75 mg/dl. The LDL
levels of healthy neonates are even today in the 30 to 70 mg/dl range.
Healthy, wild, adult primates show LDL levels of approximately 40 to 80
mg/dl (17).
In fact, modern humans are the only adult mammals, excluding some
domesticated animals, with a mean LDL level over 80 mg/dl and a total
cholesterol over 160 mg/dl (15- 16) (Figure 1).
Thus, although an LDL level of 50 to 70 mg/dl seems excessively low by
modern American standards, it is precisely the normal range for
individuals living the lifestyle and eating the diet for which we are
genetically adapted.
Abundant
data from prospective trials reveal a strong and direct relationship
between on-treatment LDL level and rate of atherosclerotic progression.
These randomized controlled trials show that whether patients were on
statin therapy or placebo, the rate of angiographic progression of
atherosclerosis was closely related to the chronic LDL level (18- 24). (Figure 2)
indicates that the threshold for atherosclerotic progression may be at
an LDL level of approximately 67 mg/dl. The strongest data on
atherosclerotic progression come from the Reversal of Atherosclerosis
with Aggressive Lipid Lowering (REVERSAL) trial (24).
In this randomized study of 654 patients with symptomatic coronary
disease and a baseline stenosis of 20% or more on coronary angiography,
patients were randomized to high-dose atorvastatin, 80 mg daily, or
pravastatin, 40 mg daily. Coronary atherosclerosis, as documented by
intravascular ultrasound, was virtually halted in the atorvastatin group
where a 48% LDL reduction led to a mean on-treatment LDL of 79 mg/dl.
The pravastatin group experienced a 28% decline to a mean on-treatment
LDL of 110 mg/dl. These differing regimens resulted in 0.4% regression
of atheroma volume in the atorvastatin versus a 2.7% mean progression
in the pravastatin group over the 18-month trial. Systemic inflammation
was also reduced at lower LDL levels as reflected by the C-reactive
protein levels, which were reduced by 36% in the group treated to a mean
LDL of 79 mg/dl compared to a 5% decrease when the LDL was 110 mg/dl (24).
Figure 2
Atherosclerosis progression varies directly with low-density lipoprotein (LDL) cholesterol. This regression line indicates that atherosclerosis does not progress when LDL is 67 mg/dl or below (18- 24). Data from randomized placebo-controlled trials using statins for preventing atherosclerosis progression (analysis for Figure 2) or preventing coronary heart disease events in primary (analysis for Figure 3) or secondary (analysis for Figure 4)
prevention were utilized for computation of the univariate regression
lines correlating LDL with outcomes. Regression estimates, model R2,
and p values for LDL effect were obtained from the unweighted
regression lines. AT = atorvastatin; CCAIT = Canadian Coronary
Atherosclerosis Intervention Trial; LCAS = Lipoprotein and Coronary
Atherosclerosis Study; MAAS = Multicentre Anti-Atheroma Study; MARS =
Monitored Atherosclerosis Regression Study; MLD = mean luminal diameter;
P = placebo; PLAC = Pravastatin Limitation of Atherosclerosis in the
Coronary Arteries study; PR = pravastatin; REGRESS = Regression Growth
Evaluation Statin Study; REVERSAL = Reversal of Atherosclerosis with
Aggressive Lipid Lowering; S = statin.
Two
recent studies using ultrasound determined carotid intima-media
thickness also found that aggressive LDL reduction halted
atherosclerosis, whereas moderate LDL lowering allowed for continued
progression. The Atorvastatin versus Simvastatin on Atherosclerosis
Progression (ASAP) trial compared atorvastatin 80 mg/day to simvastatin
40 mg/day in 325 patients with familial hypercholesterolemia (25).
Carotid intima-media thickness regressed 0.031 mm over two years in
the atorvastatin group compared with a 0.036-mm progression in the
simvastatin group. The Arterial Biology for the Investigation of the
Treatment Effects of Reducing Cholesterol (ARBITER) trial used 80 mg/day
atorvastatin versus 40 mg/day pravastatin in 161 patients with a mean
baseline LDL of 150 mg/dl (26).
