JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
VOL. 64, NO. 5, 2014
ª 2014 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
PUBLISHED BY ELSEVIER INC.
ISSN 0735-1097/$36.00
http://dx.doi.org/10.1016/j.jacc.2014.05.020
EDITORIAL COMMENT
LDL-Cholesterol Targets After the
ACC/AHA 2013 Guidelines*
Evidence That Lower Is Better?
Ori Ben-Yehuda, MD,y Anthony N. DeMaria, MDz
A
pproximately 25 years ago, the first Adult
In this issue of the Journal, Boekholdt et al. (7)
Treatment Panel (ATP) guidelines set the
report a patient-level meta-analysis of data from
stage for low-density lipoprotein cholesterol
large statin trials, which informs the discussion
(LDL-C) as both a risk factor and a target of therapy
surrounding the 2013 ACC/AHA guidelines. The
(1). Since then, ever-accumulating evidence on the
authors provide important information on the vari-
role of LDL-C in atherosclerosis, coupled with the
ability of lipoprotein levels achieved with treatment,
availability of more potent statins and data that
as well as the cardiovascular risk reduction associated
“lower is better,” have led to what appears to be an
with different lipoprotein levels attained. The key
inexorable march toward lower LDL-C goals, particu-
question they address is whether there is evidence
larly for secondary prevention. ATP-III (2), published
that patients who achieve lower LDL levels, <100
in 2001, defined the optimal LDL level as <100 mg/dl,
mg/dl, <70 mg/dl, or even <50 mg/dl, have a
to be followed in an update in 2004, which estab-
reduced cardiovascular risk. With this objective, they
lished a goal of <70 mg/dl as an option in very high-
analyzed individual patient data (provided by the
risk patients (3).
investigators) from 8 large-scale randomized trials.
In November 2013, the American College of Cardi-
The authors found that more than 40% of the
ology (ACC) and the American Heart Association
participants in these trials did not reach an LDL-C
(AHA) published a much-anticipated guideline up-
level <70 mg/dl despite being prescribed high-dose
date, in which the most surprising and controversial
statin therapy, defined as rosuvastatin 20 mg or
change was the abandonment of LDL-C targets and
atorvastatin 80 mg. Findings were similar when
dose titration (4). Instead, either moderate- or high-
the data were analyzed for apolipoprotein B and for
intensity statin therapy was recommended on the
non–high-density lipoprotein cholesterol, 2 measure-
basis of underlying risk categories, irrespective of
ments that may be better than LDL-C as risk predictors,
LDL-C response. Measurement of on-therapy LDL-C
but which are not as familiar to the general public (8).
was recommended only for the purpose of assessing
In terms of risk reduction, there was a clear rela-
adherence. Notably, the American Association of
tionship between LDL-C level attained and cardio-
Clinical Endocrinology (5) as well as the National
vascular risk, with the major cardiovascular event rate
Lipid Association (6) refused to endorse the new
at 1 year increasing incrementally from 4.4% in those
recommendations.
with LDL-C levels <50 mg/dl, to 10.9% for LDL-C
SEE PAGE 485
between 50 and <70 mg/dl, 16% between 70 and
<100 mg/dl, and up to 34.4% in those with LDL-C $190
mg/dl. This relationship supports the premise that
“lower is better” when it comes to LDL-C goals.
* Editorials published in the Journal of the American College of Cardiology
An important limitation of the large statin trials
reflect the views of the authors and do not necessarily represent the
conducted to date—and therefore by extension this
views of JACC or the American College of Cardiology.
From the yCardiovascular Research Foundation, New York, New York;
and the zDepartment of Medicine, University of California, San Diego,
meta-analysis by Boekholdt et al. (7)—is that these
trials (with the exception of the limited dose titration
San Diego, California. Both authors have reported that they have no re-
in 4S [Scandinavian Simvastatin Survival Study] [9]
lationships relevant to the contents of this paper to disclose.
and AFCAPS/TexCAPS [Air Force/Texas Coronary
496
Ben-Yehuda and DeMaria
JACC VOL. 64, NO. 5, 2014
AUGUST 5, 2014:495–7
LDL-C Targets After the Guidelines
Atherosclerosis Prevention Study] [10]) examined
statins (13), but the genetic response to statins is
fixed doses of statins. The different LDL-C levels
likely polygenetic and is still poorly understood.
