Facts, myths and misconceptions about LDL-C and HDL-C
By Michael B. Clearfield, DO
any asymptomatic individuals will succumb to cardiovascular disease (CVD),
which is the leading cause of death and
loss of disability-adjusted life-years
worldwide.1
One of the major advances in the
treatment and prevention of CVD involves lowering elevated low-density
lipoprotein cholesterol (LDL-C) to
current goals. In addition to being aggressive at treating LDL-C, osteopathic
physicians must also be aggressive
at treating other risk factors such as
hypertension, cigarette smoking and
diabetes. If we believe we are treating
more people more effectively, why isn’t
the rate of CVD decreasing to a greater
extent? The answer is very complex but
lies partly in the facts, myths and misconceptions about two lipoproteins:
LDL-C and HDL-C.
A series of large randomized endpoint trials have established statins as a
primary therapy for the prevention of
the first major fatal and non-fatal cardiovascular events in people at moderate high and high risk for cardiovascular disease.4-10
These statin trials have contributed
the majority of the evidence on which
the National Cholesterol Education
Program’s Adult Treatment Panels III
(NCEP-ATP III) guidelines and 2004
update have been formulated.2-3 The
evolution of these primary prevention
trials demonstrates that aggressive
LDL-C lowering therapy with statins in
individuals with average or even below
average LDL-C levels but with other
coexisting risk factors can significantly
reduce the number of coronary events.
M
4 Clearfield
The next question in primary prevention is how do we select whom to treat
in lower-risk groups, how aggressively
should their LDL-C be lowered, and
should additional therapy to raise
HDL-C be added to the regime?
The treatment of elevated total and
LDL cholesterol originated in patients
with documented cardiovascular disease. Such treatment has evolved over
the years into more aggressive strategies
that further lower LDL-C to a minimum goal below 100 mg/dl and to
LDL-C levels of less than 70 mg/dl in
very high risk patients.2-3 Since CV
events continue to occur even in those
reaching the goal of an LDL-C ⬍ 70
mg/dl, the next question is whether
even further lowering of LDL-C is
of any additional benefit, or should
raising HDL-C be the next primary
objective in these patients?
Facts about LDL-C in primary
prevention statin trials
1. Lowering LDL-C has consistently
been found to improve cardiovascular
endpoints.
In 2005 the Cholesterol Treatment
Trialists’ (CTT) Collaborators published a meta-analysis of 90,056 participants in 14 randomized trials using
statin therapy, of which 47% had previous CHD.11 The CTT analysis revealed
that those without previous mycardial
infarction (MI) or CHD had 18 fewer
major coronary events per 1,000 treated with statins for each mmol/L (39
mg/dl) of LDL-C reduction. The CTT
meta-analysis concluded that statin
therapy, irrespective of lipid profile or
presenting risk factors, can safely reduce
the five-year incidence of major coronary events, coronary revascularizations
and stroke by about 20% per mmol/L
(39 mg/dl) reduction of LDL-C.
The Whole Patient May 2007
1. Lowering LDL-C has not been
shown to be beneficial in women,
diabetics or the elderly.
The meta-analysis by CTT demonstrated that lowering LDL-C with
statins was beneficial in all the groups
listed above.
The Whole Patient May 2007
meet ATP III criteria for a lipid-lowering medication, 334 (5.1%) were at
moderately high risk and had an
LDL-C ⬍130 mg/dl yet benefited from
lovastatin therapy—with a 68% reduction in acute major coronary events
(95% CI 12% to 88%, p = 0.027).
These results support the ATP III
recommendation for more aggressive
treatment for primary prevention
patients at moderate high risk with a
baseline LDL-C ⬍ 130 mg/dl. Although not specifically analyzed in primary prevention patients, the concept
of lowering LDL-C more aggressively
Misconceptions about LDL-C
1. Continued lowering of LDL-C has
been definitively proven to decrease
cardiovascular events.