Atorvastatin reduced LDL by 50% to a mean LDL of 76 mg/dl compared
with a 27% drop to a mean of 110 mg/dl on pravastatin. Again, the
carotid intima-media thickness regressed 0.038 mm in the atorvastatin
group compared with a mean progression of 0.026 mm in the pravastatin
group (p = 0.021). Both of these trials demonstrated the inadequacy of
LDL reduction to current goals.
Observational
studies show a continuous positive relationship between CHD risk and
LDL levels that extends well below the average range seen in modern
populations without any definite threshold where lower LDL
concentrations are not associated with lower risk (27).
Over 100,000 patients have been randomized to statin therapy in CHD
event reduction trials. When examined in aggregate, these studies also
demonstrate a direct relationship between on-treatment LDL cholesterol
and absolute risk of CHD events (5- 12). Trials from both the setting of primary prevention (Figure 3) and secondary prevention (Figure 4)
show that the risk of suffering a CHD event during the course of the
study was closely correlated with on-treatment LDL. Interestingly, the
LDL level at which the cardiovascular event rate is predicted to
approach 0 is 57 mg/dl for primary prevention and 30 mg/dl for secondary
prevention. These data implicate LDL as a requisite catalyst in the
atherosclerosis process whereby extremely low LDL may prevent CHD events
regardless of the other risk factors.
Figure 3
Coronary
heart disease (CHD) event rates in primary prevention trials (4 to 5
years duration) are directly proportional to the on-treatment
low-density lipoprotein (LDL) cholesterol levels. The event rate is
predicted to approach 0 at an LDL level of about 57 mg/dl (5- 7).
AFCAPS = Air Force Coronary Atherosclerosis Prevention Study; ASCOT =
Anglo-Scandinavian Cardiac Outcome Trial; WOSCOPS = West Of Scotland
Coronary Prevention Study. Other abbreviations as in (Figure 2).
Figure 4
Coronary
heart disease (CHD) event rates in secondary prevention trials (5
years in duration except the PROVE-IT study, which was 2 years) were
directly proportional to low-density lipoprotein (LDL) cholesterol
levels. The event rate is predicted to approach 0 at LDL of 30 mg/dl (8- 12).
4S = Scandinavian Simvastatin Survival Study; CARE = Cholesterol And
Recurrent Events trial; HPS = Heart Protection Study; LIPID = Long-term
Intervention with Pravastatin In Ischemic Disease trial; PROVE-IT =
PRavastatin Or atorVastatin Evaluation and Infection Therapy trial.
Other abbreviations as in (Figure 2).
In the Heart Protection Study (8),
approximately 3,500 of the 20,536 (17%) participants presented with a
baseline LDL measurement that was below the “target” level of 100 mg/dl
even before initiating simvastatin or placebo. In this subset, the
mean LDL reduction from 97 mg/dl to 65 mg/dl on statin therapy produced
a 25% reduction in relative risk of CHD, which was similar to the
benefits seen in the patients presenting with baseline LDL levels
>100 mg/dl.
The
recently published PRavastatin Or atorVastatin Evaluation and
Infection Therapy (PROVE-IT) trial is the strongest verification of the
lower is better hypothesis (12).
This study randomized 4,162 acute coronary syndrome patients with a
baseline total cholesterol of 200 mg/dl or less either to atorvastatin
80 mg or pravastatin 40 mg daily. The on-treatment LDL was 62 mg/dl (51%
decrease) for the atorvastatin group versus 95 mg/dl (22% decrease)
for the pravastatin group. At the end of two years, a highly
significant 16% reduction (p < 0.001) in adverse CHD events and a
28% reduction in death were noted in the atorvastatin group (Figure 5).
This trial is especially relevant because pravastatin-treated patients
achieved a mean LDL (95 mg/dl) that was under the current target of
100 mg/dl, yet they continued to experience excess CHD events (Figure 5).