attained were therefore not due to a strategy of
Beyond the LDL-C level attained, cardiovascular
individualized goal attainment, which would have
risk reduction may also vary by underlying disease
involved dose titration and possibly the addition of
and metabolic state. In an analysis of data from the
other agents, such as ezetimibe or nicotinic acid, but
4S study, it was shown that patients with low
due to the complex interaction between the statin
HDL-C cholesterol and elevated triglycerides along
(including the dose) and the individual patient’s
with elevated LDL-C (lipid triad) benefited much
biology. Indeed, only a small number of subjects in
more from simvastatin use than did patients with
each trial achieved an LDL-C level of <50 mg/dl (11%
isolated elevated LDL-C, who had only marginal
in
benefit (14).
the
pooled
population).
These
patients
are
different from those with a less robust response;
The strengths of the meta-analysis by Boekholdt
hence, it remains unclear whether it is the LDL-C
et al. (7) include the patient-level analysis and
level achieved or the patient’s ability to respond to
the large number of patients. The main limitation,
a statin dose that is the key determinant of the better
beyond the post-hoc observational nature of the
outcomes.
data and the different inclusion criteria, which
Several important questions remain. Is it acceptable
the
authors
acknowledged,
is
that
the
LDL-C
if a patient reaches a desired LDL-C level at a less-than-
levels attained may have been influenced by a
moderate or high-intensity statin dose, or is there an
myriad of factors, which in themselves may affect
additional benefit to receiving a higher dose of a statin?
cardiovascular risk. In this regard, the present meta-
Also uncertain is whether a statin sparing combination
analysis does not disprove the 2013 ACC/AHA guide-
therapy would be as efficacious as high-intensity
lines contention (4) that there are inadequate data
agents. Although data from statin trials such as the
at the present time to indicate specific LDL-C
JUPITER (Justification for the Use of Statins in Pre-
targets of therapy. Unfortunately, even the much-
vention: an Intervention Trial Evaluating Rosuvasta-
anticipated IMPROVE-IT (Improved Reduction of
tin) study (11) suggest that adverse events in patients
Outcomes:
achieving LDL-C levels <50 mg/dl are no different from
which is randomizing patients to simvastatin alone
in those who do not, an increased incidence of diabetes
versus simvastatin/ezetimibe therapy, is unlikely to
Vytorin
Efficacy
International
Trial),
exists. In addition, there are undoubtedly patients
be definitive in this regard, as it too is largely fixed-
who cannot tolerate the highest statin doses.
dose based, with the only response related titration
There are many factors that may affect LDL-C
being the increase in simvastatin dose from 40 to
Patient
80 mg in those with LDL-C >79 mg/dl (15). It has
compliance and starting LDL-C levels are the most
been estimated that with the current ACC/AHA
obvious and probably most important. But underlying
guidelines, 56 million U.S. patients are eligible for
reduction
and
achieved
LDL-C
levels.
biology also plays a role. A relatively small population
statin therapy (16). It is indeed regrettable that more
of patients, termed “hyper-responders,” can be
than 25 years after the first ATP guidelines, we still
identified who achieve low LDL-C levels (typically on
do not have clear-cut evidence on what the appro-
relatively low doses of statins) and have very low
priate LDL-C targets of therapy should be. The find-
event rates. However, the mechanisms driving hyper-
ings from the present meta-analysis will hopefully
responsiveness
Factors
further spur the design and implementation of lipid
favoring greater LDL-C reduction that were identified
trials assessing specific LDL-C targets rather than
in a pooled analysis of data from more than 21,000
specific drug doses.
are
poorly
understood.
patients included the presence of diabetes mellitus,
black race, and male sex, but these factors had only
REPRINT REQUESTS AND CORRESPONDENCE: Dr.
a modest overall effect (12). Particularly intriguing
Ori Ben-Yehuda, Cardiovascular Research Founda-
is the possible role of the PCSK9 gene, with loss of
tion, 111 East 59th Street, New York, New York 10022.
function associated with an increased response to
E-mail: [email protected].
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KEY WORDS guidelines, LDL-cholesterol,
LDL-cholesterol goal, statins
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