In 2004, following the publication
of the aforementioned trials, the National Cholesterol Education ProgramAdult Treatment panel recommended
a modification to the 2001 guidelines
relative to primary prevention.3 Individuals free of CVD but with two or
more risk factors and a 10-20% 10year Framingham risk for CHD, classified as moderate high risk, could
be treated to an optional LDL-C goal
⬍ 100 mg/dl. A strong contributor
to this recommendation came from
the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) data where
treatment with atorvastatin was effective in hypertensive subjects with
LDL-C levels both above and below
the mean of 132 mg/dl.9
This approach recently received
additional support from a re-analysis of the Airforce/Texas Coronary
Atherosclerosis Prevention Study (AFCAPS/TexCAPS) where 35% of the
participants did not meet ATP III criteria for treatment with lipid-lowering
medication and yet were responsible for
21% of the acute major coronary
events.13 Of the subgroup who did not
{
Myths about LDL-C
2. Lowering LDL-C increases the
risk of stroke.
The CTT meta-analysis showed
a significant reduction in ischemic
stroke. In the Stroke Prevention by
Aggressive Reduction in Cholesterol
Levels (SPARCL) trial that randomized patients with prior Transient Ischemic Attacks (TIAs) or strokes but
no evident CHD, atorvastatin significantly reduced incidence of ischemic
stroke but non-significantly increased
risk of hemorrhagic stroke. 12
Cardiovascular disease
(CVD) remains the
leading cause of death
in men and women
in the United States
despite the many
advances in treating
this disease.
{
2. Lowering LDL-C in secondary
prevention statin trials improves both
cardiovascular events and mortality.
In the Cholesterol Treatment Trialists’ (CTT) Collaborators meta-analysis, participants with previous MI or
CHD were found to have 30 fewer
major coronary events per 1,000 treated with statins for each mmol/L of
LDL-C reduction. The CTT metaanalysis concluded that statin therapy
in secondary prevention was even more
effective than in primary prevention
in safely reducing the five-year incidence of major coronary events, coronary revascularizations and stroke.
was once again supported in CTT
meta-analysis, which found similar
benefits from statin therapy independent of baseline LDL-C.11
The updated guidelines now recommend an optional goal of LDL-C ⬍
100 mg/dl in those with moderate high
risk.3 However, questions still exist as
to how far and in whom should LDL-C
be lowered in primary prevention?
In a review by O’Keefe et al, it was
noted that the optimal LDL-C may be
50-70 mg/dl, which is the normal range
for native hunter-gatherers and healthy
neonates.14 O’Keefe also suggested that
CHD event rates in a primary prevenClearfield 5
tion scenario could approach zero at an
LDL-C of 55 mg/dl.
Although no randomized trial has
directly evaluated this premise, the
on-going JUPITER trial will help answer this question. JUPITER is a primary prevention study of 15,000 subjects with a baseline LDL-C ⬍ 130
mg/dl and high-sensitivity C-reactive
protein (hsCRP) ⬎ 2 mg/L randomized
to either rosuvastatin 20 mg or placebo.15
mg/dl in those with CRP levels greater
than 2 mg/L has further efficacy in
primary prevention.
2. Further lowering of LDL-C in secondary prevention has been definitively proven to decrease cardiovascular
events and mortality.
Since publication of the CTT
analysis, several additional large-scale
secondary prevention trials including
meta-analysis in which intensive highdose statins were used, the result should
reduce CV events by about 40% and
stroke by 33% in high-risk patients.