Figure 5
The
PRavastatin Or atorVastatin Evaluation and Infection Therapy
(PROVE-IT) trial randomized over 4,000 patients either to high-dose
atorvastatin (low-density lipoprotein [LDL] = 62 mg/dl) or pravastatin
(LDL = 95 mg/dl) (12). A 16% reduction in the primary end point was noted in the atorvastatin-treated group.
The
newer and more potent statins are capable of dramatically reducing LDL
cholesterol safely and tolerably in most patients. The Statin
Therapies for Elevated Lipid Levels compared Across doses to
Rosuvastatin (STELLAR) trial randomized more than 3,000 patients either
to rosuvastatin, atorvastatin, simvastatin, or pravastatin (28).
The rosuvastatin (10 mg/day), atorvastatin (80 mg/day), and
simvastatin (80 mg/day) all achieved the NCEP ATP-III LDL goal in
approximately 80% of patients. Higher doses of high-efficacy statins
are more effective in reaching goals especially when combined with diet
and agents, such as ezitimibe, niacin, or plant sterol and stanol
esters. However, today only one in three CHD patients is at or below
the more liberal current LDL goal of 100 mg/dl (29).
Much work remains to be done in the development of treatment
strategies to achieve the LDL goal of 50 to 70 mg/dl in most CHD
patients.
Some
investigators have proposed that any one specific LDL threshold is
artificial, and if clinically significant atherosclerosis develops, the
LDL cholesterol warrants treatment regardless of the absolute level (3).
Using this approach, LDL reductions of 50% for secondary prevention
patients and 30% for primary prevention can be supported by the
cumulative randomized trial experience (5- 12).
How low is too low?
Cholesterol
is an essential component of the cell membrane and an obligate
precursor for bile acid, steroid hormone, and vitamin D synthesis.
Consequently, it is likely that a physiologically ideal range of blood
cholesterol exists above and below which adverse health consequences
might be expected. Although individuals with serious chronic illnesses,
such as cancer, often develop depressed LDL levels as a result of
malnutrition, epidemiologic studies show that people with naturally low
LDL levels are associated with improved longevity (27).
The cumulative experience with statin therapy shows impressive
cardiovascular benefits that are directly proportional to LDL lowering
with no increase in adverse events such as malignancy or
non-cardiovascular mortality (5- 12,18- 26).
The incidence of the two principal adverse effects commonly attributed
to statins—liver and muscle toxicity—rise modestly as a function of
dose of statin utilized but not in relationship to the on-treatment LDL
level (5- 12).
People
with heterozygous hypobetalipoproteinemia have total cholesterol
levels as low as 80 mg/dl and LDL cholesterol levels as low as 30 mg/dl
(30). This condition is associated with longevity (31),
presumably due to the absence of atherosclerosis, but the lack of
other adverse effects that might have accompanied a low LDL level
suggests that such low levels of LDL are safe.
Unintended benefits of LDL lowering
Inflammation
and endothelial dysfunction, both important markers of abnormal
vascular biology, have been shown to be improved as LDL is lowered to
<80 mg/dl (12,24). Statin therapy has been associated with reductions in the incidence of symptomatic peripheral vascular disease (32), stroke (33), dementia (34), macular degeneration (35), aortic stenosis (36), and osteoporosis-related hip and vertebral fractures (37).
Although the mechanisms responsible for these benefits are not known,
it is possible that an elevated LDL cholesterol level may be a common
denominator predisposing to a wide variety of chronic degenerative
diseases seen in modern civilization. If our genetically determined
ideal LDL is indeed 50 to 70 mg/dl, perhaps lowering the currently
average but elevated levels closer to the physiologically normal range
may improve not just CHD but also many other diseases commonly
attributed to the aging process. For all of these reasons, and given the
safety record of statins, some investigators have suggested that
statins be considered for routine use in individuals over age 55 years (38).
The
authors would like to acknowledge Connie Smith for her assistance in
manuscript preparation, Jose Aceituno for his graphic art contributions,
and Kimberly Reid and Philip Jones for statistical analysis of the
data.