To that end, the PROVE-IT trial
showed a continued significant 16%
reduction of events in patients with
acute coronary syndrome who were
aggressively treated to an LDL-C of 62
with 80 mg of atorvastatin when compared to a less aggressive lowering of
LDL-C to 95 mg/dl with pravastatin
40 mg. This data supports that lowering
LDL-C even below the suggested optional goal of 70 mg/dl may be beneficial. In addition, LDL-C levels did not
increase any adverse events from statins
even when LDL-C levels were less than
40 mg/dl.18
Facts about HDL-C in the
prevention of CHD
The utility of combining CRP with
LDL-C as a dual goal in primary
prevention was first suggested in
AFCAPS/TexCAPS where the subgroup with LDL-C ⬍ 150 mg/dl and
CRP > 1.6 mg/L had a similar CHD
risk and benefit from lovastatin therapy to those with baseline LDL-C ⬎ 150
mg/dl, where those with LDL-C ⬍ 150
and CRP ⬍ 1.6 mg/L had a much lower
CHD risk and minimal benefit from
statin therapy.16 The results from
JUPITER should address whether
aggressive LDL-C reduction to levels
well below the optional goal of 100
6 Clearfield
both patients with stable Coronary
Artery Disease (CAD) and acute coronary syndrome were reported. In the
pooled analysis by Cannon et al, patients treated with maximal doses of
simvastatin or atorvastatin yielded a
16% additional reduction in CHD
death or MI when compared with
patients treated with a standard statin
dose.17
The CTT results using the average
standard dose of a statin reduced CV
mortality by 20%, CV events by 25%
and stroke by 17%. When the CTT
data are extrapolated to Cannon’s
1. A low HDL-C is considered a
risk factor for CHD and metabolic
syndrome.
As part of the Framingham Risk
HDL-C, levels less than 40 mg/dl are
considered an independent risk factor
for both men and women. In the ATP
III guidelines, an HDL-C ⬍ 40 mg/dl
in men and ⬍ 50 mg/dl in women are
considered a risk factor relative to the
diagnosis of metabolic syndrome. The
AFCAPS/TexCAPS trial showed that
lowering LDL-C with lovastatin negated the added risk found with a low
HDL-C, suggesting that one of the best
ways to treat the risk associated with a
low HDL-C is to lower the LDL-C.5
2. A high HDL-C is considered a
negative risk factor for CHD by
Framingham Guidelines.
As part of the NCEP-ATP III guidelines, an HDL-C ⬎ 60 mg/dl is considered protective and essentially negates
one other CHD Framingham risk facThe Whole Patient May 2007
Misconceptions
about HDL-C
tor. However, an elevated HDL-C itself does
not preclude one from
treating other risk factors. A family history is
critical for all patients
and in those with a high
HDL-C, it can help in
predicting how protective the HDL-C would
be for them.
Myths about HDL-C
1. Raising HDL-C by
any means will lower CHD events.
Unfortunately, several medications
that raise HDL-C did not result in
lowering CV event rates. Estrogen
therapy in women, while raising
HDL-C and lowering LDL-C, has not
been shown as beneficial in postmenopausal women, especially when
started several years after menopause.
Torcetrapib, a newer experimental
medication which inhibits cholesterol
ester transfer protein (CETP), has been
shown to markedly increase HDL-C
by ⬎ 50%. Recently the ILLUMINATE study, which was comparing the
efficacy of a torcetrapib/atorvastatin
combination compared to atorvastatin
alone, was discontinued because of increased mortality and CV events with
the combination treatment, despite a
marked increase in HDL-C levels with
the combination.
Raising HDL-C with fibrate therapy may also have some benefit. For example, in Helsinki Heart Trial in primary prevention and in VA-HIT in
secondary prevention there were benefits noted by raising HDL-C by 11%
and 6% respectively while having little
effect on LDL-C.19,20 However, the recent FIELD trial with fenofibrate did
not demonstrate any significant benefit in reducing CV events; however, the
The Whole Patient May 2007
HDL-C increased only 1.2% compared
to the control group.21
2. All patients with a low HDL-C are
at high CHD risk.
Although a low HDL-C is a risk factor for CHD, there are some individuals with genetic predisposition to low
HDL-C who do not appear to have increased CV risk. For example, individuals with apoA1 Milano mutation may
have very low HDL-C levels but generally are not at any increased risk for
CHD events.
Individuals with apoA1 Milano represent a small group of patients who
usually have a family history of longevity with a concomitant family history of
low HDL-C.
3. All patients with a high HDL-C are
protected from CHD.
There appears to be different types of
HDL-C. For example, HDL-C may
change during the acute phase period
and may actually be pro-inflammatory
and pro-atherogenic rather than protective. Likewise, some individuals with
very high HDL-C may actually have
an increased risk of CV events due to a
dysfunctional HDL-C particle.22
1. All HDL-C particles
are the same.
In deference to
LDL-C, the results are
consistent in that the
lower the LDL-C level
achieved the better the
decrease in major acute
coronary events. When
HDL-C is evaluated the
results are not as consistent. HDL-C particles
that are pro-inflammatory are generally smaller particles
that have an increased capacity to induce mono-cyte chemotactic activity
(MCA).23
2. Raising HDL-C in conjunction
with lowering LDL-C has been
shown to have an additive effect on
CV events.
In several smaller studies such as
FATS, HATS, ARBITER, the ability
of raising HDL-C with the addition of
niacin, while lowering LDL-C with a
statin, has resulted in some of the best
outcomes found in statin-based trials. It
is therefore speculated that the combination of lowering LDL-C while raising
HDL-C may have a significantly better
effect than either alone. However, the
recent results from ILLUMINATE,
which has generated the greatest
HDL-C increases to date, actually increased the event rates.
The medication used in ILLUMINATE was torcetrapib, a blocker of
CETP, suggesting that different medications raising HDL-C may have far
different clinical outcomes. To date
there has been no study that has selectively raised HDL-C to determine
whether raising HDL-C independent
of lowering LDL-C will improve CV
outcomes.
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Final notes
Statin therapy has been shown to be effective in multiple prospective, randomized trials for both primary and
secondary prevention of cardiovascular
events. With each progressive trial
the cutpoint for LDL-C continues to
drop, currently resulting in the updated
guidelines which recommend an optional LDL-C goal of less than 100
mg/dl for those at moderate high risk
for CHD in primary prevention and
less than 70 mg/dl in those with very
high risk.
Post-hoc analyses of several primary
prevention trials suggest that individuals with associated metabolic syndrome, especially when combined with
either a family history of premature
CHD or an elevated CRP, may portend
a higher risk than predicted by the
Framingham risk score and therefore
may be strong candidates for treating to
the optional LDL-C goal.
In secondary prevention, especially
in those post-acute coronary syndrome
(ACS), LDL-C levels that reached the
optional goal ⬍ 70 mg/dl to about 62
mg/dl revealed continued reduction in
CV events.
Raising HDL-C is a more complicated issue. Since there are no studies
that isolate the raising of HDL-C, the
best data suggests that a statin in combination with niacin and possibly a fibrate may result in the best CV outcomes. The strongest data are from
statin/niacin combinations, which in
small groups of patients have shown
the best outcomes. The AIM-HIGH
study will hopefully clarify this issue
of comparing simvastatin alone with
simvastatin plus niacin.
The data on statin/fibrate are even
less clear. The combination of a statin
plus the fibrate, gemfibrozil, is not recommended because of increased risk of
myopathy. The combination of statin
8 Clearfield
with fenofibrate has only been prospectively studied in a small subgroup of
the FIELD trial. To clarify this issue the
ACCORD trial will compare simvastatin monotherapy with simvastatin/
fenofibrate combination in 6,000
diabetics.
Lastly, a regime that includes a global risk reduction strategy appears to
have the best potential outcome for individuals with multiple risk factors to
prevent their first or a recurrent major
coronary event.
Michael B. Clearfield, DO, is dean,
Touro University College of Osteopathic
Medicine in Vallejo, Calif. He can be
reached via email at michael.clearfield@
touro.edu.
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